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The NH2tau 26-44 aa (i.e., NH2htau) is the minimal biologically active moiety of longer 20-22-kDa NH2-truncated form of human tau-a neurotoxic fragment mapping between 26 and 230 amino acids of full-length protein (htau40)-which is detectable in presynaptic terminals and peripheral CSF from patients suffering from AD and other non-AD neurodegenerative diseases. Nevertheless, whether its exogenous administration in healthy nontransgenic mice is able to elicit a neuropathological phenotype resembling human tauopathies has not been yet investigated. We explored the in vivo effects evoked by subchronic intracerebroventricular (i.c.v.) infusion of NH2htau or its reverse counterpart into two lines of young (2-month-old) wild-type mice (C57BL/6 and B6SJL). Six days after its accumulation into hippocampal parenchyma, significant impairment in memory/learning performance was detected in NH2htau-treated group in association with reduced synaptic connectivity and neuroinflammatory response. Compromised short-term plasticity in paired-pulse facilitation paradigm (PPF) was detected in the CA3/CA1 synapses from NH2htau-impaired animals along with downregulation in calcineurin (CaN)-stimulated pCREB/c-Fos pathway(s). Importantly, these behavioral, synaptotoxic, and neuropathological effects were independent from the genetic background, occurred prior to frank neuronal loss, and were specific because no alterations were detected in the control group infused with its reverse counterpart. Finally, a 2.0-kDa peptide which biochemically and immunologically resembles the injected NH2htau was endogenously detected in vivo, being present in hippocampal synaptosomal preparations from AD subjects. Given that the identification of the neurotoxic tau species is mandatory to develop a more effective tau-based immunological approach, our evidence can have important translational implications for cure of human tauopathies.

PURPOSEApproved systemic therapies for advanced gastroenteropancreatic neuroendocrine tumors (GEP-NETs) have shown limited capacity to reduce tumor burden and no antitumor activity after progression to targeted agents (TAs). We investigated the efficacy and safety of lenvatinib in patients with previously treated advanced GEP-NETs.PATIENTS AND METHODSThis was a multicenter, single-arm, open-label, phase II trial with two parallel cohorts (ClinicalTrials.gov identifier: NCT02678780 ) involving 21 institutions in 4 European countries. Eligible patients had histologically confirmed advanced grade 1-2 pancreatic (panNET) or GI (GI-NET) NETs with documented tumor progression after treatment with a TA (panNET) or somatostatin analogs (GI-NET). Patients were treated with lenvatinib 24 mg once daily until disease progression or treatment intolerance. The primary end point was overall response rate by central radiology review. Secondary end points included progression-free survival, overall survival, duration of response, and safety.RESULTSBetween September 2015 and March 2017, a total of 111 patients were enrolled, with 55 (panNET) and 56 (GI-NET) patients in each cohort. The median follow-up was 23 months. The overall response rate was 29.9% (95% CI, 21.6 to 39.6): 44.2% (panNET) and 16.4% (GI-NET). The median (range) duration of response was 19.9 (8.4-30.8) and 33.9 (10.6-38.3) months in the panNET and GI-NET groups, respectively. The median progression-free survival was 15.7 months (95% CI, 14.1 to 19.5). The most common adverse events were fatigue, hypertension, and diarrhea; 93.7% of patients required dose reductions or interruptions.CONCLUSIONWe report the highest centrally confirmed response reported to date with a multikinase inhibitor in advanced GEP-NETs, with a particularly strong response in the panNET cohort. This study provides novel evidence for the efficacy of lenvatinib in patients with disease progression following treatment with other TAs, suggesting the potential value of lenvatinib in the treatment of advanced GEP-NETs.

TG2576 mice show highest levels of the full length mutant Swedish Human Amyloid Precursor Protein (APPKM670/671LN) during prodromal and early sympotomatic stages. Interestingly, this occurs in association with the unbalanced expression of two of its RNA Binding proteins (RBPs) opposite regulators, the Fragile-X Mental Retardation Protein (FMRP) and the heteronuclear Ribonucleoprotein C (hnRNP C). Whether an augmentation in overall translational efficiency also contributes to the elevation of APP levels at those early developmental stages is currently unknown. We investigated this possibility by performing a longitudinal polyribosome profiling analysis of APP mRNA and protein in total hippocampal extracts from Tg2576 mice. Results showed that protein polysomal signals were exclusively detected in pre-symptomatic (1 months) and early symptomatic (3 months) mutant mice. Differently, hAPP mRNA polysomal signals were detected at any age, but a peak of expression was found when mice were 3-month old. Consistent with an early but transient rise of translational efficiency, the phosphorylated form of the initial translation factor eIF2α (p-eIF2α) was reduced at pre-symptomatic and early symptomatic stages, whereas it was increased at the fully symptomatic stage. Pharmacological downregulation of overall translation in early symptomatic mutants was then found to reduce hippocampal levels of full length APP, Aβspecies, BACE1 and Caspase-3, to rescue predominant LTD at hippocampal synapses, to revert dendritic spine loss and memory alterations, and to reinstate memory-induced c-fosactivation. Altogether, our findings demonstrate that overall translation is upregulated in prodromal and early symptomatic Tg2576 mice, and that restoring proper translational control at the onset of AD-like symptoms blocks the emergence of the AD–like phenotype.

Imbalances between excitatory and inhibitory synaptic transmission cause brain network dysfunction and are central to the pathogenesis of neurodevelopmental disorders. Parvalbumin interneurons are highly implicated in this imbalance. Here, we probed the social behavior and hippocampal function of mice carrying a haploinsufficiency for Ambra1, a pro-autophagic gene crucial for brain development. We show that heterozygous Ambra1 mice (Ambra+/−) are characterized by loss of hippocampal parvalbumin interneurons, decreases in the inhibition/excitation ratio, and altered social behaviors that are solely restricted to the female gender. Loss of parvalbumin interneurons in Ambra1+/− females is further linked to reductions of the inhibitory drive onto principal neurons and alterations in network oscillatory activity, CA1 synaptic plasticity, and pyramidal neuron spine density. Parvalbumin interneuron loss is underlined by increased apoptosis during the embryonic development of progenitor neurons in the medial ganglionic eminence. Together, these findings identify an Ambra1-dependent mechanism that drives inhibition/excitation imbalance in the hippocampus, contributing to abnormal brain activity reminiscent of neurodevelopmental disorders. Electronic supplementary material The online version of this article (10.1007/s12035-018-0911-5) contains supplementary material, which is available to authorized users.

The hippocampal formation is considered essential for spatial navigation. In particular, subicular projections have been suggested to carry spatial information from the hippocampus to the ventral striatum. However, possible cross-structural communication between these two brain regions in memory formation has thus far been unknown. By selectively silencing the subiculum–ventral striatum pathway we found that its activity after learning is crucial for spatial memory consolidation and learning-induced plasticity. These results provide new insight into the neural circuits underlying memory consolidation and establish a critical role for off-line cross-regional communication between hippocampus and ventral striatum to promote the storage of complex information., Spatial information is passed from the hippocampus via the subiculum to the ventral striatum. Here, the authors show that inhibiting this projection after spatial learning disrupts learning induced plasticity and spatial memory consolidation.

Degradation of the chondroitin sulfate proteoglycans of the extracellular matrix (ECM) by injections of the bacterial enzyme chondroitinase ABC (ChABC) in the basolateral amygdala (BLA) does not impair fear memory formation but accelerates its extinction and disrupts its reactivation. These observations suggest that the treatment might selectively interfere with the post-extinction features of neurons that mediate the reinstatement of fear. Here, we report that ChABC mice show regular fear memory and memory-driven c-fos activation and dendritic spine formation in the BLA. These mice then rapidly extinguish their fear response and exhibit a post-extinction concurrent reduction in c-fos activation and large dendritic spines that extends to the anterior cingulate cortex 7 days later. At this remote time point, fear renewal and fear retrieval are impaired. These findings show that a non-cellular component of the brain tissue controls post-extinction levels of neuronal activity and spine enlargement in the regions sequentially remodelled during the formation of recent and remote fear memory. By preventing BLA and aCC neurons to retain neuronal features that serve to reactivate an extinguished fear memory, ECM digestion might offer a therapeutic strategy for durable attenuation of traumatic memories.

The view that the neocortex is remotely recruited for long-term episodic memory recall is challenged by data showing that an intense transcriptional and synaptic activity is detected in this region immediately after training. By measuring markers of synaptic activity at recent and remote time points from contextual fear conditioning (CFC), we could show that pre-synaptic changes are selectively detected 1 day post-training when the memory is anchored to the training context. Differently, pre- and post-synaptic changes are detected 14 days post-training when the memory generalizes to other contexts. Confirming that coincident pre- and post-synaptic remodelling mediates the disengagement of memory from its original context, DREADDs-mediated enhancement of cortical neuron activity during CFC training anticipates expression of a schematic memory and observation of bilateral synaptic remodelling. Together, our data show that the plastic properties of cortical synapses vary over time and specialise in relation to the quality of memory.

Phosphorylation of serine/threonine residues preceding a proline regulates the fate of its targets through postphosphorylation conformational changes catalyzed by the peptidyl-prolylcis-/transisomerase Pin1. By flipping the substrate between two different functional conformations, this enzyme exerts a fine-tuning of phosphorylation signals. Pin1 has been detected in dendritic spines and shafts where it regulates protein synthesis required to sustain the late phase of long-term potentiation (LTP). Here, we demonstrate that Pin1 residing in postsynaptic structures can interact with postsynaptic density protein-95 (PSD-95), a key scaffold protein that anchors NMDA receptors (NMDARs) in PSD via GluN2-type receptor subunits. Pin1 recruitment by PSD-95 occurs at specific serine-threonine/proline consensus motifs localized in the linker region connecting PDZ2 to PDZ3 domains. Upon binding, Pin1 triggers structural changes in PSD-95, thus negatively affecting its ability to interact with NMDARs. In electrophysiological experiments, larger NMDA-mediated synaptic currents, evoked in CA1 principal cells by Schaffer collateral stimulation, were detected in hippocampal slices obtained from Pin1−/−mice compared with controls. Similar results were obtained in cultured hippocampal cells expressing a PSD-95 mutant unable to undergo prolyl-isomerization, thus indicating that the action of Pin1 on PSD-95 is critical for this effect. In addition, an enhancement in spine density and size was detected in CA1 principal cells of Pin1−/−or in Thy-1GFP mice treated with the pharmacological inhibitor of Pin1 catalytic activity PiB.Our data indicate that Pin1 controls synaptic content of NMDARs via PSD-95 prolyl-isomerization and the expression of dendritic spines, both required for LTP maintenance.SIGNIFICANCE STATEMENTPSD-95, a membrane-associated guanylate kinase, is the major scaffolding protein at excitatory postsynaptic densities and a potent regulator of synaptic strength and plasticity. The activity of PSD-95 is tightly controlled by several post-translational mechanisms including proline-directed phosphorylation. This signaling cascade regulates the fate of its targets through postphosphorylation conformational modifications catalyzed by the peptidyl-prolylcis-/transisomerase Pin1. Here, we uncover a new role of Pin1 in glutamatergic signaling. By interacting with PSD-95, Pin1 dampens PSD-95 ability to complex with NMDARs, thus negatively affecting NMDAR signaling and spine morphology. Our findings further emphasize the emerging role of Pin1 as a key modulator of synaptic transmission.

Background A consistent proportion of individuals at risk for Alzheimer’s disease show intact cognition regardless of the extensive accumulation of amyloid-β (Aβ) peptide in their brain. Several pieces of evidence indicate that overactivation of brain regions negative for Aβ can compensate for the underactivation of Aβ-positive ones to preserve cognition, but the underlying synaptic changes are still unexplored. Methods Using Golgi staining, we investigate how dendritic spines rearrange following contextual fear conditioning (CFC) in the hippocampus and amygdala of presymptomatic Tg2576 mice, a genetic model for Aβ accumulation. A molecular biology approach combined with intrahippocampal injection of a γ-secretase inhibitor evaluates the impact of Aβ fluctuations on spine rearrangements. Results Encoding of CFC increases Aβ oligomerization in the hippocampus but not in the amygdala of Tg2576 mice. The presence of Aβ oligomers predicts vulnerability to network dysfunctions, as low c-Fos activation and spine maturation are detected in the hippocampus of Tg2576 mice upon recall of CFC memory. Rather, enhanced c-Fos activation and new spines are evident in the amygdala of Tg2576 mice compared with wild-type control mice. Preventing Aβ increase in the hippocampus of Tg2576 mice restores CFC-associated spine changes to wild-type levels in both the hippocampus and amygdala. Conclusions Our study provides the first evidence of neural compensation consisting of enhanced synaptic activity in brain regions spared by Aβ load. Furthermore, it unravels an activity-mediated feedback loop through which neuronal activation during CFC encoding favors Aβ oligomerization in the hippocampus and prevents synaptic rearrangements in this region.

The functional loop involving the ventral tegmental area (VTA), dorsal hippocampus and nucleus accumbens (NAc) plays a pivotal role in the formation of spatial memory and persistent memory traces. In particular, the dopaminergic innervation from the VTA to the hippocampus is critical for hippocampal-related memory function and alterations in the midbrain dopaminergic system are frequently reported in Alzheimer's disease (AD), contributing to age-related decline in memory and non-cognitive functions. However, much less is known about the hippocampus-NAc connectivity in AD. Here, we evaluated the functioning of the hippocampus-to-NAc core connectivity in the Tg2576 mouse model of AD that shows a selective and progressive degeneration of VTA dopaminergic neurons. We show that reduced dopaminergic innervation in the Tg2576 hippocampus results in reduced synaptic plasticity and excitability of dorsal subiculum pyramidal neurons. Importantly, the glutamatergic transmission from the hippocampus to the NAc core is also impaired. Chemogenetic depolarisation of Tg2576 subicular pyramidal neurons with an excitatory Designer Receptor Exclusively Activated by Designer Drugs, or systemic administration of the DA precursor levodopa, can both rescue the deficits in Tg2576 mice. Our data suggest that the dopaminergic signalling in the hippocampus is essential for the proper functioning of the hippocampus-NAc excitatory synaptic transmission.

Background The management of advanced neuroendocrine tumors (NETs) has recently changed. We assessed the activity of pazopanib after failure of other systemic treatments in advanced NETs. Methods This was a multicenter, open-label, phase II study evaluating pazopanib as a single agent in advanced NETs (PAZONET study). The clinical benefit rate (CBR) at 6 months was the primary end point. Translational correlation of radiological response and progression-free survival (PFS) with circulating and tissue biomarkers was also evaluated. Results A total of 44 patients were enrolled. Twenty-five patients (59.5%) were progression-free at 6 months (4 partial responses, 21 stable diseases) with a median PFS of 9.5 months [95% confidence interval (CI) 4.8–14.1]. The CBR varied according to prior therapy received, with 73%, 60% and 25% in patients treated with prior multitarget inhibitors, prior mTOR inhibitors and both agents, respectively. A nonsignificant increase in PFS was observed in patients presenting lower baseline circulating tumor cell (CTC) counts (9.1 versus 5.8 months; P = 0.22) and in those with decreased levels of soluble-vascular endothelial growth factor receptor-2 (sVEGFR-2) (12.6 versus 9.1 months; P = 0.067). A trend toward reduced survival was documented in patients with VEGFR3 rs307821 and rs307826 missense polymorphisms [hazard ratio (HR): 12.3; 95% CI 1.09–139.2; P = 0.042 and HR: 6.9; 95% CI 0.96–49.9; P = 0.055, respectively]. Conclusions Pazopanib showed clinical activity in patients with advanced NETs regardless of previous treatments. Additionally, CTCs, soluble-s VEFGR-2 and VEGFR3 gene polymorphisms constitute potential biomarkers for selecting patients for pazopanib (NCT01280201). Clinical trial number NCT01280201.

D-aspartate (D-Asp) is an atypical amino acid, which is especially abundant in the developing mammalian brain, and can bind to and activate N-methyl-D-Aspartate receptors (NMDARs). In line with its pharmacological features, we find that mice chronically treated with D-Asp show enhanced NMDAR-mediated miniature excitatory postsynaptic currents and basal cerebral blood volume in fronto-hippocampal areas. In addition, we show that both chronic administration of D-Asp and deletion of the gene coding for the catabolic enzyme D-aspartate oxidase (DDO) trigger plastic modifications of neuronal cytoarchitecture in the prefrontal cortex and CA1 subfield of the hippocampus and promote a cytochalasin D-sensitive form of synaptic plasticity in adult mouse brains. To translate these findings in humans and consistent with the experiments using Ddo gene targeting in animals, we performed a hierarchical stepwise translational genetic approach. Specifically, we investigated the association of variation in the gene coding for DDO with complex human prefrontal phenotypes. We demonstrate that genetic variation predicting reduced expression of DDO in postmortem human prefrontal cortex is mapped on greater prefrontal gray matter and activity during working memory as measured with MRI. In conclusion our results identify novel NMDAR-dependent effects of D-Asp on plasticity and physiology in rodents, which also map to prefrontal phenotypes in humans. © 2014 Macmillan Publishers Limited.

ObjectivePatients' psychological reactions to multigene cancer panel testing might differ compared with the single-gene testing reactions because of the complexity and uncertainty associated with the different possible results. Understanding patients' preferences and psychological impact of multigene panel testing is important to adapt the genetic counselling model. MethodsOne hundred eighty-seven unrelated patients with clinical suspicion of hereditary cancer undergoing a 25-gene panel test completed questionnaires after pretest genetic counselling and at 1week, 3 months, and 12months after results to elicit their preferences regarding results disclosure and to measure their cancer worry and testing-specific distress and uncertainty. ResultsA pathogenic variant was identified in 38 patients (34 high penetrance and 4 moderate penetrance variants), and 54 patients had at least one variant of uncertain significance. Overall, cancer panel testing was not associated with an increase in cancer worry after results disclosure (P value=.87). Twelve months after results, carriers of a moderate penetrance variant had higher distress and uncertainty scores compared with carriers of high penetrance variants. Cancer worry prior to genetic testing predicted genetic testing specific distress after results, especially at long term (P value

$\textbf{Purpose}$ $\textit{BRCA1/2}$ mutations increase the risk of breast and prostate cancer in men. Common genetic variants modify cancer risks for female carriers of $\textit{BRCA1/2}$ mutations. We investigated-for the first time to our knowledge-associations of common genetic variants with breast and prostate cancer risks for male carriers of $\textit{BRCA1/2}$ mutations and implications for cancer risk prediction. $\textbf{Materials and Methods}$ We genotyped 1,802 male carriers of $\textit{BRCA1/2}$ mutations from the Consortium of Investigators of Modifiers of $\textit{BRCA1/2}$ by using the custom Illumina OncoArray. We investigated the combined effects of established breast and prostate cancer susceptibility variants on cancer risks for male carriers of $\textit{BRCA1/2}$ mutations by constructing weighted polygenic risk scores (PRSs) using published effect estimates as weights. $\textbf{Results}$ In male carriers of $\textit{BRCA1/2}$ mutations, PRS that was based on 88 female breast cancer susceptibility variants was associated with breast cancer risk (odds ratio per standard deviation of PRS, 1.36; 95% CI, 1.19 to 1.56; $P$ = 8.6 × 10$^{-6}$)). Similarly, PRS that was based on 103 prostate cancer susceptibility variants was associated with prostate cancer risk (odds ratio per SD of PRS, 1.56; 95% CI, 1.35 to 1.81; $P$ = 3.2 × 10$^{-9}$)). Large differences in absolute cancer risks were observed at the extremes of the PRS distribution. For example, prostate cancer risk by age 80 years at the 5th and 95th percentiles of the PRS varies from 7% to 26% for carriers of $\textit{BRCA1}$ mutations and from 19% to 61% for carriers of $\textit{BRCA2}$ mutations, respectively. $\textbf{Conclusion}$ PRSs may provide informative cancer risk stratification for male carriers of $\textit{BRCA1/2}$ mutations that might enable these men and their physicians to make informed decisions on the type and timing of breast and prostate cancer risk management.

Purpose BRCA1/2 mutations increase the risk of breast and prostate cancer in men. Common genetic variants modify cancer risks for female carriers of BRCA1/2 mutations. We investigated-for the first time to our knowledge-associations of common genetic variants with breast and prostate cancer risks for male carriers of BRCA1/ 2 mutations and implications for cancer risk prediction. Materials and Methods We genotyped 1,802 male carriers of BRCA1/2 mutations from the Consortium of Investigators of Modifiers of BRCA1/2 by using the custom Illumina OncoArray. We investigated the combined effects of established breast and prostate cancer susceptibility variants on cancer risks for male carriers of BRCA1/2 mutations by constructing weighted polygenic risk scores (PRSs) using published effect estimates as weights. Results In male carriers of BRCA1/2 mutations, PRS that was based on 88 female breast cancer susceptibility variants was associated with breast cancer risk (odds ratio per standard deviation of PRS, 1.36; 95% CI, 1.19 to 1.56; P = 8.6 × 10-6). Similarly, PRS that was based on 103 prostate cancer susceptibility variants was associated with prostate cancer risk (odds ratio per SD of PRS, 1.56; 95% CI, 1.35 to 1.81; P = 3.2 × 10-9). Large differences in absolute cancer risks were observed at the extremes of the PRS distribution. For example, prostate cancer risk by age 80 years at the 5th and 95th percentiles of the PRS varies from 7% to 26% for carriers of BRCA1 mutations and from 19% to 61% for carriers of BRCA2 mutations, respectively. Conclusion PRSs may provide informative cancer risk stratification for male carriers of BRCA1/2 mutations that might enable these men and their physicians to make informed decisions on the type and timing of breast and prostate cancer risk management. We thank Sue Healey for her contribution to CIMBA, in particular, for taking on the task of mutation classification with Olga Sinilnikova. BCFR Australia: We acknowledge Maggie Angelakos, Judi Maskiell, Gillian Dite, Helen Tsimiklis. BCFR Ontario: We thank members and participants in the Ontario Familial Breast Cancer Registry for their contributions to the study. BFBOCC-LT (Baltic Familial Breast Ovarian Cancer Consortium Lithuanian section): We acknowledge Vilius Rudaitis and Laimonas Griˇskeviˇcius. CBCS (Copenhagen Breast Cancer Study, Rigshospitalet): We thank Bent Ejlertsen Ejlertsen and Anne-Marie Gerdes for the recruitment and genetic counseling of participants. CNIO (Spanish National Cancer Centre): We thank Alicia Barroso, Rosario Alonso, and Guillermo Pita for their assistance. COH-CCGCRN (City of Hope Clinical Cancer Genomics Community Research Network): Patients were recruited for study from the City of Hope Clinical Cancer Genomics Community Research Network. CONSIT TEAM:We acknowledge Daniela Zaffaroni of the Fondazione IRCCS Istituto Nazionale Tumori (INT), Milan, Italy; Brunella Pilato of the Istituto Nazionale Tumori “Giovanni Paolo II”, Bari, Italy; and the personnel of the Cogentech Cancer Genetic Test Laboratory, Milan, Italy. FCCC (Fox Chase Cancer Center):We thank Jo EllenWeaver and Betsy Bove, MD, for their technical support. GEMO (GeneticModifiers of cancer risk in BRCA1/2 mutation carriers):We pay a tribute to Olga M. Sinilnikova, who with Dominique Stoppa-Lyonnet, initiated and coordinated GEMO until she died on June 30, 2014, and we thank all the GEMO collaborating groups for their contribution to this study. GEMO Collaborating Centers are: Coordinating Centres, Unit´e Mixte de G´en´etique Constitutionnelle des Cancers Fr´equents, Hospices Civils de Lyon–Centre L´eon B´erard, Equipe G´en´etique du cancer du sein, Centre de Rechercheen Canc´erologie de Lyon: Olga Sinilnikova (deceased), Sylvie Mazoyer, Francesca Damiola, Laure Barjhoux, Carole Verny-Pierre, M´elanie L´eone, Nadia Boutry-Kryza, Alain Calender, Sophie Giraud; and Service de G´en´etique Oncologique, Institut Curie, Paris: Dominique Stoppa-Lyonnet, Marion Gauthier-Villars, Bruno Buecher, Claude Houdayer, Etienne Rouleau, Lisa Golmard, Agn`es Collet, Virginie Moncoutier, Muriel Belotti, Antoine de Pauw, Camille Elan, Catherine Nogues, Emmanuelle Fourme, Anne-Marie Birot; Institut Gustave Roussy, Villejuif: Brigitte Bressac-de-Paillerets, Olivier Caron, Marine Guillaud- Bataille; Centre Jean Perrin, Clermont–Ferrand: Yves-Jean Bignon, Nancy Uhrhammer; Centre L´eon B´erard, Lyon: Christine Lasset, Val´erie Bonadona, Sandrine Handallou; Centre François Baclesse, Caen: Agn`es Hardouin, Pascaline Berthet, Dominique Vaur, Laurent Castera; Institut Paoli Calmettes, Marseille: Hagay Sobol, Violaine Bourdon, Tetsuro Noguchi, Audrey Remenieras, François Eisinger; CHUArnaud-de-Villeneuve,Montpellier: Isabelle Coupier, Pascal Pujol; Centre Oscar Lambret, Lille: Jean-Philippe Peyrat, Jo¨elle Fournier, Françoise R´evillion, Philippe Vennin (deceased), Claude Adenis; Centre Paul Strauss, Strasbourg: Dani`ele Muller, Jean-Pierre Fricker; Institut Bergoni´e, Bordeaux: Emmanuelle Barouk-Simonet, Françoise Bonnet, Virginie Bubien, Nicolas Sevenet, Michel Longy; Institut Claudius Regaud, Toulouse: Christine Toulas, Rosine Guimbaud, Laurence Gladieff, Viviane Feillel; CHU Grenoble: Dominique Leroux, H´el`ene Dreyfus, Christine Rebischung, Magalie Peysselon; CHU Dijon: Fanny Coron, Laurence Faivre; CHU St-Etienne: Fabienne Prieur, Marine Lebrun, Caroline Kientz; HˆotelDieu Centre Hospitalier, Chamb´ery: Sandra Fert Ferrer; Centre Antoine Lacassagne, Nice: Marc Fr´enay; CHU Limoges: Laurence V´enat-Bouvet; CHU Nantes: Capucine Delnatte; CHU Bretonneau, Tours: Isabelle Mortemousque; Groupe Hospitalier Piti´e-Salp´etri`ere, Paris: Florence Coulet, Chrystelle Colas, Florent Soubrier, MathildeWarcoin; CHU Vandoeuvre-les- Nancy: Johanna Sokolowska, Myriam Bronner; CHU Besançon: Marie-Agn`es Collonge-Rame, Alexandre Damette; Creighton University, Omaha, NE: Henry T. Lynch, Carrie L. Snyder. G-FAST (Ghent University Hospital): B.P. is a senior clinical investigator of FWO. We acknowledge the technical support of Ilse Coeneen Brecht Crombez. HCSC (Hospital Clinico San Carlos): We acknowledge Alicia Tosar and Paula Diaque for their technical assistance. HEBCS (Helsinki Breast Cancer Study):We thank Taru A. Muranen, Carl Blomqvist, MD, Kirsimari Aaltonen, MD, Irja Erkkil¨a, RN, and Virpi Palola, RN, for their help with the HEBCS data and samples. Hereditary Breast and Ovarian Cancer Research Group Netherlands (HEBON): HEBON consists of the following collaborating centers: Coordinating center: Netherlands Cancer Institute, Amsterdam: M.A. Rookus, F.B.L. Hogervorst, F.E. van Leeuwen, S. Verhoef, M.K. Schmidt, N.S. Russell, J.L. de Lange, R. Wijnands; Erasmus Medical Center: J.M. Coll´ee, A.M.W. van den Ouweland, M.J. Hooning, C. Seynaeve, C.H.M. van Deurzen, I.M. Obdeijn; Leiden University Medical Center: C.J. van Asperen, J.T. Wijnen, R.A.E.M. Tollenaar, P. Devilee, T.C.T.E.F. van Cronenburg; Radboud University NijmegenMedical Center: C.M. Kets, A.R.Mensenkamp; UniversityMedical Center Utrecht: M.G.E.M. Ausems, R.B. van der Luijt, C.C. van der Pol; Amsterdam Medical Center: C.M. Aalfs, T.A.M. van Os; Vrije Universiteit Medical Center: J.J.P. Gille, Q.Waisfisz, H.E.J. Meijers-Heijboer; University Hospital Maastricht: E.B. G´omez-Garcia, M.J. Blok; University Medical Center Groningen: J.C. Oosterwijk, A.H. van der Hout, M.J.Mourits, G.H. de Bock; The Netherlands Foundation for the Detection of Hereditary Tumours, Leiden: H.F. Vasen; The Netherlands Comprehensive Cancer Organization (IKNL): S. Siesling, J. Verloop; The Dutch Pathology Registry (PALGA): L.I.H. Overbeek. HEBON thanks the registration teams of IKNL and PALGA for part of the data collection. HUNBOCS (Molecular Genetic Studies of Breast- and Ovarian Cancer in Hungary):We thank the Hungarian Breast and Ovarian Cancer Study Group members (Janos Papp, Aniko Bozsik, Judit Franko, Maria Balogh, Gabriella Domokos, Judit Ferenczi, Department of Molecular Genetics, National Institute of Oncology, Budapest, Hungary) and the clinicians and patients for their contributions to this study. HVH (University Hospital Vall d’Hebron): We thank the Cellex Foundation for providing research facilities and equipment. ICO (Institut Catal`a d’Oncologia): We thank the ICO Hereditary Cancer Program team led by Gabriel Capella, MD. INHERIT (INterdisciplinary HEalth Research Internal Team BReast CAncer susceptibility):We thank Martine Dumont, MD, Martine Tranchant and St´ephane Dubois for QC, sample management and skillful assistance. J.S. is Chair holder of the Canada Research Chair in Oncogenetics. J.S. and P.S. were part of the QC and Genotyping coordinating group of iCOGS and Oncoarray (BCAC and CIMBA). IPOBCS (Portuguese Oncology Institute-Porto jco.org © 2017 by American Society of Clinical Oncology Polygenic Risk Scores in Male BRCA1 and BRCA2 Mutation Carriers Downloaded from ascopubs.org by CNIO-FUND on September 27, 2019 from 193.147.150.201 Copyright © 2019 American Society of Clinical Oncology. All rights reserved. Breast Cancer Study): We thank Catarina Santos, MD, for her skillful contribution to the study. kConFab (Kathleen Cuningham Consortium for Research into Familial Breast Cancer): We thank Heather Thorne, Eveline Niedermayr, all the kConFab research nurses and staff, the heads and staff of the Family Cancer Clinics, and the Clinical Follow Up Study for their contributions to this resource, and the many families who contribute to kConFab.Memorial Sloan Kettering Cancer Center:We acknowledge Lauren Jacobs, MD. OCGN (Ontario Cancer Genetics Network): We thank members and participants in the Ontario Cancer Genetics Network for their contributions to the study. OSUCCG (The Ohio State University Comprehensive Cancer Center): Kevin Sweet, Caroline Craven, Julia Cooper, Leigha Senter, and Michelle O’Conor were instrumental in accrual of study participants, ascertainment of medical records, and database management. SEABASS (South East Asian Breast Cancer Association Study): We thank Yip Cheng Har, Nur Aishah Mohd Taib, Phuah Sze Yee, Norhashimah Hassan, and all the research nurses, research assistants, and doctors involved in the MyBrCa Study for assistance in patient recruitment, data collection, and sample preparation. In addition, we thank Philip Iau, Sng Jen-Hwei, and Sharifah Nor Akmal for contributing samples from the Singapore Breast Cancer Study and the HUKM-HKL Study, respectively. SWE-BRCA (Swedish Breast Cancer Study): Swedish scientists participating as SWE-BRCA collaborators are: from Lund University and University Hospital: A° ke Borg, H°akan Olsson, Helena Jernstr¨om, Karin Henriksson, Katja Harbst, Maria Soller, Ulf Kristoffersson; from Gothenburg Sahlgrenska University Hospital: Anna O¨ fverholm, Margareta Nordling, Per Karlsson, Zakaria Einbeigi; from Stockholm and Karolinska University Hospital: Anna vonWachenfeldt, Annelie Liljegren, Annika Lindblom, Brita Arver, Gisela Barbany Bustinza, Johanna Rantala; from Ume°a University Hospital: Beatrice Melin, Christina Edwinsdotter Ardnor, Monica Emanuelsson; from Uppsala University: Hans Ehrencrona, Maritta Hellstr¨om Pigg, Richard Rosenquist; from Link¨oping University Hospital: Marie Stenmark-Askmalm, Sigrun Liedgren. University of Chicago: O.I.O. is an ACS Clinical Research Professor. We thank Cecilia Zvocec, Qun Niu, physicians, genetic counsellors, research nurses, and staff of the Cancer Risk Clinic for their contributions to this resource, and the many families who contribute to our program. VFCTG (Victorian Familial Cancer Trials Group):We acknowledge Geoffrey Lindeman, Marion Harris, Martin Delatycki of the Victorian Familial Cancer Trials Group.We thank Sarah Sawyer and Rebecca Driessen for assembling these data and Ella Thompson for performing all DNA amplification. © 2017 by American Society of Clinical Oncology JOURNAL OF CLINICAL ONCOLOGY Sí

The function of AMPA receptors phosphorylation in synaptic plasticity has been dissected in many in vitro models but its role and dynamics on experience-dependent plasticity are still unclear. Here we studied the effects of AMPA receptor manipulations in the ventral striatum, where glutamatergic transmission is known to mediate spatial memory. We first demonstrate that intra-ventral striatal administrations of the AMPA receptors blocker, NBQX, dose dependently impair performance in the Morris water maze. We also report that spatial learning induced a time-limited increase in GluA1 phosphorylation in this same brain region. Finally, through focal, time-controlled ventral striatal administrations of an RNA aptamer interfering with GluA1-S845 phosphorylation, we demonstrate that phosphorylation at this site is a necessary requirement for spatial memory formation and for the synaptic remodeling underlying it. These results suggest that modulation of AMPA receptors by S845 phosphorylation could act as an essential starting signal leading to long-term stabilization of spatial memories. © 2014 Springer-Verlag Berlin Heidelberg.

Rationale: Compulsive symptoms develop in patients exposed to pramipexole (PPX), a dopaminergic agonist with high selectivity for the D3 receptor. Consistently, we demonstrated that PPX produces an exaggerated increase in contrafreeloading (CFL) for water, a repetitive and highly inflexible behavior that models core aspects of compulsive disorders. Objectives: Given the role of the hippocampus in behavioral flexibility, motivational control, and visuospatial working memory, we investigated the role of hippocampus in the expression of PPX-induced CFL. To this aim, rats were subjected to CFL under chronic PPX, and then examined for the electrophysiological, structural, and molecular properties of their hippocampus. Methods: We measured long-term potentiation (LTP) at CA1 Schaffer collaterals, dendritic spine density in CA1 pyramidal neurons, and then glutamate release and expression of pre and postsynaptic proteins in hippocampal synaptosomes. The effects of PPX on hippocampal-dependent working memory were assessed through the novel object recognition (NOR) test. Results: We found that PPX-treated rats showing CFL exhibited a significant decrease in hippocampal LTP and failed to exhibit the expected increase in hippocampal spine density. Glutamate release and PSD-95 expression were decreased, while pSYN expression was increased in hippocampal synaptosomes of PPX-treated rats showing CFL. Despite a general impairment of hippocampal synaptic function, working memory was unaffected by PPX treatment. Conclusions: Our findings demonstrate that chronic PPX affects synaptic function in the hippocampus, an area that is critically involved in the expression of flexible, goal-centered behaviors. We suggest that the hippocampus is a promising target in the pharmacotherapy of compulsive disorders.

Amyotrophic lateral sclerosis (ALS) is a lethal disorder characterized by the gradual degeneration of motor neurons in the cerebrospinal axis. Whether upper motor neuron hyperexcitability, which is a feature of ALS, provokes dysfunction of glutamate metabolism and degeneration of lower motor neurons via an anterograde process is undetermined. To examine whether early changes in upper motor neuron activity occur in association with glutamatergic alterations, we performed whole-cell patch-clamp recordings to analyze excitatory properties of Layer V cortical motor neurons and excitatory postsynaptic currents (EPSCs) in presymptomatic G93A mice modeling familial ALS (fALS). We found that G93A Layer V pyramidal neurons exhibited altered EPSC frequency and rheobase values indicative of their hyperexcitability status. Biocytin loading of these hyperexcitable neurons revealed an expansion of their basal dendrite arborization. Moreover, we detected increased expression levels of the vesicular glutamate transporter 2 in cortical Layer V of G93A mice. Altogether our data show that functional and structural neuronal alterations associate with abnormal glutamatergic activity in motor cortex of presymptomatic G93A mice. These abnormalities, expected to enhance glutamate release and to favor its accumulation in the motor cortex, provide strong support for the view that upper motor neurons are involved early on in the pathogenesis of ALS.

With increasing age, there may be a decrease in femoral blood flow. In some patients, this may result in local ischaemia, which subsequently may lead to local degenerative changes. Consequently, bone blood flow may play an important role in the aetiology of osteoarthritis of the hip. Little is known about bone blood flow in the femoral head of patients with advanced hip osteoarthritis. The purpose of this study was to evaluate bone blood flow and metabolism in vivo in patients with osteoarthritis of the hip. Ten patients with symptomatic osteoarthritis of the hip were enrolled prospectively. Femoral bone blood flow and metabolism were measured using positron emission tomography together with H₂(15)O and [(18)F]fluoride, respectively. Blood flow was 0.054 ± 0.032 mL cm(-3) min(-1) and 0.041 ± 0.012 mL cm(-3) min(-1) in symptomatic and contralateral femoral heads, respectively (p = 0.435). The net flux of fluoride from plasma to bone mineral (K i ) was significantly (p = 0.027) higher in the femoral head of the osteoarthritic hip (0.022 ± 0.012 mL cm(-3) min(-1)) than in that of the contralateral hip (0.007 ± 0.005 mL cm(-3) min(-1)). This study showed significant increase in bone metabolism in the proximal femur of patients with symptomatic osteoarthritis of the hip joint. There was no evidence of decreased blood flow.

The modulation of synaptic strength associated with learning is post-synaptically regulated by changes in density and shape of dendritic spines. The transcription factor CREB (cAMP response element binding protein) is required for memory formation and in vitro dendritic spine rearrangements, but its role in learning-induced remodeling of neurons remains elusive. Using transgenic mice conditionally expressing a dominant-negative CREB (CREBS133A: mCREB) mutant, we found that inhibiting CREB function does not alter spine density, spine morphology, and levels of polymerized actin in naive CA1 neurons. CREB inhibition, however, impaired contextual fear conditioning and produced a learning-induced collapse of spines associated with a blockade of learning-dependent increase in actin polymerization. Blocking mCREB expression with doxycycline rescued memory and restored a normal pattern of learning-induced spines, demonstrating that CREB controls structural adaptations of neurons selectively involved in memory formation.

Context:Stimulation of thermogenesis in brown adipose tissue (BAT) is a potential target to treat obesity. We earlier demonstrated that BAT activity is relatively low in obese subjects. It is unknown whether BAT can be recruited in adult humans.Objective:To study the dynamics of BAT, we observed BAT activity in morbidly obese subjects before and after weight loss induced by bariatric surgery.Design:This was an observational prospective cohort study.Setting:The study was conducted at a referral center.Patients:Ten morbidly obese subjects eligible for laparoscopic adjustable gastric banding surgery were studied before and 1 yr after bariatric surgery.Main Outcome Measure:The main outcome measure was BAT activity, as determined after acute cold stimulation using (18)F-fluorodeoxyglucose positron emission tomography and computed tomography.Results:Before surgery, only two of 10 subjects showed active BAT. One year after surgery, the number of subjects with active BAT was increased to five. After weight loss, BAT-positive subjects had significantly higher nonshivering thermogenesis compared with BAT-negative subjects (P < 0.05).Conclusions:The results show that in humans BAT can be recruited in the regions in which it was also reported in lean subjects before. These results for the first time show recruitment of BAT in humans and may open the door for BAT-targeted treatments of obesity.

Structural synaptic changes occur in medial prefrontal cortex circuits during remote memory formation. Whether extinction reverts or further reshapes these circuits is, however, unknown. Here we show that the number and the size of spines were enhanced in anterior cingulate (aCC) and infralimbic (ILC) cortices 36 d following contextual fear conditioning. Upon extinction, aCC spine density returned to baseline, but the enhanced proportion of large spines did not. Differently, ILC spine density remained elevated, but the size of spines decreased dramatically. Thus, extinction partially erases the remote memory network, suggesting that the preserved network properties might sustain reactivation of extinguished conditioned fear.

Purpose 18F-Fluoride PET/CT is a relatively undervalued diagnostic test to measure bone metabolism in bone diseases. Hyperostosis cranialis interna (HCI) is a (hereditary) bone disease characterised by endosteal hyperostosis and osteosclerosis of the skull and the skull base. Bone overgrowth causes entrapment and dysfunction of several cranial nerves. The aim of this study is to compare standardised uptake values (SUVs) at different sites in order to quantify bone metabolism in the affected anatomical regions in HCI patients. Methods Nine affected family members, seven non-affected family members and nine non-HCI non-family members underwent 18F-fluoride PET/CT scans. SUVs were systematically measured in the different regions of interest: frontal bone, sphenoid bone, petrous bone and clivus. Moreover, the average 18F-fluoride uptake in the entire skull was measured by assessing the uptake in axial slides. Visual assessment of the PET scans of affected individuals was performed to discover the process of disturbed bone metabolism in HCI. Results 18F-Fluoride uptake is statistically significantly higher in the sphenoid bone and clivus regions of affected family members. Visual assessment of the scans of HCI patients is relevant in detecting disease severity and the pattern of disturbed bone metabolism throughout life. Conclusion 18F-Fluoride PET/CT is useful in quantifying the metabolic activity in HCI and provides information about the process of disturbed bone metabolism in this specific disorder. Limitations are a narrow window between normal and pathological activity and the influence of age. This study emphasises that 18F-fluoride PET/CT may also be a promising diagnostic tool for other metabolic bone disorders, even those with an indolent course.

Objectives Ultrasound-guided foam sclerotherapy (UGFS) is a technique in which a mixture of sclerosing drug and gas is used to treat varicose veins. Several authors have demonstrated transient systemic effects after UGFS. These effects are not well understood but probably originate from a systemic distribution of the sclerosing foam. Therefore, safety measures have been developed to prevent foam from flowing into the deep venous system. The aim of the study is to evaluate whether blockage of the saphenofemoral (SF) junction by either manual compression or surgical ligation prevents microbubbles from leaking into the deep venous circulation. Methods To detect the distribution of microbubbles, radioactive pertechnetate ( 99m TcO 4 − ) was added to the foam solution. Initially, in vitro trials were performed in the laboratory to investigate the effect of 99m Tc on foam stability. The time taken for foam to liquefy was measured for foam alone and for the mixture with 99m Tc. In subsequent research, eight varicose great saphenous veins (GSVs) were treated by UGFS. In three patients, this treatment was preceded by surgical ligation of the SF junction. In three patients, the groin was manually compressed during UGFS. In two patients, UGFS was performed without compression of the groin. Results In vitro , 99m Tc did not influence foam stability; after 2.6 min all foam had reduced to liquid, regardless of whether 99m Tc had been added or not. In vivo trials showed that all patients showed a decrease in the cumulative amount of 99m Tc detected in the GSV following polidocanol- 99m Tc mixture injection. However, the decrease of radioactivity was slightly reduced when compression or ligation of the SF junction was performed. Conclusions Blocking the SF junction during UGFS using either manual compression or ligation does not prevent, but may reduce the flow of foam into the femoral vein.

Introduction The clinical feasibility of noninvasive imaging of interstitial alterations after myocardial infarction (MI) was assessed using a technetium-99m-labeled RGD imaging peptide (RIP). In experimental studies, RIP has been shown to target integrins associated with collagen-producing myofibroblasts (MFB). Methods and Results Ten patients underwent myocardial perfusion imaging (MPI) within the first week after MI. At 3 and 8 weeks after MI, RIP was administered intravenously and SPECT images acquired for interstitial imaging. RIP imaging was compared to initial MPI and to the extent of scar formation defined by late gadolinium-enhanced (LGE) cardiac magnetic resonance (CMR) imaging 1 year after MI. RIP uptake was observed in 7 of the 10 patients at both 3 and 8 weeks. Although, RIP uptake corresponded to areas of perfusion defects, it usually extended beyond the infarct zone to a variable extent; 2 of 7 patients showed tracer uptake throughout myocardium. In all positive cases, RIP uptake was similar to the extent of scar observed at 1 year by LGE-CMR imaging. Conclusion This study demonstrates that RGD-based imaging early after MI may predict the eventual extent of scar formation, which often exceeds initial MPI deficit but colocalizes with LGE in CMR imaging performed subsequently.

PURPOSE: To evaluate the results of selective nodal irradiation on basis of (18)F-deoxyglucose positron emission tomography (PET) scans in patients with limited-disease small-cell lung cancer (LD-SCLC) on isolated nodal failure.METHODS AND MATERIALS: A prospective study was performed of 60 patients with LD-SCLC. Radiotherapy was given to a dose of 45 Gy in twice-daily fractions of 1.5 Gy, concurrent with carboplatin and etoposide chemotherapy. Only the primary tumor and the mediastinal lymph nodes involved on the pretreatment PET scan were irradiated. A chest computed tomography (CT) scan was performed 3 months after radiotherapy completion and every 6 months thereafter.RESULTS: A difference was seen in the involved nodal stations between the pretreatment (18)F-deoxyglucose PET scans and computed tomography scans in 30% of patients (95% confidence interval, 20-43%). Of the 60 patients, 39 (65%; 95% confidence interval [CI], 52-76%) developed a recurrence; 2 patients (3%, 95% CI, 1-11%) experienced isolated regional failure. The median actuarial overall survival was 19 months (95% CI, 17-21). The median actuarial progression-free survival was 14 months (95% CI, 12-16). 12% (95% CI, 6-22%) of patients experienced acute Grade 3 (Common Terminology Criteria for Adverse Events, version 3.0) esophagitis.CONCLUSION: PET-based selective nodal irradiation for LD-SCLC resulted in a low rate of isolated nodal failures (3%), with a low percentage of acute esophagitis. These findings are in contrast to those from our prospective study of CT-based selective nodal irradiation, which resulted in an unexpectedly high percentage of isolated nodal failures (11%). Because of the low rate of isolated nodal failures and toxicity, we believe that our data support the use of PET-based SNI for LD-SCLC.

BACKGROUND: Studies in animals indicate that brown adipose tissue is important in the regulation of body weight, and it is possible that individual variation in adaptive thermogenesis can be attributed to variations in the amount or activity of brown adipose tissue. Until recently, the presence of brown adipose tissue was thought to be relevant only in small mammals and infants, with negligible physiologic relevance in adult humans. We performed a systematic examination of the presence, distribution, and activity of brown adipose tissue in lean and obese men during exposure to cold temperature. Brown-adipose-tissue activity was studied in relation to body composition and energy metabolism. METHODS: We studied 24 healthy men--10 who were lean (body-mass index [BMI] [the weight in kilograms divided by the square of the height in meters], < 25) and 14 who were overweight or obese (BMI, > or = 25)--under thermoneutral conditions (22 degrees C) and during mild cold exposure (16 degrees C). Putative brown-adipose-tissue activity was determined with the use of integrated (18)F-fluorodeoxyglucose positron-emission tomography and computed tomography. Body composition and energy expenditure were measured with the use of dual-energy x-ray absorptiometry and indirect calorimetry. RESULTS: Brown-adipose-tissue activity was observed in 23 of the 24 subjects (96%) during cold exposure but not under thermoneutral conditions. The activity was significantly lower in the overweight or obese subjects than in the lean subjects (P=0.007). BMI and percentage of body fat both had significant negative correlations with brown adipose tissue, whereas resting metabolic rate had a significant positive correlation. CONCLUSIONS: The percentage of young men with brown adipose tissue is high, but its activity is reduced in men who are overweight or obese. Brown adipose tissue may be metabolically important in men, and the fact that it is reduced yet present in most overweight or obese subjects may make it a target for the treatment of obesity.

Reelin, a large extracellular matrix glycoprotein, is down-regulated in the brain of schizophrenic patients and of heterozygous reeler mice (rl/+). The behavioral phenotype of rl/- mice, however, matches only partially the schizophrenia hallmarks.We recently reported (Marrone et al., Eur J Neurosci 24:20062-22070, 2006) that homozygous reeler mutants (rl/rl) exhibit reduced density of parvalbumin-positive (PV+) GABAergic interneurons in anatomically circumscribed regions of the neostriatum. Assuming that in rl/+ mice may also show regional reduction of striatal GABAergic interneurons, behavioral impairments should selectively emerge in tasks depending on specifically altered striatal circuits.We mapped the density of striatal PV+ interneurons in rl/+ and wild-type (+/+) mice and measured their performance in tasks depending on distinct striatal subregions.Our findings show that, contrary to what would be expected on the basis of gene dosage criteria, the striatal regions in which rl/rl mice exhibited decreased density of PV+ interneurons were either unaltered (rostral striatum) or equally altered (dorsomedial and ventromedial intermediate striatum, caudal striatum) in rl/+ mice. The anatomical findings were paralleled by behavioral deficits in fear extinction and latent inhibition, respectively, requiring the dorsomedial and ventromedial striatal regions. Conversely, active avoidance performance, which requires the dorsolateral region, was unaffected.Reelin haploinsufficiency alters the density of PV+ neurons in circumscribed regions of the striatum and selectively disrupts behaviors sensitive to dysfunction of these targeted regions. This aspect should be considered when designing experiments aimed at evaluating the impact of reelin haploinsufficiency in schizophrenia-associated cognitive disturbances in rl/+ mutants.

The phosphodiesterase type IV inhibitor rolipram increases cAMP response element-binding protein (CREB) phosphorylation and exerts neuroprotective effects in both the quinolinic acid rat model of Huntington's disease (DeMarch et al., 2007) and the R6/2 mouse including sparing of striatal neurons, prevention of neuronal intranuclear inclusion formation and attenuation of microglial reaction (DeMarch et al., 2008). In this study, we sought to determine if rolipram has a beneficial role in the altered distribution of CREB binding protein in striatal spiny neurons and in the motor impairments shown by R6/2 mutants. Moreover, we investigated whether rolipram treatment altered the degeneration of parvalbuminergic interneurons typical of Huntington's disease (Fusco et al., 1999). Transgenic mice and their wild-type controls from a stable colony maintained in our laboratory were treated with rolipram (1.5 mg/kg) or saline daily starting from 4 weeks of age. The cellular distribution of CREB binding protein in striatal spiny neurons was assessed by immunofluorescence, whereas parvalbuminergic neuron degeneration was evaluated by cell counts of immunohistochemically labeled tissue. Motor coordination and motor activity were also examined. We found that rolipram was effective in preventing CREB binding protein sequestration into striatal neuronal intranuclear inclusions, sparing parvalbuminergic interneurons of R6/2 mice, and rescuing their motor coordination and motor activity deficits. Our findings demonstrate the possibility of reversing pharmacologically the behavioral and neuropathological abnormalities of symptomatic R6/2 mice and underline the potential therapeutic value of phosphodiesterase type IV inhibitors in Huntington's disease.

Synaptic activity-dependent phosphorylation of the transcription factor cAMP response element binding protein (CREB) leads to CREB-dependent gene transcription, a process thought to underlie long-term hippocampal synaptic plasticity and memory formation. We previously reported that increasing CREB activity in glutamatergic neurons enhances synaptic plasticity and neuronal excitability. Whether these modifications are sufficient to promote hippocampal-dependent memory formation was not determined. Here, we provide direct evidence that a brief increase in CREB-dependent transcription in either CA1 or DG neurons, using in vivo viral vectors, is sufficient to boost memory for contextual representations, as tested in the contextual fear conditioning task, without affecting motor, pain, or anxiety behaviors. © 2008 Wiley-Liss, Inc.

Tg2576 mice over-expressing human mutant APP (hAPPswe) show progressive impairments in hippocampal plasticity and episodic memory while fronto-striatal plasticity and procedural memory remain intact. Here we examine the status of synaptic connectivity in the hippocampus and the dorsolateral striatum (DLS) of 3- and 15-month-old Tg2576 and wild-type mice through the analysis of single dendritic spines microanatomy. We found that, in each region, all mice showed a global reduction in the size of spines as a function of age. Ageing mutants, however, exhibited smaller spines with shorter necks on CA1 pyramidal neurons but larger spines with longer necks on DLS spiny neurons compared to their age-matched wild-type controls. Our findings indicate that hippocampal and DLS dendritic spines in hAPPswe mutants undergo a different pattern of morphological changes over time and point to minor alterations in the microanatomy of DLS spines as a compensatory mechanism maintaining procedural abilities in the ageing mutants.

To evaluate bone blood flow and bone formation in patients after total hip revision surgery with impacted bone grafting using H2 15O and [18F]fluoride positron emission tomography (PET). To asses bone blood flow and bone metabolism in bone allograft after impaction grafting, four patients treated with total hip revision surgery were enrolled prospectively in this study. Six patients scheduled for primary hip arthroplasties were included as a control group. The study protocol consisted of three H2 15O and [18F]fluoride PET scans in each patient. Bone blood flow increased significantly compared to the preoperative state in patients treated for primary hip arthroplasty. In patients undergoing revision surgery, bone blood flow was twofold to threefold higher compared to the preoperative state, but did not reach significance. Bone metabolism in patients undergoing revision was threefold higher 2 weeks postoperatively compared to the primary hip group. We found a significant correlation between Ki and bone blood flow. Allogeneic bone grafts induce a higher rate of local periprosthetic bone formation compared to periprosthetic bone formation after a primary total hip placement. In vivo coupling between bone blood flow and bone metabolism suggests that bone metabolism in allogeneic bone grafts may partly rely on bone blood flow adaptations.

Aims: On the basis of an MRI study it has been suggested that subendocardial hypoperfusion is present in patients with cardiac syndrome X. However, further work is required to test whether these findings can be generalized. Methods and results: MRI was used to visually and semi-quantitatively assess subendocardial and subepicardial perfusion, at rest and during an infusion of adenosine, in 20 patients with angina pectoris and normal coronary angiograms. A myocardial perfusion index (MPI) was calculated using the normalized upslope of myocardial signal enhancement. An index for myocardial perfusion reserve (MPRI) was calculated by dividing the MPI values at maximal vasodilatation by the values at rest. The MPI in our study population increased significantly during adenosine infusion in both the subendocardium (from 0.091 ± 0.020 to 0.143 ± 0.030; P < 0.001) and the subepicardium (from 0.074 ± 0.017 to 0.135 ± 0.03; P < 0.001). The overall MPRI was 1.83 ± 0.50. Conclusion: The results show that patients with chest pain and normal coronary angiograms had significant perfusion responses to adenosine in both the subendocardium and subepicardium. In the present study we found no evidence for subendocardial hypoperfusion in these patients. © The European Society of Cardiology 2007. All rights reserved.

This study tries to shed light on the paradoxical finding that two inbred strains of mice C57BL/6 (C57) and DBA/2 (DBA), with differences in hippocampal function, perform similarly in the water maze (WM). Mice from both strains were trained on WM protocols permitting or preventing the use of vestibular signals. Hippocampal involvement in performance was then assessed by estimation of post-training mossy fiber (MF) synaptogenesis. We found that C57 and DBA mice performed similarly when both visual and vestibular information were available but only C57 mice exhibited new MF synapses. Disruption of vestibular inputs impaired performance in DBA mice but not in C57 mice which still exhibited a post-training increase of hippocampal MF synaptic terminals. This strain-specific dissociation indicates that DBA mice can navigate successfully by relying on vestibular signals without engaging their hippocampus. In contrast, vestibular signals are irrelevant for C57 mice since their suppression neither disrupts their behavior nor prevents the formation of new hippocampal synapses. These findings suggest some caution is required in considering performance on standard WM protocols as an index of hippocampus-based learning. Estimating the extent of post-training mossy fiber synaptogenesis would be helpful in solving this issue.

The progression of activity and structural changes in the anterior cingulate cortex during remote contextual fear memory formation was measured by imaging c-fos expression and dendritic spines following retrieval tests administered at six post-training time points (days 1, 5, 7, 14, 21, 36). Here we report that conditioned mice exhibit robust freezing at each time point. C-fos expression starts to augment on day 5, showing a monotonic increase over the successive time points, and then stabilized in relation to the higher freezing scores. The first significant increase in mean spine density emerges on day 7. By day 14, the net number of spines remained stable, yet the distribution of single neuron spine density becomes progressively more homogeneous. Our findings reveal that activity changes precede structural remodeling of neurons in the neocortex while remodeling coherence develops gradually in cortical neuron ensembles.

Amyloid precursor protein (APP) is overexpressed in familiar and sporadic Alzheimer Disease (AD) patients suggesting that, in addition to abnormalities in APP cleavage, enhanced levels of APP full length might contribute to the pathology. Based on data showing that the two RNA binding proteins (RBPs), Fragile-X Mental Retardation Protein (FMRP) and heteronuclear Ribonucleoprotein C (hnRNP C), exert an opposite control on APP translation, we have analyzed whether expression and translation of these two RBPs vary in relation to changes in APP protein and mRNA levels in the AD brain at 1, 3, and 6 months of age. Here, we show that, as expected, human APP is overexpressed in hippocampal total extract from Tg2576 mice at all age points. APP overexpression, however, is not stable over time but reaches its maximal level in 1-month-old mutants in association with the stronger (i) reduction of FMRP and (ii) augmentation of hnRNP C. APP levels then decrease progressively as a function of age in close relationship with the gradual normalization of FMRP and hnRNP C levels. Consistent with the mouse data, expression of FMRP and hnRNP C are, respectively, decreased and increased in hippocampal synaptosomes from sporadic AD patients. Our findings identify two RBP targets that might be manipulated for reducing abnormally elevated levels of APP in the AD brain, with the hypothesis that acting upstream of amyloidogenic processing might contribute to attenuate the amyloid burden.

Genetic mutations have been identified as the cause of inherited cancer risk in some colon cancer; these mutations are estimated to account for only 5–6 % of colorectal cancer (CRC) cases overall. Up to 25–30 % of patients have a family history of CRC that suggests a hereditary component, common exposures among family members, or a combination of both. Cancers in people with a hereditary predisposition typically occur at an earlier age than in sporadic cases. A predisposition to CRC may include a predisposition to other cancers, such as endometrial cancer. We describe genetics, current diagnosis and management of CRC hereditary syndromes pointing to a multidisciplinary approach to achieve the best results in patients and family outcomes.

et al., Male breast cancer (MBC) is a rare disease that represents, This study has been supported, in part, by grants from the Asociación Española Contra el Cáncer, Spanish Health Research Fund; Carlos III Health Institute; Catalan Health Institute and Autonomous Government of Catalonia; Mutua Madrileña Foundation (FMMA); Spanish Association against Cancer (AECC08); FMM Foundation given to AV and the following projects: ISCIIIRETIC; RD06/0020/1051; RD12/0036/008; PI10/01422; PI10/00748; PI13/00285; 2009SGR290; RTICC 06/0020/1060; FISPI12/00070 and 10PXIB 9101297PR.

Huntington's disease (HD) is a fatal hereditary neurodegenerative disease causing degeneration of striatal spiny neurons, whereas cholinergic interneurons are spared. This cell-type specific pathology produces an array of abnormalities including involuntary movements, cognitive impairments, and psychiatric disorders. Although the genetic mutation responsible for HD has been identified, little is known about the early synaptic changes occurring within the striatal circuitry at the onset of clinical symptoms. We therefore studied the synaptic plasticity of spiny neurons and cholinergic interneurons in two animal models of early HD. As a pathogenetic model, we used the chronic subcutaneous infusion of the mitochondrial toxin 3-nitropropionic acid (3-NP) in rats. This treatment caused striatal damage and impaired response flexibility in the cross-maze task as well as defective extinction of conditioned fear suggesting a perseverative behavior. In these animals, we observed a loss of depotentiation in striatal spiny neurons and a lack of long-term potentiation (LTP) in cholinergic interneurons. These abnormalities of striatal synaptic plasticity were also observed in R6/2 transgenic mice, a genetic model of HD, indicating that both genetic and phenotypic models of HD show cell-type specific alterations of LTP. We also found that in control rats, as well as in wild-type (WT) mice, depotentiation of spiny neurons was blocked by either scopolamine or hemicholinium, indicating that reversal of LTP requires activation of muscarinic receptors by endogenous acetylcholine. Our findings suggest that the defective plasticity of cholinergic interneurons could be the primary event mediating abnormal functioning of striatal circuits, and the loss of behavioral flexibility typical of early HD might largely depend on cell-type specific plastic abnormalities.

The possibility of detecting progressive changes in cognitive function reflecting the spatio-temporal pattern of beta-amyloid peptide (Abeta) deposition was investigated in Tg2576 mice overexpressing the human mutant amyloid precursor protein (hAPP). Here, we show that at 7 months of age, Tg2576 mice exhibited a selective deficit in hippocampus-based operations including a defective habituation of object exploration, a lack of reactivity to spatial novelty and a disruption of allothetic orientation in a cross-shaped maze. At 14 months of age, Tg2576 mice displayed a more extended pattern of behavioral abnormalities, because they failed to react to object novelty and exclusively relied on motor-based orientation in the cross-shaped maze. However, an impaired reactivity to spatial and object novelty possibly reflecting age-related attention deficits also emerged in aged wild-type mice. These findings further underline that early cognitive markers of AD can be detected in Tg2576 mice before Abeta deposition occurs and suggest that as in humans, cognitive deterioration progressively evolves from an initial hippocampal syndrome to global dementia because of the combined effect of the neuropathology and aging.

Patients suspected of recurrent differentiated thyroid cancer (DTC) may require "blind" 131I therapy, with the disadvantage of unpredictable efficacy and toxicity. Alternatively, positron emission tomography (PET) with [18F]fluorodeoxyglucose (18FDG) can document the recurrence, thereby rationalizing therapeutic options. This study compared 18FDG uptake in vivo with biomarkers expected to be involved in the underlying biological mechanisms. Additionally, we investigated whether such features were present in the primary tumors. Preoperatively, 19 patients with recurrent DTC underwent PET. 18FDG uptake was compared with histological and immunohistochemical features in surgical specimens of recurrent and primary tumor. Thirteen of 19 recurrences were positive at PET, and 18FDG uptake was associated with the expression of hexokinase type I (HK I; P = 0.011). All lesions with HK I overexpression were positive on 18FDG PET. HK I expression in the original primary tumor and the metastases was similar in 82% (p = 0.648; P = 0.005). In suspected recurrent thyroid cancer, stratification for 18FDG PET may benefit from pretest immunohistochemical analysis of HK I of the primary tumor, as HK I negativity indicates a low likelihood of PET positivity.

C57BL/6 and DBA/2 mice with cannulae inserted bilaterally in the dorsal hippocampus or the dorsolateral striatum were released from the south arm of a cross maze and trained to find food in the east arm. Probe trials on which mice were released from the north arm were given following short or prolonged training. Prior to the probe trials, mice received intra-hippocampal or intra-striatal injections of lidocaine or saline. Results show that saline-injected C57BL/6 were fundamentally place learners whereas saline-injected DBA/2 mice did not engage any predominant system. Inactivating the hippocampus or the dorsolateral striatum in C56BL/6 mice disrupted place learning without promoting response learning. Inactivating the same brain sites in DBA/2 mice did not affect their behaviour. Thus, contrary to that observed in rats, disrupting the neural substrate of one memory system can abolish learning in that system but does not promote the use of another system in these genotypes.

Solitary pulmonary nodule (SPN, intraparenchymal lung mass

Purpose: To test the hypothesis that radiation-induced, transient G2/M arrest could potentially sensitize tumor cells to a subsequent, well-timed radiation dose. Methods: PC-3 human prostate cancer cells were treated using either radiotherapy or 186Re-labeled hydroxyethylidene diphosphonate (186Re-HEDP) treatment in different combinations. The resulting cell cycle shift and clonogenic cell death were analyzed by DNA flow cytometry and colony forming cell assay, respectively. Results: Radiation doses of 4 Gy and 8 Gy induced a transient G2/M arrest, with a maximum after approximately 16 h. The presence of 2 mM pentoxifylline effectively abrogated this radiation-induced G2 M arrest, confirming a cell-cycle checkpoint-mediated effect. A second dose of 4 Gy, timed at the height of the G2/M arrest, significantly increased clonogenic cell-kill compared to delivery after a suboptimal interval (10 h, 20 h or 25 h after the first radiation fraction). Moreover, timed second doses of 2 Gy, 3 Gy or 4 Gy yielded improved normalized treatment effects compared to non-pretreated control. Radionuclide treatment of PC-3 cells, using 186Re-HEDP (0.74 MBq/ml and 1.48 MBq/ml; total dose: 4.1 and 8.2 Gy, respectively) also induced a dose-dependent G2/M accumulation, which sensitized the cells to a subsequent external radiation dose of 2 Gy or 4 Gy. The observed pattern of cell-cycle shift towards a predominance of the G2/M phase is in line with the lack of functional p53 in this cell line. Conclusions: Radiation-induced cell-cycle shift was shown to effectively confer increased radiosensitivity to prostate tumor cells. Optimally timed combination of radiotherapy and radionuclide therapy could thus significantly increase treatment efficacy.

C57 and DBA mice were trained in a crossed maze to assess possible strain differences in place or response learning as a function of training duration (8 or 17 days) and extramaze cueing conditions. The first condition consisted of a diffuse visually cued environment (rich cueing). The second was the same plus an explicit visual cue marking the direction of the baited arm (rich cueing plus cue). The third was a featureless environment (poor cueing). During training, mice were released from the south arm and rewarded in the east arm. Probe trials on which mice were released from the north arm and allowed to choose either the east (place learning) or the west (response learning) arm were given either on the ninth (PT1) or the eighteenth (PT2) days. Strain x context differences in the activation of the dorsal hippocampus and the dorsolateral striatum were examined by analyzing Fos expression following each probe trial. Results first showed that C57 were essentially place-learners, whereas no learning modality was predominant in DBA, except on the PT2 run with the explicit cue available. Examination of Fos expression in C57 trained under "rich cueing" and "rich cueing plus cue" conditions revealed a strong and parallel increase of immunoreactivity in the hippocampus and dorsolateral striatum following PT1 that decreased under PT2. In that strain, the similar time-course variation of Fos expression in both areas suggests a simultaneous involvement of hippocampal- and striatal-based learning mechanisms, even if those controlled by the hippocampus were prevailing on those controlled by the dorsolateral striatum. In DBA mice, however, the absence of any preferential learning modality was associated with 1) a consistent hippocampal activation persistent across probe trials, and 2) a global superior activation of the dorsolateral striatum. Distinct patterns of Fos expression were therefore associated with every strain-specific learning modality. In each strain, however, each modality was found to be remarkably stable, whatever the training duration and the cueing conditions.

Latent inhibition (LI) consists of decreased associative strength between an elemental stimulus (CS: tone) paired with an unconditioned stimulus (US: footshock) following non-reinforced pre-exposure to the tone. In view of the differences shown by C57BL/6 (C57) and DBA/2 (DBA) mice in processing elemental vs. configural stimuli, the present experiments were designed (1) to assess whether these differences were likely to interfere with the capability of each strain to show LI, and (2) to verify the extent to which lesions of the nucleus accumbens, which have been reported to enhance attention towards contextual stimuli under certain conditions, might interfere with the development of LI. C57 and DBA mice with Nacc or sham lesions were given two periods (4 or 7 days) of pre-exposure to a CS (tone) then subjected to two CS-US pairings given on a single day. On the day after, freezing to the tone was examined in each group. Results show that, following the shorter period of pre-exposure, LI developed in sham-lesioned DBA but did not in sham-lesioned C57. Nacc lesions, however, were found (1) to block LI in DBA but (2) to promote LI in C57. After the longer period of pre-exposure LI was observed in both strain and lesion conditions. In general, these results confirm that strain differences in processing the tone as a single elemental cue (DBA) or, alternatively, as a part of a contextual configural stimulus (C57) can interfere with the development of LI. In addition, they indicate that Nacc lesions, that are susceptible to increase attention to the background, might modify the salience of the tone and produce opposite effect on LI according to the strain specialisation to show elemental or configural responding.

The brain cytoplasmic (BC1) RNA is a non-coding RNA (ncRNA) involved in neuronal translational control. Absence of BC1 is associated with altered glutamatergic transmission and maladaptive behavior. Here, we show that pyramidal neurons in the barrel cortex of BC1 knock out (KO) mice display larger excitatory postsynaptic currents and increased spontaneous activity in vivo. Furthermore, BC1 KO mice have enlarged spine heads and postsynaptic densities and increased synaptic levels of glutamate receptors and PSD-95. Of note, BC1 KO mice show aberrant structural plasticity in response to whisker deprivation, impaired texture novel object recognition and altered social behavior. Thus, our study highlights a role for BC1 RNA in experience-dependent plasticity and learning in the mammalian adult neocortex, and provides insight into the function of brain ncRNAs regulating synaptic transmission, plasticity and behavior, with potential relevance in the context of intellectual disabilities and psychiatric disorders., Brain cytoplasmic (BC1) RNA is a non-coding RNA that has been implicated in translational regulation, seizure, and anxiety. Here, the authors show that in the cortex, BC1 RNA is required for sensory deprivation-induced structural plasticity of dendritic spines, as well as for correct sensory learning and social behaviors.

Extreme hypernatremia in intensive care unit are frequently associated with a poor prognosis and their treatment, when associated with acute renal failure, is not consensual. We report the case of a 39-year-old man admitted in our intensive care unit for coma who presented extreme hyperosmolar hypernatremia (sodium 180 mmol/L, osmolarity 507 mOsm/L) associated with acute renal failure (urea 139.3 mmol/L, creatinine 748 μmol/L) and many other metabolic abnormalities. He was treated with hypotonic fluid administration and continuous renal replacement therapy (veno-venous hemodiafiltration) using an industrial dialysate fluid. Natremia was controlled by modulating intravenous water and sodium intake according to biological data. After 10 days, continuous renal replacement therapy was stopped and neurological exam was normal. Continuous veno-venous hemodiafiltration may be useful for treatment of extreme hypernatremia by allowing gradual correction of fluid and electrolyte disorders.

Objective: In myocardial perfusion single-photon emission computed tomography (SPECT), abdominal activity often interferes with the evaluation of perfusion in the inferior wall, especially after pharmacological stress. In this randomized study, we examined the effect of carbonated water intake versus still water intake on the quality of images obtained during myocardial perfusion images (MPI) studies. Methods: A total of 467 MIBI studies were randomized into a carbonated water group and a water group. The presence of intestinal activity adjacent to the inferior wall was evaluated by two observers. Furthermore, a semiquantitative analysis was performed in the adenosine subgroup,using a count ratio of the inferior myocardial wall and adjacent abdominal activity. Results: The need for repeated SPECT in the adenosine studies was 5.3 % in the carbonated water group versus 19.4 % in the still water group (p = 0.019). The inferior wall-to-abdomen count ratio was significantly higher in the carbonated water group compared to the still water group (2.11 ± 1.00 vs. 1.72 ± 0.73, p\0.001). The effect of carbonated water during rest and after exercise was not significant. Conclusions: This randomized study showed that carbonated water significantly reduced the interference of extra-cardiac activity in adenosine SPECT MPI. Keywords: Extra-cardiac radioactivity, Myocardial SPECT, Image quality enhancement, Carbonated water

The effect of nucleus accumbens lesions on radial maze performance of C57BL/6 and DBA/2 mice was assessed under distinct extra-maze cuing conditions. Among sham-lesioned mice, C57BL/6 performed better under rich than poor cuing conditions whereas DBA performed in the same fashion under both conditions. In C57BL/6, a disruptive effect of lesions was found only in mice tested under rich cuing. Conversely, in DBA/2, the lesions improved performance under poor cuing and disrupted performance under rich cuing. In that strain, a possible lesion-induced enhancement of attention to background stimuli improving performance under poor cuing but producing interference under rich cuing is suggested. In general, the lesions effect seemed to depend on the strain predisposition to implement configural or cue-based responding.