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Articles by Jason Stam in JoVE

 JoVE Biology

The Green Monster Process for the Generation of Yeast Strains Carrying Multiple Gene Deletions

1Department of Synthetic Biology and Bioenergy, J. Craig Venter Institute, 2Department of Microbial and Environmental Genomics, J. Craig Venter Institute, 3Donnelly Centre & Department of Molecular Genetics, University of Toronto, 4Lunenfeld Research Institute, Mt Sinai Hospital


JoVE 4072

The Green Monster method enables the rapid assembly of multiple deletions marked with a reporter gene encoding green fluorescent protein. This method is based on driving yeast strains through repeated cycles of sexual assortment of deletions and fluorescence-based enrichment of cells carrying more deletions.

Other articles by Jason Stam on PubMed

Economic Evaluation of Posaconazole Versus Fluconazole Prophylaxis in Patients with Graft-versus-host Disease (GVHD) in the Netherlands

The objective of this study was to evaluate the cost-effectiveness of posaconazole versus fluconazole for the prevention of invasive fungal infections (IFI) in graft-versus-host disease (GVHD) patients in the Netherlands. A decision analytic model was developed based on a double-blind randomized trial that compared posaconazole with fluconazole antifungal prophylaxis in recipients of allogeneic HSCT with GVHD who were receiving immunosuppressive therapy (Ullmann et al., N Engl J Med 356:335-347, 2007). Clinical events were modeled with chance nodes reflecting probabilities of IFIs, IFI-related death, and death from other causes. Data on life expectancy, quality-of-life, medical resource consumption, and costs were obtained from the literature. The total cost with posaconazole amounted to 9,428 (95% uncertainty interval 7,743-11,388), which is 4,566 (2,460-6,854) more than those with fluconazole. Posaconazole prophylaxis resulted in 0.17 (0.02-0.36) quality adjusted life year (QALY) gained compared to fluconazole prophylaxis, corresponding to an incremental cost effectiveness ratio (ICER) of 26,225 per QALY gained. A scenario analysis demonstrated that at an increased background IFI risk (from 9% to 15%) the ICER was 13,462 per QALY. Given the underlying data and assumptions, posaconazole prophylaxis is expected to be cost-effective relative to fluconazole in recipients of allogeneic HSCT developing GVHD in the Netherlands. The cost-effectiveness of posaconazole depends on the IFI risk, which can vary by hospital.

The Effect of Experimental Groin Pain on Abdominal Muscle Thickness

It is not clear whether abnormal abdominal muscle behavior in athletes with longstanding groin pain is a risk factor for groin pain or is caused by groin pain itself. Therefore, this study investigated whether anticipation of experimental groin pain influences abdominal muscle behavior.

Diagnostic, Pharmacy-based, and Self-reported Health Measures in Risk Equalization Models

Current research on the added value of self-reported health measures for risk equalization modeling does not include all types of self-reported health measures; and/or is compared with a limited set of medically diagnosed or pharmacy-based diseases; and/or is limited to specific populations of high-risk individuals.

Early Active Motion Versus Immobilization After Tendon Transfer for Foot Drop Deformity: a Randomized Clinical Trial

Immobilization after tendon transfers has been the conventional postoperative management. Several recent studies suggest early mobilization does not increase tendon pullout.

EFNS Guideline on the Treatment of Cerebral Venous and Sinus Thrombosis in Adult Patients

Cerebral venous and sinus thrombosis (CVST) is a rather rare disease which accounts for <1% of all strokes. Diagnosis is still frequently overlooked or delayed as a result of the wide spectrum of clinical symptoms and the often subacute or lingering onset. Current therapeutic measures which are used in clinical practice include the use of anticoagulants such as dose-adjusted intravenous heparin or body weight-adjusted subcutaneous low-molecular-weight heparin (LMWH), the use of thrombolysis and symptomatic therapy including control of seizures and elevated intracranial pressure.

Genetic Influence Demonstrated for MEG-recorded Somatosensory Evoked Responses

We tested for a genetic influence on magnetoencephalogram (MEG)-recorded somatosensory evoked fields (SEFs) in 20 monozygotic (MZ) and 14 dizygotic (DZ) twin pairs. Previous electroencephalogram (EEG) studies that demonstrated a genetic contribution to evoked responses generally focused on characteristics of representative brain potentials. Here we demonstrate significantly smaller amplitude differences within MZ compared to DZ twin pairs for the complete SEF time series (across left and right hand SEFs: 0.37 vs. 0.60 pT(2) and 0.28 vs. 0.39 pT(2) for primary [SI] and secondary [SII] sensory cortex activation) and higher MZ than DZ wave shape correlations (.71 vs. .44 and .52 vs. .35 for SI and SII activation). Our findings indicate a genetic influence on MEG-recorded evoked brain activity and also confirm our recent conclusion (van 't Ent, van Soelen, Stam, De Geus, & Boomsma, 2009) that higher MZ resemblance for EEG amplitudes is not trivially reflecting greater MZ concordance in intervening biological tissues.

The Role of DNA Methylation, Nucleosome Occupancy and Histone Modifications in Paramutation

Summary Paramutation is the transfer of epigenetic information between alleles that leads to a heritable change in expression of one of these alleles. Paramutation at the tissue-specifically expressed maize (Zea mays) b1 locus involves the low-expressing B' and high-expressing B-I allele. Combined in the same nucleus, B' heritably changes B-I into B'. A hepta-repeat located 100-kb upstream of the b1 coding region is required for paramutation and for high b1 expression. The role of epigenetic modifications in paramutation is currently not well understood. In this study, we show that the B' hepta-repeat is DNA-hypermethylated in all tissues analyzed. Importantly, combining B' and B-I in one nucleus results in de novo methylation of the B-I repeats early in plant development. These findings indicate a role for hepta-repeat DNA methylation in the establishment and maintenance of the silenced B' state. In contrast, nucleosome occupancy, H3 acetylation, and H3K9 and H3K27 methylation are mainly involved in tissue-specific regulation of the hepta-repeat. Nucleosome depletion and H3 acetylation are tissue-specifically regulated at the B-I hepta-repeat and associated with enhancement of b1 expression. H3K9 and H3K27 methylation are tissue-specifically localized at the B' hepta-repeat and reinforce the silenced B' chromatin state. The B' coding region is H3K27 dimethylated in all tissues analyzed, indicating a role in the maintenance of the silenced B' state. Taken together, these findings provide insight into the mechanisms underlying paramutation and tissue-specific regulation of b1 at the level of chromatin structure.

Using the Manual Ability Classification System in Young Adults with Cerebral Palsy and Normal Intelligence

The study aimed to establish whether the manual ability classification system (MACS), a valid classification system for manual ability in children with cerebral palsy (CP), is applicable in young adults with CP and normal intelligence.

The Decarboxylation of the Weak-acid Preservative, Sorbic Acid, is Encoded by Linked Genes in Aspergillus Spp

The ability to resist anti-microbial compounds is of key evolutionary benefit to microorganisms. Aspergillus niger has previously been shown to require the activity of a phenylacrylic acid decarboxylase (encoded by padA1) for the decarboxylation of the weak-acid preservative sorbic acid (2,4-hexadienoic acid) to 1,3-pentadiene. It is now shown that this decarboxylation process also requires the activity of a putative 4-hydroxybenzoic acid (3-octaprenyl-4-hydroxybenzoic acid) decarboxylase, encoded by a gene termed ohbA1, and a putative transcription factor, sorbic acid decarboxylase regulator, encoded by sdrA. The padA1,ohbA1 and sdrA genes are in close proximity to each other on chromosome 6 in the A. niger genome and further bioinformatic analysis revealed conserved synteny at this locus in several Aspergillus species and other ascomycete fungi indicating clustering of metabolic function. This cluster is absent from the genomes of A. fumigatus and A. clavatus and, as a consequence, neither species is capable of decarboxylating sorbic acid.

Effects of a Rehabilitation Programme on Daily Functioning, Participation, Health-related Quality of Life, Anxiety and Depression in Liver Transplant Recipients

Fatigue is a chronic problem in liver transplant recipients and may influence daily functioning and health-related quality of life (HRQoL). This study aimed to evaluate the effects of a fatigue-reducing physical rehabilitation programme on daily functioning, participation, HRQoL, anxiety and depression among liver transplant recipients.

A Randomised Controlled Trial of Antiplatelet Therapy in Combination with Rt-PA Thrombolysis in Ischemic Stroke: Rationale and Design of the ARTIS-Trial

Thrombolysis with intravenous rt-PA is currently the only approved acute therapy for ischemic stroke. Re-occlusion after initial recanalization occurs in up to 34% in patients treated with rt-PA, probably caused by platelet activation. In acute myocardial infarction, the combination of thrombolysis and antiplatelet therapy leads to a greater reduction of mortality compared to thrombolysis alone. In patients with acute ischemic stroke, several studies showed that patients already on antiplatelet treatment prior to thrombolysis had an equal or even better outcome compared to patients without prior antiplatelet treatment, despite an increased risk of intracerebral bleeding. Based on the fear of intracerebral haemorrhage, current international guidelines recommend postponing antiplatelet therapy until 24 hours after thrombolysis. Remarkably, prior use of antiplatelet therapy is not a contra-indication for thrombolysis. We hypothesize that antiplatelet therapy in combination with rt-PA thrombolysis will improve outcome by enhancing fibrinolysis and preventing re-occlusion.

Three Cases of Referred Sensation in Traumatic Nerve Injury of the Hand: Implications for Understanding Central Nervous System Reorganization

The aim of this observational study was to explore whether patients with traumatic peripheral nerve injury of the hand perceive referred sensations; sensations that are perceived to emanate from other areas of the body than the part being stimulated. Referred sensations have been reported following amputation, somatosensory deafferentation, local anaesthesia, stroke, brachial plexus avulsion injury, spinal cord injury and complex regional pain syndrome type 1.

[Signalling and Tackling Child Abuse]

Expression of MiR-196b is Not Exclusively MLL-driven but is Especially Linked to Activation of HOXA Genes in Pediatric Acute Lymphoblastic Leukemia

Deregulation of microRNA may contribute to hematopoietic malignancies. MicroRNA-196b (miR-196b) is highly expressed in MLL-rearranged leukemia and has been shown to be activated by MLL and MLL-fusion genes.

Prevalence and Clinical Significance of Epileptiform EEG Discharges in a Large Memory Clinic Cohort

Although EEG is not considered as standard in memory clinics, evidence indicates that epileptiform discharges are of value in diagnosing cognitive complaints as epilepsy.

'Functional Connectivity' is a Sensitive Predictor of Epilepsy Diagnosis After the First Seizure

Although epilepsy affects almost 1% of the world population, diagnosis of this debilitating disease is still difficult. The EEG is an important tool for epilepsy diagnosis and classification, but the sensitivity of interictal epileptiform discharges (IEDs) on the first EEG is only 30-50%. Here we investigate whether using 'functional connectivity' can improve the diagnostic sensitivity of the first interictal EEG in the diagnosis of epilepsy.

Prognosis of Six-month Functioning After Moderate to Severe Traumatic Brain Injury: a Systematic Review of Prospective Cohort Studies

To systematically review which determinants, assessed within the first month after a moderate to severe traumatic brain injury, predict 6-month functional outcome.

Participation and Health-related Quality of Life in Adults with Spastic Bilateral Cerebral Palsy and the Role of Self-efficacy

To assess participation and health-related quality of life in adults with bilateral spastic cerebral palsy, and explore associations with self-efficacy.

Electromagnetic Fields and the Blood-brain Barrier

The mammalian blood-brain barrier (BBB) consists of endothelial cells, linked by tight junctions, and the adjoining pericytes and extracellular matrix. It helps maintain a highly stable extracellular environment necessary for accurate synaptic transmission and protects nervous tissue from injury. An increase in its normally low permeability for hydrophilic and charged molecules could potentially be detrimental. Methods to assess the permeability of the BBB include histological staining for marker molecules in brain sections and measurement of the concentration of marker molecules in blood and brain tissue. Their advantages and disadvantages are discussed. Exposure to levels of radiofrequency electromagnetic fields (EMF) that increase brain temperature by more than 1°C can reversibly increase the permeability of the BBB for macromolecules. The balance of experimental evidence does not support an effect of 'non-thermal' radiofrequency fields with microwave and mobile phone frequencies on BBB permeability. Evidence for an effect of the EMF generated by magnetic resonance imaging on permeability is conflicting and conclusions are hampered by potential confounders and simultaneous exposure to different types and frequencies of EMF. The literature on effects of low frequency EMF, which do not cause tissue heating, is sparse and does not yet permit any conclusions on permeability changes. Studies on the potential effect of EMF exposure on permeability of the BBB in humans are virtually absent. Future permeability studies should focus on low frequency effects and effects in humans. Care should be taken to avoid the methodological limitations of earlier studies and to determine the pathophysiological relevance of any changes found.

Patient Satisfaction in Neurological Second Opinions and Tertiary Referrals

Although the number of neurological second opinions (SOs) and tertiary referrals (TRs) is increasing, only little is known about expectations and patient satisfaction in this group of patients. Therefore, the purpose of this study was to explore expectations of patients who get a neurological SO or TR and to assess patient satisfaction in these groups of patients. All new patients attending an academic neurological day-care clinic in a 6-month period were investigated. Demographic characteristics, duration of symptoms, expectations and motivation, new diagnoses and treatment consequences were studied, and patient satisfaction with the previous physician and the day-care clinic physician was assessed. Three hundred consecutive patients (183 SOs and 117 TRs) were evaluated. SO patients were younger (47 years vs. 51 years), and their duration of symptoms was longer (24 vs. 13 months) than TR patients. Most patients expected a new diagnosis or treatment (60%). SO patients were equally as satisfied with the day-care clinic consultation as TR patients (overall satisfaction using a VAS-score ranging 0-10: 7.4 vs. 7.5; p = 0.81), and significantly less satisfied with the referring physician (overall satisfaction: 5.6 vs. 7.0; p < 0.001). SO patients, in particular, were more satisfied with the degree of information and emotional support provided by the consulting neurologist as compared to the referring physician. Receiving a new diagnosis and/or treatment advice did not influence satisfaction. A day-care admission for neurological SO and TR leads to an increase of patient satisfaction, irrespective of making a new diagnosis or initiation of a new treatment.

Functional Capacity and Actual Daily Activity Do Not Contribute to Patient Satisfaction After Total Knee Arthroplasty

After total knee arthroplasty (TKA) only 75-89% of patients are satisfied. Because patient satisfaction is a prime goal of all orthopaedic procedures, optimization of patient satisfaction is of major importance. Factors related to patient satisfaction after TKA have been explored, but no studies have included two potentially relevant factors, i.e. the functional capacity of daily activities and actual daily activity. This present prospective study examines whether functional capacity and actual daily activity (in addition to an extensive set of potential factors) contribute to patient satisfaction six months after TKA.

3D Finite Compartment Modeling of Formation and Healing of Bruises May Identify Methods for Age Determination of Bruises

Simulating the spatial and temporal behavior of bruises may identify methods that allow accurate age determination of bruises to assess child abuse. We developed a numerical 3D model to simulate the spatial kinetics of hemoglobin and bilirubin during the formation and healing of bruises. Using this model, we studied how skin thickness, bruise diameter and diffusivities affect the formation and healing of circular symmetric bruises and compared a simulated bruise with a natural inhomogeneous bruise. Healing is faster for smaller bruises in thinner and less dense skin. The simulated and natural bruises showed similar spatial and temporal dynamics. The different spatio-temporal dynamics of hemoglobin and bilirubin allows age determination of model bruises. Combining our model predictions with individual natural bruises may allow optimizing our model parameters. It may particularly identify methods for more accurate age determination than currently possible to aid the assessment of child abuse.

Age-dependent Features of EEG-reactivity--spectral, Complexity, and Network Characteristics

Our goal was to measure indices characterizing EEG-reactivity in young and elderly subjects. It was hypothesized that EEG-reactivity as reflected by different measures would be lower in the elderly. In two age groups (young: N= 23, mean age = 21.5 +/- 2.2 years; old: N= 25, mean age = 66.9 +/- 3.6 years) absolute frequency spectra, Omega-complexity, synchronization likelihood and network properties (clustering coefficient and characteristic path length) of the EEG were analyzed in the delta, theta, alpha1, alpha2, beta1 and beta2 frequency bands occurring as a result of eyes opening. Absolute spectral power was higher in the young in the delta, alpha1 and alpha2 bands in the posterior area. The alpha1 peak frequency decreased following eyes opening in the young, while no change was observed in the elderly. Omega-complexity was higher in the elderly especially in the frontal area and increased following eyes opening. Values of the clustering coefficient, path length and that of the "small-world index" decreased as a result of eyes opening, the latter in the fast frequency range. The results suggest reduced reactivity in the elderly as shown by frequency spectra and decreased level of integrative activity particularly in the frontal area probably as a result of reduced interneuronal processing capacity. Indices of network characteristics reveal a shift towards more random topology especially in the beta frequencies caused by eyes opening.

Age-dependent Features of EEG-reactivity-Spectral, Complexity, and Network Characteristics

To measure indices characterizing EEG-reactivity in young and elderly subjects. It was hypothesized that EEG-reactivity as reflected by different measures would be lower in the elderly. In two age groups (young: N=23, mean age=21.5+/-2.2 years; old: N=25, mean age=66.9+/-3.6 years) absolute frequency spectra, Omega-complexity, synchronization likelihood and network properties (clustering coefficient and characteristic path length) of the EEG were analyzed in the delta, theta, alpha1, alpha2, beta1 and beta2 frequency bands occurring as a result of eyes opening. Absolute spectral power was higher in the young in the delta, alpha1 and alpha2 bands in the posterior area. The alpha1 peak frequency decreased following eyes opening in the young, while no change was observed in the elderly. Omega-complexity was higher in the elderly especially in the frontal area and increased following eyes opening. Values of the clustering coefficient, path length and that of the "small-world index" decreased as a result of eyes opening, the latter in the fast frequency range. The results suggest reduced reactivity in the elderly as shown by frequency spectra and decreased level of integrative activity particularly in the frontal area probably as a result of reduced interneuronal processing capacity. Indices of network characteristics reveal a shift towards more random topology especially in the beta frequencies caused by eyes opening.

Diagnostic Yield of Capsule Endoscopy in a Tertiary Hospital in Patients with Obscure Gastrointestinal Bleeding

Capsule endoscopy is applicable to several clinical conditions, but obscure gastrointestinal bleeding remains the main indication. This study aims at determining the diagnostic yield of capsule endoscopy for obscure gastrointestinal bleeding using a structured terminology in a large cohort in an academic hospital.

Characterization of Anatomical and Functional Connectivity in the Brain: a Complex Networks Perspective

A central question in modern neuroscience is how anatomical and functional connections between brain areas are organized to allow optimal information processing. In particular, both segregation and integration of information have to be dealt with in a single architecture of brain networks. There is strong evidence that synchronization of neural activity, both locally and between distant regions is a crucial code for functional interactions. However, a powerful theoretical framework to describe the structural and functional topology of system-wide brain networks has only become available with the discovery of 'small-world' and 'scale-free' networks in 1998 and 1999. There is now strong evidence that brain networks, ranging from simple nets of interconnected neurons up to macroscopic networks of brain areas display the typical features of complex systems: high clustering, short path lengths (both typical of 'small-world' networks), skewed degree distributions, presence of hubs, assortative mixing and the presence of modules. This has been demonstrated for anatomical and functional networks using neuroanatomical techniques, EEG, MEG and structural and functional MRI, in organisms ranging from C. elegans to man. In addition, network topology has been shown to be highly heritable, and very predictive of cognitive functioning. A short path length, which implies that from any area in the brain any other area can be reached in a small number of steps, is strongly correlated with IQ. Computational models are now beginning to reveal how the complex structure of adult brain networks could arise during development.

Venous Thromboembolic Events After Cerebral Vein Thrombosis

After cerebral vein and dural sinus thrombosis (CVT), there is an increased risk of further venous thromboembolic events (VTEs). Time to a second cerebral or systemic venous thrombotic event and risk factors for recurrence have not been investigated in large prospective studies.

Recent Developments in Effector Biology of Filamentous Plant Pathogens

Short and Mid-term Results of a Comprehensive Treatment Program for Longstanding Adductor-related Groin Pain in Athletes: a Case Series

To evaluate short and mid-term results of active physical therapy in athletes with longstanding groin pain.

Peroxidase Profiling Reveals Genetic Linkage Between Peroxidase Gene Clusters and Basal Host and Non-host Resistance to Rusts and Mildew in Barley

Higher plants possess a large multigene family encoding secreted class III peroxidase (Prx) proteins. Peroxidases appear to be associated with plant disease resistance based on observations of induction during disease challenge and the presence or absence of isozymes in resistant vs susceptible varieties. Despite these associations, there is no evidence that allelic variation of peroxidases directly determines levels of disease resistance.

Recovery of the Sit-to-stand Movement After Stroke: a Longitudinal Cohort Study

To present quantitative data on sit-to-stand (STS)-related functioning and recovery during the first year after stroke. STS-related functioning was used to evaluate independent STS movement, rising speed, and actual STS performance during normal daily life.

4-1BB-mediated Expansion Affords Superior Detection of in Vivo Primed Effector Memory CD8+ T Cells from Melanoma Sentinel Lymph Nodes

We have been studying the re-activation of tumor-associated antigen (TAA)-specific CD8(+) T cells in sentinel lymph nodes (SLN) of melanoma patients upon intradermal administration of the CpG-B oligodeoxynucleotide PF-3512676. To facilitate functional testing of T cells from small SLN samples, high-efficiency polyclonal T cell expansion is required. In this study, SLN cells were expanded via classic methodologies with plate- or bead-bound anti-CD3/CD28 antibodies and with the K562/CD32/4-1BBL artificial APC system (K32/4-1BBL aAPC) and analyzed for responsiveness to common recall or TAA-derived peptides. K32/4-1BBL-expanded T cell populations contained significantly more effector/memory CD8(+) T cells. Moreover, recall and melanoma antigen-specific CD8(+) T cells were more frequently detected in K32/4-1BBL-expanded samples as compared with anti-CD3/CD28-expanded samples. We conclude that K32/4-1BBL aAPC are superior to anti-CD3/CD28 antibodies for the expansion of in vivo-primed specific CD8(+) T cells and that their use facilitates the sensitive monitoring of functional anti-tumor T cell immunity in SLN.

Is Disturbed Intracortical Excitability a Stable Trait of Chronic Insomnia? A Study Using Transcranial Magnetic Stimulation Before and After Multimodal Sleep Therapy

Chronic insomnia is a poorly understood disorder. Risk factors for developing chronic insomnia are largely unknown, yet disturbances in brain indexes of arousal seem to accompany the disorder. We here investigate whether insomnia patients and control participants differ with respect to brain responses to direct stimulation, i.e., cortical excitability. Transcranial magnetic stimulation (TMS) offers a method to directly investigate the excitability level of the human cerebral cortex in psychiatric and neurological disease.

Epilepsy is Related to Theta Band Brain Connectivity and Network Topology in Brain Tumor Patients

Both epilepsy patients and brain tumor patients show altered functional connectivity and less optimal brain network topology when compared to healthy controls, particularly in the theta band. Furthermore, the duration and characteristics of epilepsy may also influence functional interactions in brain networks. However, the specific features of connectivity and networks in tumor-related epilepsy have not been investigated yet. We hypothesize that epilepsy characteristics are related to (theta band) connectivity and network architecture in operated glioma patients suffering from epileptic seizures. Included patients participated in a clinical study investigating the effect of levetiracetam monotherapy on seizure frequency in glioma patients, and were assessed at two time points: directly after neurosurgery (t1), and six months later (t2). At these time points, magnetoencephalography (MEG) was recorded and information regarding clinical status and epilepsy history was collected. Functional connectivity was calculated in six frequency bands, as were a number of network measures such as normalized clustering coefficient and path length.

Development of Romantic Relationships and Sexual Activity in Young Adults with Cerebral Palsy: a Longitudinal Study

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Genome-wide Association Study of Migraine Implicates a Common Susceptibility Variant on 8q22.1

Migraine is a common episodic neurological disorder, typically presenting with recurrent attacks of severe headache and autonomic dysfunction. Apart from rare monogenic subtypes, no genetic or molecular markers for migraine have been convincingly established. We identified the minor allele of rs1835740 on chromosome 8q22.1 to be associated with migraine (P = 5.38 × 10⁻⁹, odds ratio = 1.23, 95% CI 1.150-1.324) in a genome-wide association study of 2,731 migraine cases ascertained from three European headache clinics and 10,747 population-matched controls. The association was replicated in 3,202 cases and 40,062 controls for an overall meta-analysis P value of 1.69 × 10⁻¹¹ (odds ratio = 1.18, 95% CI 1.127-1.244). rs1835740 is located between MTDH (astrocyte elevated gene 1, also known as AEG-1) and PGCP (encoding plasma glutamate carboxypeptidase). In an expression quantitative trait study in lymphoblastoid cell lines, transcript levels of the MTDH were found to have a significant correlation to rs1835740 (P = 3.96 × 10⁻⁵, permuted threshold for genome-wide significance 7.7 × 10⁻⁵. To our knowledge, our data establish rs1835740 as the first genetic risk factor for migraine.

The Fault is Not in Ourselves, but in Our Methods: Comment on Schwarz

Schwarz is right to question the methodological foundations of much of contemporary personality research. I argue that he does not go far enough, opting instead to salvage the psychometric tradition for research it cannot possibly accomplish, namely the understanding of persons in an evolutionary and historical context. Furthermore he does not address the question of measurement that has bedeviled the discipline. For all its historical tenacity, the psychometric tradition has been good at classification but weak at understanding, explanation, or description of the phenomena that most interest psychologists.

Effect of Tumor Resection on the Characteristics of Functional Brain Networks

Brain functioning such as cognitive performance depends on the functional interactions between brain areas, namely, the functional brain networks. The functional brain networks of a group of patients with brain tumors are measured before and after tumor resection. In this work, we perform a weighted network analysis to understand the effect of neurosurgery on the characteristics of functional brain networks. Statistically significant changes in network features have been discovered in the beta (13-30 Hz) band after neurosurgery: the link weight correlation around nodes and within triangles increases which implies improvement in local efficiency of information transfer and robustness; the clustering of high link weights in a subgraph becomes stronger, which enhances the global transport capability; and the decrease in the synchronization or virus spreading threshold, revealed by the increase in the largest eigenvalue of the adjacency matrix, which suggests again the improvement of information dissemination.

Energy Expenditure in Adults with Cerebral Palsy Playing Wii Sports

To determine energy expenditure of adults with bilateral spastic cerebral palsy while playing Wii Sports tennis and boxing.

Feasibility of Online Seizure Detection with Continuous EEG Monitoring in the Intensive Care Unit

Continuous EEG (cEEG) is of great interest in view of the reported high prevalence of non-convulsive seizures on intensive care units (ICUs). Here, we describe our experiences applying a seizure warning system using cEEG monitoring.

Unfractionated or Low-molecular Weight Heparin for the Treatment of Cerebral Venous Thrombosis

There is no consensus whether to use unfractionated heparin or low-molecular weight heparin for the treatment of cerebral venous thrombosis. We examined the effect on clinical outcome of each type of heparin.

Emergence of Modular Structure in a Large-Scale Brain Network with Interactions Between Dynamics and Connectivity

A network of 32 or 64 connected neural masses, each representing a large population of interacting excitatory and inhibitory neurons and generating an electroencephalography/magnetoencephalography like output signal, was used to demonstrate how an interaction between dynamics and connectivity might explain the emergence of complex network features, in particular modularity. Network evolution was modeled by two processes: (i) synchronization dependent plasticity (SDP) and (ii) growth dependent plasticity (GDP). In the case of SDP, connections between neural masses were strengthened when they were strongly synchronized, and were weakened when they were not. GDP was modeled as a homeostatic process with random, distance dependent outgrowth of new connections between neural masses. GDP alone resulted in stable networks with distance dependent connection strengths, typical small-world features, but no degree correlations and only weak modularity. SDP applied to random networks induced clustering, but no clear modules. Stronger modularity evolved only through an interaction of SDP and GDP, with the number and size of the modules depending on the relative strength of both processes, as well as on the size of the network. Lesioning part of the network, after a stable state was achieved, resulted in a temporary disruption of the network structure. The model gives a possible scenario to explain how modularity can arise in developing brain networks, and makes predictions about the time course of network changes during development and following acute lesions.

"Dreadful to Behold": Frostbite on the 1910-1913 British Antarctic Expedition

Transient Hyperphosphatasemia in Children Revisited

Although transient hyperphosphatasemia (TH) has been well known for decades, its etiology and pathophysiology remain unclear. We aimed to study the clinical characteristics of children diagnosed with TH compared to older studies in order to expand our knowledge and understanding of this condition and to try and find a subgroup of children who are more prone to develop TH.

Utility of Language Comprehension Tests for Unintelligible or Non-speaking Children with Cerebral Palsy: a Systematic Review

to identify the use and utility of language comprehension tests for unintelligible or non-speaking children with severe cerebral palsy (CP).

Learn 2 Move 16-24: Effectiveness of an Intervention to Stimulate Physical Activity and Improve Physical Fitness of Adolescents and Young Adults with Spastic Cerebral Palsy; a Randomized Controlled Trial

Persons with cerebral palsy (CP) are at risk for developing an inactive lifestyle and often have poor fitness levels, which may lead to secondary health complications and diminished participation and quality of life. However, persons with CP also tend not to receive structural treatment to improve physical activity and fitness in adolescence, which is precisely the period when adult physical activity patterns are established.

Comparing Brain Networks of Different Size and Connectivity Density Using Graph Theory

Graph theory is a valuable framework to study the organization of functional and anatomical connections in the brain. Its use for comparing network topologies, however, is not without difficulties. Graph measures may be influenced by the number of nodes (N) and the average degree (k) of the network. The explicit form of that influence depends on the type of network topology, which is usually unknown for experimental data. Direct comparisons of graph measures between empirical networks with different N and/or k can therefore yield spurious results. We list benefits and pitfalls of various approaches that intend to overcome these difficulties. We discuss the initial graph definition of unweighted graphs via fixed thresholds, average degrees or edge densities, and the use of weighted graphs. For instance, choosing a threshold to fix N and k does eliminate size and density effects but may lead to modifications of the network by enforcing (ignoring) non-significant (significant) connections. Opposed to fixing N and k, graph measures are often normalized via random surrogates but, in fact, this may even increase the sensitivity to differences in N and k for the commonly used clustering coefficient and small-world index. To avoid such a bias we tried to estimate the N,k-dependence for empirical networks, which can serve to correct for size effects, if successful. We also add a number of methods used in social sciences that build on statistics of local network structures including exponential random graph models and motif counting. We show that none of the here-investigated methods allows for a reliable and fully unbiased comparison, but some perform better than others.

Loss of 'small-world' Networks in Alzheimer's Disease: Graph Analysis of FMRI Resting-state Functional Connectivity

Local network connectivity disruptions in Alzheimer's disease patients have been found using graph analysis in BOLD fMRI. Other studies using MEG and cortical thickness measures, however, show more global long distance connectivity changes, both in functional and structural imaging data. The form and role of functional connectivity changes thus remains ambiguous. The current study shows more conclusive data on connectivity changes in early AD using graph analysis on resting-state condition fMRI data.

Aberrant Frontal and Temporal Complex Network Structure in Schizophrenia: a Graph Theoretical Analysis

Brain regions are not independent. They are interconnected by white matter tracts, together forming one integrative complex network. The topology of this network is crucial for efficient information integration between brain regions. Here, we demonstrate that schizophrenia involves an aberrant topology of the structural infrastructure of the brain network. Using graph theoretical analysis, complex structural brain networks of 40 schizophrenia patients and 40 human healthy controls were examined. Diffusion tensor imaging was used to reconstruct the white matter connections of the brain network, with the strength of the connections defined as the level of myelination of the tracts as measured through means of magnetization transfer ratio magnetic resonance imaging. Patients displayed a preserved overall small-world network organization, but focusing on specific brain regions and their capacity to communicate with other regions of the brain revealed significantly longer node-specific path lengths (higher L) of frontal and temporal regions, especially of bilateral inferior/superior frontal cortex and temporal pole regions. These findings suggest that schizophrenia impacts global network connectivity of frontal and temporal brain regions. Furthermore, frontal hubs of patients showed a significant reduction of betweenness centrality, suggesting a less central hub role of these regions in the overall network structure. Together, our findings suggest that schizophrenia patients have a less strongly globally integrated structural brain network with a reduced central role for key frontal hubs, resulting in a limited structural capacity to integrate information across brain regions.

Accelerometry-based Activity Spectrum in Persons with Chronic Physical Conditions

(1) To give an overview of the impact of a variety of chronic physical conditions on accelerometry-based levels of everyday physical activity and to identify high-risk conditions; and (2) to compare these objectively assessed activity levels with the levels estimated by rehabilitation physicians.

The Lesioned Brain: Still a Small-world?

The intra-arterial amobarbital procedure (IAP or Wada test) is used to determine language lateralization and contralateral memory functioning in patients eligible for neurosurgery because of pharmaco-resistant epilepsy. During unilateral sedation, functioning of the contralateral hemisphere is assessed by means of neuropsychological tests. We use the IAP as a reversible model for the effect of lesions on brain network topology. Three artifact-free epochs (4096 samples) were selected from each electroencephalogram record before and after amobarbital injection. Functional connectivity was assessed by means of the synchronization likelihood. The resulting functional connectivity matrices were constructed for all six epochs per patient in four frequency bands, and weighted network analysis was performed. The clustering coefficient, average path length, small-world index, and edge weight correlation were calculated. Recordings of 33 patients were available. Network topology changed significantly after amobarbital injection: clustering decreased in all frequency bands, while path length decreased in the theta and lower alpha band, indicating a shift toward a more random network topology. Likewise, the edge weight correlation decreased after injection of amobarbital in the theta and beta bands. Network characteristics after injection of amobarbital were correlated with memory score: higher theta band small-world index and increased upper alpha path length were related to better memory score. The whole-brain network topology in patients eligible for epilepsy surgery becomes more random and less optimally organized after selective sedation of one hemisphere, as has been reported in studies with brain tumor patients. Furthermore, memory functioning after injection seems related to network topology, indicating that functional performance is related to topological network properties of the brain.

Promoting Physical Activity in an Adolescent and a Young Adult with Physical Disabilities

We sought to describe the design of the Active Lifestyle and Sports Participation (ALSP) intervention for adolescents and young adults with physical disabilities, and to present the first 2 cases.

Utility of Language Comprehension Tests for Unintelligible or Non-speaking Children with Cerebral Palsy: a Systematic Review

to identify the use and utility of language comprehension tests for unintelligible or non-speaking children with severe cerebral palsy (CP).

Topographical Organization of Mu and Beta Band Activity Associated with Hand and Foot Movements in Patients with Perirolandic Lesions

To study the topographical organization of mu and beta band event-related desynchronization (ERD) associated with voluntary hand and foot movements, we used magnetoencephalographic (MEG) recordings from 19 patients with perirolandic lesions. Synthetic aperture magnetometry (SAM) was used to detect and localize changes in the mu (7 - 11 Hz) and beta (13 - 30 Hz) frequency bands associated with repetitive movements of the hand and foot and overlaid on individual coregistered magnetic resonance (MR) images. Hand movements showed homotopic and contralateral ERD at the sensorimotor (S/M) cortex in the majority of cases for mu and to a lesser extent for beta rhythms. Foot movements showed an increased heterotopic distribution with bilateral and ipsilateral ERD compared to hand movements. No systematic topographical segregation between mu and beta ERD could be observed. In patients with perirolandic lesions, the mu and beta band spatial characteristics associated with hand movements retain the expected functional-anatomical boundaries to a large extent. Foot movements have altered patterns of mu and beta band ERD, which may give more insight into the differential functional role of oscillatory activity in different voluntary movements.

Physical Fitness, Everyday Physical Activity, and Fatigue in Ambulatory Adults with Bilateral Spastic Cerebral Palsy

This study assessed physical fitness and its relationships with everyday physical activity (PA) and fatigue in cerebral palsy (CP). Participants were 42 adults with ambulatory bilateral spastic CP (mean age 36.4 ± 5.8 years; 69% males; 81% with good gross motor functioning). Progressive maximal aerobic cycle tests determined VO(2peak) (L/min). Objective levels of everyday PA were measured with accelerometry and self-reported levels of everyday PA with the Physical Activity Scale for Individuals with Physical Disabilities. Fatigue was assessed with the Fatigue Severity Scale. The average aerobic capacity of adults with CP was 77% of Dutch reference values. Participants were physically active during 124 min/day (85% of Dutch reference values), and half experienced fatigue. In women, lower physical fitness was related to lower self-reported levels of PA (R(p)=0.61, P=0.03), and in men to higher levels of fatigue (R(p)=-0.37, P=0.05). Other relationships were not significant. Results suggest that ambulatory adults with CP have low levels of physical fitness, are less physically active than able-bodied age mates and often experience fatigue. We found little evidence for relationships between the level of physical fitness and everyday PA or fatigue.

Network Analysis of Resting State EEG in the Developing Young Brain: Structure Comes with Maturation

During childhood, brain structure and function changes substantially. Recently, graph theory has been introduced to model connectivity in the brain. Small-world networks, such as the brain, combine optimal properties of both ordered and random networks, i.e., high clustering and short path lengths. We used graph theoretical concepts to examine changes in functional brain networks during normal development in young children. Resting-state eyes-closed electroencephalography (EEG) was recorded (14 channels) from 227 children twice at 5 and 7 years of age. Synchronization likelihood (SL) was calculated in three different frequency bands and between each pair of electrodes to obtain SL-weighted graphs. Mean normalized clustering index, average path length and weight dispersion were calculated to characterize network organization. Repeated measures analysis of variance tested for time and gender effects. For all frequency bands mean SL decreased from 5 to 7 years. Clustering coefficient increased in the alpha band. Path length increased in all frequency bands. Mean normalized weight dispersion decreased in beta band. Girls showed higher synchronization for all frequency bands and a higher mean clustering in alpha and beta bands. The overall decrease in functional connectivity (SL) might reflect pruning of unused synapses and preservation of strong connections resulting in more cost-effective networks. Accordingly, we found increases in average clustering and path length and decreased weight dispersion indicating that normal brain maturation is characterized by a shift from random to more organized small-world functional networks. This developmental process is influenced by gender differences early in development.

The Neuronal Correlates of Mirror Therapy: an FMRI Study on Mirror Induced Visual Illusions in Patients with Stroke

To investigate the neuronal basis for the effects of mirror therapy in patients with stroke.

Mild Traumatic Brain Injury: Graph-model Characterization of Brain Networks for Episodic Memory

Episodic memory is among the cognitive functions that can be affected in the acute phase following mild traumatic brain injury (MTBI). The present study used EEG recordings to evaluate global synchronization and network organization of rhythmic activity during the encoding and recognition phases of an episodic memory task varying in stimulus type (kaleidoscope images, pictures, words, and pseudowords). Synchronization of oscillatory activity was assessed using a linear and nonlinear connectivity estimator and network analyses were performed using algorithms derived from graph theory. Twenty five MTBI patients (tested within days post-injury) and healthy volunteers were closely matched on demographic variables, verbal ability, psychological status variables, as well as on overall task performance. Patients demonstrated sub-optimal network organization, as reflected by changes in graph parameters in the theta and alpha bands during both encoding and recognition. There were no group differences in spectral energy during task performance or on network parameters during a control condition (rest). Evidence of less optimally organized functional networks during memory tasks was more prominent for pictorial than for verbal stimuli.

Effects of a Defective ERAD Pathway on Growth and Heterologous Protein Production in Aspergillus Niger

Endoplasmic reticulum associated degradation (ERAD) is a conserved mechanism to remove misfolded proteins from the ER by targeting them to the proteasome for degradation. To assess the role of ERAD in filamentous fungi, we have examined the consequences of disrupting putative ERAD components in the filamentous fungus Aspergillus niger. Deletion of derA, doaA, hrdC, mifA, or mnsA in A. niger yields viable strains, and with the exception of doaA, no significant growth phenotype is observed when compared to the parental strain. The gene deletion mutants were also made in A. niger strains containing single- or multicopies of a glucoamylase-glucuronidase (GlaGus) gene fusion. The induction of the unfolded protein response (UPR) target genes (bipA and pdiA) was dependent on the copy number of the heterologous gene and the ERAD gene deleted. The highest induction of UPR target genes was observed in ERAD mutants containing multiple copies of the GlaGus gene. Western blot analysis revealed that deletion of the derA gene in the multicopy GlaGus overexpressing strain resulted in a 6-fold increase in the intracellular amount of GlaGus protein detected. Our results suggest that impairing some components of the ERAD pathway in combination with high expression levels of the heterologous protein results in higher intracellular protein levels, indicating a delay in protein degradation.

EEG Abnormalities in Early and Late Onset Alzheimer's Disease: Understanding Heterogeneity

To compare differences in severity and type of electroencephalography (EEG) abnormalities between early and late onset Alzheimer's disease (AD) and to assess the influence of APOE genotype on this association, in order to understand the biological differences in AD according to age at onset

Growth Diagrams for Individual Finger Strength in Children Measured with the RIHM

Although grip and pinch strength provide a more global measure of a large number of digits and muscles, measuring strength of individual fingers or the thumb can provide additional and more detailed information regarding hand strength.

A Long-term Follow-up Study of 18 Patients with Sporadic Hemiplegic Migraine

Our objective was to study the long-term prognosis of sporadic hemiplegic migraine (SHM).

An Evaluation of Small-scale Genetic Diversity and the Mating System in Zostera Noltii on an Intertidal Sandflat in the Wadden Sea

The dwarf eelgrass, Zostera noltii, is a predominant inhabitant of soft-bottom intertidal regions along the coasts of northern Europe. It is a monoecious, protogynous angiosperm in which the potential for self-fertilization and inbreeding are high, especially if clone sizes exceed pollen dispersal distances. The aim of the present study was to determine the relationship between mating system and clonal structure, examine the relative roles of geitonogamous selfing and biparental inbreeding, measure pollen availability (multiple paternities) and estimate pollen dispersal.

Motor Recovery and Cortical Reorganization After Mirror Therapy in Chronic Stroke Patients: a Phase II Randomized Controlled Trial

To evaluate for any clinical effects of home-based mirror therapy and subsequent cortical reorganization in patients with chronic stroke with moderate upper extremity paresis.

EEG Abnormalities Are Associated with Different Cognitive Profiles in Alzheimer's Disease

Our purpose was to investigate associations between different cognitive profiles and their underlying functional brain changes as measured by electroencephalogram (EEG) in Alzheimer's disease (AD).

Hypermethylation of Specific MicroRNA Genes in MLL-rearranged Infant Acute Lymphoblastic Leukemia: Major Matters at a Micro Scale

MLL-rearranged acute lymphoblastic leukemia (ALL) in infants (<1 year) is the most aggressive type of childhood leukemia. To develop more suitable treatment strategies, a firm understanding of the biology underlying this disease is of utmost importance. MLL-rearranged ALL displays a unique gene expression profile, partly explained by erroneous histone modifications. We recently showed that t(4;11)-positive infant ALL is also characterized by pronounced promoter CpG hypermethylation. In this study, we investigated whether this widespread hypermethylation also affected microRNA (miRNA) expression. We identified 11 miRNAs that were downregulated in t(4;11)-positive infant ALL as a consequence of CpG hypermethylation. Seven of these miRNAs were re-activated after exposure to the de-methylating agent Zebularine. Interestingly, five of these miRNAs are associated either with MLL or MLL fusions, and for miR-152 we found both MLL and DNA methyltransferase 1 (DNMT1) as potential targeted genes. Finally, a high degree of methylation of the miR-152 CpG island was strongly correlated with a poor clinical outcome. Our data suggests that inhibitors of methylation have a potential beyond re-expression of hypermethylated protein-coding genes in t(4;11)-positive infant ALL. In this study, we provide additional evidence that they should be tested for their efficacy in MLL-rearranged infant ALL in in vivo models.

Cognition is Related to Resting-state Small-world Network Topology: an Magnetoencephalographic Study

Brain networks and cognition have recently begun to attract attention: studies suggest that more efficiently wired resting-state brain networks are indeed correlated with better cognitive performance. "Small-world" brain networks combine local segregation with global integration, hereby subserving information processing. Furthermore, recent studies implicate that gender effects may be present in both network dynamics and its correlations with cognition. This study reports on the relation between resting-state functional brain topology with overall and domain-specific cognitive performance in healthy participants and possible gender differences herein. Healthy participants underwent neuropsychological tests, of which individual scores were converted to z-scores. Network analysis was performed on resting-state, eyes-closed magnetoencephalography (MEG) data, after determining functional connectivity between each pair of sensors. The clustering coefficient (local specialization), average path length (overall integration and efficiency) and "small-world index" (i.e. ratio between clustering and path length) were calculated in six frequency bands. 14 male and 14 female participants were included. Better total cognitive performance was related to increased local connectivity in the theta band, higher clustering coefficient (in delta and theta bands) and higher small-worldness (in theta and lower gamma bands). Women showed less clustering and shorter path length in the delta band. There were no significant correlations between network topology and cognitive functioning in females. In contrast, higher cognitive scores in men were associated with increased theta band clustering and small-worldness. These results provide further evidence for the value of functional brain network topology for cognitive functioning and suggest that gender is an important factor in this respect.

Excellent Test-retest and Inter-rater Reliability for Tardieu Scale Measurements with Inertial Sensors in Elbow Flexors of Stroke Patients

Spasticity is often clinically assessed with the Tardieu Scale, using goniometry to measure the range of motion and angle of catch. However, the test-retest and inter-rater reliability of these measurements have been questioned. Inertial sensors (IS) have been developed to measure orientation in space and are suggested to be a more appropriate tool than goniometry to measure angles in Tardieu Scale measurements.

Data-driven Modeling of Phase Interactions Between Spontaneous MEG Oscillations

Synchronization between distributed rhythms in the brain is commonly assessed by estimating the synchronization strength from simultaneous measurements. This approach, however, does not elucidate the phase dynamics that underlies synchronization. For this, an explicit dynamical model is required. Based on the assumption that the recorded rhythms can be described as weakly coupled oscillators, we propose a method for characterizing their phase-interaction dynamics.

Cytotoxicity, Drug Combinability, and Biological Correlates of ABT-737 Against Acute Lymphoblastic Leukemia Cells with MLL Rearrangement

ABT-737 is a BH3 mimetic small-molecule inhibitor that binds with high affinity to Bcl-2 to induce apoptosis in malignant cells and has shown promise as an effective anti-leukemic agent in pediatric preclinical tests. This study focuses on the effects of ABT-737 on leukemia cells with MLL rearrangement and identifies some of the biological correlates of its activity.

Guidelines for Allocating Outpatient Alcohol Abusers to Levels of Care: Predictive Validity

The purpose of this study was to assess the predictive validity of guidelines for allocating outpatients with an alcohol-use disorder to different levels of care in routine alcohol outpatient treatment facilities. It was hypothesized that patients matched to the recommended level of care would have (a) better outcomes than patients treated at a less intensive level of care, and (b) outcomes equivalent to patients treated at a more intensive level of care. Patients at two Dutch substance-abuse treatment centers who completed intake and were allocated at either a brief or standard outpatient treatment (n=471) were followed prospectively to determine differential outcomes for those who were and were not treated at the recommended level of car. The former patients were allocated according to an algorithm based on their treatment history, addiction severity, psychiatric impairment and social stability at baseline. 52.9% of the original sample was successfully contacted for follow-up 11 months after intake. Outcome was measured in terms of self-reported alcohol use 30 days prior to follow up and changes in number of excessive and nonexcessive drinking days between intake and follow up. Only 21% of the patients were matched to the level of care according to the guidelines. Patients allocated to the recommended level of care did not have better outcomes than those treated at a less intensive level of care, but they had outcomes comparable to patients treated at a more intensive level of care. The a priori allocation guidelines were followed for only a minority of the patients, and using them did not improve treatment outcome. Further work is needed to improve the content of the treatment allocation guidelines.

A Rare Cause of Thunderclap Headache

Managing Victim Status in Group Therapy for Men: a Discourse Analysis

In contrast to the abundance of research on women victims, this article sheds light on the discourse of men who are self-identified as victims of their female partners' abuse. The purpose of this study was to investigate the most salient identity constructions and abuse conceptualizations among participants of group psychotherapy for men who have been abused in intimate, heterosexual partner relationships (i.e., Calgary Counselling Centre's 14-week group program titled "A Turn for the Better"). The men's identity work was examined using the methods and theoretical perspective of discourse analysis. Analysis of the talk demonstrated that the group agenda was to work through the ambiguity of abuse in the service of having the men identify themselves as victims. Thus, both the men and the group facilitators actively constructed "true victim" subject positions through their resistance to commonsense orientations of (a) "men as perpetrators" and (b) whether abuse consisted of more than physical violence. The therapeutic language of resistance was a common strategy used to manage victim status but also required further negotiation as it entailed a component of abuse (i.e., risked positioning the men as abusers rather than victims). The discussion focuses on how these findings may differ from the identity work present in women victim therapeutic groups. In addition, we note that it is difficult to uphold the victim-versus-perpetrator dichotomy in therapeutic discourse.

[Endarterectomy in Asymptomatic Carotid Stenosis: Not Worth the Risk]

A recent trial revealed a reduction in ischaemic infarcts after carotid endarterectomy in patients with asymptomatic carotid stenosis. However, the number needed to treat (NNT) was 22 to prevent 1 stroke in 10 years (including perioperative death as a primary outcome measurement). This is a modest effect in comparison to the trials with symptomatic patients with a 70-99% stenosis (NNT: 6). Furthermore, the number of surgical complications outweighs the benefits of surgery during the first 2 years after treatment. Finally, current medical treatment is significantly more effective than the medical treatment used in the control arm of this trial. Therefore, in our opinion, endarterectomy should not be performed routinely in asymptomatic patients.

Licorice Consumption As a Cause of Posterior Reversible Encephalopathy Syndrome: a Case Report

A 49-year-old woman was admitted to our hospital because of thunderclap headache and blurred vision. At the time of presentation, her blood pressure was 219/100 mmHg, her arterial pH was 7.64 and her potassium level was 2.7 mM/l.

Chromium Speciation in Coal and Biomass Co-combustion Products

Chromium speciation is vital for the toxicity of products resulting from co-combustion of coal and biomass. Therefore, understanding of formation processes has been studied using a combination of X-ray absorption fine structure (XAFS) spectroscopy and thermodynamic equilibrium calculations. The influence of cofiring on Cr speciation is very dependent on the type of fuel. Cr(VI) contents in the investigated fly ash samples from coal and cofiring average around 7% of the total chromium. An exception is cofiring 7-28% wood for which ashes exhibited Cr(VI) concentrations of 12-16% of the total chromium. Measurements are in line with thermodynamic predictions: RE factors of Cr around 1 are in line with volatile Cr only above 1400 °C; lower Cr(VI) concentrations with lower oxygen content and Cr(III) dissolved in aluminosilicate glass. Stability of Cr(VI) below 700 °C does not correlate with Cr(VI) concentrations found in the combustion products. It is indicated that Cr(VI) formation is a high-temperature process dependent on Cr evaporation (mode of occurrence in fuel, promoted by organic association), oxidation (local oxygen content), and formation of solid chromates (promoted by presence of free lime (CaO) in the ash). CaCrO(4)(s) is a probable chemical form but, given different leachable fractions (varying from 25 to 100%), different forms of Cr(VI) must be present. Clay-bound Cr is likely to dissolve in the aluminosilicate glass phase during melting of the clay.

Evaluation of Procedures for the Collection, Processing, and Analysis of Biomolecules from Low-biomass Surfaces

To comprehensively assess microbial diversity and abundance via molecular-analysis-based methods, procedures for sample collection, processing, and analysis were evaluated in depth. A model microbial community (MMC) of known composition, representative of a typical low-biomass surface sample, was used to examine the effects of variables in sampling matrices, target cell density/molecule concentration, and cryogenic storage on the overall efficacy of the sampling regimen. The MMC used in this study comprised 11 distinct species of bacterial, archaeal, and fungal lineages associated with either spacecraft or clean-room surfaces. A known cellular density of MMC was deposited onto stainless steel coupons, and after drying, a variety of sampling devices were used to recover cells and biomolecules. The biomolecules and cells/spores recovered from each collection device were assessed by cultivable and microscopic enumeration, and quantitative and species-specific PCR assays. rRNA gene-based quantitative PCR analysis showed that cotton swabs were superior to nylon-flocked swabs for sampling of small surface areas, and for larger surfaces, biological sampling kits significantly outperformed polyester wipes. Species-specific PCR revealed differential recovery of certain species dependent upon the sampling device employed. The results of this study empower current and future molecular-analysis-based microbial sampling and processing methodologies.

Red Alert for Women's Heart: the Urgent Need for More Research and Knowledge on Cardiovascular Disease in Women: Proceedings of the Workshop Held in Brussels on Gender Differences in Cardiovascular Disease, 29 September 2010

A recent report of the EuroHeart project has shown that women are still underrepresented in many cardiovascular clinical trials, while important gender differences are present within most areas of heart disease. As the burden of cardiovascular disease is increasing in middle-aged women relative to men, a more profound understanding is needed of the fundamental biological differences that exist between men and women. In the current review, we aim to address the need for more explanatory sex-specific cardiovascular research to be able to adapt existing guidelines for a better heart health in women.

Long-term Satisfaction After Neurological Second Opinions and Tertiary Referrals

The number of second opinions (SO) and tertiary referrals (TR) in neurology is increasing. Previously, we showed that a day-care admission for neurological SO's and TR's often results in a new diagnosis and/or treatment advice and increases patient satisfaction. However, long-term satisfaction for these consultations has never been studied. The main purpose of this study was to investigate long-term satisfaction in these groups of patients.

Epilepsy with Central Spikes Provoked by Fever with a Benign Disease Course

Intensive Management of Hyperglycaemia in Acute Coronary Syndromes. Study Design and Rationale of the BIOMArCS 2 Glucose Trial

Elevated admission plasma glucose is associated with increased mortality in patients who are admitted with an acute coronary syndrome. This may be mediated by increased inflammation, apoptosis and coagulation, and by a disturbed endothelial function that can be found in hyperglycaemic patients. Insulin has several characteristics that may potentially counteract these mechanisms.

Validation of the Physical Activity Scale for Individuals with Physical Disabilities

To determine the criterion validity of the Physical Activity Scale for Individuals With Physical Disabilities (PASIPD) by means of daily physical activity levels measured by using a validated accelerometry-based activity monitor in a large group of persons with a physical disability.

A Nonproductive Cough That Would Give Most People a Headache, but Not This Patient!

Comparative Genomics of Citric-acid-producing Aspergillus Niger ATCC 1015 Versus Enzyme-producing CBS 513.88

The filamentous fungus Aspergillus niger exhibits great diversity in its phenotype. It is found globally, both as marine and terrestrial strains, produces both organic acids and hydrolytic enzymes in high amounts, and some isolates exhibit pathogenicity. Although the genome of an industrial enzyme-producing A. niger strain (CBS 513.88) has already been sequenced, the versatility and diversity of this species compel additional exploration. We therefore undertook whole-genome sequencing of the acidogenic A. niger wild-type strain (ATCC 1015) and produced a genome sequence of very high quality. Only 15 gaps are present in the sequence, and half the telomeric regions have been elucidated. Moreover, sequence information from ATCC 1015 was used to improve the genome sequence of CBS 513.88. Chromosome-level comparisons uncovered several genome rearrangements, deletions, a clear case of strain-specific horizontal gene transfer, and identification of 0.8 Mb of novel sequence. Single nucleotide polymorphisms per kilobase (SNPs/kb) between the two strains were found to be exceptionally high (average: 7.8, maximum: 160 SNPs/kb). High variation within the species was confirmed with exo-metabolite profiling and phylogenetics. Detailed lists of alleles were generated, and genotypic differences were observed to accumulate in metabolic pathways essential to acid production and protein synthesis. A transcriptome analysis supported up-regulation of genes associated with biosynthesis of amino acids that are abundant in glucoamylase A, tRNA-synthases, and protein transporters in the protein producing CBS 513.88 strain. Our results and data sets from this integrative systems biology analysis resulted in a snapshot of fungal evolution and will support further optimization of cell factories based on filamentous fungi.

Magnetoencephalography As a Putative Biomarker for Alzheimer's Disease

Alzheimer's Disease (AD) is the most common dementia in the elderly and is estimated to affect tens of millions of people worldwide. AD is believed to have a prodromal stage lasting ten or more years. While amyloid deposits, tau filaments, and loss of brain cells are characteristics of the disease, the loss of dendritic spines and of synapses predate such changes. Popular preclinical detection strategies mainly involve cerebrospinal fluid biomarkers, magnetic resonance imaging, metabolic PET scans, and amyloid imaging. One strategy missing from this list involves neurophysiological measures, which might be more sensitive to detect alterations in brain function. The Magnetoencephalography International Consortium of Alzheimer's Disease arose out of the need to advance the use of Magnetoencephalography (MEG), as a tool in AD and pre-AD research. This paper presents a framework for using MEG in dementia research, and for short-term research priorities.

Sublingual Microvascular Changes in Patients with Cerebral Small Vessel Disease

It is unknown whether changes in cerebral small vessel disease (SVD) are limited to the brain or part of a generalized vascular disorder.

Can Color Inhomogeneity of Bruises Be Used to Establish Their Age?

Bruises become spatially inhomogeneous during the healing process; a smaller red-blue core area, caused by hemoglobin, is surrounded by a larger yellow area, caused by bilirubin, which is enzymatically formed from hemoglobin. These two areas develop at different rates and hence carry information about the age of the bruise. We present a proof of principle demonstration that the age of bruises can be determined via an inverse procedure using a mathematical model and daily measurements of these two areas using a hyperspectral imaging system. The inaccuracy found is 2.3% for fresh bruises and 3 to 24% for bruises up to 3 days old. In conclusion, color inhomogeneity of bruises can be used to determine their age. We expect that future age determination of bruises by the inverse procedure described here, possibly also including the distribution of concentrations in the areas will open up a new phase in clinical bruise classification.

Relationship Between the Time Interval from Antenatal Corticosteroid Administration Until Preterm Birth and the Occurrence of Respiratory Morbidity

The purpose of this study was to assess the relationship between neonatal respiratory morbidity and the interval between antenatal corticosteroids (ACS) administration and birth.

Rapid Visualization of Human Tumor Xenografts Through Optical Imaging with a Near-infrared Fluorescent Anti-Epidermal Growth Factor Receptor Nanobody

Given that overexpression of the epidermal growth factor receptor (EGFR) is found in many types of human epithelial cancers, noninvasive molecular imaging of this receptor is of great interest. A number of studies have employed monoclonal antibodies as probes; however, their characteristic long half-life in the bloodstream has encouraged the development of smaller probes. In this study, an anti-EGFR nanobody-based probe was developed and tested in comparison with cetuximab for application in optical molecular imaging. To this aim, the anti-EGFR nanobody 7D12 and cetuximab were conjugated to the near-infrared fluorophore IRDye800CW. 7D12-IR allowed the visualization of tumors as early as 30 minutes postinjection, whereas with cetuximab-IR, no signal above background was observed at the tumor site. Quantification of the IR-conjugated proteins in the tumors revealed ≈ 17% of injected dose per gram 2 hours after injection of 7D12-IR, which was significantly higher than the tumor uptake obtained 24 hours after injection of cetuximab-IR. This difference is associated with the superior penetration and distribution of 7D12-IR within the tumor. These results demonstrate that this anti-EGFR nanobody conjugated to the NIR fluorophore has excellent properties for rapid preclinical optical imaging, which holds promise for its future use as a complementary diagnostic tool in humans.

Comparison of Innovative Molecular Approaches and Standard Spore Assays for Assessment of Surface Cleanliness

A bacterial spore assay and a molecular DNA microarray method were compared for their ability to assess relative cleanliness in the context of bacterial abundance and diversity on spacecraft surfaces. Colony counts derived from the NASA standard spore assay were extremely low for spacecraft surfaces. However, the PhyloChip generation 3 (G3) DNA microarray resolved the genetic signatures of a highly diverse suite of microorganisms in the very same sample set. Samples completely devoid of cultivable spores were shown to harbor the DNA of more than 100 distinct microbial phylotypes. Furthermore, samples with higher numbers of cultivable spores did not necessarily give rise to a greater microbial diversity upon analysis with the DNA microarray. The findings of this study clearly demonstrated that there is not a statistically significant correlation between the cultivable spore counts obtained from a sample and the degree of bacterial diversity present. Based on these results, it can be stated that validated state-of-the-art molecular techniques, such as DNA microarrays, can be utilized in parallel with classical culture-based methods to further describe the cleanliness of spacecraft surfaces.

Sexuality of Young Adults with Cerebral Palsy: Experienced Limitations and Needs

Objective of this study is to describe the problems young adults with Cerebral Palsy (CP) experience in the various stages of the sexual response cycle, and the physical and emotional obstacles they experience with sexuality. In this prospective cohort study 74 young adults (46 men; 28 women) with CP and average intelligence participated, aged 20-24 years. Twenty percent of these young adults with CP experienced anorgasmia, 80% reported physical problems with sex related to CP and 45% emotional inhibition to initiate sexual contact. In 90% of the participants, sexuality had not been discussed during the rehabilitation treatment. Many adolescents reported wanting information about the impact of CP on sexuality and reproduction (35%), about interventions (26%), tools and medicines (16%) and about problems with their partner (14%). Young adults with CP can experience various problems or challenges with sexuality. For preventing sexual difficulties and treating sexual problems, health care professionals need to proactively take the initiative to inform young people with CP about sexuality.

N Latex FLC - New Monoclonal High-performance Assays for the Determination of Free Light Chain Kappa and Lambda

High serum concentrations of monoclonal free light chain (FLC) kappa or lambda are markers of plasma cell dyscrasia.

Time to Delivery After the First Course of Antenatal Corticosteroids: a Cohort Study

The optimal time interval between administration of antenatal corticosteroids and delivery is 1 to 7 days. This study evaluates the timing of the first course of antenatal corticosteroids in clinical practice. We performed a retrospective cohort study of consecutive women who had received antenatal corticosteroids and/or delivered between 24 and 34 weeks of gestation. Time between administration of corticosteroids and delivery was compared between women with different causes of anticipated preterm deliveries: symptomatic preterm labor with intact membranes; preterm premature rupture of the membranes; (pre)eclampsia; hemolysis, elevated liver enzymes, and low platelet count; intrauterine growth restriction; vaginal blood loss; and suspected fetal distress. We included 439 women of whom 348 (79%) completed the course of corticosteroids. In women with a complete course, 143 (41%) delivered within 7 days. The median interval between the course and delivery was 11 days and varied between 41 days in women with vaginal blood loss, 25 days in women with spontaneous preterm labor with intact membranes, and 8 days in women with preeclampsia ( P  <  0.001). In women with spontaneous preterm labor with intact membranes and in women with vaginal blood loss, we can benefit substantially from a more accurate discrimination of women who need corticosteroids immediately and women who do not.

Rigidity of Unilateral External Fixators--a Biomechanical Study

External fixation is the primary choice of temporary fracture stabilisation for specific polytrauma patients. Adequate initial fracture healing requires sufficient stability at the fracture site. The purpose of this study was to compare the rigidity of the Dynafix DFS(®) Standard Fixator (4 joints) with the Orthofix ProCallus Fixator(®) (2 joints), which differ in possibilities for adapting the configuration for clinical needs.

Ethnicity and Thrombolysis in Ischemic Stroke: a Hospital Based Study in Amsterdam

Ethnic differences have been reported with regard to several medical therapies. The aim of this study was to investigate the relation between ethnicity and thrombolysis in stroke patients.

Energy Expenditure in Chronic Stroke Patients Playing Wii Sports: a Pilot Study

Stroke is one of the leading causes of long-term disability in modern western countries. Stroke survivors often have functional limitations which might lead to a vicious circle of reduced physical activity, deconditioning and further physical deterioration. Current evidence suggests that routine moderate- or vigorous-intensity physical activity is essential for maintenance and improvement of health among stroke survivors. Nevertheless, long-term participation in physical activities is low among people with disabilities. Active video games, such as Nintendo Wii Sports, might maintain interest and improve long-term participation in physical activities; however, the intensity of physical activity among chronic stroke patients while playing Wii Sports is unknown. We investigated the energy expenditure of chronic stroke patients while playing Wii Sports tennis and boxing.

Rate of Progression and Predictive Factors for Pulmonary Outcome in Children and Adults with Pompe Disease

Respiratory insufficiency is a serious threat to patients with Pompe disease, a neuromuscular disorder caused by lysosomal acid alpha-glucosidase deficiency. Innovative therapeutic options which may stabilize pulmonary function have recently become available. We therefore determined proportion and severity of pulmonary involvement in patients with Pompe disease, the rate of progression of pulmonary dysfunction, and predictive factors for poor respiratory outcome. In a single-center, prospective, cohort study, we measured vital capacity (VC) in sitting and supine positions, as well as maximum inspiratory (MIP) and expiratory (MEP) mouth pressures, and end expiratory CO(2) in 17 children and 75 adults with Pompe disease (mean age 42.7 years, range 5-76 years). Seventy-four percent of all patients, including 53% of the children, had some degree of respiratory dysfunction. Thirty-eight percent had obvious diaphragmatic weakness. Males appeared to have more severe pulmonary involvement than females: at a group level, their mean VC was significantly lower than that of females (p<0.001), they used mechanical ventilation more often than females (p=0.042) and the decline over the course of the disease was significantly different between males and females (p=0.003). Apart from male gender, severe skeletal muscle weakness and long disease duration were the most important predictors of poor respiratory status. During follow-up (average 1.6 years, range 0.5-4.2 years), three patients became ventilator dependent. Annually, there were average decreases in VC in upright position of 0.9% points (p=0.09), VC in supine position of 1.2% points (p=0.049), MIP of 3.2% points (p=0.018) and MEP of 3.8% points (p<0.01). We conclude that pulmonary dysfunction in Pompe disease is much more common than generally thought. Males, patients with severe muscle weakness, and those with advanced disease duration seem most at risk.

Head Tremor Related to CACNA1A Mutations

Familial hemiplegic migraine (FHM) is characterized by the familial occurrence of migraine attacks with fully reversible transient hemiplegia. Mutations in three different genes have been identified; CACNA1A (FHM1), ATP1A2 (FHM2) and SCN1A (FHM3). Besides hemiplegia, several other symptoms have been described in FHM 1-3 mutation carriers, including epilepsy and cerebellar symptoms.

Decompressive Surgery in Cerebrovenous Thrombosis: a Multicenter Registry and a Systematic Review of Individual Patient Data

Herniation attributable to unilateral mass effect is the major cause of death in cerebral venous thrombosis (CVT). Decompressive surgery may be lifesaving in these patients.

A Mixture of Three Prebiotics Does Not Affect Vaccine Specific Antibody Responses in Healthy Term Infants in the First Year of Life

Previous studies have shown, that prebiotics can modulate the immune response in infants at risk for allergy, leading to a lower incidence of atopic dermatitis. Few studies have evaluated the effect of prebiotic carbohydrates alone on the vaccine-specific antibody response as a marker for the development of the immune system in healthy infants not at risk for allergy.

Upper Limb Function in Adults with Duchenne Muscular Dystrophy

To determine upper limb function and associated factors in adults with Duchenne muscular dystrophy.

Anticoagulation for Cerebral Venous Sinus Thrombosis

Treatment of cerebral venous sinus thrombosis with anticoagulants has been controversial. Anticoagulants may prevent new venous infarcts, neurologic deterioration and pulmonary embolism but may also promote haemorrhages.

[Limited Benefit of Diagnostic Second Opinions in a Neurology Department]

To describe the short and long term results of neurological second opinions with regard to medical aspects and patient satisfaction.

Treatment Variations in Cerebral Venous Thrombosis: an International Survey

Validation of the Web-based LUMINA Questionnaire for Recruiting Large Cohorts of Migraineurs

To assess validity of a self-administered web-based migraine-questionnaire in diagnosing migraine aura for the use of epidemiological and genetic studies.

Integrated Megavoltage Portal Imaging with a 1.5 T MRI Linac

In this note, the feasibility of complementing our hybrid 1.5 T MRI linac (MRL) with a megavoltage (MV) portal imager is investigated. A standard aSi MV detector panel is added to the system and both qualitative and quantitative performances are determined. Simultaneous MR imaging and transmission imaging can be performed without mutual interference. The MV image quality is compromised by beam transmission and longer isocentre distance; still, the field edges and bony anatomy can be detected at very low dose levels of 0.4 cGy. MV imaging integrated with the MRL provides an independent and well-established position verification tool, a field edge check and a calibration for alignment of the coordinate systems of the MRI and the accelerator. The portal imager can also be a valuable means for benchmarking MRI-guided position verification protocols on a patient-specific basis in the introductory phase.

Complexity Analysis of Resting-state MEG Activity in Early-stage Parkinson's Disease Patients

The aim of the present study was to analyze resting-state brain activity in patients with Parkinson's disease (PD), a degenerative disorder of the nervous system. Magnetoencephalography (MEG) signals were recorded with a 151-channel whole-head radial gradiometer MEG system in 18 early-stage untreated PD patients and 20 age-matched control subjects. Artifact-free epochs of 4 s (1250 samples) were analyzed with Lempel-Ziv complexity (LZC), applying two- and three-symbol sequence conversion methods. The results showed that MEG signals from PD patients are less complex than control subjects' recordings. We found significant group differences (p-values <0.01) for the 10 major cortical areas analyzed (e.g., bilateral frontal, central, temporal, parietal, and occipital regions). In addition, using receiver-operating characteristic curves with a leave-one-out cross-validation procedure, a classification accuracy of 81.58% was obtained. In order to investigate the best combination of LZC results for classification purposes, a forward stepwise linear discriminant analysis with leave-one out cross-validation was employed. LZC results (three-symbol sequence conversion) from right parietal and temporal brain regions were automatically selected by the model. With this procedure, an accuracy of 84.21% (77.78% sensitivity, 90.0% specificity) was achieved. Our findings demonstrate the usefulness of LZC to detect an abnormal type of dynamics associated with PD.

Effects of Visual Context Upon Functional Connectivity During Observation of Biological Motions

The aim of this study was to examine brain responses, in particular functional connectivity, to different visual stimuli depicting familiar biological motions. Ten subjects actively observed familiar biological motions embedded in point-light and video displays. Electroencephalograms were recorded from 64 electrodes. Activity was considered in three frequency bands (4-8 Hz, 8-10 Hz, and 10-13 Hz) using a non-linear measure of functional connectivity. In the 4-8 Hz and 8-10 Hz frequency bands, functional connectivity for the SMA was greater during the observation of biological motions presented in a point-light display compared to the observation of motions presented in a video display. The reverse was observed for the 4-8 Hz frequency band for the left temporal area. Explanations related to: (i) the task demands (i.e., attention and mental effort), (ii) the role(s) of theta and alpha oscillations in cognitive processes, and (iii) the function(s) of cortical areas are discussed. It has been suggested that attention was required to process human biological motions under unfamiliar viewing conditions such as point-light display.

Fluorescent Cell Barcoding As a Tool to Assess the Age-related Development of Intracellular Cytokine Production in Small Amounts of Blood from Infants

Fluorescent Cell Barcoding (FCB) is a flow cytometric technique which has been used for assessing signaling proteins. This FCB technique has the potential to be applied in other multiparameter analyses. Since data on antigen (Ag)-specific T-cell immune responses, like intracellular cytokine production, are still lacking in infants because limited blood volumes can be obtained for analysis, the FCB technique could be very useful for this purpose. The objectives of this study were to modify the FCB method to be able to measure multiple Ag-specific cytokine reponses in T-cells upon simultaneous stimulation by various antigens and mitogens in small amounts of blood and to investigate the cytokine pattern of T-cell subsets in healthy infants aged six and twelve months. Blood samples, collected from 20 healthy infants aged six and twelve months, were stimulated in vitro with the antigens: phorbol-myristate-acetate (PMA), purified-protein-derivative (PPD), Tetanus-toxoid (TT), Staphylococcal-enterotoxin-B (SEB), and phytohemagglutinin (PHA). Each stimulus was barcoded by labelling with different intensities of fluorescent cell barcoding (FCB) markers. Intracellular production of interleukin-2, interferon-gamma, and tumor necrosis factor-alpha was measured simultaneously in just one blood sample of 600 µl whole blood. Significant age-related differences in cytokine production were shown for PMA, PHA, and TT in CD4(+) T-cells, and for PMA, PHA, SEB, and TT in CD8(+) T-cells. The intracellular cytokine production by CD4(+) and CD8(+) T-cells was higher at twelve months compared to six months of age for all antigens, except for PMA, which was lower at the age of twelve months. Based on the consistency in both T-cell subsets, we conclude that the new FCB method is a promising tool to investigate the age-related development of intracellular cytokine production in infants.

Does Sleep Restore the Topology of Functional Brain Networks?

Previous studies have shown that healthy anatomical as well as functional brain networks have small-world properties and become less optimal with brain disease. During sleep, the functional brain network becomes more small-world-like. Here we test the hypothesis that the functional brain network during wakefulness becomes less optimal after sleep deprivation (SD). Electroencephalography (EEG) was recorded five times a day after a night of SD and after a night of normal sleep in eight young healthy subjects, both during eyes-closed and eyes-open resting state. Overall synchronization was determined with the synchronization likelihood (SL) and the phase lag index (PLI). From these coupling strength matrices the normalized clustering coefficient C (a measurement of local clustering) and path length L (a measurement of global integration) were computed. Both measures were normalized by dividing them by their corresponding C-s and L-s values of random control networks. SD reduced alpha band C/C-s and L/L-s and theta band C/C-s during eyes-closed resting state. In contrast, SD increased gamma-band C/C-s and L/L-s during eyes-open resting state. Functional relevance of these changes in network properties was suggested by their association with sleep deprivation-induced performance deficits on a sustained attention simple reaction time task. The findings indicate that SD results in a more random network of alpha-coupling and a more ordered network of gamma-coupling. The present study shows that SD induces frequency-specific changes in the functional network topology of the brain, supporting the idea that sleep plays a role in the maintenance of an optimal functional network. Hum Brain Mapp, 2011. © 2011 Wiley Periodicals, Inc.

Resting-state Networks in Awake Five- to Eight-year Old Children

During the first 6-7 years of life children undergo a period of major neurocognitive development. Higher-order cognitive functions such as executive control of attention, encoding and retrieving of stored information and goal-directed behavior are present but less developed compared to older individuals. There is only very limited information from functional magnetic resonance imaging (fMRI) studies about the level of organization of functional networks in children in the early school period. In this study we perform continuous resting-state functional connectivity MRI in 5- to 8-year-old children in an awake state to identify and characterize resting-state networks (RSNs). Temporal concatenation independent component analysis (ICA) approach was applied to analyze the data. We identified 14 components consisting of regions known to be involved in visual and auditory processing, motor function, attention control, memory, and the default mode network (DMN). Most networks, in particular those supporting basic motor function and sensory related processing, had a robust functional organization similar to mature adult patterns. In contrast, the DMN and other RSNs involved in higher-order cognitive functions had immature characteristics, revealing incomplete and fragmented patterns indicating less developed functional connectivity. We therefore conclude that the DMN and other RSNs involved in higher order cognitive functioning are detectable, yet in an immature state, at an age when these cognitive abilities are mastered.

Comparison of Diagnostic Criteria to Detect Undiagnosed Diabetes in Hyperglycaemic Patients with Acute Coronary Syndrome

Elevated plasma glucose levels on admission (APG) are very common in patients with acute coronary syndrome (ACS) and can be the first indication of diabetes mellitus.

Decompressive Hemicraniectomy Followed by Endovascular Thrombosuction in a Patient with Cerebral Venous Thrombosis

Impact of Triplicate Testing on HIV Genotypic Tropism Prediction in Routine Clinical Practice

Guidelines state that the CCR5-inhibitor Maraviroc should be prescribed to patients infected with R5-tropic HIV-1 only. Therefore, viral tropism needs to be assessed phenotypically or genotypically. Preliminary clinical trial data suggest that genotypic analysis in triplicate is associated with improved prediction of virological response by increasing the detection of X4-tropic variants. Our objective was to evaluate the impact of triplicate genotypic analysis on prediction of co-receptor usage in routine clinical practice. Samples from therapy-naive and therapy-experienced patients were collected for routine tropism testing at three European clinical centres. Viral RNA was isolated from plasma and proviral DNA from peripheral blood mononuclear cells. Gp120-V3 was amplified in a triplicate nested RT-PCR procedure and sequenced. Co-receptor usage was predicted using the Geno2Pheno([coreceptor]) algorithm and analysed with a false-positive rate (FPR) of 5.75%, 10%, or an FPR of 20% and according to the current European guidelines on the clinical management of HIV-1 tropism testing. A total of 266 sequences were obtained from 101 patient samples. Discordance in tropism prediction for the triplicates was observed in ten samples using an FPR of 10%. Triplicate testing resulted in a 16.7% increase in X4-predicted samples and to reclassification from R5 to X4 tropism for four cases rendering these patients ineligible for Maraviroc treatment. In conclusion, triplicate genotypic tropism testing increases X4 tropism detection in individual cases, which may prove to be pivotal when CCR5-inhibitor therapy is applied.

Gender-related Differences in Functional Connectivity in Multiple Sclerosis

Gender effects are strong in multiple sclerosis (MS), with male patients showing a worse clinical outcome than female patients. Functional reorganization of neural activity may contribute to limit disability, and possible gender differences in this process may have important clinical implications.

The Oomycete Broad-host-range Pathogen Phytophthora Capsici

Phytophthora capsici is a highly dynamic and destructive pathogen of vegetables. It attacks all cucurbits, pepper, tomato and eggplant, and, more recently, snap and lima beans. The disease incidence and severity have increased significantly in recent decades and the molecular resources to study this pathogen are growing and now include a reference genome. At the population level, the epidemiology varies according to the geographical location, with populations in South America dominated by clonal reproduction, and populations in the USA and South Africa composed of many unique genotypes in which sexual reproduction is common. Just as the impact of crop loss as a result of P. capsici has increased in recent decades, there has been a similar increase in the development of new tools and resources to study this devastating pathogen. Phytophthora capsici presents an attractive model for understanding broad-host-range oomycetes, the impact of sexual recombination in field populations and the basic mechanisms of Phytophthora virulence. TAXONOMY: Kingdom Chromista; Phylum Oomycota; Class Oomycetes; Order Peronosporales; Family Peronosporaceae; Genus Phytophthora; Species capsici. DISEASE SYMPTOMS: Symptoms vary considerably according to the host, plant part infected and environmental conditions. For example, in dry areas (e.g. southwestern USA and southern France), infection on tomato and bell or chilli pepper is generally on the roots and crown, and the infected plants have a distinctive black/brown lesion visible at the soil line (Fig. 1). In areas in which rainfall is more common (e.g. eastern USA), all parts of the plant are infected, including the roots, crown, foliage and fruit (Fig. 1). Root infections cause damping off in seedlings, whereas, in older plants, it is common to see stunted growth, wilting and, eventually, death. For tomatoes, it is common to see significant adventitious root growth just above an infected tap root, and the stunted plants, although severely compromised, may not die. For many cucurbit fruit, the expanding lesions produce fresh sporangia over days (or even weeks depending on the size of the fruit) and the fruit often look as if they have been dipped in white powdered confectioner's sugar (Fig. 1). Generally, hyphae do not emerge from infected plants or fruit (common with Pythium infections) and all that is visible on the surface of an infected plant is sporangia. IMPORTANCE: Phytophthora capsici presents an oomycete worst-case scenario to growers as it has a broad host range, often produces long-lived dormant sexual spores, has extensive genotypic diversity and has an explosive asexual disease cycle. It is becoming increasingly apparent that novel control strategies are needed to safeguard food production from P. capsici and other oomycetes. Considering that P. capsici is easy to grow, mate and manipulate in the laboratory and infects many plant species, this pathogen is a robust model for investigations, particularly those related to sexual reproduction, host range and virulence. USEFUL WEBSITES: Phytophthora capsici genome database: http://genome.jgi-psf.org/Phyca11/Phyca11.home.html. Molecular tools to identify Phytophthora isolates: http://phytophthora-id.org.

Connectivity Mapping Identifies HDAC Inhibitors for the Treatment of T(4;11)-positive Infant Acute Lymphoblastic Leukemia

MLL-rearranged infant acute lymphoblastic leukemia (ALL) is an aggressive type of leukemia characterized by a unique gene-expression profile. We uncovered that the activation of particular (proto-onco)genes is mediated by promoter hypomethylation. In search for therapeutic agents capable of targeting these potential cancer-promoting genes, we applied connectivity mapping on a gene expression signature based on the genes most significantly hypomethylated in t(4;11)-positive infant ALL as compared with healthy bone marrows. This analysis revealed histone deacetylase (HDAC) inhibitors as suitable candidates to reverse the unfavorable gene signature. We show that HDAC inhibitors effectively induce leukemic cell death in t(4;11)-positive primary infant ALL cells, accompanied by downregulation of MYC, SET, RUNX1, RAN as well as the MLL-AF4 fusion product. Furthermore, DNA methylation was restored after HDAC inhibitor exposure. Our data underlines the essential role for epigenetic de-regulation in MLL-rearranged ALL. Furthermore, we show, for the first time, that connectivity mapping can indirectly be applied on DNA methylation patterns, providing a rationale for HDAC inhibition in t(4;11)-positive leukemias. Given the presented potential of HDAC inhibitors to target important proto-oncogenes including the leukemia-specific MLL fusion in vitro, these agents should urgently be tested in in vivo models and subsequent clinical trials.

Cognitive and Neurological Outcome at the Age of 5-8 Years of Preterm Infants with Post-hemorrhagic Ventricular Dilatation Requiring Neurosurgical Intervention

Preterm infants with progressive post-hemorrhagic ventricular dilatation (PHVD) in the absence of associated parenchymal lesions may have a normal neurodevelopmental outcome.

Clinical Comparison of New Monoclonal Antibody-based Nephelometric Assays for Free Light Chain Kappa and Lambda to Polyclonal Antibody-based Assays and Immunofixation Electrophoresis

New monoclonal antibody-based assays for serum-free light chains (FLC) have become available.

Renshaw Cell Interneuron Specialization is Controlled by a Temporally Restricted Transcription Factor Program

The spinal cord contains a diverse array of physiologically distinct interneuron cell types that subserve specialized roles in somatosensory perception and motor control. The mechanisms that generate these specialized interneuronal cell types from multipotential spinal progenitors are not known. In this study, we describe a temporally regulated transcriptional program that controls the differentiation of Renshaw cells (RCs), an anatomically and functionally discrete spinal interneuron subtype. We show that the selective activation of the Onecut transcription factors Oc1 and Oc2 during the first wave of V1 interneuron neurogenesis is a key step in the RC differentiation program. The development of RCs is additionally dependent on the forkhead transcription factor Foxd3, which is more broadly expressed in postmitotic V1 interneurons. Our demonstration that RCs are born, and activate Oc1 and Oc2 expression, in a narrow temporal window leads us to posit that neuronal diversity in the developing spinal cord is established by the composite actions of early spatial and temporal determinants.

Young Alzheimer Patients Show Distinct Regional Changes of Oscillatory Brain Dynamics

The objective of this study was to examine the differences in oscillatory brain dynamics in Alzheimer's disease (AD) according to age at onset using quantitative electroencephalography (EEG). We examined resting state electroencephalograms of 320 probable AD patients and 246 controls, both categorized into a young (≤ 65 years) and old (> 65 years) group. Relative power in 4 different frequency bands was calculated. The effect of age on global and regional relative power was examined. Globally, young AD patients showed lower alpha- and higher delta-power than old AD patients. Regional analysis showed that these differences were most pronounced in the parieto-occipital region. Young AD patients had lower beta- and higher theta-power than old patients in all but the temporal regions. In controls, there was no age effect on global relative power in any frequency band. Young AD patients present with more severe slowing of spontaneous oscillatory activity than old AD patients, which is most pronounced in the posterior brain areas. This finding supports the hypothesis that early onset AD presents with a distinct endophenotype.

Decompressive Hemicraniectomy in Severe Cerebral Venous Thrombosis: a Prospective Case Series

Small retrospective case series suggest that decompressive hemicraniectomy can be life saving in patients with cerebral venous thrombosis (CVT) and impending brain herniation. Prospective studies of consecutive cases are lacking. Thus, a single centre, prospective study was performed. In 2006 we adapted our protocol for CVT treatment to perform acute decompressive hemicraniectomy in patients with impending herniation, in whom the prognosis with conservative treatment was considered infaust. We included all consecutive patients with CVT between 2006 and 2010 who underwent hemicraniectomy. Outcome was assessed at 12 months with the modified Rankin Scale (mRS). Ten patients (8 women) with a median age of 41 years (range 26-52 years) were included. Before surgery 5 patients had GCS < 9, 9 patients had normal pupils, 1 patient had a unilaterally fixed and dilated pupil. All patients except one had space-occupying intracranial hemorrhagic infarcts. The median preoperative midline shift was 9 mm (range 3-14 mm). Unilateral hemicraniectomy was performed in 9 patients and bilateral hemicraniectomy in one. Two patients died from progressive cerebral edema and expansion of the hemorrhagic infarcts. Five patients recovered without disability at 12 months (mRS 0-1). Two patients had some residual handicap (one minor, mRS 2; one moderate, mRS 3). One patient was severely handicapped (mRS 5). Our prospective data show that decompressive hemicraniectomy in the most severe cases of cerebral venous thrombosis was probably life saving in 8/10 patients, with a good clinical outcome in six. In 2 patients death was caused by enlarging hemorrhagic infarcts.

Frequency-dependent Functional Connectivity Within Resting-state Networks: an Atlas-based MEG Beamformer Solution

The brain consists of functional units with more-or-less specific information processing capabilities, yet cognitive functions require the co-ordinated activity of these spatially separated units. Magnetoencephalography (MEG) has the temporal resolution to capture these frequency-dependent interactions, although, due to volume conduction and field spread, spurious estimates may be obtained when functional connectivity is estimated on the basis of the extra-cranial recordings directly. Connectivity estimates on the basis of reconstructed sources may similarly be affected by biases introduced by the source reconstruction approach. Here we propose an analysis framework to reliably determine functional connectivity that is based around two main ideas: (i) functional connectivity is computed for a set of atlas-based ROIs in anatomical space that covers almost the entire brain, aiding the interpretation of MEG functional connectivity/network studies, as well as the comparison with other modalities; (ii) volume conduction and similar bias effects are removed by using a functional connectivity estimator that is insensitive to these effects, namely the Phase Lag Index (PLI). Our analysis approach was applied to eyes-closed resting-state MEG data for thirteen healthy participants. We first demonstrate that functional connectivity estimates based on phase coherence, even at the source-level, are biased due to the effects of volume conduction and field spread. In contrast, functional connectivity estimates based on PLI are not affected by these biases. We then looked at mean PLI, or weighted degree, over areas and subjects and found significant mean connectivity in three (alpha, beta, gamma) of the five (including theta and delta) classical frequency bands tested. These frequency-band dependent patterns of resting-state functional connectivity were distinctive; with the alpha and beta band connectivity confined to posterior and sensorimotor areas respectively, and with a generally more dispersed pattern for the gamma band. Generally, these patterns corresponded closely to patterns of relative source power, suggesting that the most active brain regions are also the ones that are most-densely connected. Our results reveal for the first time, using an analysis framework that enables the reliable characterisation of resting-state dynamics in the human brain, how resting-state networks of functionally connected regions vary in a frequency-dependent manner across the cortex.

Acute Effects of Whole-body Vibration on Jump Force and Jump Rate of Force Development: a Comparative Study of Different Devices

The goal of this study was to compare the acute effects of whole-body vibration (WBV) delivered by 3 devices with different mechanical behavior on jump force (JF) and jump rate of force development (JRFD). Twelve healthy persons (4 women and 8 men; age 30.5 ± 8.8 years; height 178.6 ± 7.3 cm; body mass 74.8 ± 9.7 kg) were exposed to WBV for 15 and 40 seconds using 2 professional devices (power plate [PP; vertical vibration] and Galileo 2000 [GA; oscillatory motion around the horizontal axis in addition to vertical vibration]) and a home-use device [Power Maxx, PM; horizontal vibration]). The JF and JRFD were evaluated before, immediately after, and 5 minutes after WBV. The JF measured immediately after 40 seconds of vibration by the GA device was reduced (3%, p = 0.05), and JRFD measured after 5 minutes of rest after 40 seconds of vibration by the PM device was reduced (12%, p < 0.05) compared with the baseline value. The acute effects of WBV (15 or 40 seconds) on JF and JRFD were not significantly different among the 3 devices. In conclusion, our hypothesis that WBV devices with different mechanical behaviors would result in different acute effects on muscle performance was not confirmed.

Biological and Technical Considerations Regarding the Removal of Bacteriotoxins in Sepsis with Emphasis on Toxic Shock Syndrome Toxin 1

Severe sepsis is characterized by rapid development of multiple organ failure associated with high mortality. Bacterial toxin release triggers a sequence of events that activates intracellular pathways to produce inflammatory mediators and nitric oxide. There have been numerous attempts to interrupt this devastating cascade by removing toxins, removing or inhibiting mediators, and by blocking receptors of mediators. This review considers toxin properties with a strong focus on toxic shock syndrome toxin 1 and the potential of various removal technologies in relation to these properties. The distribution of toxins in vivo forms a key issue but is nevertheless poorly defined. For toxic shock syndrome toxin 1, either a high clearance or a high degree of compartmentalization to a space not accessible by pheresis or immunoabsorption technologies seems likely. Attempts to remove toxins to treat sepsis may appear futile if we cannot access this space or when the level of induced clearance is too low compared with natural clearance. The impact of these considerations is highly dependent on the exact toxin biology in vivo. Extrapolated to other toxins, we indicate a set of general requirements to be met to facilitate successful toxin removal by a pheresis technique.

Subjective Caregiver Burden of Parents of Adults with Duchenne Muscular Dystrophy

To describe subjective caregiver burden of parents of adults with Duchenne muscular dystrophy (DMD) and to identify factors associated with the level of subjective burden.

Disrupted Modular Brain Dynamics Reflect Cognitive Dysfunction in Alzheimer's Disease

The relation between pathology and cognitive dysfunction in dementia is still poorly understood, although disturbed communication between different brain regions is almost certainly involved. In this study we combine magneto-encephalography (MEG) and network analysis to investigate the role of functional sub-networks (modules) in the brain with regard to cognitive failure in Alzheimer's disease. Whole-head resting-state (MEG) was performed in 18 Alzheimer patients (age 67 ± 9, 6 females, MMSE 23 ± 5) and 18 healthy controls (age 66 ± 9, 11 females, MMSE 29 ± 1). We constructed functional brain networks based on interregional synchronization measurements, and performed graph theoretical analysis with a focus on modular organization. The overall modular strength and the number of modules changed significantly in Alzheimer patients. The parietal cortex was the most highly connected network area, but showed the strongest intramodular losses. Nonetheless, weakening of intermodular connectivity was even more outspoken, and more strongly related to cognitive impairment. The results of this study demonstrate that particularly the loss of communication between different functional brain regions reflects cognitive decline in Alzheimer's disease. These findings imply the relevance of regarding dementia as a functional network disorder.

Can the Dutch Government Really Be Abandoning Smokers to Their Fate?

EEG Synchronization Characteristics of Functional Connectivity and Complex Network Properties of Memory Maintenance in the Delta and Theta Frequency Bands

Task-dependent changes of nonlinear-linear synchronization features and graph theoretical properties of the delta and theta frequencies were analyzed in the present EEG study that were related to episodic memory maintenance processes. Synchronization was found to increase with respect to both the delta and theta bands within the frontal and parietal areas and also between these regions. Results of graph theoretical analysis indicated a task-related shift towards small-world network topology in the theta band.

Gene Expression Profiles Predictive of Outcome and Age in Infant Acute Lymphoblastic Leukemia: a Children's Oncology Group Study

Gene expression profiling was performed on 97 cases of infant ALL from Children's Oncology Group Trial P9407. Statistical modeling of an outcome predictor revealed 3 genes highly predictive of event-free survival (EFS), beyond age and MLL status: FLT3, IRX2, and TACC2. Low FLT3 expression was found in a group of infants with excellent outcome (n = 11; 5-year EFS of 100%), whereas differential expression of IRX2 and TACC2 partitioned the remaining infants into 2 groups with significantly different survivals (5-year EFS of 16% vs 64%; P < .001). When infants with MLL-AFF1 were analyzed separately, a 7-gene classifier was developed that split them into 2 distinct groups with significantly different outcomes (5-year EFS of 20% vs 65%; P < .001). In this classifier, elevated expression of NEGR1 was associated with better EFS, whereas IRX2, EPS8, and TPD52 expression were correlated with worse outcome. This classifier also predicted EFS in an independent infant ALL cohort from the Interfant-99 trial. When evaluating expression profiles as a continuous variable relative to patient age, we further identified striking differences in profiles in infants less than or equal to 90 days of age and those more than 90 days of age. These age-related patterns suggest different mechanisms of leukemogenesis and may underlie the differential outcomes historically seen in these age groups.

Letter by Coutinho Et Al Regarding Article, "Mortality of Cerebral Venous-sinus Thrombosis in a Large National Sample"

How the Blood Pool Properties at Onset Affect the Temporal Behavior of Simulated Bruises

The influence of initial blood pool properties on the temporal behavior of bruises is currently unknown. We addressed this important issue by utilizing three typical classes of bruises in our three-layered finite compartment model. We simulated the effects of their initial shapes, regularity of boundaries and initial blood concentration distributions (gaussian vs. homogeneous) on the hemoglobin and bilirubin areas in the dermal top layer. Age determination of bruises with gaussian hemoglobin concentration was also addressed. We found that the initial blood pool properties strongly affect bruise behavior. We determined the age of a 200-h simulated bruise with gaussian hemoglobin concentration with 3 h uncertainty. In conclusion, bruise behavior depends non-intuitively on the initial blood pool properties; hence, a model that includes shape, area and concentration distribution at onset is indispensable. Future age determination, including inhomogeneous hemoglobin distributions, will likely be based on the presented method for gaussian distributions.

Elevated S100A8/S100A9 Expression Causes Glucocorticoid Resistance in MLL-rearranged Infant Acute Lymphoblastic Leukemia

MLL-rearranged acute lymphoblastic leukemia (ALL) in infants is characterized by a poor clinical outcome and resistance to glucocorticoids (for example, prednisone and dexamethasone). As both the response to prednisolone in vitro and prednisone in vivo are predictive for clinical outcome, understanding and overcoming glucocorticoid resistance remains an essential step towards improving prognosis. Prednisolone-induced apoptosis depends on glucocorticoid-evoked Ca(2+) fluxes from the endoplasmic reticulum towards the mitochondria. Here, we demonstrate that in MLL-rearranged infant ALL, over-expression of S100A8 and S100A9 is associated with failure to induce free-cytosolic Ca(2+) and prednisolone resistance. Furthermore, we demonstrate that enforced expression of S100A8/S100A9 in prednisolone-sensitive MLL-rearranged ALL cells, rapidly leads to prednisolone resistance as a result of S100A8/S100A9 mediated suppression of prednisolone-induced free-cytosolic Ca(2+) levels. In addition, the Src kinase inhibitor PP2 markedly sensitized MLL-rearranged ALL cells otherwise resistant to prednisolone, via downregulation of S100A8 and S100A9, which allowed prednisolone-induced Ca(2+) fluxes to reach the mitochondria and trigger apoptosis. On the basis of this novel mechanism of prednisolone resistance, we propose that developing more specific S100A8/S100A9 inhibitors may well be beneficial for prednisolone-resistant MLL-rearranged infant ALL patients.

Genome-wide Analysis of CpG Island Methylation in Bladder Cancer Identified TBX2, TBX3, GATA2, and ZIC4 As PTa-specific Prognostic Markers

DNA methylation markers could serve as useful biomarkers, both as markers for progression and for urine-based diagnostic assays.

Low Impact of Congenital Hand Differences on Health-related Quality of Life

To evaluate health-related quality of life (HRQoL) and its determinants in children with congenital hand differences (CHDs).

The Effect of RTMS on Auditory Hallucinations: Clues from an EEG-rTMS Study

Repetitive transcranial magnetic stimulation (rTMS) to the temporoparietal region has been proposed as a therapeutic option for auditory verbal hallucinations (AVH). However, most large randomized controlled trials failed to demonstrate a superior effect of rTMS treatment as compared to sham. Previous studies applied daily rTMS sessions for one or more weeks to summate its effects. However, the effect of a single rTMS treatment on AVH-severity has never been studied, making it unclear if there is an initial effect that could be increased by repeated treatment.

MLL-AF4 Driven Leukemogenesis: What Are We Missing?

Personal and Environmental Factors Contributing to Participation in Romantic Relationships and Sexual Activity of Young Adults with Cerebral Palsy

To study determinants of romantic relationships and sexual activity of young adults with cerebral palsy (CP), focusing on personal and environmental factors.

Effectiveness of Audio Feedback for Partial Weight-bearing in and Outside the Hospital: a Randomized Controlled Trial

To determine the effectiveness of partial weight-bearing (PWB) training with audio feedback in patients after total hip arthroplasty (THA).

Combined Immunotherapy with Granulocyte-macrophage Colony-stimulating Factor-transduced Allogeneic Prostate Cancer Cells and Ipilimumab in Patients with Metastatic Castration-resistant Prostate Cancer: a Phase 1 Dose-escalation Trial

BACKGROUND: The granulocyte-macrophage colony-stimulating factor-transduced allogeneic prostate cancer cells vaccine (GVAX) has antitumour activity against prostate cancer; preclinical studies have shown potent synergy when combined with ipilimumab, an antibody that blocks cytotoxic T-lymphocyte antigen 4. We aimed to assess the safety of combined treatment with GVAX and ipilimumab in patients with metastatic castration-resistant prostate cancer (mCRPC). METHODS: We did an open-labelled, single-centre, dose-escalation study of ipilimumab concurrent with a fixed dose of GVAX, with a subsequent expansion phase, both at the VU University Medical Centre (Amsterdam, Netherlands). Eligible patients had documented mCRPC and had not been previously treated with chemotherapy. All patients received a 5×10(8) cell priming dose of GVAX intradermally on day 1 with subsequent intradermal injections of 3×10(8) cells every 2 weeks for 24 weeks. The vaccinations were combined with intravenous ipilimumab every 4 weeks. We enrolled patients in cohorts of three; each cohort received an escalating dose of ipilimumab at 0·3, 1·0, 3·0, or 5·0 mg/kg. Our primary endpoint was safety. This study is registered with ClinicalTrials.gov, number NCT01510288. FINDINGS: We enrolled 12 patients into our dose-escalation cohort. We did not record any severe immune-related adverse events at the first two dose levels. At the 3·0 mg/kg dose level, one patient had grade 2 and two patients grade 3 hypophysitis; at the 5·0 mg/kg dose level, two patients had grade 3 hypophysitis and one patient developed grade 4 sarcoid alveolitis (a dose-limiting toxic effect). Due to observed clinical activity and toxic events, we decided to expand the 3·0 mg/kg dose level, rather than enrol a further three patients at the 5·0 mg/kg level. 16 patients were enrolled in the expansion cohort, two of whom developed grade 2 hypophysitis, three colitis (one grade 1 and two grade 2), and one grade 3 hepatitis-all immune-related adverse events. The most common adverse events noted in all 28 patients were injection-site reactions (grade 1-2 events seen in all patients), fatigue (grade 1-2 in 20 patients, grade 3 in two), and pyrexia (grade 1-2 in 15 patients, grade 3 in one). 50% or greater declines in prostate-specific antigen from baseline was recorded in seven patients (25%); all had received 3·0 mg/kg or 5·0 mg/kg ipilimumab. INTERPRETATION: GVAX combined with 3·0 mg/kg ipilimumab is tolerable and safe for patients with mCRPC. Further research on the combined treatment of patients with mCRPC with vaccination and ipilimumab is warranted. FUNDING: Cell Genesys Inc, Prostate Cancer Foundation, Dutch Cancer Society (KWF-VU 2006-3697), and Foundation Stichting VUmc Cancer Center Amsterdam.

Thrombolysis or Anticoagulation for Cerebral Venous Thrombosis: Rationale and Design of the TO-ACT Trial

RATIONALE: Endovascular thrombolysis, with or without mechanical clot removal, may be beneficial for a subgroup of patients with cerebral venous sinus thrombosis (CVT) who have a poor prognosis despite treatment with heparin. Published experience with endovascular thrombolysis is promising but only based on case series and not on controlled trials. AIM: The objective of the Thrombolysis or Anticoagulation for Cerebral Venous Thrombosis (TO-ACT) trial is to determine if endovascular thrombolysis improves the functional outcome of patients with a severe form of CVT. DESIGN: The TO-A C T trial is a multicenter, prospective, randomized, open-label, blinded endpoint trial. Patients are eligible if they have a radiologically proven CVT, a high probability of poor outcome (defined by presence of one or more of the following risk factors: mental status disorder, coma, intracranial hemorrhagic lesion, or thrombosis of the deep cerebral venous system), and if the responsible physician is uncertain if endovascular thrombolysis or standard anticoagulant treatment is better. One hundred sixty-four patients (82 in each treatment arm) will be included to detect a 50% relative reduction (from 40% to 20%) of poor outcomes. STUDY: Patients will be randomized to receive either endovascular thrombolysis or standard therapy (therapeutic doses of heparin). Endovascular thrombolysis is composed of local application of rt-plasminogen activator (PA) or urokinase within the thrombosed sinuses, mechanical thrombosuction, or a combination of both. Patients randomized to endovascular thrombolysis will be treated with heparin before and after the interventional procedure, according to international guidelines. OUTCOMES: The primary endpoint is the modified Rankin score (mRS) at 12 months, with a score ≥2 defined as poor outcome. Secondary outcomes are six-months mRS, mortality, and recanalization rate. Major intracranial and extracranial hemorrhagic complications within one-week after the intervention are the principal safety outcomes. Results will be analyzed according to the 'intention-to-treat' principle. Blinded assessors not involved in the treatment of the patient will assess endpoints with standardized questionnaires.

The Organization of Physiological Brain Networks

One of the central questions in neuroscience is how communication in the brain is organized under normal conditions and how this architecture breaks down in neurological disease. It has become clear that simple activation studies are no longer sufficient. There is an urgent need to understand the brain as a complex structural and functional network. Interest in brain network studies has increased strongly with the advent of modern network theory and increasingly powerful investigative techniques such as "high-density EEG", MEG, functional and structural MRI. Modern network studies of the brain have demonstrated that healthy brains self-organize towards so-called "small-world networks" characterized by a combination of dense local connectivity and critical long-distance connections. In addition, normal brain networks display hierarchical modularity, and a connectivity backbone that consists of interconnected hub nodes. This complex architecture is believed to arise under genetic control and to underlie cognition and intelligence. Optimal brain network organization becomes disrupted in neurological disease in characteristic ways. This review gives an overview of modern network theory and its applications to healthy brain function and neurological disease, in particular using techniques from clinical neurophysiology, such as EEG and MEG.

Planetary Science: In Search of Biosignatures

Ultrasonographic Assessment of Flexor Tendon Mobilization: Effect of Different Protocols on Tendon Excursion

Different mobilization protocols have been proposed for rehabilitation after hand flexor tendon repair to provide tendon excursion sufficient to prevent adhesions. Several cadaver studies have shown that the position of the neighboring fingers influences tendon excursions of the injured finger. We hypothesized that the positions of adjacent fingers influence the long finger flexor digitorum profundus tendon excursion, measured both absolutely and relative to the surrounding tissue of the tendon.

Prognosis of Cerebral Vein Thrombosis Presenting As Isolated Headache: Early Vs. Late Diagnosis

To analyse the outcome of cerebral venous thrombosis (CVT) patients presenting with isolated headache, specifically to compare isolated headache patients with early vs. late CVT diagnosis.

Rapid Visualization of Human Tumor Xenografts Through Optical Imaging with a Near-infrared Fluorescent Anti-epidermal Growth Factor Receptor Nanobody

Given that overexpression of the epidermal growth factor receptor (EGFR) is found in many types of human epithelial cancers, noninvasive molecular imaging of this receptor is of great interest. A number of studies have employed monoclonal antibodies as probes; however, their characteristic long half-life in the bloodstream has encouraged the development of smaller probes. In this study, an anti-EGFR nanobody-based probe was developed and tested in comparison with cetuximab for application in optical molecular imaging. To this aim, the anti-EGFR nanobody 7D12 and cetuximab were conjugated to the near-infrared fluorophore IRDye800CW. 7D12-IR allowed the visualization of tumors as early as 30 minutes postinjection, whereas with cetuximab-IR, no signal above background was observed at the tumor site. Quantification of the IR-conjugated proteins in the tumors revealed ≈ 17% of injected dose per gram 2 hours after injection of 7D12-IR, which was significantly higher than the tumor uptake obtained 24 hours after injection of cetuximab-IR. This difference is associated with the superior penetration and distribution of 7D12-IR within the tumor. These results demonstrate that this anti-EGFR nanobody conjugated to the NIR fluorophore has excellent properties for rapid preclinical optical imaging, which holds promise for its future use as a complementary diagnostic tool in humans.

Mechanical Thrombectomy Cannot Be Considered As First-line Treatment for Cerebral Venous Thrombosis

Poor Agreement on Health-related Quality of Life Between Children with Congenital Hand Differences and Their Parents

To determine agreement between children with congenital hand differences (CHDs) and their parents on health-related quality of life (HRQOL) and to explore whether characteristic variables were associated with this agreement on different domains of HRQOL.

Quantifying Nonuse in Chronic Stroke Patients: a Study into Paretic, Nonparetic, and Bimanual Upper-limb Use in Daily Life

Michielsen ME, Selles RW, Stam HJ, Ribbers GM, Bussmann JB. Quantifying nonuse in chronic stroke patients: a study into paretic, nonparetic, and bimanual upper-limb use in daily life.

Disruption of Functional Brain Networks in Alzheimer's Disease: What Can We Learn from Graph Spectral Analysis of Resting-state Magnetoencephalography?

In Alzheimer's disease (AD), structural and functional brain network organization is disturbed. However, many of the present network analysis measures require a priori assumptions and methodological choices that influence outcomes and interpretations. Graph spectral analysis (GSA) is a more direct algebraic method that describes network properties, which might lead to more reliable results. In this study, GSA was applied to magnetoencephalography (MEG) data to explore functional network integrity in AD. Sensor-level resting-state MEG was performed in 18 Alzheimer patients (age 67 ± 9, 6 women) and 18 healthy controls (age 66 ± 9, 11 women). Weighted, undirected graphs were constructed based on functional connectivity analysis using the Synchronization likelihood, and GSA was performed with a focus on network connectivity, synchronizability, and node centrality. The main outcomes were a global loss of network connectivity and altered synchronizability in most frequency bands. Eigenvector centrality mapping confirmed the hub status of the parietal areas, and demonstrated a low centrality of the left temporal region in the theta band in AD patients that was strongly related to the mini mental state examination (global cognitive function test) score (r=0.67, p=0.001). Summarizing, GSA is a theoretically solid approach that is able to detect the disruption of functional network topology in AD. In addition to the previously reported overall connectivity losses and parietal area hub status, impaired network synchronizability and a clinically relevant left temporal centrality loss were found in AD patients. Our findings imply that GSA is valuable for the purpose of studying altered brain network topology and dynamics in AD.

Ultrasonographic Assessment of Longitudinal Median Nerve and Hand Flexor Tendon Dynamics in Carpal Tunnel Syndrome

Changes in subsynovial connective tissue (SSCT) in carpal tunnel syndrome (CTS) patients may result in altered dynamics; consequently, quantification of these dynamics might support objective diagnosis of CTS.

Beta Functional Connectivity Modulation During the Maintenance of Motion Information in Working Memory: Importance of the Familiarity of the Visual Context

The purpose of this study was to examine whether mechanisms, involved during the maintenance of familiar movement information in memory, were influenced by the degree of familiarity of the display in which the movements were embedded. Twelve gymnasts who possessed high visual and motor familiarity with the movements employed in this study, were recruited. They were invited to retain for a short period of time familiar movements viewed previously and presented under different displays with the aim of recognizing them at a later stage. The first display was a realistic, familiar display which presented videos of movements. The second display was an unfamiliar impoverished display never experienced in every day life which showed point-light movements. Activity during the maintenance period was considered in five frequency bands (4-8 Hz, 8-10 Hz, 10-13 Hz, 13-20 Hz, 20-30 Hz) using a non-linear measure of functional connectivity. The results in the 13-20 Hz frequency band showed that functional connectivity was greater within the frontal and right temporal areas during the unfamiliar display (i.e., point-light maintenance condition) compared to the familiar display (i.e., video maintenance condition). Differences in functional connectivity between the two maintenance conditions in the beta frequency band are mainly discussed in the light of the process of anticipation. Subjects' perception of the expected difficulty of the upcoming recognition task is discussed.

A Pill for Cholesterol and a Capsule for Bleeding

Impact of Cerebral Palsy on Health-related Physical Fitness in Adults: Systematic Review

To conduct a systematic review of the impact of cerebral palsy (CP) on the level of health-related physical fitness (body composition, cardiorespiratory endurance, flexibility, muscular endurance, and strength) in adults with CP compared with able-bodied adults.

Anticoagulation for Cerebral Venous Sinus Thrombosis

Efficacy of Etoricoxib, Celecoxib, Lumiracoxib, Non-selective NSAIDs, and Acetaminophen in Osteoarthritis: a Mixed Treatment Comparison

To compare the efficacy of etoricoxib, lumiracoxib, celecoxib, non-selective (ns) NSAIDs and acetaminophen in the treatment of osteoarthritis (OA) METHODS: Randomized placebo controlled trials investigating the effects of acetaminophen 4000mg, diclofenac 150mg, naproxen 1000mg, ibuprofen 2400mg, celecoxib 100-400mg, lumiracoxib 100-400mg, and etoricoxib 30-60mg with treatment duration of at least two weeks were identified with a systematic literature search. The endpoints of interest were pain, physical function and patient global assessment of disease status (PGADS). Pain and physical function reported on different scales (VAS or LIKERT) were translated into effect sizes (ES). An ES 0.2 - 0.5 was defined as a "small" treatment effect, whereas ES of 0.5 - 0.8 and > 0.8 were defined as "moderate" and "large", respectively. A negative effect indicated superior effects of the treatment group compared to the control group. Results of all trials were analyzed simultaneously with a Bayesian mixed treatment comparison.

The Brain Matures with Stronger Functional Connectivity and Decreased Randomness of Its Network

We investigated the development of the brain's functional connectivity throughout the life span (ages 5 through 71 years) by measuring EEG activity in a large population-based sample. Connectivity was established with Synchronization Likelihood. Relative randomness of the connectivity patterns was established with Watts and Strogatz' (1998) graph parameters C (local clustering) and L (global path length) for alpha (~10 Hz), beta (~20 Hz), and theta (~4 Hz) oscillation networks. From childhood to adolescence large increases in connectivity in alpha, theta and beta frequency bands were found that continued at a slower pace into adulthood (peaking at ~50 yrs). Connectivity changes were accompanied by increases in L and C reflecting decreases in network randomness or increased order (peak levels reached at ~18 yrs). Older age (55+) was associated with weakened connectivity. Semi-automatically segmented T1 weighted MRI images of 104 young adults revealed that connectivity was significantly correlated to cerebral white matter volume (alpha oscillations: r = 33, p<01; theta: r = 22, p<05), while path length was related to both white matter (alpha: max. r = 38, p<001) and gray matter (alpha: max. r = 36, p<001; theta: max. r = 36, p<001) volumes. In conclusion, EEG connectivity and graph theoretical network analysis may be used to trace structural and functional development of the brain.

Go with the Flow: Use of a Directed Phase Lag Index (dPLI) to Characterize Patterns of Phase Relations in a Large-scale Model of Brain Dynamics

We introduce a directed phase lag index to investigate the spatial and temporal pattern of phase relations of oscillatory activity in a model of macroscopic structural and functional brain networks. Direction of information flow was determined with the directed phase lag index (dPLI) defined as the probability that the instantaneous phase of X was smaller than the phase of Y (modulo π). X was said to phase-lead Y if 0.5

Antibiotic Use in Infants in the First Year of Life in Five European Countries

To assess in infants the number of illness episodes treated with antibiotics and prescription rates in five European countries.

Genome Sequencing and Mapping Reveal Loss of Heterozygosity As a Mechanism for Rapid Adaptation in the Vegetable Pathogen Phytophthora Capsici

The oomycete vegetable pathogen Phytophthora capsici has shown remarkable adaptation to fungicides and new hosts. Like other members of this destructive genus, P. capsici has an explosive epidemiology, rapidly producing massive numbers of asexual spores on infected hosts. In addition, P. capsici can remain dormant for years as sexually recombined oospores, making it difficult to produce crops at infested sites, and allowing outcrossing populations to maintain significant genetic variation. Genome sequencing, development of a high-density genetic map, and integrative genomic or genetic characterization of P. capsici field isolates and intercross progeny revealed significant mitotic loss of heterozygosity (LOH) in diverse isolates. LOH was detected in clonally propagated field isolates and sexual progeny, cumulatively affecting >30% of the genome. LOH altered genotypes for more than 11,000 single-nucleotide variant sites and showed a strong association with changes in mating type and pathogenicity. Overall, it appears that LOH may provide a rapid mechanism for fixing alleles and may be an important component of adaptability for P. capsici.

Vitamin D and Gestational Diabetes: a Systematic Review and Meta-analysis

Conflicting results currently exists on the association between vitamin D and glucose metabolism. The role of maternal vitamin D status in gestational diabetes mellitus (GDM) is not clear. This meta-analysis aimed to examine this role in women with GDM compared with normal glucose tolerance (NGT).

3C Technologies in Plants

Chromosome conformation capture (3C) and 3C-based technology have revolutionized studies on chromosomal interactions and their role in gene regulation and chromosome organization. 3C allows the in vivo identification of physical interactions between chromosomal regions. Such interactions are shown to play a role in various aspects of gene regulation, for example transcriptional activation of genes by remote enhancer sequences, or the silencing by Polycomb-group complexes. The last few years the number of publications involving chromosomal interactions increased significantly. Until now, however, the vast majority of the studies reported are performed in yeast or animal systems. So far, studies on plant systems are extremely limited, possibly due to the plant-specific characteristics that hamper the implementation of the 3C technique. In this paper we provide a plant-specific 3C protocol, optimized for maize tissue, and an extensive discussion on (i) plant-specific adjustments to the protocol, and (ii) solutions to problems that may arise when optimizing the protocol for the tissue or plant of interest. Together, this paper should facilitate the application of 3C technology to plant tissue and stimulate studies on the 3D conformation of chromosomal regions and chromosomes in plants.

Efficacy of Souvenaid in Mild Alzheimer's Disease: Results from a Randomized, Controlled Trial

Souvenaid aims to improve synapse formation and function. An earlier study in patients with Alzheimer's disease (AD) showed that Souvenaid increased memory performance after 12 weeks in drug-naïve patients with mild AD. The Souvenir II study was a 24-week, randomized, controlled, double-blind, parallel-group, multi-country trial to confirm and extend previous findings in drug-naïve patients with mild AD. Patients were randomized 1:1 to receive Souvenaid or an iso-caloric control product once daily for 24 weeks. The primary outcome was the memory function domain Z-score of the Neuropsychological Test Battery (NTB) over 24 weeks. Electroencephalography (EEG) measures served as secondary outcomes as marker for synaptic connectivity. Assessments were done at baseline, 12, and 24 weeks. The NTB memory domain Z-score was significantly increased in the active versus the control group over the 24-week intervention period (p = 0.023; Cohen's d = 0.21; 95% confidence interval [-0.06]-[0.49]). A trend for an effect was observed on the NTB total composite z-score (p = 0.053). EEG measures of functional connectivity in the delta band were significantly different between study groups during 24 weeks in favor of the active group. Compliance was very high (96.6% [control] and 97.1% [active]). No difference between study groups in the occurrence of (serious) adverse events. This study demonstrates that Souvenaid is well tolerated and improves memory performance in drug-naïve patients with mild AD. EEG outcomes suggest that Souvenaid has an effect on brain functional connectivity, supporting the underlying hypothesis of changed synaptic activity.

Fear and Attitudes Towards Torture and Preventive War

This paper examines the association between individuals' beliefs that the world is a dangerous place and their support for a variety of national security policies. We find that the source of the covariance between perceived danger and support for aggressive national security policies is primarily due to a common genetic factor. Latent genetic factors that influence individuals' perception of danger also appear to influence their positions on policies purported to alleviate such danger. Covariation between individuals' experiences and genes suggests that priming messages alone do not drive the covariation between feelings of danger and acceptance of policy changes.

Characterization of Functional and Structural Integrity in Experimental Focal Epilepsy: Reduced Network Efficiency Coincides with White Matter Changes

Although focal epilepsies are increasingly recognized to affect multiple and remote neural systems, the underlying spatiotemporal pattern and the relationships between recurrent spontaneous seizures, global functional connectivity, and structural integrity remain largely unknown.

Chronic Pain, Fatigue, and Depressive Symptoms in Adults with Spastic Bilateral Cerebral Palsy

To investigate the prevalence and co-occurrence of chronic pain, fatigue, and depressive symptoms in adults with spastic bilateral cerebral palsy (SBCP) and explore associations of chronic pain and fatigue with depressive symptoms and daily functioning.

Genetic Control of Functional Brain Network Efficiency in Children

The human brain is a complex network of interconnected brain regions. In adulthood, the brain's network was recently found to be under genetic influence. However, the extent to which genes influence the functional brain network early in development is not yet known. We report on the heritability of functional brain efficiency during early brain development. Using a twin design, young children underwent resting-state functional magnetic resonance imaging brain scans (N=86 from 21MZ and 22DZ twin-pairs, age=12 years). Functional connectivity, defined as the temporal dependency of neuronal activation patterns of anatomically separated brain regions, was explored using graph theory and its heritability was examined using structural equation modeling. Our findings suggest that 'global efficiency of communication' among brain regions is under genetic control (h(2)lambda=42%), irrespectively of the total number of brain connections (connectivity density). In addition, no influence of genes or common environment to local clustering (gamma) was found, suggesting a less pronounced effect of genes on local information segregation. Thus our findings suggest that a set of genes is shaping the underlying architecture of functional brain communication during development.

Disturbed Oscillatory Brain Dynamics in Subcortical Ischemic Vascular Dementia

White matter hyperintensities (WMH) can lead to dementia but the underlying physiological mechanisms are unclear. We compared relative oscillatory power from electroencephalographic studies (EEGs) of 17 patients with subcortical ischemic vascular dementia, based on extensive white matter hyperintensities (SIVD-WMH) with 17 controls to investigate physiological changes underlying this diagnosis.

[Underlying Causes of Diabetes Mellitus]

In patients with hyperglycaemia plus obesity and cardiovascular disease, the diagnosis of type 2 diabetes mellitus is likely to be made and this is usually followed by the start of antihyperglycaemic therapy. This pragmatic approach, however, does not always turn out to be the correct one. We describe two patients with occult conditions that had caused or aggravated diabetes mellitus (DM): a 46-year-old man with acromegaly and a 41-year-old woman with Cushing's disease. After neurosurgeries were performed, the requirement for antihyperglycaemic treatment markedly decreased (case 2) or even disappeared (case 1). Physicians treating patients with DM should ask themselves what the cause of the disease could be; the recognition and treatment of that underlying condition may substantially decrease the amount of insulin required and may even cause the disappearance of DM altogether.

Oscillatory Cortical Network Involved in Auditory Verbal Hallucinations in Schizophrenia

Auditory verbal hallucinations (AVH), a prominent symptom of schizophrenia, are often highly distressing for patients. Better understanding of the pathogenesis of hallucinations could increase therapeutic options. Magnetoencephalography (MEG) provides direct measures of neuronal activity and has an excellent temporal resolution, offering a unique opportunity to study AVH pathophysiology.

Cognitive Dysfunction in Early Multiple Sclerosis: Altered Centrality Derived from Resting-state Functional Connectivity Using Magneto-encephalography

Cognitive dysfunction in multiple sclerosis (MS) is frequent. Insight into underlying mechanisms would help to develop therapeutic strategies.

T Cell Profiling Reveals High CD4(+)CTLA-4 (+) T Cell Frequency As Dominant Predictor for Survival After Prostate GVAX/ipilimumab Treatment

Immune checkpoint blockade enhances antitumor responses, but can also lead to severe immune-related adverse events (IRAE). To avoid unnecessary exposure to these potentially hazardous agents, it is important to identify biomarkers that correlate with clinical activity and can be used to select patients that will benefit from immune checkpoint blockade. To understand the consequences of CTLA-4 blockade and identify biomarkers for clinical efficacy and/or survival, an exploratory T cell monitoring study was performed in a phase I/II dose escalation/expansion trial (n = 28) of combined Prostate GVAX/ipilimumab immunotherapy. Phenotypic T cell monitoring in peripheral blood before and after Prostate GVAX/ipilimumab treatment revealed striking differences between patients who benefited from therapy and patients that did not. Treatment-induced rises in absolute lymphocyte counts, CD4(+) T cell differentiation, and CD4(+) and CD8(+) T cell activation were all associated with clinical benefit. Moreover, significantly prolonged overall survival (OS) was observed for patients with high pre-treatment frequencies of CD4(+)CTLA-4(+), CD4(+)PD-1(+), or differentiated (i.e., non-naive) CD8(+) T cells or low pre-treatment frequencies of differentiated CD4(+) or regulatory T cells. Unsupervised clustering of these immune biomarkers revealed cancer-related expression of CTLA-4(+) in CD4(+) T cells to be a dominant predictor for survival after Prostate GVAX/ipilimumab therapy and to thus provide a putative and much-needed biomarker for patient selection prior to therapeutic CTLA4 blockade.

Activity Dependent Degeneration Explains Hub Vulnerability in Alzheimer's Disease

Brain connectivity studies have revealed that highly connected 'hub' regions are particularly vulnerable to Alzheimer pathology: they show marked amyloid-β deposition at an early stage. Recently, excessive local neuronal activity has been shown to increase amyloid deposition. In this study we use a computational model to test the hypothesis that hub regions possess the highest level of activity and that hub vulnerability in Alzheimer's disease is due to this feature. Cortical brain regions were modeled as neural masses, each describing the average activity (spike density and spectral power) of a large number of interconnected excitatory and inhibitory neurons. The large-scale network consisted of 78 neural masses, connected according to a human DTI-based cortical topology. Spike density and spectral power were positively correlated with structural and functional node degrees, confirming the high activity of hub regions, also offering a possible explanation for high resting state Default Mode Network activity. 'Activity dependent degeneration' (ADD) was simulated by lowering synaptic strength as a function of the spike density of the main excitatory neurons, and compared to random degeneration. Resulting structural and functional network changes were assessed with graph theoretical analysis. Effects of ADD included oscillatory slowing, loss of spectral power and long-range synchronization, hub vulnerability, and disrupted functional network topology. Observed transient increases in spike density and functional connectivity match reports in Mild Cognitive Impairment (MCI) patients, and may not be compensatory but pathological. In conclusion, the assumption of excessive neuronal activity leading to degeneration provides a possible explanation for hub vulnerability in Alzheimer's disease, supported by the observed relation between connectivity and activity and the reproduction of several neurophysiologic hallmarks. The insight that neuronal activity might play a causal role in Alzheimer's disease can have implications for early detection and interventional strategies.

Absence of Global Hypomethylation in Promoter Hypermethylated Mixed Lineage Leukaemia-rearranged Infant Acute Lymphoblastic Leukaemia

BACKGROUND: Mixed Lineage Leukaemia (MLL)-rearranged acute lymphoblastic leukaemia (ALL) in infants represents a highly aggressive type of leukaemia that is often characterised by severe promoter CpG island hypermethylation. Consequently, MLL-rearranged ALL cells respond well to demethylating cytosine analogue drugs. In human cancer cells, enhanced promoter methylation is typically accompanied by global loss of methylation in non-promoter regions of the genome. In turn, global hypomethylation usually leads to genomic instability, which may have contributed to cancer development. DESIGN AND METHODS: Here we examined global methylation densities in MLL-rearranged infant ALL (n=45) samples in comparison with germline MLL infant ALL (n=11), non-infant B-cell precursor ALL (n=11) and normal paediatric bone marrow (n=9) samples. For this we performed high-resolution bisulfite pyrosequencing to determine methylation levels at the repetitive elements LINE-1, Alu and satellite α (SAT-α). As an additional measure of global methylation levels we used the LUminometric Methylation Assay (LUMA). RESULTS: We found that MLL-rearranged infant ALL is not characterised by global hypomethylation, despite its characteristic promoter CpG hypermethylation patterns. Instead we observed a moderate trend towards global hypermethylation and demonstrated that these methylated non-promoter sequences are responsive to demethylating agents. CONCLUSIONS: MLL-rearranged infant ALL cells are characterised by an overall methylated genomic state, and both promoter and non-promoter methylation responds to demethylating agents, which may further explain the remarkable sensitivity of these cells for the methylation-inhibiting therapeutics.

Ain't No Sunshine When She's Gone: Pseudohypoparathyroidism Discovered in an Adult

An 18-year-old negroid woman presented with progressive cramps in both hands. She was Jamaican and had moved to The Netherlands 8 months before. On physical examination Trousseau's sign was positive. Laboratory analysis showed severe hypocalcaemia (1.17 mmol/L) and hyperphosphatemia (2.0 mmol/L). Urinary excretion of both calcium (0.8 mmol/day) and phosphate (5 mmol/day) was low, as is seen in hypoparathyroidism. However, the PTH level was increased (22.1 pmol/L), whereas 25-(OH)-vitamin D was low (31 nmol/L). An Ellsworth-Howard test showed only a fivefold increase in urinary phosphate excretion after administration of synthetic PTH, supporting the diagnosis pseudohypoparathyroidism. Upon treatment with calcium supplementation and alfacalcidol, her symptoms disappeared. Pseudohypoparathyroidism (PHP) is a rare hereditary disorder resembling hypoparathyroidism, although plasma PTH levels are elevated. PHP is caused by alterations in the PTH receptor, inducing target tissue resistance to PTH. This results in hypocalcaemia and hyperphosphatemia, while PTH levels are elevated. The diagnosis is confirmed by the Ellsworth-Howard test, which will show a 100-fold increase in phosphate excretion if the PTH receptor functions properly. Treatment is lifelong supplementation of calcium and alfacalcidol. In our patient, symptoms were probably evoked by the lack of sunlight in Dutch winter, decreasing vitamin D levels and thereby aggravating hypocalcaemia.

Woman's Right to Know Act: a Legislative History

This article provides a comprehensive legislative history of North Carolina's Woman's Right to Know Act of 2011. The Act requires informed consent and a mandatory twenty-four hour waiting period for abortion, thus protecting a woman's right to make an informed choice. Informed consent provisions and mandatory waiting periods give individuals making decisions the information and time necessary to make informed choices. The Act further provides that an ultrasound be performed and explained no less than four hours and no more than seventy-two hours before the abortion. The article first provides a brief overview of sources of legislative history recognized in North Carolina. It then details the history of the Woman's Right to Know Act, from the first informed consent bill introduced in 1981, to the passage of the 201l law, and to the federal court case that followed. Finally it provides specific objections that were raised against the bill and responses to each. Legislators considering similar legislation need to be aware of the opposition they inevitably will encounter when passing such a bill. The author expects that this history and the ultimate success of North Carolina will encourage other states' legislators and lawyers and give them the tools to make their case effectively.

An Odd Looking Man

Our Time: A Call to Save Preventable Death From Cardiovascular Disease (Heart Disease and Stroke)

Our Time: a Call to Save Preventable Death from Cardiovascular Disease (heart Disease and Stroke)

Our Time: a Call to Save Preventable Death from Cardiovascular Disease (heart Disease and Stroke)

The Incidence of Cerebral Venous Thrombosis: a Cross-sectional Study

The purpose of this study was to determine the incidence of adult cerebral venous thrombosis.

Local Thrombolysis for Severe Cerebral Venous Sinus Thrombosis

CBL Mutations Do Not Frequently Occur in Paediatric Acute Myeloid Leukaemia

RAS-pathway mutations, causing a proliferative advantage, occur in acute myeloid leukaemia (AML) and MLL-rearranged leukaemia. Recently, mutations in the Casitas B lineage lymphoma (CBL) gene were reported to be involved in RAS-pathway activation in various myeloid malignancies, but their role in paediatric AML is still unknown. We performed mutation analysis of 283 newly diagnosed and 33 relapsed paediatric AML cases. Only two mutant cases (0·7%) were identified in the newly diagnosed paediatric AML samples, of which one was MLL-rearranged. Both mutant cases showed CBL mRNA expression in the range of the non-mutated cases. Phosphorylated extracellular signal-regulated kinase (pERK) was not correlated with CBL protein expression (n = 11). In conclusion, we report a very low CBL mutation frequency in paediatric AML, which, together with the lack of difference in protein and mRNA expression, illustrates the limited role of CBL in paediatric AML.

Navigators for Motion Detection During Real-time MRI-guided Radiotherapy

An MRI-linac system provides direct MRI feedback and with that the possibility of adapting radiation treatments to the actual tumour position. This paper addresses the use of fast 1D MRI, pencil-beam navigators, for this feedback. The accuracy of using navigators was determined on a moving phantom. The possibility of organ tracking and breath-hold monitoring based on navigator guidance was shown for the kidney. Navigators are accurate within 0.5 mm and the analysis has a minimal time lag smaller than 30 ms as shown for the phantom measurements. The correlation of 2D kidney images and navigators shows the possibility of complete organ tracking. Furthermore the breath-hold monitoring of the kidney is accurate within 1.5 mm, allowing gated radiotherapy based on navigator feedback. Navigators are a fast and precise method for monitoring and real-time tracking of anatomical landmarks. As such, they provide direct MRI feedback on anatomical changes for more precise radiation delivery.

Randomized Controlled Trial of a Self-management Intervention in Persons with Spinal Cord Injury: Design of the HABITS (Healthy Active Behavioural IntervenTion in SCI) Study

Purpose: To evaluate the effectiveness of a 16-week self-management intervention on physical activity level and self-management skills (self-efficacy, proactive coping and problem solving skills) in persons with chronic SCI. Method and design: Multicenter randomized controlled trial (RCT). Eighty persons with a SCI for at least 10 years and aged 18 to 65 will randomly be assigned to the intervention (self-management) or the control group (information provision). During the 16-week self-management intervention (one home-visit, five group and five individual sessions) active lifestyle will be stimulated and self-management skills will be taught. Data will be collected at baseline (T0), 16 (T1) and 42 (T2) weeks after baseline. Primary outcome measure is level of daily physical activity (self-report/objectively measured). Secondary outcome measures are self-managements skills, stage of behaviour change and attitude. Conclusion: This is the first RCT on self-management in people with chronic spinal cord injury. This trial will provide knowledge on the effects of a self-management intervention on physical active lifestyle in persons with a long-term SCI. [Box: see text].

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Adjunctive Sitagliptin Therapy in Postoperative Cardiac Surgery Patients: a Pilot Study

Aim. We aimed to determine if sitagliptin added to standard postoperative standardized sliding-scale insulin regimens improved blood glucose. Methods. A prospective, randomized, double-blind, placebo-controlled pilot study was conducted in diabetic cardiac surgery patients. Patients received sitagliptin or placebo after surgery for 4 days. The primary endpoint was to estimate the effect of adjunctive sitagliptin versus placebo on overall mean blood glucose in the 4-day period after surgery. Results. Sixty-two patients participated. Repeated measures tests indicated no significant difference between the groups in the overall mean blood glucose level with a mean of 147.2 ± 4.8 mg/dL and 153.0 ± 4.6 mg/dL for the test and the control group, respectively (P = 0.388). Conclusions. Sitagliptin added to normal postoperative glucose management practices did not improve overall mean blood glucose control in diabetic patients in the postoperative setting.

Growing Trees in Child Brains: Graph Theoretical Analysis of EEG Derived Minimum Spanning Tree in 5 and 7 Year Old Children Reflects Brain Maturation

The child brain is a small-world network which is hypothesized to change towards more ordered configurations with development. In graph theoretical studies, comparing network topologies under different conditions remains a critical point. Constructing a minimum spanning tree (MST) might present a solution since it does not require setting a threshold and uses a fixed number of nodes and edges. In this study, the MST method is introduced to examine developmental changes in functional brain network topology in young children. Resting-state electroencephalography (EEG) was recorded from 227 children twice at 5 and 7 years of age. Synchronization likelihood (SL) weighted matrices were calculated in three different frequency bands from which "minimum spanning trees" were constructed, which represent constructs of the most important routes for information flow in a network. From these trees, several parameters were calculated to characterize developmental change in network organization. MST diameter and eccentricity significantly increased, while leaf number and hierarchy significantly decreased in the alpha band with development. Boys showed significant higher leaf number, betweenness, degree and hierarchy and significant lower SL, diameter and eccentricity than girls in theta band. The developmental changes indicate a shift towards more decentralized line-like trees, which supports the previously hypothesized increase towards regularity of brain networks with development. Additionally, girls showed more line-like decentralized configurations, which is consistent with the view that girls are ahead of boys in brain development. MST provides an elegant method sensitive to capture subtle developmental changes in network organization without the bias of network comparison.

[Can Staging and Profiling Ensure That the Costs of Quality Care Are Adequately Reimbursed?]

The current system for financing effective mental health can improve or reduce the quality of care provided. The system of financing includes reimbursing the care-provider, a risk-adjustment system for the health insurer and personal payments by the patient. Care-providers, patients and health insurers are worried that the current system is detrimental to quality care.

Migraine is Not Associated with Enhanced Atherosclerosis

AimMigraine, in particular with aura, has been associated with an increased risk for ischemic stroke and coronary heart disease. The underlying mechanism is unknown. In a cross-sectional case control study we investigated whether an enhanced risk of atherosclerosis in migraineurs explains this increased cardiovascular risk.MethodsSubjects were participants from the population-based Erasmus Rucphen Family study. Atherosclerosis was assessed in 360 migraineurs (209 without aura and 151 with aura) and 617 subjects without migraine or severe headache. Atherosclerosis was quantified by intima media thickness, pulse wave velocity and ankle-brachial index.ResultsMigraineurs, especially with aura, were found more likely to smoke, have diabetes or a modestly decreased HDL-cholesterol. No differences were found for the atherosclerosis parameters.ConclusionIn this large population-based study, migraineurs have no increased risk of atherosclerosis. Therefore, enhanced atherosclerosis is an unlikely explanation for the increased cardiovascular risk seen in migraineurs.

Physical Strain of Walking Relates to Activity Level in Adults with Cerebral Palsy

OBJECTIVE: To gain insight into underlying mechanisms of inactive lifestyles among adults with spastic bilateral CP with a focus on aerobic capacity, oxygen consumption, and physical strain during walking at preferred walking speed, as well as fatigue. DESIGN: Cross sectional SETTING: University hospital PARTICIPANTS: Thirty-six adults, aged 25-45 years, with spastic bilateral cerebral palsy, walking with (n=6) or without, (n=30) walking aids. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Physical strain during walking was defined as oxygen uptake during walking, expressed as percentage of peak aerobic capacity. Participants with spastic bilateral CP walked their preferred walking speed while oxygen uptake was measured using a portable gas analyzer. Peak aerobic capacity was measured during maximal cycle ergometry. An accelerometry-based Activity Monitor measured total daily walking time. Regression analyses were performed to assess the relation between aerobic capacity, oxygen uptake and physical strain of walking on the one hand and total daily walking time on the other hand. RESULTS: Neither aerobic capacity nor oxygen uptake during walking was related to total daily walking time (r2=0.29, p=0.10 and r2=0.27, p=0.16). Physical strain of walking at preferred walking speed was inversely related to total daily walking time (r2=0.44, p<0.01). CONCLUSION: Physical strain during walking is moderately related to total daily walking time, implying that people with high physical strain during walking at preferred walking speed likely walk less in daily life.

Structure out of Chaos: Functional Brain Network Analysis with EEG, MEG, and Functional MRI

The brain is the characteristic of a complex structure. By representing brain function, measured with EEG, MEG, and fMRI, as an abstract network, methods for the study of complex systems can be applied. These network studies have revealed insights in the complex, yet organized, architecture that is evidently present in brain function. We will discuss some technical aspects of formation and assessment of the functional brain networks. Moreover, the results that have been reported in this respect in the last years, in healthy brains as well as in functional brain networks of subjects with a neurological or psychiatrical disease, will be reviewed.

MEG Network Differences Between Low- and High-Grade Glioma Related to Epilepsy and Cognition

To reveal possible differences in whole brain topology of epileptic glioma patients, being low-grade glioma (LGG) and high-grade glioma (HGG) patients. We studied functional networks in these patients and compared them to those in epilepsy patients with non-glial lesions (NGL) and healthy controls. Finally, we related network characteristics to seizure frequency and cognitive performance within patient groups.

Familial and Sporadic Hemiplegic Migraine: Diagnosis and Treatment

OPINION STATEMENT: Hemiplegic migraine (HM) is a rare subtype of migraine with aura, characterized by transient hemiparesis during attacks. Diagnosis is based on the International Classification of Headache Disorders criteria (ICHD-II). Two types of HM are recognized: familial (FHM) and sporadic hemiplegic migraine (SHM). HM is genetically heterogeneous. Three genes have been identified (CACNA1A, ATP1A2, and SCN1A) but more, so far unknown genes, are involved. Clinically, attacks of the 3 subtypes cannot be distinguished. The diagnosis can be confirmed but not ruled out by genetic testing, because in some HM patients other, not yet identified, genes are involved. The presence of additional symptoms (such as chronic ataxia or epilepsy) may increase the likelihood of identifying a mutation. Additional diagnostics like imaging, CSF analysis, or an EEG are mainly performed to exclude other causes of focal neurological symptoms associated with headache. Conventional cerebral angiography is contraindicated in HM because this may provoke an attack. Because HM is a rare condition, no clinical treatment trials are available in this specific subgroup of migraine patients. Thus, the treatment of HM is based on empirical data, personal experience of the treating neurologist, and involves a trial-and-error strategy. Acetaminophen and NSAIDs often are the first choice in acute treatment. Although controversial in HM, triptans can be prescribed when headaches are not relieved sufficiently with common analgesics. An effective treatment for the severe and often prolonged aura symptoms is more warranted, but currently no such acute treatment is available. Prophylactic treatment can be considered when attack frequency exceeds 2 attacks per month, or when severe attacks pose a great burden that requires reduction of severity and frequency. In no strictly preferred order, flunarizine, sodium valproate, lamotrigine, verapamil, and acetazolamide can be tried. While less evidence is available for prophylactic treatment with topiramate, candesartan, and pizotifen, these drugs can also be considered. The use of propranolol in HM is more controversial, but evidence of adverse effects is insufficient to contraindicate beta-blockers.

Eugen Bleuler (1857-1939), an Early Pioneer of Evidence Based Medicine

The Desirability of Education in Didactic Skills According to Medical Interns

Since all doctors at some point in their career will be faced with their role as a teacher, it appears desirable that future doctors are educated in didactic skills. At present, however, there are no formal opportunities for developing didactic skills at the majority of Dutch medical faculties. The main question of this study is: How do medical interns perceive the quality and quantity of their education in didactic skills? The Dutch Association for Medical Interns (LOCA) ran a national survey among 1,008 medical interns that measured the interns' self-assessed needs for training in didactic skills during medical school. Almost 80 % of the respondents argue that the mastery of didactic skills composes an essential competency for doctors, with the skill of providing adequate feedback considered to be the most important didactic quality for doctors. Of the respondents, 41 % wish to be educated in didactic skills, both during their medical undergraduate degree and during their subsequent training to become a resident. Teaching while being observed and receiving feedback in this setting is regarded as a particularly valuable didactic method by 74 % of the medical interns. Of the respondents, 82 % would invest time to follow training for the development of didactic skills if it was offered. Medical interns stress the importance of doctors' didactic skills during their clinical internships. Compared with current levels, most interns desire increased attention to the formal development of didactic skills during medical school. Considering the importance of didactic skills and the need for more extensive training, the LOCA advises medical faculties to include more formal didactic training in the medical curriculum.

Functional Connectivity Changes in Multiple Sclerosis Patients: A Graph Analytical Study of MEG Resting State Data

Multiple sclerosis (MS) is characterized by extensive damage in the central nervous system. Within this field, there is a strong need for more advanced, functional imaging measures, as abnormalities measured with structural imaging insufficiently explain clinicocognitive decline in MS. In this study we investigated functional connectivity changes in MS using resting-state magnetoencephalography (MEG). Data from 34 MS patients and 28 age and gender-matched controls was assessed using synchronization likelihood (SL) as a measure of functional interaction strength between brain regions, and graph analysis to characterize topological patterns of connectivity changes. Cognition was assessed using extensive neuropsychological evaluation. Structural measures included brain and lesion volumes, using MRI. Results show SL increases in MS patients in theta, lower alpha and beta bands, with decreases in the upper alpha band. Graph analysis revealed a more regular topology in the lower alpha band in patients, indicated by an increased path length (λ) and clustering coefficient (γ). Attention and working memory domains were impaired, with decreased brain volumes. A stepwise linear regression model using clinical, MRI and MEG parameters as predictors revealed that only increases in lower alpha band γ predicted impaired cognition. Cognitive impairments and related altered connectivity patterns were found to be especially predominant in male patients. These results show specific functional changes in MS as measured with MEG. Only changes in network topology were related to poorer cognitive outcome. This indicates the value of graph analysis beyond traditional structural and functional measures, with possible implications for diagnostic and/or prognostic purposes in MS. Hum Brain Mapp, 2013. © 2011 Wiley Periodicals, Inc.

Cognitive Decline in Parkinson's Disease is Associated with Slowing of Resting-state Brain Activity: a Longitudinal Study

The pathophysiological mechanisms of Parkinson's disease (PD)-related dementia (PDD) are still poorly understood. Previous studies using electroencephalography (EEG) and magnetoencephalography (MEG) have demonstrated widespread slowing of oscillatory brain activity as a neurophysiological characteristic of PD-related dementia. Here, we use MEG to longitudinally study early changes in oscillatory brain activity in initially nondemented PD patients that may be associated with cognitive decline. Using a longitudinal design, resting-state MEG recordings were performed twice at an approximate 4-year interval in 14 healthy controls and 49 PD patients. Changes in peak frequency and in relative spectral power for 10 brain regions were analyzed in relation to clinical measures of cognitive and motor function. In contrast to healthy controls, PD patients showed a slowing of the dominant peak frequency. Furthermore, analysis per frequency band revealed an increase in theta power over time, along with decreases in alpha1 and alpha2 power. In PD patients, decreasing cognitive performance was associated with increases in delta and theta power, as well as decreases in alpha1, alpha2, and gamma power, whereas increasing motor impairment was associated with a theta power increase only. The present longitudinal study revealed widespread progressive slowing of oscillatory brain activity in initially nondemented PD patients, independent of aging effects. The slowing of oscillatory brain activity strongly correlated with cognitive decline and therefore holds promise as an early marker for the development of dementia in PD.

Making Fate and Exposure Models for Freshwater Ecotoxicity in Life Cycle Assessment Suitable for Organic Acids and Bases

Freshwater fate and exposure factors were determined for organic acids and bases, making use of the knowledge on electrical interaction of ionizing chemicals and their sorption to particles. The fate factor represents the residence time in the environment whereas exposure factors equal the dissolved fraction of a chemical. Multimedia fate, exposure, and effect model USES-LCA was updated to take into account the influence of ionization, based upon the acid dissociation constant (pK(a)) of a chemical, and the environmental pH. Freshwater fate (FF) and exposure (XF) factors were determined for 415 acids and 496 bases emitted to freshwater, air, and soil. The relevance of taking account of the degree of ionization of chemicals was tested by determining the ratio (R) of the new vs. fate and exposure factors determined with USES-LCA suitable for neutral chemicals only. Our results show that the majority of freshwater fate and exposure factors of chemicals that are largely ionized in the environment are larger with the ionics model compared to the factors determined with the neutrals model version. R(FF) ranged from 2.4×10(-1) to 1.6×10(1) for freshwater emissions, from 1.2×10(-2) to 2.0×10(4) for soil emissions and from 5.8×10(-2) to 6.0×10(3) for air emissions, and R(XF) from 5.3×10(-1) to 2.2×10(1). Prediction of changed solid-water partitioning, implying a change in runoff and in removal via sedimentation, and prediction of negligible air-water partition coefficient, leading to negligible volatilization were the main contributors to the changes in freshwater fate factors.

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