bluuebunny/crossref_metadata_2025 huggingface dataset:
EEG Alpha Asymmetry in Schizophrenia, Depression, PTSD, Panic Disorder, ADHD and Conduct Disorder
Authors: Gordon Evian , Palmer Donna M. , Cooper Nicholas
Published: February 2012

Models of laterality infer distinct aspects of EEG alpha asymmetry in clinical disorders, which has been replicated for over three decades. This biomarker now requires a more fine-grained assessment of its clinical utility as a diagnostic and treatment predictive marker. Here, within the same study we assessed resting brain laterality across six clinical disorders, for which deviant laterality has been implicated as core dysfunction. These disorders were evaluated in comparison to a large normative dataset (∼1,900) from the Brain Resource International Database. EEG alpha asymmetry was assessed in the frontocentral region, for resting Eyes Closed and Eyes Open conditions. Schizophrenia was characterized by significantly greater left lateralized alpha power than controls, indicating a deficit in left frontal activity at rest, which may relate to “disconnections” across wider fronto-temporal networks. The depression group showed a trend-level tendency towards the opposite pattern of greater right-lateralized activity than controls. The remaining anxiety and behavioral disorders did not show any significant deviance in alpha asymmetry from the normative control group. However, at a non-significant level laterality for these groups was generally consistent with expected directions, suggesting a propensity towards a particular lateralization but still remaining within the normative range. Overall, the results of the current study indicate that EEG alpha asymmetry may show the most clinical utility as a biomarker for schizophrenia and depression in comparison to other clinical disorders.
Fuzzy Synchronization Likelihood with Application to Attention-Deficit/Hyperactivity Disorder
Authors: Ahmadlou Mehran , Adeli Hojjat
Published: February 2012

Synchronization as a measure of quantification of similarities in dynamic systems is an important concept in many scientific fields such as nonlinear science, neuroscience, cardiology, ecology, and economics. When interdependencies and connections of coupled dynamic systems are not directly accessible and measurable such as those of the neurons of the brain, quantification of similarities between their time series outputs is the best possible way to detect the existent interdependencies among them. In recent years, Synchronization Likelihood (SL) has been used as one of the most suitable algorithms in highly nonlinear and non-stationary systems. In this method, the likelihood of patterns is measured statistically, and then it is determined which patterns of the time series are similar to each other considering a threshold. But the degree of similarities is not considered in the decision. In this paper, a new measure of synchronization, fuzzy SL, is presented using the theory of fuzzy logic and Gaussian membership functions. The new fuzzy SL is compared with the conventional SL using both a standard problem from the chaos literature and a complicated real life neurological diagnostic problem, that is, the EEG-based diagnosis of Attention-Deficit/Hyperactivity Disorder (ADHD). The results of ANOVA analysis indicate the interdependencies measured by the fuzzy SL are more reliable than the conventional SL for discriminating ADHD patients from healthy individuals.
Rapid Automatized Naming and Lexical Decision in Children from an Electrophysiological Perspective
Authors: González-Garrido A. A. , Gómez-Velázquez F. R. , Zarabozo D. , Ruiz-Villeda B. A. , de la Tuya J. M. Serna
Published: February 2012

Rapid Automatized Naming (RAN) deficits have been associated with less developed orthographic abilities that may affect lexical decisions. The effects of Spanish-speaking children's RAN performance on lexical decisions were evaluated by analyzing ERP and behavioral measures. Based upon their naming speed in four RAN tasks, 28 normal IQ, right-handed, 7-year-old children were selected and divided uniformly into two groups: average-naming (AN), and slow-naming (SN). ERPs were obtained during a lexical decision task consisting of 100 strings of four sequentially-presented letters that completed words (50 trials) or pseudowords (also 50 trials). The SN group showed major reading difficulties when compared to the AN group, as well as a significantly lower number of correct responses and slower reaction times in the lexical task. Two main ERP components were observed: parietal N320, interpreted as analogous to N170/N200; and a subsequent P3-like component (P500) with a higher amplitude for pseudowords, which probably reflects higher cognitive demands. Better reading comprehension and fewer misread pseudowords correlated with minor N320 latencies, while lower N320 amplitudes for words correlated with faster reading speeds, lower naming times and fewer errors while reading a text. The present results suggest that naming speed and ERP seem to be valuable in distinguishing early orthographic stored code retrieval abilities through a lexical decision task. Moreover, RAN and ERP emerge as accurate tools for evaluating reading processes in the early stages of reading acquisition.
On the Origin and Suddenness of Absences in Genetic Absence Models
Authors: van Luijtelaar Gilles , Sitnikova Evgenia , Luttjohann Annika
Published: February 2012

The origin of spike-wave discharges (SWDs), typical for absences, has been debated for at least half a century. While most classical views adhere to a thalamic oscillatory machinery and an active role of the cortex in modifying normal oscillations into pathological SWDs, recent studies in genetic models such as WAG/Rij and GAERS rats have challenged this proposal. It seems now well established that SWDs originate from the deep layers of the somatosensory cortex, that the activity quickly spreads over the cortex and invades the thalamus. The reticular thalamic nucleus and other thalamic nuclei provide a resonance circuitry for the amplification, spreading and entrainment of the SWDs. Conclusive evidence has been found that the changed functionality of HCN1 channels is a causative factor for the changes in local excitability and age-dependent increase in SWD. Furthermore, upregulation of two subtypes of Na+ channels, reduction of GABAB and mGlu 2/3 receptors might also play a role in the local increased excitability in WAG/Rij rats. Signal analytical studies have also challenged the view that SWDs occur suddenly from a normal background EEG. SWDs are recruited cortical responses and they develop from increasing associations within and between cortical layers and subsequently subcortical regions, triggered by the simultaneous occurrence of theta and delta precursor activity in the cortex and thalamus in case both structures are in a favorable condition, and increased directional coupling between cortex and thalamus. It is hypothesized that the cortex is the driving force throughout the whole SWD and is also responsible for its end.
Improving Alzheimer's Disease Diagnosis with Machine Learning Techniques
Authors: Trambaiolli Lucas R. , Lorena Ana C. , Fraga Francisco J. , Kanda Paulo A.M. , Anghinah Renato , Nitrini Ricardo
Published: February 2012

There is not a specific test to diagnose Alzheimer's disease (AD). Its diagnosis should be based upon clinical history, neuropsychological and laboratory tests, neuroimaging and electroencephalography (EEG). Therefore, new approaches are necessary to enable earlier and more accurate diagnosis and to follow treatment results. In this study we used a Machine Learning (ML) technique, named Support Vector Machine (SVM), to search patterns in EEG epochs to differentiate AD patients from controls. As a result, we developed a quantitative EEG (qEEG) processing method for automatic differentiation of patients with AD from normal individuals, as a complement to the diagnosis of probable dementia. We studied EEGs from 19 normal subjects (14 females/5 males, mean age 71.6 years) and 16 probable mild to moderate symptoms AD patients (14 females/2 males, mean age 73.4 years. The results obtained from analysis of EEG epochs were accuracy 79.9% and sensitivity 83.2%. The analysis considering the diagnosis of each individual patient reached 87.0% accuracy and 91.7% sensitivity.
The Diagnostic Value of Clinical EEG in Detecting Abnormal Synchronicity in Panic Disorder
Authors: Adamaszek Michael , Olbrich Sebastian , Gallinat Jürgen
Published: February 2012

Electroencephalographic (EEG) findings repeatedly reported abnormal synchronous or even epileptiform discharges in panic disorder. Although less frequently occurring in patients with panic disorder, these deviant EEG features during panic attacks were also observed in intracranial EEG. For this purpose, our article reviews the consideration of abnormal synchronous neuronal activity in different neurocircuits, particularly limbic, as a suggested condition of panic attacks. Therapeutic approaches of anticonvulsants have shown reductions of symptoms and frequency of attacks in numerous patients suffering from panic disorder, supporting the presumption of underlying abnormal synchronous neuronal activity. Thus, scalp EEG recordings are still recommended for discovering indications of abnormal synchronous neuronal activity in panic patients.
EEG Complexity and Attentional Processes Related to Dissociative States
Authors: Bob Peter , Golla Megan , Epstein Phillip , Konopka Lukasz
Published: February 2012

Reported findings indicate that attentional narrowing is related to decreased complexity and increased inhibition of neural assemblies. These findings suggest that analysis of electroencephalogram (EEG) complexity could present a useful method for research of attentional changes related to dissociation. To examine this model we used a case study to test the two hypotheses: (1) that successful anticonvulsant medication would result in dissociative symptom alleviation, improvement of inhibitory neural functions, and decreased EEG complexity, and (2) that cognitive conflict, related to aversive events in the patient's past experience, during reliving of a dissociative state would lead to greater allocation of attention and decreased EEG complexity.

Three EEG studies recorded in the eyes closed non-drowsy state were performed: (1) at baseline, (2) post-induction of dissociative state, and (3) post-anticonvulsant medication following induction of dissociative state. A dissociative state was achieved following an interview regarding the patient's aversive past experiences through use of the Peritraumatic Dissociative Experiences Questionnaire (PDEQ). The patient's level of dissociation was measured using the Dissociative Experiences Scale-II (DES-II). The PDEQ interview and DES-II assessment were also used one hour following the oral consumption of an anticonvulsant medication (clonazepam 2mg).

Analysis of the data revealed that complexity values (PD2) are significantly lower following the oral consumption of clonazepam (2mg) in the majority of EEG channels. Additionally, complexity during the reliving of a dissociative state was statistically significantly lower than both the baseline and post-medication conditions in all but two EEG channels. Results of the case study suggest that changes in attentional processes linked to dissociation are related to: (1) decreased complexity when attention is extremely focused because of attentional narrowing to the disturbing past experience, and (2) increased complexity during ordinary experiences when attention is less narrowly focused.
Intractable Epilepsy, Audio-Visual Hallucinations and Charcot-Marie-Tooth Disease 1A in an African-American Boy
Authors: Tsao Chang Y.
Published: February 2012

Charcot-Marie-Tooth disease 1A (CMT1A) is the most common autosomal dominant demyelinating sensorimotor polyneuropathy. A few patients with Charcot-Marie-Tooth disease were reported in the literature to have epilepsy. We report on an African-American boy with CMT1A, with duplication of peripheral myelin protein 22 gene, who also developed intractable generalized tonic-clonic seizures and audiovisual hallucinations.
Asynchronous P300-Based Brain-Computer Interface to Control a Virtual Environment: Initial Tests on End Users
Authors: Aloise Fabio , Schettini Francesca , Aricò Pietro , Salinari Serenella , Guger Christoph , Rinsma Johanna , Aiello Marco , Mattia Donatella , Cincotti Febo
Published: February 2012

Motor disability and/or ageing can prevent individuals from fully enjoying home facilities, thus worsening their quality of life. Advance s in the field of accessible user interfaces for domotic appliances can represent a valuable way to improve the independence of these persons. An asynchronous P300-based Brain-Computer Interface (BCI) system was recently validated with the participation of healthy young volunteers for environmental control.

In this study, the asynchronous P300-based BCI for the interaction with a virtual home environment was tested with the participation of potential end-users (clients of a Frisian home care organization) with limited autonomy due to ageing and/or motor disabilities. System testing revealed that the minimum number of stimulation sequences needed to achieve correct classification had a higher intra-subject variability in potential end-users with respect to what was previously observed in young controls. Here we show that the asynchronous modality performed significantly better as compared to the synchronous mode in continuously adapting its speed to the users' state. Furthermore, the asynchronous system modality confirmed its reliability in avoiding misclassifications and false positives, as previously shown in young healthy subjects.

The asynchronous modality may contribute to filling the usability gap between BCI systems and traditional input devices, representing an important step towards their use in the activities of daily living.
A Self-Paced Motor Imagery Based Brain-Computer Interface for Robotic Wheelchair Control
Authors: Tsui Chun Sing Louis , Gan John Q. , Hu Huosheng
Published: February 2012

This paper presents a simple self-paced motor imagery based brain-computer interface (BCI) to control a robotic wheelchair. An innovative control protocol is proposed to enable a 2-class self-paced BCI for wheelchair control, in which the user makes path planning and fully controls the wheelchair except for the automatic obstacle avoidance based on a laser range finder when necessary. In order for the users to train their motor imagery control online safely and easily, simulated robot navigation in a specially designed environment was developed. This allowed the users to practice motor imagery control with the core self-paced BCI system in a simulated scenario before controlling the wheelchair. The self-paced BCI can then be applied to control a real robotic wheelchair using a protocol similar to that controlling the simulated robot. Our emphasis is on allowing more potential users to use the BCI controlled wheelchair with minimal training; a simple 2-class self-paced system is adequate with the novel control protocol, resulting in a better transition from offline training to online control. Experimental results have demonstrated the usefulness of the online practice under the simulated scenario, and the effectiveness of the proposed self-paced BCI for robotic wheelchair control.
The Quantitative Electroencephalogram and the Low-Resolution Electrical Tomographic Analysis in Posttraumatic Stress Disorder
Authors: Todder Doran , Levine Joseph , Abujumah Ahmad , Mater Michael , Cohen Hagit , Kaplan Zeev
Published: February 2012

The electroencephalogram (EEG) is the recording of the brain electrical activity as measured on the scalp. Using mathematical algorithms, the 3-dimensional (3D) distribution of the electrical potential inside the brain can be calculated. One of the methods to calculate it is the low-resolution electrical tomographic analysis (LORETA). In this research, we seek to find the brain structures that differentiate patients with posttraumatic stress disorder (PTSD) from controls. Ten right-handed consenting adult male patients were recruited from a PTSD clinic. All patients fulfilled Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition, Text Revision [ DSM-IV-TR]) criteria for chronic PTSD (duration >2 years.) and were on drug treatment regimens that had been stable for at least 2 months (involving only serotonin reuptake inhibitors [SSRIs] and benzodiazepines).The control group consisted of 10 healthy hospital staff members. All study participants underwent 19 channel EEG measurements according to current standards of practice. All artifact-free EEG strips were examined for spectral as well as LORETA analysis focusing on the theta (4-7 Hz) band which is suggested to reflect the activity of the limbic system. The theta band showed a statistically significant difference ( P < .05) between the 2 groups in the right temporal lobe and in both the right and left frontal lobes. Our findings support existing research data obtained via other imaging technologies, which demonstrated structural alterations in the right temporal and frontal areas in PTSD. These results indicate that combining quantitative EEG (QEEG) and the LORETA method, among other methods, may improve the neuroanatomical resolution of EEG data analysis.
Relationship Between Sleep Spindles and Clinical Recovery in Patients With Traumatic Brain Injury
Authors: Urakami Yuko
Published: February 2012

Few methods can predict the prognosis and outcome of traumatic brain injury. Electroencephalographic (EEG) examinations have prognostic significance in the acute stage of posttraumatic coma, and some EEG variables have been correlated with outcome. Furthermore, spindle activity and reactivity in the acute stage have been associated with good recovery. Assessments of consciousness based on EEG and magnetoencephalographic (MEG) recordings provide valuable information for evaluating residual function, forming differential diagnoses and estimating prognosis. This study objectively investigated how fast spindles could relate to the recovery of consciousness and cognitive function during the post-acute to chronic stages of diffuse axonal injuries (DAIs). Sleep stage 2 was examined in 7 healthy participants and 8 patients with DAIs. Simultaneous EEG and MEG recordings were performed in the post-acute (mean 80 days) and chronic (mean 151 days) stages of recovery. Magnetoencephalography enabled equivalent current dipole estimates of fast spindle sources. Clinical recovery was evaluated by consciousness, neuropsychological examination, and outcome. Six severe and two moderate injuries were studied in patients with favorable 1-year outcomes. In the sub-acute stage, significant decreases were detected in the frequency, amplitude, and cortical activation source strengths of spindle activities, but these recovered during the chronic stage. In the chronic stage, the Wechsler adult intelligence factor scale and subset patterning revealed significant improvement in cognitive function. These results suggested that spindles may reflect recovery of consciousness and cognitive function following a DAI.
Sensory Gating-Out and Gating-In in Normal and Schizophrenic Participants
Authors: Hu Lingli , Boutros Nash N. , Jansen Ben H.
Published: February 2012

In contrast to sensory gating, the brain’s ability to re-respond to relevant stimuli and the potential differences between healthy and schizophrenic participants have not been studied in great detail. Here, we explore what auditory paradigms are useful to measure this re-responding ability. Evoked potentials (EPs) were obtained from the Cz channel using 3 paired stimulus paradigms (pairs with equal stimuli {PE}, the second stimulus being lower {PL} or higher {PH} in frequency) and 2 short-train paradigms in which 5 identical stimuli were followed by a lower frequency stimulus (train lower {TL}) or higher frequency stimulus (train higher {TH}). Data were collected from 17 healthy control participants (NC) and 17 age and gender-matched patients with schizophrenia (SZ). Up to 4 data sets obtained on 4 different days were available for each participant. Ensemble averages were computed for each session, from which the P50, N100, and P200 latencies and amplitudes were obtained. No significant differences in amplitude or latency of the various EP components were found between the responses to the second stimulus obtained with the 5 paradigms. Neither did the responses to the fifth and sixth stimuli differ for the TL and TH paradigm, with the exception of the N100 latency of the fifth stimulus, which was longer for TH than TL for NC. Healthy participants had larger amplitudes and shorter latencies than the patients with schizophrenia for the responses to the first stimuli, with the latency differences continuing for the fifth and sixth response. Also, the amplitude and latency of the first response was larger than for the second response in both populations. In conclusion, none of the paradigms studied here, with the employed parameters, are useful to measure the re-responding ability of the brain. Also, the shorter latencies for the repeated stimulus suggest that the neural mechanism underlying attenuation of repeated stimuli is of a facilitating nature.
Application of Multiscale Amplitude Modulation Features and Fuzzy C-Means to Brain–Computer Interface
Authors: Hsu Wei-Yen , Li Yu-Chuan , Hsu Chien-Yeh , Liu Chien-Tsai , Chiu Hung-Wen
Published: February 2012

This study proposed a recognized system for electroencephalogram (EEG) data classification. In addition to the wavelet-based amplitude modulation (AM) features, the fuzzy c-means (FCM) clustering is used for the discriminant of left finger lifting and resting. The features are extracted from discrete wavelet transform (DWT) data with the AM method. The FCM is then applied to recognize extracted features. Compared with band power features, k-means clustering, and linear discriminant analysis (LDA) classifier, the results indicate that the proposed method is satisfactory in applications of brain–computer interface (BCI).
Evaluation of Maturation and Function of Visual Pathways in Neonates
Authors: Chayasirisobhon Sirichai , Gurbani Saumya , Chai Edward E. , Spurgeon Benjamin , Yu Luke , Bosu Sogba , Gurbani Suresh
Published: February 2012

The purpose of our study was to establish the guidelines for interpreting neonatal flash visual-evoked potentials (FVEPs) by examining the correlation between maturation of the waveforms and conceptual age (CA). We retrospectively analyzed 220 consecutive neonatal FVEPs performed on premature and full-term infants. The CA of the participants ranged from 28 to 52 weeks. The FVEPs were categorized into 6 groups according to CA: 28 to 31+ weeks, 32  to 35+ weeks, 36 to 39+ weeks, 40 to 43+ weeks, 44 to 47+weeks, and 48 to 52 weeks. The data were analyzed in each group and compared among these 6 groups. The waveforms changed from 28 weeks to 52 weeks of CA. In the CA age range 28 to 31+ weeks N3 was well visualized, followed by P3. The morphology of P2 including both latency and amplitude became prominent starting from CA age range 32 to 35+ weeks. The triphasic waveform with clear negative-positive-negative components (N2-P2-N3) presented after 32 weeks. Mean P2 latencies decreased steadily with increasing age. Mean amplitudes of all waveforms (P2-N3 and N3-P3) varied except that of N2-P2 which increased steadily with CA. We conclude that FVEPs can be useful in the evaluation of maturation and function of the visual pathway in neonates. The FVEP is abnormal when the waveforms N3 and P3 are nondetectable in neonates at 28 weeks of CA or older; and when the waveform P2 is non-detectable, or has low amplitude or prolonged latency, in neonates at 36 weeks of CA or older.
Passive P300 Response in Different Attentional States and in Traumatic Brain Injury
Authors: Rappaport Maurice
Published: February 2012

Abstract of presentation at the March 1990 meeting of AMEEGA, Scottsdale, Arizona.
Triangulation, Respondent Validation, and Democratic Participation in Mixed Methods Research
Authors: Torrance Harry
Published: February 2012

Over the past 10 years or so the “Field” of “Mixed Methods Research” (MMR) has increasingly been exerting itself as something separate, novel, and significant, with some advocates claiming paradigmatic status. Triangulation is an important component of mixed methods designs. Triangulation has its origins in attempts to validate research findings by generating and comparing different sorts of data, and different respondents’ perspectives, on the topic under investigation. Respondent validation has sometimes been included in such processes, but it is an element that has not attracted significant attention from the MMR community. The article argues that attention to respondent validation is a significant issue for methodological debate and that it should be an important aspect of the development of democratic participation in MMR.
Citizenship education and philosophical enquiry: Putting thinking back into practice
Authors: Garratt Dean , Piper Heather
Published: February 2012

In this article, we argue for a purposeful re-introduction of philosophical enquiry to the process and pedagogy of citizenship education. We suggest the development of philosophy and critical thinking skills may usefully improve social and political awareness in young people. Moving beyond the boundary of the formal curriculum, we encourage the development of synergy between the international movement of philosophy for children and the expanding tradition of community philosophy as a means to promote more open and democratic enquiry. We suggest this will produce important benefits for young people, helping to promote responsible judgements on social affairs, develop intergenerational relationships and enhance freedom for the young to think rationally and autonomously as critically informed citizens. However, this is likely to occur only if teachers and schools are more willing and prepared to challenge dominant, reductive notions of education in favour of more active and democratic conceptions of the secondary curriculum.
Silent cerebral infarcts: a review on a prevalent and progressive cause of neurologic injury in sickle cell anemia
Authors: DeBaun Michael R. , Armstrong F. Daniel , McKinstry Robert C. , Ware Russell E. , Vichinsky Elliot , Kirkham Fenella J.
Published: February 2012

Silent cerebral infarct (SCI) is the most common form of neurologic disease in children with sickle cell anemia (SCA). SCI is defined as abnormal magnetic resonance imaging (MRI) of the brain in the setting of a normal neurologic examination without a history or physical findings associated with an overt stroke. SCI occurs in 27% of this population before their sixth, and 37% by their 14th birthdays. In adults with SCA, the clinical history of SCI is poorly defined, although recent evidence suggests that they too may have ongoing risk of progressive injury. Risk factors for SCI include male sex, lower baseline hemoglobin concentration, higher baseline systolic blood pressure, and previous seizures. Specific morbidity associated with SCI includes a decrement in general intellectual abilities, poor academic achievement, progression to overt stroke, and progressive SCI. In addition, children with previous stroke continue to have both overt strokes and new SCI despite receiving regular blood transfusion therapy for secondary stroke prevention. Studies that only include overt stroke as a measure of CNS injury significantly underestimate the total cerebral injury burden in this population. In this review, we describe the epidemiology, natural history, morbidity, medical management, and potential therapeutic options for SCI in SCA.
Redefining interferon-producing killer dendritic cells as a novel intermediate in NK-cell differentiation
Authors: Guimont-Desrochers Fanny , Boucher Geneviève , Dong Zhongjun , Dupuis Martine , Veillette André , Lesage Sylvie
Published: February 2012

The cell lineage origin of IFN-producing killer dendritic cells (IKDCs), which exhibit prominent antitumoral activity, has been subject to debate. Although IKDCs were first described as a cell type exhibiting both plasmacytoid DC and natural killer (NK) cell properties, the current view reflects that IKDCs merely represent activated NK cells expressing B220, which were thus renamed B220+ NK cells. Herein, we further investigate the lineage relation of B220+ NK cells with regard to other NK-cell subsets. We surprisingly find that, after adoptive transfer, B220− NK cells did not acquire B220 expression, even in the presence of potent activating stimuli. These findings strongly argue against the concept that B220+ NK cells are activated NK cells. Moreover, we unequivocally show that B220+ NK cells are highly proliferative and differentiate into mature NK cells after in vivo adoptive transfer. Additional phenotypic, functional, and transcriptional characterizations further define B220+ NK cells as immediate precursors to mature NK cells. The characterization of these novel attributes to B220+ NK cells will guide the identification of their ortholog in humans, contributing to the design of potent cancer immunotherapies.
Tumor-targeted T cells modified to secrete IL-12 eradicate systemic tumors without need for prior conditioning
Authors: Pegram Hollie J. , Lee James C. , Hayman Erik G. , Imperato Gavin H. , Tedder Thomas F. , Sadelain Michel , Brentjens Renier J.
Published: February 2012

Adoptive cell therapy with tumor-targeted T cells is a promising approach to cancer therapy. Enhanced clinical outcome using this approach requires conditioning regimens with total body irradiation, lymphodepleting chemotherapy, and/or additional cytokine support. However, the need for prior conditioning precludes optimal application of this approach to a significant number of cancer patients intolerant to these regimens. Herein, we present preclinical studies demonstrating that treatment with CD19-specific, chimeric antigen receptor (CAR)–modified T cells that are further modified to constitutively secrete IL-12 are able to safely eradicate established disease in the absence of prior conditioning. We demonstrate in a novel syngeneic tumor model that tumor elimination requires both CD4+ and CD8+ T-cell subsets, autocrine IL-12 stimulation, and subsequent IFNγ secretion by the CAR+ T cells. Importantly, IL-12–secreting, tumor-targeted T cells acquire intrinsic resistance to T regulatory cell–mediated inhibition. Based on these preclinical data, we anticipate that adoptive therapy using CAR-targeted T cells modified to secrete IL-12 will obviate or reduce the need for potentially hazardous conditioning regimens to achieve optimal antitumor responses in cancer patients.
Interaction of HmC1q with leech microglial cells: involvement of C1qBP-related molecule in the induction of cell chemotaxis
Authors: Tahtouh Muriel , Garçon-Bocquet Annelise , Croq Françoise , Vizioli Jacopo , Sautière Pierre-Eric , Van Camp Christelle , Salzet Michel , Nagnan-le Meillour Patricia , Pestel Joël , Lefebvre Christophe
Published: February 2012

Background

In invertebrates, the medicinal leech is considered to be an interesting and appropriate model to study neuroimmune mechanisms. Indeed, this non-vertebrate animal can restore normal function of its central nervous system (CNS) after injury. Microglia accumulation at the damage site has been shown to be required for axon sprouting and for efficient regeneration. We characterized HmC1q as a novel chemotactic factor for leech microglial cell recruitment. In mammals, a C1q-binding protein (C1qBP alias gC1qR), which interacts with the globular head of C1q, has been reported to participate in C1q-mediated chemotaxis of blood immune cells. In this study, we evaluated the chemotactic activities of a recombinant form of HmC1q and its interaction with a newly characterized leech C1qBP that acts as its potential ligand.

Methods

Recombinant HmC1q (rHmC1q) was produced in the yeast Pichia pastoris. Chemotaxis assays were performed to investigate rHmC1q-dependent microglia migration. The involvement of a C1qBP-related molecule in this chemotaxis mechanism was assessed by flow cytometry and with affinity purification experiments. The cellular localization of C1qBP mRNA and protein in leech was investigated using immunohistochemistry and in situ hybridization techniques.

Results

rHmC1q-stimulated microglia migrate in a dose-dependent manner. This rHmC1q-induced chemotaxis was reduced when cells were preincubated with either anti-HmC1q or anti-human C1qBP antibodies. A C1qBP-related molecule was characterized in leech microglia.

Conclusions

A previous study showed that recruitment of microglia is observed after HmC1q release at the cut end of axons. Here, we demonstrate that rHmC1q-dependent chemotaxis might be driven via a HmC1q-binding protein located on the microglial cell surface. Taken together, these results highlight the importance of the interaction between C1q and C1qBP in microglial activation leading to nerve repair in the medicinal leech.
Involvement of PPAR-γ in the neuroprotective and anti-inflammatory effects of angiotensin type 1 receptor inhibition: effects of the receptor antagonist telmisartan and receptor deletion in a mouse MPTP model of Parkinson's disease
Authors: Garrido-Gil Pablo , Joglar Belen , Rodriguez-Perez Ana I , Guerra Maria J , Labandeira-Garcia Jose L
Published: February 2012

Background

Several recent studies have shown that angiotensin type 1 receptor (AT1) antagonists such as candesartan inhibit the microglial inflammatory response and dopaminergic cell loss in animal models of Parkinson's disease. However, the mechanisms involved in the neuroprotective and anti-inflammatory effects of AT1 blockers in the brain have not been clarified. A number of studies have reported that AT1 blockers activate peroxisome proliferator-activated receptor gamma (PPAR γ). PPAR-γ activation inhibits inflammation, and may be responsible for neuroprotective effects, independently of AT1 blocking actions.

Methods

We have investigated whether oral treatment with telmisartan (the most potent PPAR-γ activator among AT1 blockers) provides neuroprotection against dopaminergic cell death and neuroinflammation, and the possible role of PPAR-γ activation in any such neuroprotection. We used a mouse model of parkinsonism induced by the dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and co-administration of the PPAR-γ antagonist GW9662 to study the role of PPAR-γ activation. In addition, we used AT1a-null mice lesioned with MPTP to study whether deletion of AT1 in the absence of any pharmacological effect of AT1 blockers provides neuroprotection, and investigated whether PPAR-γ activation may also be involved in any such effect of AT1 deletion by co-administration of the PPAR-γ antagonist GW9662.

Results

We observed that telmisartan protects mouse dopaminergic neurons and inhibits the microglial response induced by administration of MPTP. The protective effects of telmisartan on dopaminergic cell death and microglial activation were inhibited by co-administration of GW9662. Dopaminergic cell death and microglial activation were significantly lower in AT1a-null mice treated with MPTP than in mice not subjected to AT1a deletion. Interestingly, the protective effects of AT1 deletion were also inhibited by co-administration of GW9662.

Conclusion

The results suggest that telmisartan provides effective neuroprotection against dopaminergic cell death and that the neuroprotective effect is mediated by PPAR-γ activation. However, the results in AT1-deficient mice show that blockage of AT1, unrelated to the pharmacological properties of AT1 blockers, also protects against dopaminergic cell death and neuroinflammation. Furthermore, the results show that PPAR-γ activation is involved in the anti-inflammatory and neuroprotective effects of AT1 deletion.
Adherence to Stage-Specific Treatment Guidelines for Patients With Colon Cancer
Authors: Chagpar Ryaz , Xing Yan , Chiang Yi-Ju , Feig Barry W. , Chang George J. , You Y. Nancy , Cormier Janice N.
Published: February 2012

Purpose

Adherence to evidence-based treatment guidelines has been proposed as a measure of cancer care quality. We sought to determine rates of and factors associated with adherence to the National Comprehensive Cancer Network (NCCN) treatment guidelines for colon cancer.

Patients and Methods

Patients within the National Cancer Data Base treated for colon adenocarcinoma (2003 to 2007) were identified. Adherence to stage-specific NCCN guidelines was determined based on disease stage. Hierarchical regression analyses were performed to identify factors predictive of adherence, overtreatment, and undertreatment.

Results

A total of 173,243 patients were included in the final cohort, 123,953 (71%) of whom were treated according to NCCN guidelines. Patients with stage I disease were more likely to receive guideline-based treatment (96%) than patients with stage II (low risk, 66%; high risk, 36%), III (71%), or IV (73%) disease (P < .001). Adherence to consensus-based guidelines increased over time. Factors associated with adherence across all stages included age, Charlson-Deyo comorbidity index score, later year of diagnosis, and insurance status. Among patients with high-risk stage II or stage III disease, older patients with pre-existing comorbidities and patients with lower socioeconomic status were less likely to be offered adjuvant chemotherapy. Among patients with stage I and II disease, young, healthy patients were more likely to be recommended chemotherapy, in discordance with NCCN guidelines.

Conclusion

Significant variation exists in the treatment of colon cancer, particularly in treatment of high-risk stage II and stage III disease. The impact of nonadherence to guidelines on patient outcomes needs to be further elucidated.
The Mitochondrial Citrate Carrier (CIC) Is Present and Regulates Insulin Secretion by Human Male Gamete
Authors: Cappello Anna R. , Guido Carmela , Santoro Antonella , Santoro Marta , Capobianco Loredana , Montanaro Daniela , Madeo Marianna , Andò Sebastiano , Dolce Vincenza , Aquila Saveria
Published: February 2012

The mechanisms through which sperm manage their energy metabolism are poorly understood. The present study provides biochemical and morphological evidence that mitochondrial citrate carrier (CIC) is present in ejaculated human sperm and is restricted to the midpiece. The inhibition of CIC with the specific substrate analog 1,2,3-benzenetricarboxylate resulted in the reduction of cholesterol efflux, protein tyrosine phosphorylation, phospho-AKT, phospho-p60src, hyperactivated motility and acrosome reaction, suggesting a role for this mitochondrial carrier in sperm physiology. Furthermore, inhibition of CIC by 1,2,3-benzenetricarboxylate resulted in a reduction of glucose-stimulated insulin secretion and autocrine insulin secretion by sperm. Remarkably, blocking CIC also reduced glucose-6-phosphate dehydrogenase activity, probably in accordance with its regulation on insulin secretion. Capacitation and glucose metabolism were stimulated by glucose as well as citrate, the specific substrate of CIC, implying a similar action because glucose and citrate both induced insulin secretion by sperm. In the present finding, we discovered a new site of action for CIC in the regulation of metabolism, and it may be assumed that CIC works with other factors in the regulation of sperm energy metabolism to sustain capacitation process and acrosome reaction.
Angiotensin Receptor Blockade Increases Pancreatic Insulin Secretion and Decreases Glucose Intolerance during Glucose Supplementation in a Model of Metabolic Syndrome
Authors: Rodriguez Ruben , Viscarra Jose A. , Minas Jacqueline N. , Nakano Daisuke , Nishiyama Akira , Ortiz Rudy M.
Published: February 2012

Renin-angiotensin system blockade improves glucose intolerance and insulin resistance, which contribute to the development of metabolic syndrome. However, the contribution of impaired insulin secretion to the pathogenesis of metabolic syndrome is not well defined. To assess the contributions of angiotensin receptor type 1 (AT1) activation and high glucose intake on pancreatic function and their effects on insulin signaling in skeletal muscle and adipose tissue, an oral glucose tolerance test (oGTT) was performed in five groups (n = 10/group) of rats: 1) lean strain-control 2) obese Otsuka Long-Evans Tokushima Fatty (OLETF), 3) OLETF + angiotensin receptor blocker (ARB; 10 mg/kg · d olmesartan for 6 wk; OLETF ARB), 4) OLETF + 5% glucose water (HG) for 6 wk (OLETF HG), and 5) OLETF + HG + ARB (OLETF HG/ARB). The glucose response to the oGTT increased 58% in OLETF compared with lean-strain control, whereas glucose supplementation increased it an additional 26%. Blockade of angiotensin receptor reduced the oGTT response 19% in the ARB-treated groups and increased pancreatic insulin secretion 64 and 113% in OLETF ARB and OLETF HG/ARB, respectively. ARB treatment in OLETF ARB and OLETF HG/ARB did not have an effect on insulin signaling proteins in skeletal muscle; however, it reduced pancreatic AT1 protein expression 20 and 27%, increased pancreatic glucagon-like peptide-1 (GLP-1) receptor protein expression 41 and 88%, respectively, and increased fasting plasma GLP-1 approximately 2.5-fold in OLETF ARB. The results suggest that improvement of glucose intolerance is independent of an improvement in muscle insulin signaling, but rather by improved glucose-stimulated insulin secretion associated with decreased pancreatic AT1 activation and increased GLP-1 signaling.
The role of ubiquitylation in receptor endocytosis and endosomal sorting
Authors: Haglund Kaisa , Dikic Ivan
Published: February 2012

Ligand-induced activation of transmembrane receptors activates intracellular signaling cascades that control vital cellular processes, such as cell proliferation, differentiation, migration and survival. Receptor signaling is modulated by several mechanisms to ensure that the correct biological outcome is achieved. One such mechanism, which negatively regulates receptor signaling, involves the modification of receptors with ubiquitin. This post-translational modification can promote receptor endocytosis and targets receptors for lysosomal degradation, thereby ensuring termination of receptor signaling. In this Commentary, we review the roles of ubiquitylation in receptor endocytosis and degradative endosomal sorting by drawing on the epidermal growth factor receptor (EGFR) as a well-studied example. Furthermore, we elaborate on the molecular basis of ubiquitin recognition along the endocytic pathway through compartment-specific ubiquitin-binding proteins and highlight how endocytic sorting machineries control these processes. In addition, we discuss the importance of ubiquitin-dependent receptor endocytosis for the maintenance of cellular homeostasis and in the prevention of diseases such as cancer.
Integrating dynamic energy budget (DEB) theory with traditional bioenergetic models
Authors: Nisbet Roger M. , Jusup Marko , Klanjscek Tin , Pecquerie Laure
Published: February 2012

Dynamic energy budget (DEB) theory offers a systematic, though abstract, way to describe how an organism acquires and uses energy and essential elements for physiological processes, in addition to how physiological performance is influenced by environmental variables such as food density and temperature. A ‘standard’ DEB model describes the performance (growth, development, reproduction, respiration, etc.) of all life stages of an animal (embryo to adult), and predicts both intraspecific and interspecific variation in physiological rates. This approach contrasts with a long tradition of more phenomenological and parameter-rich bioenergetic models that are used to make predictions from species-specific rate measurements. These less abstract models are widely used in fisheries studies; they are more readily interpretable than DEB models, but lack the generality of DEB models. We review the interconnections between the two approaches and present formulae relating the state variables and fluxes in the standard DEB model to measured bioenergetic rate processes. We illustrate this synthesis for two large fishes: Pacific bluefin tuna (Thunnus orientalis) and Pacific salmon (Oncorhynchus spp.). For each, we have a parameter-sparse, full-life-cycle DEB model that requires adding only a few species-specific features to the standard model. Both models allow powerful integration of knowledge derived from data restricted to certain life stages, processes and environments.
Behaviour and control of influenza in institutions and small societies
Authors: Finnie Thomas James Ronald , Hall Ian M , Leach Steve
Published: February 2012

A literature review was undertaken to assess the impact of influenza in enclosed societies. The literature spanned 120 years and included both readily accessible material from online keyword searches, as well as more obscure paper documents found through in-depth library research. Enclosed societies have been predominantly found in some type of institution through this period although noticeable similarities exist in communities isolated by distance and geography. We observe that no matter how isolated a community is, it is not necessarily insulated from infection by influenza and that even where there are no complicating factors, such as the age distribution or the presence of individuals with greater susceptibility in the enclosed population, their organization tends to increase influenza transmission and the risk of secondary infection. The collected accounts demonstrate important features of outbreaks in such societies and the necessity of considering them in pandemic planning: in particular, rapid intervention is essential for the control of influenza spread in such circumstances. Recent experience has shown that administration of modern antiviral drugs, such as neuraminidase inhibitors are effective at moderating outbreaks of influenza, but only in combination with other methods of control. In more remote communities where such drugs are not, or less, readily available, and medical care is limited, such outbreaks can still pose particular difficulties. In all cases delay in correct diagnosis, detection of an outbreak or the implementation of control measures can result in the majority of the enclosed population succumbing to the disease.