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Freeman, W., Vitiello, G.
Matter and mind are entangled in two streams of images guiding behavior and informing the subject through awareness
(2016) Mind and Matter, 14 (1), pp. 7-24. 
https://www.scopus.com/inward/record.uri?eid=2-s2.0-84979759202&partnerID=40&md5=fb610f45aa130c866ff0629c03fdaf86

AFFILIATIONS: Department of Molecular and Cell Biology, University of California, Berkeley, United States; 
Department of Physics ‘E.R. Caianiello’, University of Salerno, Fisciano, Salerno, Italy; 
National Institute of Nuclear Physics, Italy
ABSTRACT: Brains acquire knowledge by acting into the environment to confirm or reject hypotheses imagined from memory in the actionperception cycle. Memories are created and updated through phase transitions from a gas-like ground state to a liquid-like condensate that we model as a dissipative quantum field. Each retrieved memory is imposed in the amplitude modulation (AM) of a narrow band carrier frequency of a macroscopic wave packet in the beta-gamma range of brain waves. Brains imagine hypotheses about the world by copying AM patterns and mirroring them in time. We postulate that the AM patterns in forward thermodynamic time implements action (matter), while the time-reversed copy (mirrored time) governs perception (mind, awareness). They are entangled dynamical modes that we distinguish by patterns of phase modulation that accompany the AM patterns in the electrocorticogram. © 2016 Imprint Academic.
DOCUMENT TYPE: Article

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Grumetto, L., Russo, G., Barbato, F.
Immobilized Artificial Membrane HPLC Derived Parameters vs PAMPA-BBB Data in Estimating in Situ Measured Blood-Brain Barrier Permeation of Drugs
(2016) Molecular Pharmaceutics, 13 (8), pp. 2808-2816. 
https://www.scopus.com/inward/record.uri?eid=2-s2.0-84980037570&partnerID=40&md5=328a6061785337d981265ff91bda45fc

DOI: 10.1021/acs.molpharmaceut.6b00397
AFFILIATIONS: Dipartimento di Farmacia, Università degli Studi di Napoli Federico II, Via D. Montesano, 49, Naples, Italy
ABSTRACT: The affinity indexes for phospholipids (log kW IAM) for 42 compounds were measured by high performance liquid chromatography (HPLC) on two different phospholipid-based stationary phases (immobilized artificial membrane, IAM), i.e., IAM.PC.MG and IAM.PC.DD2. The polar/electrostatic interaction forces between analytes and membrane phospholipids (Δlog kW IAM) were calculated as the differences between the experimental values of log kW IAM and those expected for isolipophilic neutral compounds having polar surface area (PSA) = 0. The values of passage through a porcine brain lipid extract (PBLE) artificial membrane for 36 out of the 42 compounds considered, measured by the so-called PAMPA-BBB technique, were taken from the literature (P0 PAMPA-BBB). The values of blood-brain barrier (BBB) passage measured in situ, P0 in situ, for 38 out of the 42 compounds considered, taken from the literature, represented the permeability of the neutral forms on "efflux minimized" rodent models. The present work was aimed at verifying the soundness of Δlog kW IAM at describing the potential of passage through the BBB as compared to data achieved by the PAMPA-BBB technique. In a first instance, the values of log P0 PAMPA-BBB (32 data points) were found significantly related to the n-octanol lipophilicity values of the neutral forms (log PN) (r2 = 0.782) whereas no significant relationship (r2 = 0.246) was found with lipophilicity values of the mixtures of ionized and neutral forms existing at the experimental pH 7.4 (log D7.4) as well as with either log kW IAM or Δlog kW IAM values. log P0 PAMPA-BBB related moderately to log P0 in situ values (r2 = 0.604). The latter did not relate with either n-octanol lipophilicity indexes (log PN and log D7.4) or phospholipid affinity indexes (log kW IAM). In contrast, significant inverse linear relationships were observed between log P0 in situ (38 data points) and Δlog kW IAM values for all the compounds but ibuprofen and chlorpromazine, which behaved as moderate outliers (r2 = 0.656 and r2 = 0.757 for values achieved on IAM.PC.MG and IAM.PC.DD2, respectively). Since log P0 in situ refer to the "intrinsic permeability" of the analytes regardless their ionization degree, no correction for ionization of Δlog kW IAM values was needed. Furthermore, log P0 in situ were found roughly linearly related to log BB values (i.e., the logarithm of the ratio brain concentration/blood concentration measured in vivo) for all the analytes but those predominantly present at the experimental pH 7.4 as anions. These results suggest that, at least for the data set considered, Δlog kW IAM parameters are more effective than log P0 PAMPA-BBB at predicting log P0 in situ values for all the analytes. Furthermore, ionization appears to affect differently, and much more markedly, BBB passage of acids (yielding anions) than that of the other ionizable compounds. © 2016 American Chemical Society.
CORRESPONDENCE ADDRESS: Barbato, F.; Dipartimento di Farmacia, Università degli Studi di Napoli Federico II, Via D. Montesano, 49, Italy; email: fbarbato@unina.it

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Curcio, M., Salazar, I.L., Mele, M., Canzoniero, L.M.T., Duarte, C.B.
Calpains and neuronal damage in the ischemic brain: The swiss knife in synaptic injury
(2016) Progress in Neurobiology, 143, pp. 1-35. 
https://www.scopus.com/inward/record.uri?eid=2-s2.0-84979684030&partnerID=40&md5=19a8615887ad35ddb4085a6682819135

DOI: 10.1016/j.pneurobio.2016.06.001
AFFILIATIONS: CNC – Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal; 
Doctoral Programme in Experimental Biology and Biomedicine, Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504, Coimbra, Portugal, Institute for Interdisciplinary Research, University of Coimbra (IIIUC), Coimbra, Portugal; 
Department of Science and Technology, University of Sannio, Benevento, Italy; 
Department of Life Sciences, University of Coimbra, Coimbra, Portugal
ABSTRACT: The excessive extracellular accumulation of glutamate in the ischemic brain leads to an overactivation of glutamate receptors with consequent excitotoxic neuronal death. Neuronal demise is largely due to a sustained activation of NMDA receptors for glutamate, with a consequent increase in the intracellular Ca2+ concentration and activation of calcium- dependent mechanisms. Calpains are a group of Ca2+-dependent proteases that truncate specific proteins, and some of the cleavage products remain in the cell, although with a distinct function. Numerous studies have shown pre- and post-synaptic effects of calpains on glutamatergic and GABAergic synapses, targeting membrane- associated proteins as well as intracellular proteins. The resulting changes in the presynaptic proteome alter neurotransmitter release, while the cleavage of postsynaptic proteins affects directly or indirectly the activity of neurotransmitter receptors and downstream mechanisms. These alterations also disturb the balance between excitatory and inhibitory neurotransmission in the brain, with an impact in neuronal demise. In this review we discuss the evidence pointing to a role for calpains in the dysregulation of excitatory and inhibitory synapses in brain ischemia, at the pre- and post-synaptic levels, as well as the functional consequences. Although targeting calpain-dependent mechanisms may constitute a good therapeutic approach for stroke, specific strategies should be developed to avoid non-specific effects given the important regulatory role played by these proteases under normal physiological conditions. © 2016 Elsevier Ltd
CORRESPONDENCE ADDRESS: Duarte, C.B.; Center for Neuroscience and Cell Biology, University of CoimbraPortugal; email: cbduarte@ci.uc.pt

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Barbosa, J.S., Di Giaimo, R., Götz, M., Ninkovic, J.
Single-cell in vivo imaging of adult neural stem cells in the zebrafish telencephalon
(2016) Nature Protocols, 11 (8), pp. 1360-1370. 
https://www.scopus.com/inward/record.uri?eid=2-s2.0-84979955029&partnerID=40&md5=dc36b57cc622515087ad96a41260fc22
DOI: 10.1038/nprot.2016.077
AFFILIATIONS: Institute of Stem Cell Research, Helmholtz Center Munich, Neuherberg/Munich, Germany; 
Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal; 
Department of Biology, University of Naples Federico II, Naples, Italy; 
Biomedical Center, University of Munich, Munich, Germany; 
Excellence Cluster of Systems Neurology SYNERGY, Ludwig Maximilian University of Munich, Munich, Germany
ABSTRACT: Adult neural stem cells (aNSCs) in zebrafish produce mature neurons throughout their entire life span in both the intact and regenerating brain. An understanding of the behavior of aNSCs in their intact niche and during regeneration in vivo should facilitate the identification of the molecular mechanisms controlling regeneration-specific cellular events. A greater understanding of the process in regeneration-competent species may enable regeneration to be achieved in regeneration-incompetent species, including humans. Here we describe a protocol for labeling and repetitive imaging of aNSCs in vivo. We label single aNSCs, allowing nonambiguous re-identification of single cells in repetitive imaging sessions using electroporation of a red-reporter plasmid in Tg(gfap:GFP)mi2001 transgenic fish expressing GFP in aNSCs. We image using two-photon microscopy through the thinned skull of anesthetized and immobilized fish. Our protocol allows imaging every 2 d for a period of up to 1 month. This methodology allowed the visualization of aNSC behavior in vivo in their natural niche, in contrast to previously available technologies, which rely on the imaging of either dissociated cells or tissue slices. We used this protocol to follow the mode of aNSC division, fate changes and cell death in both the intact and injured zebrafish telencephalon. This experimental setup can be widely used, with minimal prior experience, to assess key factors for processes that modulate aNSC behavior. A typical experiment with data analysis takes up to 1.5 months. © 2016 Nature America, Inc.
CORRESPONDENCE ADDRESS: Ninkovic, J.; Institute of Stem Cell Research, Helmholtz Center MunichGermany; email: ninkovic@helmholtz-muenchen.de

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Bisogno, T., Oddi, S., Piccoli, A., Fazio, D., Maccarrone, M.
Type-2 cannabinoid receptors in neurodegeneration
(2016) Pharmacological Research, 111, pp. 721-730. 
https://www.scopus.com/inward/record.uri?eid=2-s2.0-84979937169&partnerID=40&md5=dfc5717e41ba31feb9afe4df57b4006f
DOI: 10.1016/j.phrs.2016.07.021
AFFILIATIONS: Endocannabinoid Research Group, Institute of Biomolecular Chemistry, National Research Council, Pozzuoli, Italy; 
Department of Medicine, Campus Bio-Medico University of Rome, Via Alvaro del Portillo 21, Rome, Italy; 
Faculty of Veterinary Medicine, University of Teramo, Via Balzarini 1, Teramo, Italy; 
European Center for Brain Research/IRCCS Santa Lucia Foundation, Via del Fosso di Fiorano 64, Rome, Italy
ABSTRACT: Based on its wide expression in immune cells, type-2 cannabinoid (CB2) receptors were traditionally thought to act as “peripheral receptors” with an almost exclusively immunomodulatory function. However, their recent identification in mammalian brain areas, as well as in distinct neuronal cells, has opened the way to a re-consideration of CB2 signaling in the context of brain pathophysiology, synaptic plasticity and neuroprotection. To date, accumulated evidence from several independent preclinical studies has offered new perspectives on the possible involvement of CB2 signaling in brain and spinal cord traumatic injury, as well as in the most relevant neurodegenerative disorders like Alzheimer's disease, Parkinson's disease and Huntington's chorea. Here, we will review available information on CB2 in these disease conditions, along with data that support also its therapeutic potential to treat them. © 2016 Elsevier Ltd
CORRESPONDENCE ADDRESS: Maccarrone, M.; Department of Medicine, Campus Bio-Medico University of Rome, Via Alvaro del Portillo 21, Italy; email: m.maccarrone@unicampus.it

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Fraldi, A., Klein, A.D., Medina, D.L., Settembre, C.
Brain Disorders Due to Lysosomal Dysfunction
(2016) Annual Review of Neuroscience, 39, pp. 277-295. 
https://www.scopus.com/inward/record.uri?eid=2-s2.0-84979620089&partnerID=40&md5=31b0b4e2a9538270f88c9eb948228824
DOI: 10.1146/annurev-neuro-070815-014031
AFFILIATIONS: Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Italy; 
Dulbecco Telethon Institute, Pozzuoli, Italy; 
Medical Genetics Unit, Department of Medical and Translational Science, Federico II University, Naples, Italy
ABSTRACT: Recent studies of autophagic and lysosomal pathways have significantly changed our understanding of lysosomes; once thought to be simple degradative and recycling centers, lysosomes are now known to be organelles capable of influencing signal transduction, via the mammalian target of rapamycin complex 1 (mTORC1), and regulating gene expression, via transcription factor EB (TFEB) and other transcription factors. These pathways are particularly relevant to maintaining brain homeostasis, as dysfunction of the endolysosomal and autophagic pathways has been associated with common neurodegenerative diseases, such as Alzheimer's, Parkinson's, and Huntington's, and lysosomal storage disorders, a group of inherited disorders characterized by the intralysosomal buildup of partially degraded metabolites. This review focuses on the cellular biology of lysosomes and discusses the possible mechanisms by which disruption of their function contributes to neurodegeneration. We also review and discuss how targeting TFEB and lysosomes may offer innovative therapeutic approaches for treating a wide range of neurological conditions. Copyright ©2016 by Annual Reviews.

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Perruolo, G., Viggiano, D., Fiory, F., Cassese, A., Nigro, C., Liotti, A., Miele, C., Beguinot, F., Formisano, P.
Parkinson-like phenotype in insulin-resistant PED/PEA-15 transgenic mice
(2016) Scientific Reports, 6, art. no. 29967, . 
https://www.scopus.com/inward/record.uri?eid=2-s2.0-84979255279&partnerID=40&md5=359954aae715e26e786f82d060364862

DOI: 10.1038/srep29967
AFFILIATIONS: URT- Genomica del Diabete, Istituto di Endocrinologia ed Oncologia Sperimentale (IEOS-CNR), Naples, Italy; 
Dipartimento di Scienze Mediche Traslazionali, Università degli Studi di Napoli Federico II, Naples, Italy; 
Dept Medicine and Health Sciences, Univ. Molise, Italy
ABSTRACT: Neurological abnormalities, such as Parkinson-like disorders (PlD), are often co-morbidities of Type 2 Diabetic (T2D) patients, although the epidemiological link between these two disorders remains controversial. The PED/PEA-15 protein represents a possible candidate linking T2D and PD, because it is increased in subjects with T2D and is highly expressed in the brain. To test this hypothesis, we have analyzed the neurological and neurochemical phenotype of transgenic mice overexpressing PED/PEA-15 (tgPED). These mice develop impaired glucose tolerance and insulin resistance, accompanied by neurological features resembling PlD: feet clasping, slow and delayed locomotor movements in different behavioral tests in absence of clear cognitive deficits, ataxia or anxiety. Morphological analysis of the brains showed selective modifications of metabolic activity in the striatal region. In the same region, we have observed 26% decrease of dopamine fibers, confirmed by immunohistochemistry and Western Blot for tyrosine hydroxylase. Moreover, they also showed 48% reduction of dopamine levels in the striatum. Thus the tgPED mice may represent a genetic animal model of neurological disease linked to T2D.
CORRESPONDENCE ADDRESS: Formisano, P.; URT- Genomica del Diabete, Istituto di Endocrinologia ed Oncologia Sperimentale (IEOS-CNR)Italy; email: fpietro@unina.it

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Lanzillo, R., Quarantelli, M., Pozzilli, C., Trojano, M., Amato, M.P., Marrosu, M.G., Francia, A., Florio, C., Orefice, G., Tedeschi, G., Bellantonio, P., Annunziata, P., Grimaldi, L.M., Comerci, M., Brunetti, A., Bonavita, V., Alfano, B., Marini, S., Brescia Morra, V.
No evidence for an effect on brain atrophy rate of atorvastatin add-on to interferon β1b therapy in relapsing-remitting multiple sclerosis (the ARIANNA study)
(2016) Multiple Sclerosis, 22 (9), pp. 1163-1173. 
https://www.scopus.com/inward/record.uri?eid=2-s2.0-84979581719&partnerID=40&md5=1efece7e8bacbab087d89b4901da92df
DOI: 10.1177/1352458515611222
AFFILIATIONS: Department of Neurosciences, Reproductive and Odontostomatological Sciences, Federico II University of Naples, Via Pansini 5, Italy; 
National Research Council (CNR), Biostructure and Bioimaging Institute (IBB), Naples Multiple Sclerosis Centre, Italy; 
Department of Neurology and Psychiatry, Sapienza University, Italy; 
Department of Neurosciences and Organs of Senses, University of Bari, Italy; 
Department of NEUROFARBA, University of Florence, Italy; 
Department of Public Health, Clinical and Molecular Medicine, University of Cagliari, Italy; 
Multiple Sclerosis Regional Center, Azienda Ospedaliera Antonio Cardarelli, Italy; 
Department of Medical, Surgical, Neurological, Metabolic and Aging Sciences, Second University of Naples, Italy; 
IRCCS Neuromed-Pozzilli (IS), Italy; 
Department of Neurological, Neurosurgical and Behavioural Sciences, University of Siena, Italy; 
Neurology Unit, Fondazione Istituto San Raffaele G. Giglio, Italy; 
Department of Biomedical Advanced Sciences, Federico II University, Italy; 
IDC Hermitage Capodimonte, Italy; 
Dimensione Ricerca S.r.l., Italy
ABSTRACT: Background: A previous phase 2 trial has suggested that statins might delay brain atrophy in secondary progressive multiple sclerosis. Objectives: The objective of this study was to evaluate the effect of atorvastatin add-on therapy on cerebral atrophy in relapsing-remitting multiple sclerosis. Methods: This randomised, placebo-controlled study compared atorvastatin 40 mg or placebo add-on therapy to interferon β1b for 24 months. Brain magnetic resonance imaging, multiple sclerosis functional composite score, Rao neuropsychological battery and expanded disability status scale were evaluated over 24 months. Results: A total of 154 patients were randomly assigned, 75 in the atorvastatin and 79 in the placebo arms, with a comparable drop-out rate (overall 23.4%). Brain atrophy over 2 years was not different in the two arms (-0.38% and -0.32% for the atorvastatin and placebo groups, respectively). Relapse rate, expanded disability status scale, multiple sclerosis functional composite score or cognitive changes were not different in the two arms. Patients withdrawing from the study had a higher number of relapses in the previous 2 years (P=0.04) and a greater probability of relapsing within 12 months. Conclusions: Our results suggest that the combination of atorvastatin and interferon β1b is not justified in early relapsing-remitting multiple sclerosis and adds to the body of evidence indicating an absence of significant radiological and clinical benefit of statins in relapsing-remitting multiple sclerosis. © SAGE Publications.
CORRESPONDENCE ADDRESS: Lanzillo, R.; Department of Neurosciences, Reproductive and Odontostomatological Sciences, Federico II University of Naples, Via Pansini 5, Italy; email: robertalanzillo@libero.it

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Esposito, C.L., Nuzzo, S., Kumar, S.A., Rienzo, A., Lawrence, C.L., Pallini, R., Shaw, L., Alder, J.E., Ricci-Vitiani, L., Catuogno, S., de Franciscis, V.
A combined microRNA-based targeted therapeutic approach to eradicate glioblastoma stem-like cells
(2016) Journal of Controlled Release, 238, pp. 43-57. 
https://www.scopus.com/inward/record.uri?eid=2-s2.0-84979645423&partnerID=40&md5=e6e2a50bdbe5bc664a5fcc89b202676b
DOI: 10.1016/j.jconrel.2016.07.032
AFFILIATIONS: Istituto di Endocrinologia ed Oncologia Sperimentale “G. Salvatore”, CNR, Naples, Italy; 
School of Pharmacy & Biomedical Sciences, University of Central Lancashire, Preston, United Kingdom; 
Institute of Neurosurgery, Università Cattolica del Sacro Cuore, Rome, Italy; 
Istituto Superiore di Sanità, Department of Hematology, Oncology and Molecular Medicine, Rome, Italy
ABSTRACT: A minor population of glioblastoma stem-like cells (GSCs) has been implicated in the relapse and resistance of glioblastoma to therapeutic treatments. Based on knowledge of the involvement of multiple microRNAs in GSC propagation, we designed a combinational approach to target the GSC population with multiple miRNA-based therapeutics. As carriers for the targeted delivery we took advantage of two aptamers that bind to, and inhibit, the receptor tyrosine kinases, Axl and PDGFRβ. We showed that the aptamer conjugates are transported through an in vitro blood-brain barrier (BBB) model. Furthermore, combining miR-137 and antimiR-10b synergizes with the receptor inhibitory function of aptamer carriers and prevents GSC expansion. Results highlighted the potential of combining multifunctional RNA-based therapeutics for selective targeting of GSCs and offer a proof of principle strategy to potentially fulfill the still unmet need for effective and safe treatment of glioma. © 2016
CORRESPONDENCE ADDRESS: de Franciscis, V.; IEOS-CNR, Via T. de Amicis 95, Italy; email: defranci@unina.it

L' NBG ha il patrocinio morale dell'Università di Napoli "Federico II"

In data 2 Agosto 2016 (Rettorato Tit I-14) al Neapolitan Brain Group è stato concesso dal Rettore Manfredi il patrocinio morale dell'Università degli studi di Napoli "Federico II".

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Figure 4. Triphenyl tetrazolium chloride, (TTC) staining of coronal brain slices from a rat submitted to BCCAO and RE (A). TTC staining of coronal brain slices from a rat treated with higher dose malvidin (18 mg/kg b.w.) (B). The lesion in the striatum is outlined by the dashed black line.

Lapi, D.a , Chiurazzi, M.a , Di Maro, M.a , Mastantuono, T.a , Battiloro, L.a , Sabatino, L.b , Ricci, S.c , Di Carlo, A.d , Starita, N.a , Guida, B.a , Santillo, M.a , Colantuoni, A.a 
Malvidin’s effects on rat pial microvascular permeability changes due to hypoperfusion and reperfusion injury
(2016) Frontiers in Cellular Neuroscience, 10 (Jun), art. no. 153, . 
https://www.scopus.com/inward/record.uri?eid=2-s2.0-84977559483&partnerID=40&md5=f9ac5aa6fd6345eac74d296e07d87f54
DOI: 10.3389/fncel.2016.00153
AFFILIATIONS: aDepartment of Clinical Medicine and Surgery, School of Medicine, University of Naples Federico II, Naples, Italy; 
bDepartment of Science and Technology, University of Sannio, Benevento, Italy; 
cDepartment of Translational Medicine, University of Naples Federico II, Naples, Italy; 
dDepartment of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Rome, Italy
ABSTRACT: The present study was aimed to evaluate the malvidin’s protective effects on damage induced by 30 min bilateral common carotid artery occlusion (BCCAO) and 60 min reperfusion (RE) in rat pial microcirculation. Rat pial microcirculation was observed using fluorescence microscopy through a closed cranial window. Western blotting analysis was performed to investigate the endothelial nitric oxide synthase (eNOS), phosphorylated eNOS (p-eNOS) and matrix metalloproteinase 9 (MMP-9) expression. Moreover, MMP-9 activity was evaluated by zymography. Finally, neuronal damage and radical oxygen species (ROS) formation were assessed. In all animals, pial arterioles were classified in five orders of branching according to Strahler’s method. In hypoperfused rats, 30 min BCCAO and 60 min RE caused a decrease in arteriolar diameter, an increase in microvascular leakage and leukocyte adhesion, accompanied by decreased capillary perfusion and red blood cell velocity (VRBC). Moreover, marked neuronal damage and evident ROS generation were detected. Conversely, malvidin administration induced arteriolar dilation in dose-related manner, reducing microvascular leakage as well as leukocyte adhesion. Capillary perfusion and VRBC were protected. Nitric oxide (NO) synthase inhibition significantly attenuated malvidin’s effects on arteriolar diameter. Western blotting analysis revealed an increase in eNOS and p-eNOS expression, while zymography indicated a decrease in MMP-9 activity after malvidin’s administration. Furthermore, malvidin was able to prevent neuronal damage and to decrease ROS generation. In conclusion, malvidin protects rat pial microcirculation against BCCAO/RE injury, preventing blood-brain impairment and neuronal loss. Malvidin’s effects appear to be mediated by eNOS activation and scavenger activity. © 2016 Lapi, Chiurazzi, Di Maro, Mastantuono, Battiloro, Sabatino, Ricci, Di Carlo, Starita, Guida, Santillo and Colantuoni.
AUTHOR KEYWORDS: Bilateral common carotid artery occlusion;  Endothelial nitric oxide synthase;  Malvidin;  Metalloproteinases;  Pial microcirculation;  Radical oxygen species;  Reperfusion;  Zymography

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Pagliano, P.a , Ascione, T.a , Boccia, G.b , De Caro, F.b , Esposito, S.c 
Listeria monocytogenes meningitis in the elderly: Epidemiological, clinical and therapeutic findings
(2016) Infezioni in Medicina, 24 (2), pp. 105-111. 
https://www.scopus.com/inward/record.uri?eid=2-s2.0-84977545426&partnerID=40&md5=8ecf65975e6a899966891cf2f5b3ecb4

AFFILIATIONS: aAORN dei Colli, D. Cotugno Hospital, Department of Infectious Diseases, Naples, Italy; 
bInstitute of Hygiene, University of Salerno, Italy; 
cDepartment of Infectious Diseases, University of Salerno, Italy
ABSTRACT: Listeria monocytogenes is a Gram-positive bacillus and facultative intracellular bacterium whose transmission occurs mainly through the consumption of contaminated food, L. monocytogenes invades the host cells using various protein and can escape to the human T-cell immune system by cell-to-cell spreading. If the infection is not controlled at the stage in which the bacterium is in the liver, for instance, due to a severe immunodepression, a secondary bacteraemia can be developed and L. monocytogenes reaches the preferred sites transgressing the blood-brain barrier or the placental barrier. Individuals with T-cell dysfunction, such as pregnant women, the elderly, and those receiving immunosuppressive therapy are at the highest risk of contracting the disease. Average life expectancy throughout developed countries has rapidly increased during the latter half of the 20th century and geriatric infectious diseases have become an increasingly important issue. L. monocytogenes meningitis in young previously healthy adults has been reported only in anecdotal observations. Differently, L. monocytogenes is the third most common cause of bacterial meningitis in the elderly population, after Streptococcus pneumoniae and Neisseria meningitidis. Patients with L. monocytogenes meningitis presented with signs and symptoms that were similar to thoseof the general population with community-acquired bacterial meningitis, but reported a longer prodromal phase. According to literature data, the prevalence of the classic triad of fever, neck stiffness, and altered mental status is 43%, and almost all patients present with at least 2 of the 4 classic symptoms of headache, fever, neck stiffness, and altered mental status. On the basis of our published data, in patients aged over 50 years, diagnosing L. monocytogenes meningitis was more challenging than pneumococcal meningitis, as demonstrated by the lower percentage of cases receiving a correct diagnosis within 48 hours from the onset of symptoms. No significant difference was observed in respect to the presenting symptoms, but progression to respiratory failure was not as rapid as pneumococcal meningitis. Findings of cerebrospinal-fluid (CSF) analysis demonstrated higher glucose concentration and a less evident neutrophil prevalence in patients with L. monocytogenes meningitis. Meningitis sustained by L. monocytogenes is reported with a higher frequency in elderly, clinical findings cannot support a presumptive diagnosis, but findings of CSF analysis have to be considered. © 2016, EDIMES Edizioni Medico Scientifiche. All rights reserved.
AUTHOR KEYWORDS: Diagnosis;  Elderly;  Listeria monocytogenes;  Meningitis;  Streptococcus pneumoniae

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Hay Mele, B.a , Citro, V.b , Andreotti, G.c , Cubellis, M.V.b 
Drug repositioning can accelerate discovery of pharmacological chaperones
(2015) Orphanet Journal of Rare Diseases, 10 (1), art. no. 10, . 
https://www.scopus.com/inward/record.uri?eid=2-s2.0-84976402620&partnerID=40&md5=3516171793496d8f0d57eb789fc7165f

DOI: 10.1186/s13023-015-0273-2
AFFILIATIONS: aDepartment of Agricultural and Food Sciences, University Federico II, Naples, Italy; 
bDepartment of Biology, University Federico II, Naples, Italy; 
Istituto di Chimica Biomolecolare -CNR, Pozzuoli, Italy
ABSTRACT: A promising strategy for the treatment of genetic diseases, pharmacological chaperone therapy, has been proposed recently. It exploits small molecules which can be administered orally, reach difficult tissues such as the brain and have low cost. This strategy has a vast field of application. In order to make drug development as fast as possible, it is important to exploit drug repositioning. We evaluated the impact and limitations of this approach for rare diseases and we provide a shortcut in finding drugs for off-target usage. © 2015 Hay Mele et al.; licensee BioMed Central.
AUTHOR KEYWORDS: Drug repositioning;  Pharmacological chaperone
DOCUMENT TYPE: Article

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D'andrea, A.a , Conte, M.a , Scarafile, R.a , Riegler, L.a , Cocchia, R.a , Pezzullo, E.a , Cavallaro, M.a , Carbone, A.a , Natale, F.a , Russo, M.G.a , Gregorio, G.b , Calabrò, R.a 
Transcranial Doppler ultrasound: Physical principles and principal applications in Neurocritical care unit
(2016) Journal of Cardiovascular Echography, 26 (2), pp. 28-41. 
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DOI: 10.4103/2211-4122.183746
AFFILIATIONS: aDepartment of Cardiology, Integrated Diagnostic Cardiology, Second University of Neaples, Monaldi Hospital, Via M. Schipa 44, Naples, Italy; 
bDepartment of Cardiology, San Luca Hospital, Vallo della Lucania, Salerno, Italy
ABSTRACT: Transcranial Doppler (TCD) ultrasonography is a noninvasive ultrasound study, which has been extensively applied on both outpatient and inpatient settings. It involves the use of a low-frequency (≤2 MHz) transducer, placed on the scalp, to insonate the basal cerebral arteries through relatively thin bone windows and to measure the cerebral blood flow velocity and its alteration in many different conditions. In neurointensive care setting, TCD is useful for both adults and children for day-to-day bedside assessment of critical conditions including vasospasm in subarachnoid hemorrhage, traumatic brain injury, acute ischemic stroke, and brain stem death. It also allows to investigate the cerebrovascular autoregulation in setting of carotid disease and syncope. In this review, we will describe physical principles underlying TCD, flow indices most frequently used in clinical practice and critical care applications in Neurocritical Unit care. © 2016 Journal of Cardiovascular Echography Published by Wolters Kluwer - Medknow 27.
AUTHOR KEYWORDS: Brain stem death;  cryptogenic stroke;  mean cerebral brain flow;  Neurocritical Unit Care;  paradoxical embolism;  patent foramen ovale;  subarachnoid hemorrhage;  transcranial Doppler ultrasonography;  traumatic brain injury;  vasospasm
DOCUMENT TYPE: Review

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Trojano, L.a  b , Gainotti, G.c  d 
Drawing Disorders in Alzheimer's Disease and Other Forms of Dementia
(2016) Journal of Alzheimer's Disease, 53 (1), art. no. JAD160009, pp. 31-52. 
https://www.scopus.com/inward/record.uri?eid=2-s2.0-84976439986&partnerID=40&md5=f65537681d8ac1946bf40f5826294096

DOI: 10.3233/JAD-160009
AFFILIATIONS: aDepartment of Psychology, Second University of Naples, Viale Ellittico 31, Caserta, Italy; 
bS. Maugeri Foundation, Scientific Institute of Telese Terme (BN), Italy; 
cCenter for Neuropsychological Research, Institute of Neurology, Catholic University, Rome, Italy; 
IRCCS Fondazione Santa Lucia, Department of Clinical and Behavioral Neurology, Rome, Italy
ABSTRACT: Drawing is a multicomponential process that can be impaired by many kinds of brain lesions. Drawing disorders are very common in Alzheimer's disease and other forms of dementia, and can provide clinical information for the distinction of the different dementing diseases. In our review we started from an overview of the neural and cognitive bases of drawing, and from a recollection of the drawing tasks more frequently used for assessing individuals with dementia. Then, we analyzed drawing disorders in dementia, paying special attention to those observed in Alzheimer's disease, from the prodromal stages of the amnesic mild cognitive impairment to the stages of full-blown dementia, both in the sporadic forms with late onset in the entorhino-hippocampal structures and in those with early onset in the posterior neocortical structures. We reviewed the drawing features that could differentiate Alzheimer's disease from vascular dementia and from the most frequent forms of degenerative dementia, namely frontotemporal dementia and Lewy body disease. Finally, we examined some peculiar aspects of drawing disorders in dementia, such as perseverations, rotations, and closing-in. We argue that a careful analysis of drawing errors helps to differentiate the different forms of dementia more than overall accuracy in drawing.
AUTHOR KEYWORDS: Alzheimer's disease;  constructional apraxia;  drawing disorders;  frontotemporal dementia;  Lewy body disease;  vascular dementia
DOCUMENT TYPE: Review

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Cacialli, P.a  b , Gueguen, M.-M.a , Coumailleau, P.a , D'angelo, L.b , Kah, O.a , Lucini, C.b , Pellegrini, E.a 
BDNF Expression in larval and adult zebrafish brain: Distribution and cell identification
(2016) PLoS ONE, 11 (6), art. no. e0158057, . 
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DOI: 10.1371/journal.pone.0158057
AFFILIATIONS: INSERM U1085, aEnvironment and Occupation Research Institute in Health (IRSET), University of Rennes 1, Rennes, France; 
bDepartment of Veterinary Medicine and Animal Productions, University of Naples Federico II, Napoli, Italy
ABSTRACT: Brain-derived neurotrophic factor (BDNF), a member of the neurotrophin family, has emerged as an active mediator in many essential functions in the central nervous system of mammals. BDNF plays significant roles in neurogenesis, neuronal maturation and/or synaptic plasticity and is involved in cognitive functions such as learning and memory. Despite the vast literature present in mammals, studies devoted to BDNF in the brain of other animal models are scarse. Zebrafish is a teleost fish widely known for developmental genetic studies and is emerging as model for translational neuroscience research. In addition, its brain shows many sites of adult neurogenesis allowing higher regenerative properties after traumatic injuries. To add further knowledge on neurotrophic factors in vertebrate brain models, we decided to determine the distribution of bdnf mRNAs in the larval and adult zebrafish brain and to characterize the phenotype of cells expressing bdnf mRNAs by means of double staining studies. Our results showed that bdnf mRNAs were widely expressed in the brain of 7 days old larvae and throughout the whole brain of mature female and male zebrafish. In adults, bdnf mRNAs were mainly observed in the dorsal telencephalon, preoptic area, dorsal thalamus, posterior tuberculum, hypothalamus, synencephalon, optic tectum and medulla oblongata. By combining immunohistochemistry with in situ hybridization, we showed that bdnf mRNAs were never expressed by radial glial cells or proliferating cells. By contrast, bdnf transcripts were expressed in cells with neuronal phenotype in all brain regions investigated. Our results provide the first demonstration that the brain of zebrafish expresses bdnf mRNAs in neurons and open new fields of research on the role of the BDNF factor in brain mechanisms in normal and brain repairs situations. © 2016 Cacialli et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author 

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Colombatti, R.a , Lucchetta, M.b , Montanaro, M.a , Rampazzo, P.b , Ermani, M.b , Talenti, G.b , Baracchini, C.b , Favero, A.b , Basso, G.a , Manara, R.c , Sainati, L.a 
Cognition and the default mode network in children with sickle cell disease: A resting state functional MRI study
(2016) PLoS ONE, 11 (6), art. no. e0157090, . 
https://www.scopus.com/inward/record.uri?eid=2-s2.0-84975491816&partnerID=40&md5=c2fcf8192933b3c7c71a01fda13bec81
DOI: 10.1371/journal.pone.0157090
AFFILIATIONS: aClinic of Pediatric Hematology-Oncology, Department of Child and Maternal Health, Azienda Ospedaliera-University of Padova, Padova, Italy; 
bDepartment of Neurosciences, Azienda Ospedaliera-University of Padova, Padova, Italy; 
cDepartment of Neurosciences, Neuroradiology Unit, University of Salerno, Salerno, Italy
ABSTRACT: Cerebrovascular complications are frequent events in children with sickle cell disease, yet routinely used techniques such as Transcranial Doppler (TCD), Magnetic Resonance (MRI) and Angiography (MRA), insufficiently explain the cause of poor cognitive performances. Forty children with SS-Sβ° (mean age 8 years) underwent neurocognitive evaluation and comprehensive brain imaging assessment with TCD, MRI, MRA, Resting State (RS) Functional MRI with evaluation of the Default Mode Network (DMN). Sixteen healthy age-matched controls underwent MRI, MRA and RS functional MRI.Children with SCD display increased brain connectivity in the DMN even in the absence of alterations in standard imaging techniques. Patients with low neurocognitive scores presented higher brain connectivity compared to children without cognitive impairment or controls, suggesting an initial compensatory mechanism to maintain performances. In our cohort steady state haemoglobin level was not related to increased brain connectivity, but SatO2<97% was. Our findings provide novel evidence that SCD is characterized by a selective disruption of connectivity among relevant regions of the brain, potentially leading to reduced cognition and altered functional brain dynamics. RS functional MRI could be used as a useful tool to evaluate cognition and cerebral damage in SCD in longitudinal trials. © 2016 Colombatti et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
DOCUMENT TYPE: Article

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Panichelli, P.a , Villano, C.b , Cistaro, A.c , Bruno, A.d , Barbato, F.e , Piccardo, A.f , Duatti, A.g 
Imaging of Brain Tumors with Copper-64 Chloride: Early Experience and Results
(2016) Cancer Biotherapy and Radiopharmaceuticals, 31 (5), pp. 159-167. 
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DOI: 10.1089/cbr.2016.2028
AFFILIATIONS: aAdvanced Center of Oncology, ACOM, Macerata, Italy; 
bHospital ''santo Spirito'', Pescara, Italy; 
cPositron Emission Tomography Centre, IRMET, Affidea, Turin, Italy; 
dASST ''papa Giovanni XXIII'', Bergamo, Italy; 
eCMO Center, Naples, Italy; 
fOspedali Galliera, Genoa, Italy; 
Department of Chemical and Pharmaceutical Sciences, University of Ferrara, via L. Borsari, 46, Ferrara, Italy
ABSTRACT: Objectives: To conduct the first investigational study that is aimed at evaluating the ability of the simple salt 64CuCl2 to diagnose cerebral tumors in patients affected by glioblastoma multiforme (GBM). Methods: Nineteen patients with a documented history and radiologic evidence of brain tumors were enrolled in the study. Eighteen patients were diagnosed with GBM, and one patient was diagnosed with grade II astrocytoma. After initial cerebral magnetic resonance imaging (MRI), patients were administered with 64CuCl2 (13 MBq/kg) and brain positron emission tomography (PET)/computed tomography (CT) imaging was performed at 1, 3, and 24 hours after administration. Standardized uptake values (SUVs) were calculated and used to figure out the pharmacokinetic profile of the tracer. Absorbed radiation doses were estimated using OLINDA/EXM. Results: Copper-64 chloride clearly visualized brain cancerous lesions within 1 hour after injection, with stable retention of radioactivity at 3 and 24 hours. Excellent agreement was found between PET/CT and MRI. No uptake of the tracer was observed in low-grade astrocytoma. The agent cleared rapidly from the blood and was mostly excreted through the liver, without significant kidney washout. Analysis of time variation of SUVmax values showed persistent uptake in malignant tissues with a slight increase of radioactive concentration at 24 hours. Conclusions: Copper-64 chloride has favorable biological properties for brain imaging and warrants further investigation as a diagnostic tracer for GBM. © Copyright 2016, Mary Ann Liebert, Inc. 2016.
AUTHOR KEYWORDS: brain tumors;  copper-64;  copper-64 chloride;  glioblastoma multiforme;  neuroimaging;  PET imaging
DOCUMENT TYPE: Article

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Lacivita, E.a , Podlewska, S.b  c , Speranza, L.d , Niso, M.a , Satała, G.b , Perrone, R.a , Perrone-Capano, C.d  e , Bojarski, A.J.b , Leopoldo, M.a 
Structural modifications of the serotonin 5-HT7 receptor agonist N -(4-cyanophenylmethyl)-4-(2-biphenyl)-1-piperazinehexanamide (LP-211) to improve in vitro microsomal stability: A case study
(2016) European Journal of Medicinal Chemistry, 120, pp. 363-379. 
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DOI: 10.1016/j.ejmech.2016.05.005
AFFILIATIONS: aDipartimento di Farmacia - Scienze Del Farmaco, Università degli Studi di Bari 'A. Moro', via Orabona, 4, Bari, Italy; 
bDepartment of Medicinal Chemistry, Institute of Pharmacology, Polish Academy of Sciences, Smetna 12, Kraków, Poland; 
cFaculty of Chemistry, Jagiellonian University, Ingardena 3, Kraków, Poland; 
dInstitute of Genetics and Biophysics 'Adriano Buzzati Traverso', CNR, Via P. Castellino 111, Naples, Italy; 
eDepartment of Pharmacy, University of Naples Federico II, Via D. Montesano 49, Naples, Italy
ABSTRACT: The 5-HT7 serotonin receptor is revealing a promising target for innovative therapeutic strategies of neurodevelopmental and neuropsychiatric disorders. Here, we report the synthesis of thirty long-chain arylpiperazine analogs of the selective and brain penetrant 5-HT7 receptor agonist LP-211 (1) designed to enhance stability towards microsomal oxidative metabolism. Commonly used medicinal chemistry strategies were used (i.e., reduction of overall lipophilicity, introduction of electron-withdrawing groups, blocking of potential vulnerable sites of metabolism), and in vitro microsomal stability was tested. The data showed that the adopted design strategy does not directly translate into improvements in stability. Instead, the metabolic stability of the compounds was related to the presence of specific substituents in well-defined regions of the molecule. The collected data allowed for the construction of a machine learning model that, in a given chemical space, is able to describe and quantitatively predict the metabolic stability of the compounds. The majority of the synthesized compounds maintained high affinity for 5-HT7 receptors and showed selectivity towards 5-HT6 and dopamine D2 receptors and different selectivity for 5-HT1A and α1 adrenergic receptors. Compound 50 showed 3-fold higher in vitro stability towards oxidative metabolism than 1 and was able to stimulate neurite outgrowth in neuronal primary cultures through the 5-HT7 receptor in a shorter time and at a lower concentration than the agonist 1. A preliminary disposition study in mice revealed that compound 50 was metabolically stable and was able to pass the blood-brain barrier, thus representing a new tool for studying the pharmacotherapeutic potential of 5-HT7 receptor in vivo. © 2016 Elsevier Masson SAS. All rights reserved.
AUTHOR KEYWORDS: 5-HT7 receptor;  Arylpiperazine;  Machine learning;  Microsomal stability;  Neurite outgrowth
DOCUMENT TYPE: Article

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Tomassini, V.a  b  c , d'Ambrosio, A.a  b  d , Petsas, N.e , Wise, R.G.b , Sbardella, E.e , Allen, M.b , Tona, F.e , Fanelli, F.e , Foster, C.b , Carnì, M.e , Gallo, A.d , Pantano, P.e  f , Pozzilli, C.e 
The effect of inflammation and its reduction on brain plasticity in multiple sclerosis: MRI evidence
(2016) Human Brain Mapping, 37 (7), pp. 2431-2445. 
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DOI: 10.1002/hbm.23184
AFFILIATIONS: aInstitute of Psychological Medicine and Clinical Neurosciences, Cardiff University School of Medicine, United Kingdom; 
bCardiff University Brain Research Imaging Centre (CUBRIC), Cardiff University School of Psychology, United Kingdom; 
cIRCCS Fondazione Santa Lucia, Rome, Italy; 
dDepartment of Medical, Surgical, Neurological, Metabolic and Aging Sciences, Second University of Naples, Italy; 
eDepartment of Neurology and Psychiatry, Sapienza University of Rome, Italy; 
fIRCCS NeuroMed, Pozzilli, IS, Iceland
ABSTRACT: Brain plasticity is the basis for systems-level functional reorganization that promotes recovery in multiple sclerosis (MS). As inflammation interferes with plasticity, its pharmacological modulation may restore plasticity by promoting desired patterns of functional reorganization. Here, we tested the hypothesis that brain plasticity probed by a visuomotor adaptation task is impaired with MS inflammation and that pharmacological reduction of inflammation facilitates its restoration. MS patients were assessed twice before (sessions 1 and 2) and once after (session 3) the beginning of Interferon beta (IFN beta), using behavioural and structural MRI measures. During each session, 2 functional MRI runs of a visuomotor task, separated by 25-minutes of task practice, were performed. Within-session between-run change in task-related functional signal was our imaging marker of plasticity. During session 1, patients were compared with healthy controls. Comparison of patients' sessions 2 and 3 tested the effect of reduced inflammation on our imaging marker of plasticity. The proportion of patients with gadolinium-enhancing lesions reduced significantly during IFN beta. In session 1, patients demonstrated a greater between-run difference in functional MRI activity of secondary visual areas and cerebellum than controls. This abnormally large practice-induced signal change in visual areas, and in functionally connected posterior parietal and motor cortices, was reduced in patients in session 3 compared with 2. Our results suggest that MS inflammation alters short-term plasticity underlying motor practice. Reduction of inflammation with IFN beta is associated with a restoration of this plasticity, suggesting that modulation of inflammation may enhance recovery-oriented strategies that rely on patients' brain plasticity. Hum Brain Mapp 37:2431–2445, 2016. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.
AUTHOR KEYWORDS: brain plasticity;  functional MRI;  inflammation;  interferon beta;  multiple sclerosis
DOCUMENT TYPE: Article