Persistence of Human Herpesvirus 7 in Normal Tissues Detected by Expression of a Structural Antigen

Human herpesvirus 7 (HHV-7) infection in histologically normal human tissues was investigated by immunohistochemical detection of the 85-kDa tegument phosphoprotein (pp85) encoded by the U14 gene. So far, two cell types were recognized as sites of HHV-7 infection in vivo: CD4+ T lymphocytes, believed to be the site of latent infection, and epithelial cells of salivary glands, the site of productive infection and viral shedding. Unexpectedly, cells expressing the HHV-7 structural antigen were detectable in lungs, skin, and mammary glands. Morphologically and phenotypically, they were distinct from lymphocytes. Liver, kidney, and tonsils were positive, although the number of HHV-7-positive cells was low. Large intestine, spleen, and brain were negative. Different from the current notion of the state of HHV-7 in humans, the results show that a variety of tissues harbor cells at a late stage of infection and suggest that HHV-7 causes a persistent rather than a true latent infectio

An EEG-fMRI Study on the Termination of Generalized Spike-And-Wave Discharges in Absence Epilepsy

INTRODUCTION: Different studies have investigated by means of EEG-fMRI coregistration the brain networks related to generalized spike-and-wave discharges (GSWD) in patients with idiopathic generalized epilepsy (IGE). These studies revealed a widespread GSWD-related neural network that involves the thalamus and regions of the default mode network. In this study we investigated which brain regions are critically involved in the termination of absence seizures (AS) in a group of IGE patients. METHODS: Eighteen patients (6 male; mean age 25 years) with AS were included in the EEG-fMRI study. Functional data were acquired at 3T with continuous simultaneous video-EEG recording. Event-related analysis was performed with SPM8 software, using the following regressors: (1) GSWD onset and duration; (2) GSWD offset. Data were analyzed at single-subject and at group level with a second level random effect analysis. RESULTS: A mean of 17 events for patient was recorded (mean duration of 4.2 sec). Group-level analysis related to GSWD onset respect to rest confirmed previous findings revealing thalamic activation and a precuneus/posterior cingulate deactivation. At GSWD termination we observed a decrease in BOLD signal over the bilateral dorsolateral frontal cortex respect to the baseline (and respect to GSWD onset). The contrast GSWD offset versus onset showed a BOLD signal increase over the precuneus-posterior cingulate region bilaterally. Parametric correlations between electro-clinical variables and BOLD signal at GSWD offset did not reveal significant effects. CONCLUSION: The role of the decreased neural activity of lateral prefrontal cortex at GSWD termination deserve future investigations to ascertain if it has a role in promoting the discharge offset, as well as in the determination of the cognitive deficits often present in patients with AS. The increased BOLD signal at precuneal/posterior cingulate cortex might reflect the recovery of neural activity in regions that are "suspended" during spike and waves activity, as previously hypothesized

Centrotemporal spikes during NREM sleep: The promoting action of thalamus revealed by simultaneous EEG and fMRI coregistration

Benign childhood epilepsy with centrotemporal spikes (BECTS) has been investigated through EEG\u2013fMRI with the aim of localizing the generators of the epileptic activity, revealing, in most cases, the activation of the sensory\u2013motor cortex ipsilateral to the centrotemporal spikes (CTS). In this case report, we investigated the brain circuits hemodynamically involved by CTS recorded during wakefulness and sleep in one boy with CTS and a language disorder but without epilepsy. For this purpose, the patient underwent EEG\u2013fMRI coregistration. During the \u201cawake session\u201d, fMRI analysis of right-sided CTS showed increments of BOLD signal in the bilateral sensory\u2013motor cortex. During the \u201csleep session\u201d, BOLD increments related to right-sided CTS were observed in a widespread bilateral cortical\u2013subcortical network involving the thalamus, basal ganglia, sensory\u2013motor cortex, perisylvian cortex, and cerebellum. In this patient, who fulfilled neither the diagnostic criteria for BECTS nor that for electrical status epilepticus in sleep (ESES), the transition from wakefulness to sleep was related to the involvement of a widespread cortical\u2013subcortical network related to CTS. In particular, the involvement of a thalamic\u2013perisylvian neural network similar to the one previously observed in patients with ESES suggests a common sleep-related network dysfunction even in cases with milder phenotypes without seizures. This finding, if confirmed in a larger cohort of patients, could have relevant therapeutic implication

Up-regulation of a death receptor renders antiviral T cells susceptible to NK cell-mediated deletion

This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).This work was funded by the Medical Research Council (Clinical Research Training Fellowship to DP and grant G0801213 to M.K. Maini)

Alterazioni di RM strutturale e funzionale in pazienti con epilessia del lobo temporale candidabili alla chirurgia: uno studio sul contributo di tecniche di neuroimmagini non invasive nella pianificazione chirurgica.

L’epilessia del lobo temporale (ELT) può essere associata a diverse eziologie come sclerosi dell’ippocampo, displasie corticali focali, tumori di basso grado e altre lesioni focali, o può essere definita “a causa sconosciuta” quando non vengono identificate alterazioni corticali attraverso la risonanza magnetica (RM). E’ ormai accertato il beneficio dell’intervento chirurgico in pazienti con ELT farmaco-resistente, anche se gli studi indicano che nel 50% dei casi non viene raggiunta la libertà da crisi epilettiche dopo l’intervento (De Tisi et al., 2011). La qualità di vita di questi pazienti è inoltre influenzata, oltre che dal risultato chirurgico, anche dalle comorbidità cognitive e psichiatriche. E’ stato effettuato uno studio prospettico multicentrico su pazienti con epilessia del lobo temporale candidati alla chirurgia resettiva. Sono stati raccolti i dati anamnestici clinici, elettroencefalografici ottenuti da monitoraggi video-EEG, i dati sulle comorbidità cognitive e psichiatriche e sulle terapie farmacologiche. I dati di neuroimmagini derivano dalle acquisizioni con una risonanza magnetica cerebrale ad alto campo (3 Tesla). L’EEG è stato acquisito contemporaneamente alla RM per effettuare la co-registrazione con la RM funzionale (EEG-fMRI). Sono stati effettuati i seguenti studi: 1) descrizione dell’attuale stato dell’arte dei pazienti con epilessia del lobo temporale candidati alla chirurgia, basata sui database di 4 diversi Centri Epilessia del Nord-Centro Italia, e confronto con database del passato. 2) Verifica del contributo alla pianificazione chirurgica di tecniche di neuroimmagine non invasive come la co-registrazione EEG-fMRI, attraverso l’identificazione di cambiamenti del segnale fMRI in concomitanza con anomalie epilettiche critiche o intercrritiche (utilizzo del software Brainvision per l’analisi del segnale EEG e di MATLAB/spm 12 per l’analisi di RM funzionale): a) identificazione della zona epilettogena attraverso le mappe funzionali utilizzando l’outcome chirurgico come gold standard, b) confronto con i risultati di analisi EEG-fMRI descritti in letteratura. 3) analisi delle alterazioni della connettività funzionale (resting states) attraverso una “seed-based analysis” utilizzando come regioni di interesse l’ippocampo e il claustro. 4) analisi di morfometria volumentrica focalizzata sulla struttura interna dell’ippocampo, con l’obiettivo di identificare eventuali correlazioni tra modifiche volumetriche delle strutture dell’ippocampo e le diverse eziologie. I dati di risonanza magnetica funzionale e di volumetria sono stati correlati con diversi item, come l’eziologia, la lateralizzazione emisferica e le terapie farmacologiche. Il punto di forza del progetto è dato dalla numerosità del campione (più di 120 pazienti arruolati) e dalla disomogeneità dei pazienti arruolati in 4 diversi centri: le alterazioni riscontrate nei pazienti rispetto al gruppo dei controlli rappresentano il “core network” dell’epilessia del lobo temporale e possono portare ad una miglior comprensione di come le scariche epilettiche interferiscano con il cervello fisiologico. In futuro un ulteriore ampliamento del campione porterebbe ad un maggior potere statistico dei risultati; inoltre sarebbe interessante confrontare i risultati ottenuti dall’analisi EEG-fMRI con i dati funzionali di registrazioni intracraniche con elettrodi intracerebrali.Temporal lobe epilepsy (TLE) can be associated to different etiologies such as hippocampal sclerosis, focal cortical dysplasia, low grade tumors and other focal lesions, or it can be defined of “unknown cause” when no cortical alterations are detectable on MRI. The benefit of surgical treatment in patients with drug resistant TLE is well established, although in almost 50% of the cases long-term seizure freedom is not achieved after surgery (De Tisi et al., 2011). The quality of life in these patients is influenced, apart from surgery outcome, also by cognitive and psychiatric co-morbidities. A prospective multi-centric study was conducted in patients with drug-resistant TLE eligible for surgery. Patients’ history on clinical, electroencephalographic data obtained by video-EEG monitoring, cognitive and psychiatric comorbidities, and drug therapies, were collected. Neuroimaging data were obtained for each patient through 3T brain MRI; EEG was recorder simultaneously for EEG and functional MRI (EEG-fMRI) co-registration. Multiple sub-studies were performed: 1) to describe the actual state of the art of patients with TLE eligible for surgery based on the databases obtained by four Epilepsy Centers located in the North- Centre of Italy, and comparison with old databases. 2) to verify the contribution of non invasive techniques such as EEG-fMRI in the surgical planning, through the identification of BOLD changes related to interictal or ictal epileptiform activity (Brainvision software used for EEG post processing and epileptic spikes detection; MATLAB-spm12 used for fMRI analysis): a) identification of the epileptogenic zone through fMRI maps using surgery outcome as gold standard; b) comparison with results available in literature. 3) Investigation of resting- states functional connectivity (MATLAB-spm12) in patients with TLE with seed-based analysis (hippocampus and claustrum used as region of interest). 4) Investigation of the relationship between hippocampus’s structures volume and different etiologies of TLE through MRI morphometry (Freesurfer software). Functional and volumetric neuroimaging data were correlated with different items such as etiology, lateralization of TLE, and drug therapies. The strength of the project is based on the large cross-sectional cohort (more than 120 patients enrolled) and on the heterogeneity of patients studied in 4 different centers. The alterations in the brain networks observed in the patients compared to the control group represent the core network of temporal lobe epilepsy and may lead to a better comprehension of how the epileptic discharges interfere with the physiological brain. Future studies with larger samples of patients would add statistical power to the results; a comparison of the results of EEG-fMRI with functional data obtained by intracerebral electrodes would also add significance to our findings

Long-term surgery outcome for epilepsy and psychogenic nonepileptic seizures in a child with anterior cingulate gyrus dysplasia

We present the case of a 13-year-old child with nocturnal frontal lobe epilepsy (NFLE) related to a right cingulate gyrus cortical dysplasia, who also presented with psychogenic nonepileptic seizures (PNES) and interictal antisocial behavior. The association of drug-resistant epilepsy with behavioral disorders is well established, but the role of epilepsy surgery in these patients is still controversial, especially in children. The key finding is represented by the excellent long-term outcome on both epilepsy and behavioral dysfunction after the surgical excision of the cingulate gyrus cortical dysplasia

Trafficking to the Plasma Membrane of the Seven-Transmembrane Protein Encoded by Human Herpesvirus 6 U51 Gene Involves a Cell-Specific Function Present in T Lymphocytes

The sequence of human herpesvirus 6 (HHV-6) U51 open reading frame predicts a protein of 301 amino acid residues with seven transmembrane domains. To identify and characterize U51, we derived antipeptide polyclonal antibodies and developed a transient expression assay. We ascertained that U51 was synthesized in cord blood mononuclear cells infected with either variant A- or variant B-HHV-6 and was transported to the surface of productively infected cells. When synthesized in transient expression systems, U51 intracellular trafficking was regulated in a cell-type-dependent fashion. In human monolayer HEK-293 and 143tk− cells, U51 accumulated predominantly in the endoplasmic reticulum and failed to be transported to the cell surface. In contrast, in T-lymphocytic cell lines J-Jhan, Molt-3, and Jurkat, U51 was successfully transported to the plasma membrane. We infer that transport of U51 to the cell surface requires a cell-specific function present in activated T lymphocytes and T-cell lines

Development of Subjective Recollection: Understanding of and Introspection on Memory States

The development of subjective recollection was investigated in participants aged 6\u201318 years. In Experiment 1 (N = 90), age-related improvements were found in understanding of the subjective experience of recollection, although robust levels of understanding were observed even in the youngest group. In Experiment 2 (N = 100), age-related differences were found in subjective recollection during a memory task, suggesting development not only in the ability to reflect on memory states, but also in the informational basis of subjec- tive recollection. Lower understanding of memory states was associated with increased propensity to claim recollection. These results indicate that subjective recollection develops considerably during childhood and suggest that the development of metamemory supports this capacity

The Ectodomain of a Novel Member of the Immunoglobulin Subfamily Related to the Poliovirus Receptor Has the Attributes of a Bona Fide Receptor for Herpes Simplex Virus Types 1 and 2 in Human Cells

We report on the functional cloning of a hitherto unknown member of the immunoglobulin (Ig) superfamily selected for its ability to confer susceptibility to herpes simplex virus (HSV) infection on a highly resistant cell line (J1.1-2 cells), derived by exposure of BHKtk− cells to a recombinant HSV-1 expressing tumor necrosis factor alpha (TNF-α). The sequence of herpesvirus Ig-like receptor (HIgR) predicts a transmembrane protein with an ectodomain consisting of three cysteine-bracketed domains, one V-like and two C-like. HIgR shares its ectodomain with and appears to be an alternative splice variant of the previously described protein PRR-1 (poliovirus receptor-related protein). Both HIgR and PRR-1 conferred on J1.1-2 cells susceptibility to HSV-1, HSV-2, and bovine herpesvirus 1. The viral ligand of HIgR and PRR-1 is glycoprotein D, a constituent of the virion envelope long known to mediate viral entry into cells through interaction with cellular receptor molecules. Recently, PRR-1, renamed HveC (herpesvirus entry mediator C), and the related PRR-2, renamed HveB, were reported to mediate the entry of HSV-1, HSV-2, and bovine herpesvirus 1, and the homologous poliovirus receptor was reported to mediate the entry of pseudorabies virus (R. J. Geraghty, C. Krummenacher, G. H. Cohen, R. J. Eisenberg, and P. G. Spear, Science 280:1618–1620, 1998; M. S. Warner, R. J. Geraghty, W. M. Martinez, R. I. Montgomery, J. C. Whitbeck, R. Xu, R. J. Eisenberg, G. H. Cohen, and P. G. Spear, Virology 246:179–189, 1998). Here we further show that HIgR or PRR-1 proteins detected by using a monoclonal antibody to PRR-1 are widely distributed among human cell lines susceptible to HSV infection and commonly used for HSV studies. The monoclonal antibody neutralized virion infectivity in cells transfected with HIgR or PRR-1 cDNA, as well as in the human cell lines, indicating a direct interaction of virions with the receptor molecule, and preliminarily mapping this function to the ectodomain of HIgR and PRR-1. Northern blot analysis showed that HIgR or PRR-1 mRNAs were expressed in human tissues, with the highest expression being detected in nervous system samples. HIgR adds a novel member to the cluster of Ig superfamily members able to mediate the entry of alphaherpesviruses into cells. The wide distribution of HIgR or PRR-1 proteins among human cell lines susceptible to HSV infection, coupled with the neutralizing activity of the antibody in the same cells, provides direct demonstration of the actual use of this cluster of molecules as HSV-1 and HSV-2 entry receptors in human cell lines. The high level of expression in samples from nervous system makes the use of these proteins in human tissues very likely. This cluster of molecules may therefore be considered to constitute bona fide receptors for HSV-1 and HSV-2