DUSP4 appears to be a highly localized endogenous inhibitor of epileptic signaling in human neocortex.

BACKGROUND: We previously identified the Mitogen Activated Protein Kinase (MAPK) pathway as focally upregulated in brain regions with high epileptic activity and showed that inhibition of MAPK signaling reduces epileptic spiking in an animal model. Here we examined how activators and inhibitors of the MAPK pathway are expressed in human epileptic cortex and how these could contribute to the localization of epileptic signaling. METHODS: We localized gene and protein expression in human epileptic neocortical tissues based on epileptic activities from 20 patients based on long-term intracranial recordings. Follow-up mechanistic studies by depolarization of human Sh-SY5Y cell line were used to model epileptic activity in the human brain. RESULTS: A clustering algorithm of differentially expressed genes identified a unique gene expression cluster distinct from other MAPK genes. Within this cluster was dual specificity phosphatase 4 (DUSP4), a potent MAPK inhibitor. In situ hybridization studies revealed focal patches of DUSP4 mRNA in layer 2/3 brain regions associated with a dramatic reduction in MAPK signaling genes. In vitro depolarization led to the rapid and transient induction of DUSP4 protein, which, in turn, reduced MAPK activity. Activity-dependent induction of DUSP4 protein was transient and required MAPK signaling. Human epileptic brain regions with lower epileptic activity had lower MAPK activity and higher DUSP4 protein levels. DISCUSSION: DUSP4 is a highly localized, endogenous feedback inhibitor of pro-epileptogenic MAPK signaling in the human epileptic brain. Increasing DUSP4 expression could therefore be a novel therapeutic approach to prevent the development and spread of epileptic circuits. SIGNIFICANCE STATEMENT: Epilepsy is a chronic debilitating disease. Once it develops, epileptic circuits often persist throughout life. Fortunately, in focal forms of epilepsy, these circuits can remain highly localized and are amenable to surgical resections, suggesting that endogenous mechanisms restrict their spread to other brain regions. Using a high-throughput genomic analysis of human epileptic brain regions, we identified DUSP4 as an activity-dependent inhibitor of MAPK signaling expressed in focal patches surrounding human neocortical epileptic brain regions. Our results suggest that DUSP4, through local inhibition of MAPK signaling, acts as an endogenous, spatially segregated safety mechanism to prevent the spread of epileptic activity. Augmenting DUSP4 expression could be a novel disease-modifying approach to prevent or treat human epilepsy.

Neuroimaging Insights Into Early Stages of HIV-Progressive Multifocal Leukoencephalopathy: A Case Report.

This report aims to enhance the understanding of early longitudinal neuroimaging features of progressive multifocal leukoencephalopathy (PML) in human immunodeficiency virus (HIV). Neuroimaging has become crucial in the diagnosis and early recognition of PML. Recognition of magnetic resonance imaging (MRI) features in the early stages of PML is paramount to avoid misdiagnosis and facilitate the delivery of treatments aimed at reducing disease progression. A 49-year-old white man with HIV presented with 4-month progressive left-sided weakness. Neurological examination revealed mild cognitive impairment, left-sided hemiparesis, and somatosense impairment to all modalities. Brain MRI revealed a punctate pattern with innumerable T2-FLAIR (fluid attenuated inversion recovery) hyperintensities in the cortex, brainstem, cerebellum, subcortical, and periventricular areas. Susceptibility-weighted imaging (SWI) revealed hypointensities involving subcortical U-fibers and cortical architecture. A comprehensive diagnostic evaluation was inconclusive. John Cunningham virus (JCV) PCR in cerebrospinal fluid (CSF) was indeterminate. He was started on antiretroviral therapy. Repeat brain MRI performed 1.5 months later, in the setting of further neurological decline, demonstrated progression of the T2-hyperintensities into a large confluent white matter lesion in the right frontoparietal lobe. Despite an indeterminate JCV PCR, the appearance and characteristic progression of the lesions in successive imaging in the setting of severe immunosuppression, with extensive negative infectious workup, was indicative of PML. This clinical experience illustrates unique neuroimaging features of HIV-PML in early stages and its progression over time. It especially highlights the relevance of the SWI sequence in the diagnosis and features observed with disease evolution. Short-term imaging follow-up may assist with the recognition of MRI features consistent with the biology of the infection.

Central sulcus is a barrier to causal propagation in epileptic networks.

the functional interactions of different brain regions are dependent of their underlying structural connectivity. These interactions are important for normal brain activity as well as in epileptic disorders where spontaneous epileptic discharges are generated. To understand the effects of brain topography on both normal and epileptic functional networks, we evaluated propagation frequency with respect to geodesic distance and the specific role of sulcal patterns in modulating these functional connections. We implemented a multimodal approach combining Electrocorticography (ECoG) and magnetic resonance imaging (MRI) to evaluate the relationships between epileptic and non-epileptic networks as they are related to structural connectivity in the human brain. We analyzed interictal ECoG along with MRI 3D reconstructions from seven epileptic patients and found that interictal full-dataset network propagations travel to both nearby and distant cortical locations, however with longer distance the propagations occurrence attenuates dramatically. We also discovered that the central sulcus acts as a strong barrier allowing only 30% of the propagation to cross central sulcus whereas the rest of the 70% propagations are observed on the same side of the sulcus. Epileptic spike propagations, however, were more highly localized with significantly less distant spread and had further reduction in spread across sulci. This is a novel approach to explore the structural influence of brain topography on the functional network and would help understand the interaction of different brain regions and how these are altered in patients with epilepsy. This approach could assist physician decision making during epilepsy surgery by revealing an appropriate brain network and cortical interactions.

Neocortical slices from adult chronic epileptic rats exhibit discharges of higher voltages and broader spread.

Much of the current understanding of epilepsy mechanisms has been built on data recorded with one or a few electrodes from temporal lobe slices of normal young animals stimulated with convulsants. Mechanisms of adult, extratemporal, neocortical chronic epilepsy have not been characterized as much. A more advanced understanding of epilepsy mechanisms can be obtained by recording epileptiform discharges simultaneously from multiple points of an epileptic focus so as to define their sites of initiation and pathways of spreading. Brain slice recordings can characterize epileptic mechanisms in a simpler, more controlled preparation than in vivo. Yet, the intrinsic hyper-excitability of a chronic epileptic focus may not be entirely preserved in slices following the severing of connections in slice preparation. This study utilizes recordings of multiple electrode arrays to characterize which features of epileptic hyper-excitability present in in vivo chronic adult neocortical epileptic foci are preserved in brain slices. After tetanus toxin somatosensory cortex injections, adult rats manifest chronic spontaneous epileptic discharges both in the injection site (primary focus) and in the contralateral side (secondary focus). We prepared neocortical slices from these epileptic animals. When perfused with 4-Aminopyridine in a magnesium free medium, epileptic rat slices exhibit higher voltage discharges and broader spreading than control rat slices. Rates of discharges are similar in slices of epileptic and normal rats, however. Ictal and interictal discharges are distributed over most cortical layers, though with significant differences between primary and secondary foci. A chronic neocortical epileptic focus in slices does not show increased spontaneous pacemakers initiating epileptic discharges but shows discharges with higher voltages and broader spread, consistent with an enhanced synchrony of cellular and synaptic generators over wider surfaces.

Intracranial EEG analysis in tumor-related epilepsy: Evidence of distant epileptic abnormalities.

OBJECTIVE: In patients with tumor-related epilepsy (TRE), surgery traditionally focuses on tumor resection; but identification and removal of associated epileptogenic zone may improve seizure outcome. Here, we study spatial relationship of tumor and seizure onset and early spread zone (SOSz). We also perform quantitative analysis of interictal epileptiform activities in patients with both TRE and non-lesional epilepsy in order to better understand the electrophysiological basis of epileptogenesis. METHODS: Twenty-five patients (11 with TRE and 14 with non-lesional epilepsy) underwent staged surgery using intracranial electrodes. Tumors were outlined on MRI and images were coregistered with post-implantation CT images. For each electrode, distance to the nearest tumor margin was measured. Electrodes were categorized based on distance from tumor and involvement in seizure. Quantitative EEG analysis studying frequency, amplitude, power, duration and slope of interictal spikes was performed. RESULTS: At least part of the SOSz was located beyond 1.5 cm from the tumor margin in 10/11 patients. Interictally, spike frequency and power were higher in the SOSz and spikes near tumor were smaller and less sharp. Interestingly, peritumoral electrodes had the highest spike frequencies and sharpest spikes, indicating greatest degree of epileptic synchrony. A complete resection of the SOSz resulted in excellent seizure outcome. CONCLUSIONS: Seizure onset and early spread often involves brain areas distant from the tumor. SIGNIFICANCE: Utilization of epilepsy surgery approach for TRE may provide better seizure outcome and study of the intracranial EEG may provide insight into pathophysiology of TRE.

Morphology-based automatic seizure detector for intracerebral EEG recordings.

In this paper, a new seizure detection system aimed at assisting in a rapid review of prolonged intracerebral EEG recordings is described. It is based on quantifying the sharpness of the waveform, one of the most important electrographic EEG features utilized by experts for an accurate and reliable identification of a seizure. The waveform morphology is characterized by a measure of sharpness as defined by the slope of the half-waves. A train of abnormally sharp waves resulting from subsequent filtering are used to identify seizures. The method was optimized using 145 h of single-channel depth EEG from seven patients, and tested on another 158 h of single-channel depth EEG from another seven patients. Additionally, 725 h of depth EEG from 21 patients was utilized to assess the system performance in a multichannel configuration. Single-channel test data resulted in a sensitivity of 87% and a specificity of 71%. The multichannel test data reported a sensitivity of 81% and a specificity of 58.9%. The new system detected a wide range of seizure patterns that included rhythmic and nonrhythmic seizures of varying length, including those missed by the experts. We also compare the proposed system with a popular commercial system.

A novel unsupervised spike sorting algorithm for intracranial EEG.

This paper presents a novel, unsupervised spike classification algorithm for intracranial EEG. The method combines template matching and principal component analysis (PCA) for building a dynamic patient-specific codebook without a priori knowledge of the spike waveforms. The problem of misclassification due to overlapping classes is resolved by identifying similar classes in the codebook using hierarchical clustering. Cluster quality is visually assessed by projecting inter- and intra-clusters onto a 3D plot. Intracranial EEG from 5 patients was utilized to optimize the algorithm. The resulting codebook retains 82.1% of the detected spikes in non-overlapping and disjoint clusters. Initial results suggest a definite role of this method for both rapid review and quantitation of interictal spikes that could enhance both clinical treatment and research studies on epileptic patients.

An animal model to study the clinical significance of interictal spiking.

Interictal spikes (IIS) are paroxysmal discharges commonly observed in patients with epilepsy which represent an abnormally-synchronized population of hyperexcitable neurons firing as an aggregate. Due to conflicting studies on the clinical significance of IIS, research focusing on IIS has been sparse. However, recent attention on IIS has increased for patients undergoing surgery for intractable epilepsy as a means to identify epileptic foci for surgical resection. There is growing evidence that IIS are not asymptomatic as has been commonly accepted. Other than epilepsy, IIS have been associated with a wide range of behavioral and psychiatric disorders, including attention deficit disorder, anxiety disorders and psychoses. For these reasons, a well-characterized animal model of interictal spiking which accurately mimics the human phenomenon would be a valuable tool to gain, insights both into the pathophysiology of epilepsy as well as a broad variety of human neuropsychiatric diseases. Here, we review the literature on the clinical significance of IIS in humans and on animal models where IIS has been observed. We then demonstrate the utility of using tetanus toxin to generate a reproducible pattem of progressive IIS for future studies into their clinical significance.

The adoption of smoke-free hospital campuses in the United States.

BACKGROUND: The adoption of a smoke-free hospital campus policy is often a highly publicised local event. National media coverage suggests that the trend towards adopting these policies is growing, and this publicity can frequently lead hospital administrators to consider the adoption of such policies within their own institutions. Little is actually known, however, about the prevalence of these policies or their impact. OBJECTIVES: To determine the national prevalence of smoke-free hospital campus policies and the relation between these policies and performance on nationally standardised measures for smoking cessation counselling in US hospitals. METHODS: 4494 Joint Commission-accredited hospitals were invited to complete a web-based questionnaire assessing current smoking policies and future plans. Smoking cessation counselling rates were assessed through nationally standardised measures. RESULTS: The 1916 hospitals responding to the survey (43%) were statistically similar to non-responders with respect to performance measure rates, smoking policies and demographic characteristics. Approximately 45% of responders reported an existing smoke-free hospital campus policy. With respect to demographics, higher proportions of smoke-free campus policies were reported in non-teaching and non-profit hospitals. Smoke-free campus hospitals were also more likely to provide smoking cessation counselling to patients with acute myocardial infarction, heart failure and pneumonia who smoke (p<0.001). CONCLUSIONS: By February 2008, 45% of US hospitals (up from approximately 3% in 1992) had adopted a smoke-free campus policy; another 15% reported actively pursuing the adoption of such a policy. By the end of 2009, it is likely that the majority of US hospitals will have a smoke-free campus.

Adverse-event-reporting practices by US hospitals: results of a national survey.

CONTEXT: Little is known about hospitals' adverse-event-reporting systems, or how they use reported data to improve practices. This information is needed to assess effects of national patient-safety initiatives, including implementation of the Patient Safety and Quality Improvement Act of 2005 (PSQIA). This survey generated baseline information on the characteristics of hospital adverse-event-reporting systems and processes, for use in assessing progress in improvements to reporting. METHODS: The Adverse Event Reporting Survey, developed by Westat, was administered in September 2005 through January 2006, using a mixed-mode (mail/telephone) survey with a stratified random sample of 2050 non-federal US hospitals. Risk managers were the respondents. An 81% response rate was obtained, for a sample of 1652 completed surveys. RESULTS: Virtually all hospitals reported they have centralised adverse-event-reporting systems, although characteristics varied. Scores on four performance indexes suggest that only 32% of hospitals have established environments that support reporting, only 13% have broad staff involvement in reporting adverse events, and 20-21% fully distribute and consider summary reports on identified events. Because survey responses are self-reported by risk managers, these may be optimistic assessments of hospital performance. CONCLUSIONS: Survey findings document the current status of hospital adverse-event-reporting systems and point to needed improvements in reporting processes. PSQIA liability protections for hospitals reporting data to patient-safety organisations should also help stimulate improvements in hospitals' internal reporting processes. Other mechanisms that encourage hospitals to strengthen their reporting systems, for example, strong patient-safety programmes, also would be useful.

Compressed EEG pattern analysis for critically ill neurological-neurosurgical patients.

Recent advances in continuous electroencephalogram (EEG) monitoring with digital EEG acquisition, storage, and quantitative analysis allow uninterrupted assessment of cerebral cortical activity in critically ill neurological-neurosurgical patients. Early recognition of worsening brain function can prove of vital importance as one can initiate measures aimed to prevent further brain damage. Although continuous EEG monitoring provides adequate spatial and temporal resolution and is able to continuously assess brain function in these critically ill patients, it requires a trained electroencephalographer to interpret the massive amounts of data generated. This limitation impedes the widespread use of EEG in assessing real-time brain function in critically ill patients. Here, we demonstrate the utility of a novel method of automated EEG analysis that segments and extracts EEG features, classifies and groups them according to various patterns, and then presents them in a compressed fashion. This permits real-time viewing of several hours of EEG on a single page. Examples are presented from three patients, two with recurrent seizures and one with diagnosis of subarachnoid hemorrhage. These patients illustrate the ability of this novel method to detect important real-time physiological changes in brain function that could enable early interventions aimed to prevent irreversible brain damage.

Treatment of neurocysticercosis: current status and future research needs.

Here we put forward a roadmap that summarizes important questions that need to be answered to determine more effective and safer treatments. A key concept in management of neurocysticercosis is the understanding that infection and disease due to neurocysticercosis are variable and thus different clinical approaches and treatments are required. Despite recent advances, treatments remain either suboptimal or based on poorly controlled or anecdotal experience. A better understanding of basic pathophysiologic mechanisms including parasite survival and evolution, nature of the inflammatory response, and the genesis of seizures, epilepsy, and mechanisms of anthelmintic action should lead to improved therapies.

Calcific neurocysticercosis and epileptogenesis.

Neurocysticercosis is responsible for increased rates of seizures and epilepsy in endemic regions. The most common form of the disease, chronic calcific neurocysticercosis, is the end result of the host's inflammatory response to the larval cysticercus of Taenia solium. There is increasing evidence indicating that calcific cysticercosis is not clinically inactive but a cause of seizures or focal symptoms in this population. Perilesional edema is at times also present around implicated calcified foci. A better understanding of the natural history, frequency, epidemiology, and pathophysiology of calcific cysticercosis and associated disease manifestations is needed to define its importance, treatment, and prevention.

Neuregulin-heparan-sulfate proteoglycan interactions produce sustained erbB receptor activation required for the induction of acetylcholine receptors in muscle.

Neuregulins bind to and activate members of the EGF receptor family of tyrosine kinases that initiate a signaling cascade that induces acetylcholine receptor synthesis in the postsynaptic membrane of neuromuscular synapses. In addition to an EGF-like domain, sufficient for receptor binding and tyrosine auto-phosphorylation, many spliced forms also have an IG-like domain that binds HSPGs and maintains a high concentration of neuregulin at synapses. Here, we show that the IG-like domain functions to keep the EGF-like domain at sufficiently high concentrations for a sufficiently long period of time necessary to induce acetylcholine receptor gene expression in primary chick myotubes. Using recombinant neuregulins with and without the IG-like domain, we found that IG-like domain binding to endogenous HSPGs produces a 4-fold increase in receptor phosphorylation. This enhancement of activity was blocked by soluble heparin or by pretreatment of muscle cells with heparitinase. We show that at least 12-24 h of neuregulin exposure was required to turn on substantial acetylcholine receptor gene expression and that the erbB receptors need to be kept phosphorylated during this time. The need for sustained erbB receptor activation may be the reason why neuregulins are so highly concentrated in the extracellular matrix of synapses.

The ORYX initiative: goals and potential application to physician quality improvement efforts.

Demands for public accountability in health care are more widespread today than at any time in the past. A number of national performance measurement efforts, including the ORYX initiative of the Joint Commission on Accreditation of Healthcare Organizations, represent an effort to provide stakeholders with the data they need to make judgments about the quality of health care provided to the public. The underlying premise of performance measurement is that organizations and clinicians can only improve what they can measure. Clinicians are the natural leaders in effecting broad-based change because of their direct influence on patient care and the respect they command in the health care environment. As performance measurement initiatives evolve, the ability of health care organizations to implement empirically based, structured improvement will increase and become commonplace.

Women with eating disorder tendencies display altered cardiovascular, neuroendocrine, and psychosocial profiles.

OBJECTIVE: Cardiovascular, neuroendocrine, and psychosocial profiles were investigated in women with eating disorder tendencies, but who had never met clinical criteria for an eating disorder, and in healthy controls. METHODS: Twenty-six women who scored in the highest distribution of the Eating Disorder Inventory bulimia subscale (HEDI women) and 27 women who scored in the lowest distribution (LEDI women) completed psychosocial questionnaires, underwent a speech reactivity task for measures of blood pressure and heart rate reactivity, and also underwent 24-hour ambulatory blood pressure monitoring and urinary neuroendocrine collection. RESULTS: The HEDI women exhibited increased blood pressure and heart rate reactivity to the speech task and increased 24-hour urinary cortisol, but decreased 24-hour urinary norepinephrine compared with LEDI women. There were no overall group differences in 24-hour ambulatory blood pressure levels, but negative mood and tension were associated with greater systolic blood pressures for all women. Finally, HEDI women reported greater depressive symptoms and anxiety, lower self-esteem and sense of mastery, less social support, poor coping skills, and greater emotional impact of daily stressors relative to LEDI women. CONCLUSIONS: These results indicate that the same pattern of neuroendocrine and psychosocial profiles seen in prior studies of bulimia nervosa are also present in women with eating disorder tendencies.

Saccharomyces cerevisiae G1 cyclins are differentially involved in invasive and pseudohyphal growth independent of the filamentation mitogen-activated protein kinase pathway.

Several lines of evidence suggest that the morphogenetic transition from the yeast form to pseudohyphae in Saccharomyces cerevisiae may be regulated by the cyclin-dependent kinase (Cdk). To examine this hypothesis, we mutated all of the G1 cyclin genes in strains competent to form pseudohyphae. Interestingly, mutation of each G1 cyclin results in a different filamentation phenotype, varying from a significant defect in cln1/cln1 strains to enhancement of filament production in cln3/cln3 strains. cln1 cln2 double mutants are more defective in pseudohyphal development and haploid invasive growth than cln1 strains. FLO11 transcription, which correlates with the level of invasive growth, is low in cln1 cln2 mutants and high in grr1 cells (defective in proteolysis of Cln1,2), suggesting that Cln1,2/Cdks regulate the pseudohyphal transcriptional program. Epistasis analysis reveals that Cln1,2/Cdk and the filamentation MAP kinase pathway function in parallel in regulating filamentous and invasive growth. Cln1 and Cln2, but not Ste20 or Ste12, are responsible for most of the elevated FLO11 transcription in grr1 strains. Furthermore, phenotypic comparison of various filamentation mutants illustrates that cell elongation and invasion/cell-cell adhesion during filamentation are separable processes controlled by the pseudohyphal transcriptional program. Potential targets for G1 cyclin/Cdks during filamentous growth are discussed.

Integrating performance measure data into the Joint Commission accreditation process.

This article describes the Joint Commission's implementation plans, experience, and results to date of incorporating performance measurement data into the accreditation process. These plans have evolved in response to changes in the health care environment, feedback from accredited organizations, and both technical and political obstacles encountered. During the late 1980s, the Joint Commission developed a national performance measurement system, the IMSystem, to incorporate information about the process and outcomes of care into the accreditation process. In 1995, the ORYX initiative was introduced to offer health care organizations significant flexibility in selecting a measurement system and measures while promoting organizational self-improvement and accountability. Recently, the plans have evolved to incorporate standardized core measures that are known to be valid and reliable. These initiatives have moved the field much closer to the day when quality assessment will reflect a comprehensive view of organizational performance, based, in part, on performance measurement data.

Enhanced expression of transgenes from adeno-associated virus vectors with the woodchuck hepatitis virus posttranscriptional regulatory element: implications for gene therapy.

The woodchuck hepatitis virus posttranscriptional regulatory element (WPRE) evolved to stimulate the expression of intronless viral messages. To determine whether this ability to enhance expression could be useful in nonviral and heterologous viral gene delivery systems, we analyzed the ability of the WPRE to elevate the expression of a cDNA encoding the green fluorescent protein (GFP) in these contexts. We find that the WPRE can stimulate the expression of GFP when the gene is delivered by transfection or transduction with recombinant adeno-associated virus (AAV). Enhancement occurred both during transient expression and when the gene is stably incorporated into the genome of target cells. This enhancement required that the WPRE be located in cis within the GFP message, and was observed in both transformed cell lines and primary human fibroblasts. These results demonstrate that the WPRE will be an effective tool for increasing the long-term expression of transgenes in gene therapy.