45 results on '"Risterucci C"'
Search Results
2. A new perspective for schizophrenia: TAAR1 agonists reveal antipsychotic- and antidepressant-like activity, improve cognition and control body weight
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Revel, F G, Moreau, J-L, Pouzet, B, Mory, R, Bradaia, A, Buchy, D, Metzler, V, Chaboz, S, Groebke Zbinden, K, Galley, G, Norcross, R D, Tuerck, D, Bruns, A, Morairty, S R, Kilduff, T S, Wallace, T L, Risterucci, C, Wettstein, J G, and Hoener, M C
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- 2013
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3. Effects of aripiprazole/OPC-14597 on motor activity, pharmacological models of psychosis, and brain activity in rats
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Nordquist, R. E., Risterucci, C., Moreau, J. L., von Kienlin, M., Künnecke, B., Maco, M., Freichel, C., Riemer, C., and Spooren, W.
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- 2008
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4. S4 NEUROIMAGING IN ANIMAL MODELS OF PSYCHIATRIC DISORDERS
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Risterucci, C., Von Kienlin, M., and Moreau, J.-L.
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- 2005
5. MEDIAL PREFRONTAL CORTEX LESIONS AND REACTION TIME IN RATS
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Risterucci, C., Terramorsi, D., and Amalric, M.
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- 1998
6. Sparse multivariate measures of similarity between intra-modal neuroimaging datasets
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Rosa, M.J., Mehta, M.A., Merlo Pich, E., Risterucci, C., Zelaya, F., Reinders, A.A.T.S., Williams, S., Dazzan, P., Doyle, O.M., and Marquand, A.F.
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220 Statistical Imaging Neuroscience - Abstract
Contains fulltext : 151733.pdf (Publisher’s version ) (Open Access) An increasing number of neuroimaging studies are based on either combining more than one data modality (inter-modal) or combining more than one measurement from the same modality (intra-modal). To date, most intra-modal studies using multivariate statistics have focused on differences between datasets, for instance relying on classifiers to differentiate between effects in the data. However, to fully characterize these effects, multivariate methods able to measure similarities between datasets are needed. One classical technique for estimating the relationship between two datasets is canonical correlation analysis (CCA). However, in the context of high-dimensional data the application of CCA is extremely challenging. A recent extension of CCA, sparse CCA (SCCA), overcomes this limitation, by regularizing the model parameters while yielding a sparse solution. In this work, we modify SCCA with the aim of facilitating its application to high-dimensional neuroimaging data and finding meaningful multivariate image-to-image correspondences in intra-modal studies. In particular, we show how the optimal subset of variables can be estimated independently and we look at the information encoded in more than one set of SCCA transformations. We illustrate our framework using Arterial Spin Labeling data to investigate multivariate similarities between the effects of two antipsychotic drugs on cerebral blood flow. 10 p.
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- 2015
7. Estimating multivariate similarity between neuroimaging datasets with sparse canonical correlation analysis: an application to perfusion imaging
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Rosa, M.J., Mehta, M.A., Pich, E.M., Risterucci, C., Zelaya, F., Reinders, A.A.T.S., Williams, S.C.R., Dazzan, P., Doyle, O.M., and Marquand, A.F.
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Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7] - Abstract
Contains fulltext : 152198.pdf (Publisher’s version ) (Open Access) An increasing number of neuroimaging studies are based on either combining more than one data modality (inter-modal) or combining more than one measurement from the same modality (intra-modal). To date, most intra-modal studies using multivariate statistics have focused on differences between datasets, for instance relying on classifiers to differentiate between effects in the data. However, to fully characterize these effects, multivariate methods able to measure similarities between datasets are needed. One classical technique for estimating the relationship between two datasets is canonical correlation analysis (CCA). However, in the context of high-dimensional data the application of CCA is extremely challenging. A recent extension of CCA, sparse CCA (SCCA), overcomes this limitation, by regularizing the model parameters while yielding a sparse solution. In this work, we modify SCCA with the aim of facilitating its application to high-dimensional neuroimaging data and finding meaningful multivariate image-to-image correspondences in intra-modal studies. In particular, we show how the optimal subset of variables can be estimated independently and we look at the information encoded in more than one set of SCCA transformations. We illustrate our framework using Arterial Spin Labeling data to investigate multivariate similarities between the effects of two antipsychotic drugs on cerebral blood flow.
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- 2015
8. Species-conserved reconfigurations of brain network topology induced by ketamine
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Becker, R, primary, Braun, U, additional, Schwarz, A J, additional, Gass, N, additional, Schweiger, J I, additional, Weber-Fahr, W, additional, Schenker, E, additional, Spedding, M, additional, Clemm von Hohenberg, C, additional, Risterucci, C, additional, Zang, Z, additional, Grimm, O, additional, Tost, H, additional, Sartorius, A, additional, and Meyer-Lindenberg, A, additional
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- 2016
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9. Excitotoxic lesions of the prelimbic-infralimbic areas of the rodent prefrontal cortex disrupt motor preparatory processes
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Risterucci, C., Terramorsi, D., Nieoullon, A., Amalric, Marianne, Institut de Biologie du Développement de Marseille (IBDM), and Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS)
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[SDV.BC]Life Sciences [q-bio]/Cellular Biology - Published
- 2003
10. P.1.g.008 Sub-anesthetic ketamine modulates intrinsic BOLD connectivity between the hippocampus and the prefrontal cortex in the rat
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Gass, N., primary, Schwarz, A.J., additional, Sartorius, A., additional, Schenker, E., additional, Risterucci, C., additional, Spedding, M., additional, Zheng, L., additional, Meyer-Lindenberg, A., additional, and Weber-Fahr, W., additional
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- 2013
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11. P.2.003 Sub-anaesthetic ketamine modulates intrinsic blood oxygen level-dependent (BOLD) connectivity between the hippocampus and the prefrontal cortex in the rat
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Gass, N., primary, Sartorius, A., additional, Schwarz, A.J., additional, Schenker, E., additional, Risterucci, C., additional, Spedding, M., additional, Zheng, L., additional, Meyer-Lindenberg, A., additional, and Weber-Fahr, W., additional
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- 2013
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12. The low-frequency blood oxygenation level-dependent functional connectivity signature of the hippocampal–prefrontal network in the rat brain
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Schwarz, A.J., primary, Gass, N., additional, Sartorius, A., additional, Zheng, L., additional, Spedding, M., additional, Schenker, E., additional, Risterucci, C., additional, Meyer-Lindenberg, A., additional, and Weber-Fahr, W., additional
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- 2013
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13. A new perspective for schizophrenia: TAAR1 agonists reveal antipsychotic- and antidepressant-like activity, improve cognition and control body weight
- Author
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Revel, F G, primary, Moreau, J-L, additional, Pouzet, B, additional, Mory, R, additional, Bradaia, A, additional, Buchy, D, additional, Metzler, V, additional, Chaboz, S, additional, Groebke Zbinden, K, additional, Galley, G, additional, Norcross, R D, additional, Tuerck, D, additional, Bruns, A, additional, Morairty, S R, additional, Kilduff, T S, additional, Wallace, T L, additional, Risterucci, C, additional, Wettstein, J G, additional, and Hoener, M C, additional
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- 2012
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14. P.1.e.007 Atypical and typical antipsychotics differentially reverse abnormal brain functional MRI signals in a neurodevelopmental model of schizophrenia
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Moreau, J.L., primary, Jeanneau, K., additional, and Risterucci, C., additional
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- 2006
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15. The metabotropic glutamate receptor subtype 5 antagonist MPEP and the Na+ channel blocker riluzole show different neuroprotective profiles in reversing behavioral deficits induced by excitotoxic prefrontal cortex lesions
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Risterucci, C., primary, Coccurello, R., additional, Banasr, M., additional, Stutzmann, J.M., additional, Amalric, M., additional, and Nieoullon, A., additional
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- 2006
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16. Antipsychotic treatment normalizes abnormal brain fMRI signals in an animal model of schizophrenia
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Risterucci, C, primary and Moreau, JL, additional
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- 2005
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17. S.04.07 Neuroimaging changes in an animal model of schizophrenia
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Risterucci, C., primary, Jeanneau, K., additional, Moreau, J.L., additional, Schoeppenthau, S., additional, Bielser, T., additional, Kuennecke, B., additional, and Von Kienlin, M., additional
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- 2004
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18. PREFRONTAL CORTEX LESIONS IN RATS AND POSSIBLE RELEVANCE TO SCHIZOPHRENIA
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Amalric, M., primary, Terramorsi, D., additional, and Risterucci, C., additional
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- 2000
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19. D2 DOPAMINE RECEPTOR BLOCKADE REVERSE THE DEFICITS INDUCED BY PREFRONTAL CORTICAL LESION ON REACTION TIME PERFORMANCE
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Risterucci, C., primary
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- 1999
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20. The metabotropic glutamate receptor subtype 5 antagonist MPEP and the Na+ channel blocker riluzole show different neuroprotective profiles in reversing behavioral deficits induced by excitotoxic prefrontal cortex lesions
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Risterucci, C., Coccurello, R., Banasr, M., Stutzmann, J.M., Amalric, M., and Nieoullon, A.
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AMYOTROPHIC lateral sclerosis , *EXCITATORY amino acids , *OPACITY (Optics) , *REACTION time - Abstract
Abstract: Overactivation of excitatory amino acid receptors has been involved in several neurodegenerative diseases. The present study aims at investigating the potential neuroprotective action of 2-methyl-6-(phenylethylnyl)-pyridine (MPEP), a selective non-competitive antagonist of metabotropic glutamate receptor subtype 5, and 2-amino-6-trifluoro methoxy-benzothiole (riluzole), a Na+ channel blocker exhibiting anti-glutamatergic properties, on the ibotenate-induced damage to the rat medial prefrontal cortex. The neuroprotective efficacy of these compounds was assessed on the recovery from behavioral deficits induced by prefrontal cortical excitotoxic lesions in a reaction time task. MPEP (3, 10 or 30mg/kg) or riluzole (2, 4 or 8mg/kg) was administered i.p. 30 min before and after medial prefrontal cortex lesions. As previously found, lesions to the medial prefrontal cortex significantly altered the motor preparatory processes involved in the reaction time task. These deficits were prevented by MPEP 3mg/kg and riluzole 2mg/kg while higher doses of either compound were ineffective. Furthermore, the neuron-specific nuclear protein immunostaining of the lesioned cortical area in animals treated with the efficient dose of either compound revealed that MPEP reduced the volume of the lesion whereas riluzole reversed the decrease of neuronal density within the lesioned area. Altogether, these results suggest a neuroprotective action of MPEP as well as riluzole at both behavioral and cellular levels on excitatory amino acid-induced toxicity. [Copyright &y& Elsevier]
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- 2006
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21. P.4.18 Neuroimaging changes in an animal model of schizophrenia
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Risterucci, C., Jeanneau, K., Schoeppenthau, S., Bielser, T., Kuennecke, B., Von Kienlin, M., and Moreau, J.L.
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- 2004
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22. PREFRONTAL CORTEX LESION OF RATS DISRUPT TIME ESTIMATION IN A REACTION TIME TASK.
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Risterucci, C., Terramorsi, D., and Amalric, M.
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- 1999
23. Ganaplacide (KAF156) plus lumefantrine solid dispersion formulation combination for uncomplicated Plasmodium falciparum malaria: an open-label, multicentre, parallel-group, randomised, controlled, phase 2 trial.
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Ogutu B, Yeka A, Kusemererwa S, Thompson R, Tinto H, Toure AO, Uthaisin C, Verma A, Kibuuka A, Lingani M, Lourenço C, Mombo-Ngoma G, Nduba V, N'Guessan TL, Nassa GJW, Nyantaro M, Tina LO, Singh PK, El Gaaloul M, Marrast AC, Chikoto H, Csermak K, Demin I, Mehta D, Pathan R, Risterucci C, Su G, Winnips C, Kaguthi G, Fofana B, and Grobusch MP
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- Adult, Adolescent, Child, Humans, Lumefantrine pharmacology, Lumefantrine therapeutic use, Fluorenes therapeutic use, Fluorenes pharmacology, Ethanolamines therapeutic use, Ethanolamines pharmacology, Artemether pharmacology, Artemether therapeutic use, Drug Combinations, Plasmodium falciparum, Treatment Outcome, Artemisinins, Antimalarials, Malaria, Falciparum drug therapy, Malaria, Falciparum parasitology, Malaria drug therapy
- Abstract
Background: Emergence of drug resistance demands novel antimalarial drugs with new mechanisms of action. We aimed to identify effective and well tolerated doses of ganaplacide plus lumefantrine solid dispersion formulation (SDF) in patients with uncomplicated Plasmodium falciparum malaria., Methods: This open-label, multicentre, parallel-group, randomised, controlled, phase 2 trial was conducted at 13 research clinics and general hospitals in ten African and Asian countries. Patients had microscopically-confirmed uncomplicated P falciparum malaria (>1000 and <150 000 parasites per μL). Part A identified the optimal dose regimens in adults and adolescents (aged ≥12 years) and in part B, the selected doses were assessed in children (≥2 years and <12 years). In part A, patients were randomly assigned to one of seven groups (once a day ganaplacide 400 mg plus lumefantrine-SDF 960 mg for 1, 2, or 3 days; ganaplacide 800 mg plus lumefantrine-SDF 960 mg as a single dose; once a day ganaplacide 200 mg plus lumefantrine-SDF 480 mg for 3 days; once a day ganaplacide 400 mg plus lumefantrine-SDF 480 mg for 3 days; or twice a day artemether plus lumefantrine for 3 days [control]), with stratification by country (2:2:2:2:2:2:1) using randomisation blocks of 13. In part B, patients were randomly assigned to one of four groups (once a day ganaplacide 400 mg plus lumefantrine-SDF 960 mg for 1, 2, or 3 days, or twice a day artemether plus lumefantrine for 3 days) with stratification by country and age (2 to <6 years and 6 to <12 years; 2:2:2:1) using randomisation blocks of seven. The primary efficacy endpoint was PCR-corrected adequate clinical and parasitological response at day 29, analysed in the per protocol set. The null hypothesis was that the response was 80% or lower, rejected when the lower limit of two-sided 95% CI was higher than 80%. This study is registered with EudraCT (2020-003284-25) and ClinicalTrials.gov (NCT03167242)., Findings: Between Aug 2, 2017, and May 17, 2021, 1220 patients were screened and of those, 12 were included in the run-in cohort, 337 in part A, and 175 in part B. In part A, 337 adult or adolescent patients were randomly assigned, 326 completed the study, and 305 were included in the per protocol set. The lower limit of the 95% CI for PCR-corrected adequate clinical and parasitological response on day 29 was more than 80% for all treatment regimens in part A (46 of 50 patients [92%, 95% CI 81-98] with 1 day, 47 of 48 [98%, 89-100] with 2 days, and 42 of 43 [98%, 88-100] with 3 days of ganaplacide 400 mg plus lumefantrine-SDF 960 mg; 45 of 48 [94%, 83-99] with ganaplacide 800 mg plus lumefantrine-SDF 960 mg for 1 day; 47 of 47 [100%, 93-100] with ganaplacide 200 mg plus lumefantrine-SDF 480 mg for 3 days; 44 of 44 [100%, 92-100] with ganaplacide 400 mg plus lumefantrine-SDF 480 mg for 3 days; and 25 of 25 [100%, 86-100] with artemether plus lumefantrine). In part B, 351 children were screened, 175 randomly assigned (ganaplacide 400 mg plus lumefantrine-SDF 960 mg once a day for 1, 2, or 3 days), and 171 completed the study. Only the 3-day regimen met the prespecified primary endpoint in paediatric patients (38 of 40 patients [95%, 95% CI 83-99] vs 21 of 22 [96%, 77-100] with artemether plus lumefantrine). The most common adverse events were headache (in seven [14%] of 51 to 15 [28%] of 54 in the ganaplacide plus lumefantrine-SDF groups and five [19%] of 27 in the artemether plus lumefantrine group) in part A, and malaria (in 12 [27%] of 45 to 23 [44%] of 52 in the ganaplacide plus lumefantrine-SDF groups and 12 [50%] of 24 in the artemether plus lumefantrine group) in part B. No patients died during the study., Interpretation: Ganaplacide plus lumefantrine-SDF was effective and well tolerated in patients, especially adults and adolescents, with uncomplicated P falciparum malaria. Ganaplacide 400 mg plus lumefantrine-SDF 960 mg once daily for 3 days was identified as the optimal treatment regimen for adults, adolescents, and children. This combination is being evaluated further in a phase 2 trial (NCT04546633)., Funding: Novartis and Medicines for Malaria Venture., Competing Interests: Declaration of interests CW, KC, ID, RP, HC, and DM are employees of Novartis. GS and CR are employees and stockholders of Novartis. ACM and MEG are employees of Medicines for Malaria Venture. MPG received fees from Novartis for advisory work related to malaria. All other authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)
- Published
- 2023
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24. Prescription patterns and compliance with World Health Organization recommendations for the management of uncomplicated and severe malaria: A prospective, real-world study in sub-Saharan Africa.
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Baraka V, Nhama A, Aide P, Bassat Q, David A, Gesase S, Gwasupika J, Hachizovu S, Makenga G, Ntizimira CR, Obunge O, Tshefu KA, Cousin M, Otsyula N, Pathan R, Risterucci C, Su G, and Manyando C
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- Humans, Infant, Newborn, Artemether, Lumefantrine Drug Combination therapeutic use, Prospective Studies, Artemether therapeutic use, Prescriptions, World Health Organization, Tanzania, Drug Combinations, Antimalarials, Malaria diagnosis, Malaria drug therapy, Malaria, Falciparum drug therapy
- Abstract
Background: This study aimed to evaluate the gap between guidelines and local clinical practice for diagnosis and treatment of uncomplicated and severe malaria, the patient characteristics, diagnostic approach, treatment, and compliance to standard guideline recommendations., Methods: This was a multicentre, observational study conducted between October 2020 and March 2021 in which patients of all ages with symptoms suggestive of malaria and who visited a healthcare facility were prospectively enrolled in six countries in sub-Saharan Africa (The Democratic Republic of the Congo, Mozambique, Nigeria, Rwanda, The United Republic of Tanzania, and Zambia)., Results: Of 1001 enrolled patients, 735 (73.4%) patients had confirmed malaria (based on overall judgment by investigator) at baseline (uncomplicated malaria: 598 [81.4%] and severe malaria: 137 [18.6%]). Of the confirmed malaria patients, 533 (72.5%) were administered a malaria rapid diagnostic test. The median age of patients was 11 years (range: 2 weeks-91 years) with more patients coming from rural (44.9%) than urban (30.6%) or suburban areas (24.5%). At the community level, 57.8% of patients sought advice or received treatment for malaria and 56.9% of patients took one or more drugs for their illness before coming to the study site. In terms of early access to care, 44.1% of patients came to the study site for initial visit ≥ 48 h after symptom onset. In patients with uncomplicated malaria, the most prescribed treatments were artemisinin-based combination therapy (ACT; n = 564 [94.3%]), primarily using artemether-lumefantrine (82.3%), in line with the World Health Organization (WHO) treatment guidelines. In addition, these patients received antipyretics (85.6%) and antibiotics (42.0%). However, in those with severe malaria, only 66 (48.2%) patients received parenteral treatment followed by oral ACT as per WHO guidelines, whereas 62 (45.3%) received parenteral treatment only. After receiving ambulatory care, 88.6% of patients with uncomplicated malaria were discharged and 83.2% of patients with severe malaria were discharged after hospitalization. One patient with uncomplicated malaria having multiple co-morbidities and three patients with severe malaria died., Conclusions: The findings of this study suggest that the prescribed treatment in most patients with uncomplicated malaria, but not of those with severe malaria, was in alignment with the WHO recommended guidelines., (© 2023. The Author(s).)
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- 2023
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25. Discovery of Balovaptan, a Vasopressin 1a Receptor Antagonist for the Treatment of Autism Spectrum Disorder.
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Schnider P, Bissantz C, Bruns A, Dolente C, Goetschi E, Jakob-Roetne R, Künnecke B, Mueggler T, Muster W, Parrott N, Pinard E, Ratni H, Risterucci C, Rogers-Evans M, von Kienlin M, and Grundschober C
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- Adolescent, Adult, Animals, Antidiuretic Hormone Receptor Antagonists chemical synthesis, Antidiuretic Hormone Receptor Antagonists pharmacokinetics, Autism Spectrum Disorder metabolism, Benzodiazepines chemical synthesis, Benzodiazepines pharmacokinetics, Brain metabolism, Child, Clinical Trials as Topic, Drug Discovery, Female, Humans, Male, Mammals, Pyridines chemical synthesis, Pyridines pharmacokinetics, Triazoles chemical synthesis, Triazoles pharmacokinetics, Antidiuretic Hormone Receptor Antagonists therapeutic use, Autism Spectrum Disorder drug therapy, Benzodiazepines therapeutic use, Pyridines therapeutic use, Receptors, Vasopressin metabolism, Triazoles therapeutic use
- Abstract
We recently reported the discovery of a potent, selective, and brain-penetrant V1a receptor antagonist, which was not suitable for full development. Nevertheless, this compound was found to improve surrogates of social behavior in adults with autism spectrum disorder in an exploratory proof-of-mechanism study. Here we describe scaffold hopping that gave rise to triazolobenzodiazepines with improved pharmacokinetic properties. The key to balancing potency and selectivity while minimizing P-gp mediated efflux was fine-tuning of hydrogen bond acceptor basicity. Ascertaining a V1a antagonist specific brain activity pattern by pharmacological magnetic resonance imaging in the rat played a seminal role in guiding optimization efforts, culminating in the discovery of balovaptan (RG7314, RO5285119) 1 . In a 12-week clinical phase 2 study in adults with autism spectrum disorder balovaptan demonstrated improvements in Vineland-II Adaptive Behavior Scales, a secondary end point comprising communication, socialization, and daily living skills. Balovaptan entered phase 3 clinical development in August 2018.
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- 2020
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26. Cerebral blood flow predicts differential neurotransmitter activity.
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Dukart J, Holiga Š, Chatham C, Hawkins P, Forsyth A, McMillan R, Myers J, Lingford-Hughes AR, Nutt DJ, Merlo-Pich E, Risterucci C, Boak L, Umbricht D, Schobel S, Liu T, Mehta MA, Zelaya FO, Williams SC, Brown G, Paulus M, Honey GD, Muthukumaraswamy S, Hipp J, Bertolino A, and Sambataro F
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- Adult, Anesthetics, Dissociative administration & dosage, Antidepressive Agents, Second-Generation administration & dosage, Antipsychotic Agents administration & dosage, Central Nervous System Stimulants administration & dosage, Female, Healthy Volunteers, Humans, Male, Young Adult, Central Nervous System diagnostic imaging, Cerebrovascular Circulation, Magnetic Resonance Imaging methods, Neurophysiological Monitoring methods, Neurotransmitter Agents metabolism
- Abstract
Application of metabolic magnetic resonance imaging measures such as cerebral blood flow in translational medicine is limited by the unknown link of observed alterations to specific neurophysiological processes. In particular, the sensitivity of cerebral blood flow to activity changes in specific neurotransmitter systems remains unclear. We address this question by probing cerebral blood flow in healthy volunteers using seven established drugs with known dopaminergic, serotonergic, glutamatergic and GABAergic mechanisms of action. We use a novel framework aimed at disentangling the observed effects to contribution from underlying neurotransmitter systems. We find for all evaluated compounds a reliable spatial link of respective cerebral blood flow changes with underlying neurotransmitter receptor densities corresponding to their primary mechanisms of action. The strength of these associations with receptor density is mediated by respective drug affinities. These findings suggest that cerebral blood flow is a sensitive brain-wide in-vivo assay of metabolic demands across a variety of neurotransmitter systems in humans.
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- 2018
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27. An investigation of regional cerebral blood flow and tissue structure changes after acute administration of antipsychotics in healthy male volunteers.
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Hawkins PCT, Wood TC, Vernon AC, Bertolino A, Sambataro F, Dukart J, Merlo-Pich E, Risterucci C, Silber-Baumann H, Walsh E, Mazibuko N, Zelaya FO, and Mehta MA
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- Adult, Antipsychotic Agents blood, Benzodiazepines blood, Brain diagnostic imaging, Brain physiology, Brain Mapping, Cerebrovascular Circulation physiology, Cross-Over Studies, Dose-Response Relationship, Drug, Double-Blind Method, Haloperidol blood, Humans, Magnetic Resonance Imaging, Male, Olanzapine, Risperidone blood, Young Adult, Antipsychotic Agents pharmacology, Benzodiazepines pharmacology, Brain drug effects, Cerebrovascular Circulation drug effects, Haloperidol pharmacology, Risperidone pharmacology
- Abstract
Chronic administration of antipsychotic drugs has been linked to structural brain changes observed in patients with schizophrenia. Recent MRI studies have shown rapid changes in regional brain volume following just a single dose of these drugs. However, it is not clear if these changes represent real volume changes or are artefacts ("apparent" volume changes) due to drug-induced physiological changes, such as increased cerebral blood flow (CBF). To address this, we examined the effects of a single, clinical dose of three commonly prescribed antipsychotics on quantitative measures of T1 and regional blood flow of the healthy human brain. Males (n = 42) were randomly assigned to one of two parallel groups in a double-blind, placebo-controlled, randomized, three-period cross-over study design. One group received a single oral dose of either 0.5 or 2 mg of risperidone or placebo during each visit. The other received olanzapine (7.5 mg), haloperidol (3 mg), or placebo. MR measures of quantitative T1, CBF, and T1-weighted images were acquired at the estimated peak plasma concentration of the drug. All three drugs caused localized increases in striatal blood flow, although drug and region specific effects were also apparent. In contrast, all assessments of T1 and brain volume remained stable across sessions, even in those areas experiencing large changes in CBF. This illustrates that a single clinically relevant oral dose of an antipsychotic has no detectable acute effect on T1 in healthy volunteers. We further provide a methodology for applying quantitative imaging methods to assess the acute effects of other compounds on structural MRI metrics. Hum Brain Mapp 39:319-331, 2018. © 2017 Wiley Periodicals, Inc., (© 2017 Wiley Periodicals, Inc.)
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- 2018
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28. Longitudinal characterization of biomarkers for spinal muscular atrophy.
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Bonati U, Holiga Š, Hellbach N, Risterucci C, Bergauer T, Tang W, Hafner P, Thoeni A, Bieri O, Gerlach I, Marquet A, Khwaja O, Sambataro F, Bertolino A, Dukart J, Fischmann A, Fischer D, and Czech C
- Abstract
Objective: Recent advances in understanding Spinal Muscular Atrophy (SMA) etiopathogenesis prompted development of potent intervention strategies and raised need for sensitive outcome measures capable of assessing disease progression and response to treatment. Several biomarkers have been proposed; nevertheless, no general consensus has been reached on the most feasible ones. We observed a wide range of measures over 1 year to assess their ability to monitor the disease status and progression., Methods: 18 SMA patients and 19 healthy volunteers (HV) were followed in this 52-weeks observational study. Quantitative-MRI (qMRI) of both thighs and clinical evaluation of motor function was performed at baseline, 6, 9 and 12 months follow-up. Blood samples were taken in patients for molecular characterization at screening, 9 and 12 month follow-up. Progression, responsiveness and reliability of collected indices were quantified. Correlation analysis was performed to test for potential associations., Results: QMRI indices, clinical scales and molecular measures showed high to excellent reliability. Significant differences were found between qMRI of SMA patients and HV. Significant associations were revealed between multiple qMRI measures and functional clinical scales. None of the qMRI, clinical, or molecular measures was able to detect significant disease progression over 1 year., Interpretation: We probed a variety of quantitative measures for SMA in a slowly-progressing disease population over 1 year. The presented measures demonstrated potential to provide a closer link to underlying disease biology as compared to conventional functional scales. The proposed biomarker framework can guide implementation of more sensitive endpoints in future clinical trials and prove their utility in search for novel disease-modifying therapies.
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- 2017
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29. Statistical power and prediction accuracy in multisite resting-state fMRI connectivity.
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Dansereau C, Benhajali Y, Risterucci C, Pich EM, Orban P, Arnold D, and Bellec P
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- Adolescent, Adult, Female, Humans, Male, Middle Aged, Models, Neurological, Monte Carlo Method, Multicenter Studies as Topic, Rest, Support Vector Machine, Young Adult, Brain physiology, Brain Mapping methods, Image Processing, Computer-Assisted methods, Magnetic Resonance Imaging methods, Neural Pathways physiology
- Abstract
Connectivity studies using resting-state functional magnetic resonance imaging are increasingly pooling data acquired at multiple sites. While this may allow investigators to speed up recruitment or increase sample size, multisite studies also potentially introduce systematic biases in connectivity measures across sites. In this work, we measure the inter-site effect in connectivity and its impact on our ability to detect individual and group differences. Our study was based on real, as opposed to simulated, multisite fMRI datasets collected in N=345 young, healthy subjects across 8 scanning sites with 3T scanners and heterogeneous scanning protocols, drawn from the 1000 functional connectome project. We first empirically show that typical functional networks were reliably found at the group level in all sites, and that the amplitude of the inter-site effects was small to moderate, with a Cohen's effect size below 0.5 on average across brain connections. We then implemented a series of Monte-Carlo simulations, based on real data, to evaluate the impact of the multisite effects on detection power in statistical tests comparing two groups (with and without the effect) using a general linear model, as well as on the prediction of group labels with a support-vector machine. As a reference, we also implemented the same simulations with fMRI data collected at a single site using an identical sample size. Simulations revealed that using data from heterogeneous sites only slightly decreased our ability to detect changes compared to a monosite study with the GLM, and had a greater impact on prediction accuracy. However, the deleterious effect of multisite data pooling tended to decrease as the total sample size increased, to a point where differences between monosite and multisite simulations were small with N=120 subjects. Taken together, our results support the feasibility of multisite studies in rs-fMRI provided the sample size is large enough., (Copyright © 2017. Published by Elsevier Inc.)
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- 2017
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30. Defining the brain circuits involved in psychiatric disorders: IMI-NEWMEDS.
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Artigas F, Schenker E, Celada P, Spedding M, Lladó-Pelfort L, Jurado N, Núñez M, Santana N, Troyano-Rodriguez E, Riga MS, van den Munkhof H, Castañé A, Shaban H, Jay TM, Tripathi A, Godsil BP, Sebban C, Mariani J, Faure P, Takkilah S, Hughes ZA, Siok CJ, Hajos M, Wicke K, Gass N, Weber-Fahr W, Sartorius A, Becker R, Didriksen M, Bastlund JF, Tricklebank M, Risterucci C, Meyer-Lindenberg A, and Schwarz AJ
- Subjects
- Antidepressive Agents therapeutic use, Antipsychotic Agents therapeutic use, Depressive Disorder drug therapy, Depressive Disorder physiopathology, Drug Industry, Humans, Schizophrenia drug therapy, Schizophrenia physiopathology, Antidepressive Agents pharmacology, Antipsychotic Agents pharmacology, Mental Disorders physiopathology, Neural Pathways physiopathology
- Abstract
Despite the vast amount of research on schizophrenia and depression in the past two decades, there have been few innovative drugs to treat these disorders. Precompetitive research collaborations between companies and academic groups can help tackle this innovation deficit, as illustrated by the achievements of the IMI-NEWMEDS consortium.
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- 2017
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31. Ketamine Suppresses the Ventral Striatal Response to Reward Anticipation: A Cross-Species Translational Neuroimaging Study.
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Francois J, Grimm O, Schwarz AJ, Schweiger J, Haller L, Risterucci C, Böhringer A, Zang Z, Tost H, Gilmour G, and Meyer-Lindenberg A
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- Acoustic Stimulation, Animals, Anticipation, Psychological drug effects, Brain Mapping, Conditioning, Classical, Conditioning, Operant, Humans, Ketamine pharmacokinetics, Magnetic Resonance Imaging, Male, Oxygen metabolism, Rats, Rats, Sprague-Dawley, Species Specificity, Translational Research, Biomedical, Ventral Striatum drug effects, Ventral Striatum metabolism, Anticipation, Psychological physiology, Ketamine administration & dosage, Psychoses, Substance-Induced physiopathology, Reward, Ventral Striatum physiopathology
- Abstract
Convergent evidence implicates regional neural responses to reward anticipation in the pathogenesis of several psychiatric disorders, such as schizophrenia, where blunted ventral striatal responses to positive reward are observed in patients and at-risk populations. In vivo oxygen amperometry measurements in the ventral striatum in awake, behaving rats reveal reward-related tissue oxygen changes that closely parallel blood oxygen level dependent (BOLD) signal changes observed in human functional magnetic resonance imaging (fMRI), suggesting that a cross-species approach targeting this mechanism might be feasible in psychopharmacology. The present study explored modulatory effects of acute, subanaesthetic doses of ketamine-a pharmacological model widely used in psychopharmacological research, both preclinically and clinically-on ventral striatum activity during performance of a reward anticipation task in both species, using fMRI in humans and in vivo oxygen amperometry in rats. In a region-of-interest analysis conducted following a cross-over placebo and ketamine study in human subjects, an attenuated ventral striatal response during reward anticipation was observed following ketamine relative to placebo during performance of a monetary incentive delay task. In rats, a comparable attenuation of ventral striatal signal was found after ketamine challenge, relative to vehicle, in response to a conditioned stimulus that predicted delivery of reward. This study provides the first data in both species demonstrating an attenuating effect of acute ketamine on reward-related ventral striatal (O2) and fMRI signals. These findings may help elucidate a deeper mechanistic understanding of the potential role of ketamine as a model for psychosis, show that cross-species pharmacological experiments targeting reward signaling are feasible, and suggest this phenotype as a promising translational biomarker for the development of novel compounds, assessment of disease status, and treatment efficacy.
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- 2016
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32. Acute ketamine challenge increases resting state prefrontal-hippocampal connectivity in both humans and rats.
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Grimm O, Gass N, Weber-Fahr W, Sartorius A, Schenker E, Spedding M, Risterucci C, Schweiger JI, Böhringer A, Zang Z, Tost H, Schwarz AJ, and Meyer-Lindenberg A
- Subjects
- Adult, Animals, Female, Humans, Magnetic Resonance Imaging, Male, Neural Pathways drug effects, Rats, Rats, Sprague-Dawley, Young Adult, Hippocampus drug effects, Ketamine pharmacology, Prefrontal Cortex drug effects
- Abstract
Rationale: Aberrant prefrontal-hippocampal (PFC-HC) connectivity is disrupted in several psychiatric and at-risk conditions. Advances in rodent functional imaging have opened the possibility that this phenotype could serve as a translational imaging marker for psychiatric research. Recent evidence from functional magnetic resonance imaging (fMRI) studies has indicated an increase in PFC-HC coupling during working-memory tasks in both schizophrenic patients and at-risk populations, in contrast to a decrease in resting-state PFC-HC connectivity. Acute ketamine challenge is widely used in both humans and rats as a pharmacological model to study the mechanisms of N-methyl-D-aspartate (NMDA) receptor hypofunction in the context of psychiatric disorders., Objectives: We aimed to establish whether acute ketamine challenge has consistent effects in rats and humans by investigating resting-state fMRI PFC-HC connectivity and thus to corroborate its potential utility as a translational probe., Methods: Twenty-four healthy human subjects (12 females, mean age 25 years) received intravenous doses of either saline (placebo) or ketamine (0.5 mg/kg body weight). Eighteen Sprague-Dawley male rats received either saline or ketamine (25 mg/kg). Resting-state fMRI measurements took place after injections, and the data were analyzed for PFC-HC functional connectivity., Results: In both species, ketamine induced a robust increase in PFC-HC coupling, in contrast to findings in chronic schizophrenia., Conclusions: This translational comparison demonstrates a cross-species consistency in pharmacological effect and elucidates ketamine-induced alterations in PFC-HC coupling, a phenotype often disrupted in pathological conditions, which may give clue to understanding of psychiatric disorders and their onset, and help in the development of new treatments.
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- 2015
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33. Estimating multivariate similarity between neuroimaging datasets with sparse canonical correlation analysis: an application to perfusion imaging.
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Rosa MJ, Mehta MA, Pich EM, Risterucci C, Zelaya F, Reinders AA, Williams SC, Dazzan P, Doyle OM, and Marquand AF
- Abstract
An increasing number of neuroimaging studies are based on either combining more than one data modality (inter-modal) or combining more than one measurement from the same modality (intra-modal). To date, most intra-modal studies using multivariate statistics have focused on differences between datasets, for instance relying on classifiers to differentiate between effects in the data. However, to fully characterize these effects, multivariate methods able to measure similarities between datasets are needed. One classical technique for estimating the relationship between two datasets is canonical correlation analysis (CCA). However, in the context of high-dimensional data the application of CCA is extremely challenging. A recent extension of CCA, sparse CCA (SCCA), overcomes this limitation, by regularizing the model parameters while yielding a sparse solution. In this work, we modify SCCA with the aim of facilitating its application to high-dimensional neuroimaging data and finding meaningful multivariate image-to-image correspondences in intra-modal studies. In particular, we show how the optimal subset of variables can be estimated independently and we look at the information encoded in more than one set of SCCA transformations. We illustrate our framework using Arterial Spin Labeling data to investigate multivariate similarities between the effects of two antipsychotic drugs on cerebral blood flow.
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- 2015
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34. "Domain gauges": A reference system for multivariate profiling of brain fMRI activation patterns induced by psychoactive drugs in rats.
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Bruns A, Mueggler T, Künnecke B, Risterucci C, Prinssen EP, Wettstein JG, and von Kienlin M
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- Algorithms, Animals, Anti-Anxiety Agents pharmacology, Antidepressive Agents pharmacology, Antipsychotic Agents pharmacology, Discriminant Analysis, Male, Multivariate Analysis, Rats, Rats, Inbred F344, Rats, Sprague-Dawley, Reproducibility of Results, Brain drug effects, Magnetic Resonance Imaging methods, Psychotropic Drugs pharmacology
- Abstract
Pharmacological magnetic resonance imaging (phMRI) of the brain has become a widely used tool in both preclinical and clinical drug research. One of its challenges is to condense the observed complex drug-induced brain-activation patterns into semantically meaningful metrics that can then serve as a basis for informed decision making. To aid interpretation of spatially distributed activation patterns, we propose here a set of multivariate metrics termed "domain gauges", which have been calibrated based on different classes of marketed or validated reference drugs. Each class represents a particular "domain" of interest, i.e., a specific therapeutic indication or mode of action. The drug class is empirically characterized by the unique activation pattern it evokes in the brain-the "domain profile". A domain gauge provides, for any tested intervention, a "classifier" as a measure of response strength with respect to the domain in question, and a "differentiator" as a measure of deviation from the domain profile, both along with error ranges. Capitalizing on our in-house database with an unprecedented wealth of standardized perfusion-based phMRI data obtained from rats subjected to various validated treatments, we exemplarily focused on 3 domains based on therapeutic indications: an antipsychotic, an antidepressant and an anxiolytic domain. The domain profiles identified as part of the gauge definition process, as well as the outputs of the gauges when applied to both reference and validation data, were evaluated for their reconcilability with prior biological knowledge and for their performance in drug characterization. The domain profiles provided quantitative activation patterns with high biological plausibility. The antipsychotic profile, for instance, comprised key areas (e.g., cingulate cortex, nucleus accumbens, ventral tegmental area, substantia nigra) which are believed to be strongly involved in mediating an antipsychotic effect, and which are in line with network-level dysfunctions observed in schizophrenia. The domain gauges plausibly positioned the vast majority of the pharmacological and even non-pharmacological treatments. The results also suggest the segregation of sub-domains based on, e.g., the mode of action. Upon judicious selection of domains and careful calibration of the gauges, our approach represents a valuable analytical tool for biological interpretation and decision making in drug discovery., (Copyright © 2015 Elsevier Inc. All rights reserved.)
- Published
- 2015
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35. Sub-anesthetic ketamine modulates intrinsic BOLD connectivity within the hippocampal-prefrontal circuit in the rat.
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Gass N, Schwarz AJ, Sartorius A, Schenker E, Risterucci C, Spedding M, Zheng L, Meyer-Lindenberg A, and Weber-Fahr W
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- Analgesics blood, Animals, Dose-Response Relationship, Drug, Heart Rate drug effects, Image Processing, Computer-Assisted, Ketamine blood, Magnetic Resonance Imaging, Male, Nerve Net drug effects, Oxygen blood, Rats, Rats, Sprague-Dawley, Statistics as Topic, Analgesics pharmacology, Hippocampus blood supply, Hippocampus drug effects, Ketamine pharmacology, Nerve Net blood supply, Prefrontal Cortex blood supply, Prefrontal Cortex drug effects
- Abstract
Dysfunctional connectivity within the hippocampal-prefrontal circuit (HC-PFC) is associated with schizophrenia, major depression, and neurodegenerative disorders, and both the hippocampus and prefrontal cortex have dense populations of N-methyl-D-aspartate (NMDA) receptors. Ketamine, a potent NMDA receptor antagonist, is of substantial current interest as a mechanistic model of glutamatergic dysfunction in animal and human studies, a psychotomimetic agent and a rapidly acting antidepressant. In this study, we sought to understand the modulatory effect of acute ketamine administration on functional connectivity in the HC-PFC system of the rat brain using resting-state fMRI. Sprague-Dawley rats in four parallel groups (N=9 per group) received either saline or one of three behaviorally relevant, sub-anesthetic doses of S-ketamine (5, 10, and 25 mg/kg, s.c.), and connectivity changes 15- and 30-min post-injection were studied. The strongest effects were dose- and exposure-dependent increases in functional connectivity within the prefrontal cortex and in anterior-posterior connections between the posterior hippocampus and retrosplenial cortex, and prefrontal regions. The increased prefrontal connectivity is consistent with ketamine-induced increases in HC-PFC electroencephalographic gamma band power, possibly reflecting a psychotomimetic aspect of ketamine's effect, and is contrary to the data from chronic schizophrenic patients suggesting that ketamine effect does not necessarily parallel the disease pattern but might rather reflect a hyperglutamatergic state. These findings may help to clarify the brain systems underlying different dose-dependent behavioral profiles of ketamine in the rat.
- Published
- 2014
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36. Chronic metabotropic glutamate receptor 5 inhibition corrects local alterations of brain activity and improves cognitive performance in fragile X mice.
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Michalon A, Bruns A, Risterucci C, Honer M, Ballard TM, Ozmen L, Jaeschke G, Wettstein JG, von Kienlin M, Künnecke B, and Lindemann L
- Subjects
- Animals, Avoidance Learning drug effects, Brain blood supply, Disease Models, Animal, Electroshock adverse effects, Excitatory Amino Acid Antagonists pharmacokinetics, Extinction, Psychological drug effects, Fragile X Mental Retardation Protein genetics, Fragile X Mental Retardation Protein metabolism, Fragile X Syndrome genetics, Fragile X Syndrome pathology, Imidazoles therapeutic use, Mice, Mice, Knockout, Oximes pharmacokinetics, Oxygen blood, Pyridines pharmacokinetics, Pyridines therapeutic use, Receptor, Metabotropic Glutamate 5 metabolism, Tritium pharmacokinetics, Brain drug effects, Cognition drug effects, Excitatory Amino Acid Antagonists therapeutic use, Fragile X Syndrome drug therapy, Receptor, Metabotropic Glutamate 5 antagonists & inhibitors
- Abstract
Background: Fragile X syndrome (FXS) is the most common genetic cause for intellectual disability. Fmr1 knockout (KO) mice are an established model of FXS. Chronic pharmacological inhibition of metabotropic glutamate receptor 5 (mGlu5) in these mice corrects multiple molecular, physiological, and behavioral phenotypes related to patients' symptoms. To better understand the pathophysiology of FXS and the effect of treatment, brain activity was analyzed using functional magnetic resonance imaging in relation to learning and memory performance., Methods: Wild-type (WT) and Fmr1 KO animals receiving chronic treatment with the mGlu5 inhibitor CTEP or vehicle were evaluated consecutively for 1) learning and memory performance in the inhibitory avoidance and extinction test, and 2) for the levels of brain activity using continuous arterial spin labeling based functional magnetic resonance imaging. Neural activity patterns were correlated with cognitive performance using a multivariate regression analysis. Furthermore, mGlu5 receptor expression in brains of untreated mice was analyzed by autoradiography and saturation analysis using [(3)H]-ABP688., Results: Chronic CTEP treatment corrected the learning deficit observed in Fmr1 KO mice in the inhibitory avoidance and extinction test and prevented memory extinction in WT and Fmr1 KO animals. Chronic CTEP treatment normalized perfusion in the amygdala and the lateral hypothalamus in Fmr1 KO mice and furthermore decreased perfusion in the hippocampus and increased perfusion in primary sensorimotor cortical areas. No significant differences in mGlu5 receptor expression levels between Fmr1 WT and KO mice were detected., Conclusions: Chronic mGlu5 inhibition corrected the learning deficits and partially normalized the altered brain activity pattern in Fmr1 KO mice., (Copyright © 2014 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)
- Published
- 2014
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37. Haloperidol modulates midbrain-prefrontal functional connectivity in the rat brain.
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Gass N, Schwarz AJ, Sartorius A, Cleppien D, Zheng L, Schenker E, Risterucci C, Meyer-Lindenberg A, and Weber-Fahr W
- Subjects
- Animals, Dopaminergic Neurons metabolism, Functional Neuroimaging, Globus Pallidus drug effects, Globus Pallidus metabolism, Gyrus Cinguli drug effects, Gyrus Cinguli metabolism, Hippocampus drug effects, Hippocampus metabolism, Magnetic Resonance Imaging, Male, Mesencephalon metabolism, Motor Cortex drug effects, Motor Cortex metabolism, Nerve Net metabolism, Nerve Tissue Proteins antagonists & inhibitors, Nerve Tissue Proteins metabolism, Prefrontal Cortex metabolism, Random Allocation, Rats, Rats, Sprague-Dawley, Receptors, Dopamine D2 metabolism, Substantia Nigra drug effects, Substantia Nigra metabolism, Dopamine Antagonists pharmacology, Dopamine D2 Receptor Antagonists, Dopaminergic Neurons drug effects, Haloperidol pharmacology, Mesencephalon drug effects, Nerve Net drug effects, Prefrontal Cortex drug effects
- Abstract
Dopamine D₂ receptor antagonists effectively reduce positive symptoms in schizophrenia, implicating abnormal dopaminergic neurotransmission as an underlying mechanism of psychosis. Despite the well-established, albeit incomplete, clinical efficacies of D₂ antagonists, no studies have examined their effects on functional interaction between brain regions. We hypothesized that haloperidol, a widely used antipsychotic and D₂ antagonist, would modulate functional connectivity in dopaminergic circuits. Ten male Sprague-Dawley rats received either haloperidol (1 mg/kg, s.c.) or the same volume of saline a week apart. Resting-state functional magnetic resonance imaging data were acquired 20 min after injection. Connectivity analyses were performed using two complementary approaches: correlation analysis between 44 atlas-derived regions of interest, and seed-based connectivity mapping. In the presence of haloperidol, reduced correlation was observed between the substantia nigra and several brain regions, notably the cingulate and prefrontal cortices, posterodorsal hippocampus, ventral pallidum, and motor cortex. Haloperidol induced focal changes in functional connectivity were found to be the most strongly associated with ascending dopamine projections. These included reduced connectivity between the midbrain and the medial prefrontal cortex and hippocampus, possibly relating to its therapeutic action, and decreased coupling between substantia nigra and motor areas, which may reflect dyskinetic effects. These data may help in further characterizing the functional circuits modulated by antipsychotics that could be targeted by innovative drug treatments., (Copyright © 2012 Elsevier B.V. and ECNP. All rights reserved.)
- Published
- 2013
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38. Anti-correlated cortical networks of intrinsic connectivity in the rat brain.
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Schwarz AJ, Gass N, Sartorius A, Risterucci C, Spedding M, Schenker E, Meyer-Lindenberg A, and Weber-Fahr W
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- Animals, Brain Mapping methods, Cerebral Cortex blood supply, Gyrus Cinguli blood supply, Hippocampus blood supply, Magnetic Resonance Imaging methods, Male, Neural Pathways physiology, Oxygen blood, Rats, Rats, Sprague-Dawley, Rest physiology, Cerebral Cortex physiology, Gyrus Cinguli physiology, Hippocampus physiology, Nerve Net physiology
- Abstract
In humans, resting-state blood oxygen level-dependent (BOLD) signals in the default mode network (DMN) are temporally anti-correlated with those from a lateral cortical network involving the frontal eye fields, secondary somatosensory and posterior insular cortices. Here, we demonstrate the existence of an analogous lateral cortical network in the rat brain, extending laterally from anterior secondary sensorimotor regions to the insular cortex and exhibiting low-frequency BOLD fluctuations that are temporally anti-correlated with a midline "DMN-like" network comprising posterior/anterior cingulate and prefrontal cortices. The primary nexus for this anti-correlation relationship was the anterior secondary motor cortex, close to regions that have been identified with frontal eye fields in the rat brain. The anti-correlation relationship was corroborated after global signal removal, underscoring this finding as a robust property of the functional connectivity signature in the rat brain. These anti-correlated networks demonstrate strong anatomical homology to networks identified in human and monkey connectivity studies, extend the known preserved functional connectivity relationships between rodent and primates, and support the use of resting-state functional magnetic resonance imaging as a translational imaging method between rat models and humans.
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- 2013
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39. Imaging trait anxiety in high anxiety F344 rats: Focus on the dorsomedial prefrontal cortex.
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Prinssen EP, Nicolas LB, Klein S, Grundschober C, Lopez-Lopez C, Kessler MS, Bruns A, von Kienlin M, Wettstein JG, Moreau JL, and Risterucci C
- Subjects
- Animals, Avoidance Learning, Brain Mapping, Disease Models, Animal, Image Processing, Computer-Assisted, Male, Oxygen blood, Prefrontal Cortex injuries, Proto-Oncogene Proteins c-fos metabolism, Rats, Rats, Inbred F344, Rats, Sprague-Dawley, Social Behavior, Anxiety genetics, Anxiety pathology, Magnetic Resonance Imaging, Prefrontal Cortex blood supply, Prefrontal Cortex metabolism
- Abstract
Functional magnetic resonance imaging (fMRI) has become an important method in clinical psychiatry research whereas there are still only few comparable preclinical investigations. Herein, we report that fMRI in rats can provide key information regarding brain areas underlying anxiety behavior. Perfusion as surrogate for neuronal activity was measured by means of arterial spin labeling-based fMRI in various brain areas of high anxiety F344 rats and control Sprague-Dawley rats. In one of these areas, the dorsomedial prefrontal cortex (dmPFC), c-Fos labeling was compared between these two strains with immunolabeling. The effects of a neurotoxic ibotenic acid lesion of the dmPFC in F344 rats were examined in a social approach-avoidance anxiety procedure and fMRI. Regional brain activity of high anxiety F344 rats was different in selective cortical and subcortical areas as compared to that of low anxiety Sprague-Dawley rats; the largest difference (i.e. hyperactivity) was measured in the dmPFC. Independently, c-Fos labeling confirmed that F344 rats show increased dmPFC activity. The functional role was confirmed by neurotoxic lesion of the dmPFC that reversed the high anxiety-like behavior and partially normalized the brain activity pattern of F344 rats. The current findings may have translational value as increased activity is reported in an equivalent cortical area in patients with social anxiety, suggesting that pharmacological or functional inhibition of activity in this brain area should be explored to alleviate social anxiety in patients., (Copyright © 2011 Elsevier B.V. and ECNP. All rights reserved.)
- Published
- 2012
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40. fMRI fingerprint of unconditioned fear-like behavior in rats exposed to trimethylthiazoline.
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Kessler MS, Debilly S, Schöppenthau S, Bielser T, Bruns A, Künnecke B, Kienlin Mv, Wettstein JG, Moreau JL, and Risterucci C
- Subjects
- Animals, Magnetic Resonance Imaging, Neurons physiology, Rats, Rats, Wistar, Thiazoles pharmacology, Behavior, Animal physiology, Brain physiology, Fear physiology, Freezing Reaction, Cataleptic physiology, Odorants
- Abstract
Unconditioned fear plays an important yet poorly understood role in anxiety disorders, and only few neuroimaging studies have focused on evaluating the underlying neuronal mechanisms. In rodents the predator odor trimethylthiazoline (TMT), a synthetic component of fox feces, is commonly used to induce states of unconditioned fear. In this study, arterial spin labeling-based functional magnetic resonance imaging (fMRI) was applied to detect TMT-induced regional modulations of neuronal activity in Wistar rats. During TMT exposure the rats displayed increased freezing behavior and reduced exploration in the odor-associated area. Neuronal activity was selectively increased in the dorsal periaqueductal gray, superior colliculus and medial thalamus and reduced in the median raphe, locus coeruleus, nucleus accumbens shell, ventral tegmental area, ventral pallidum and entorhinal piriform cortex. This fMRI fingerprint involving distinct neuronal pathways was used to describe a schematic model of fear processing. Key brain areas known to underlie fear and anxiety-related autonomic and behavioral responses as well as centers of motivational processing were identified as being part of this functional circuitry of innate fear. Thus, preclinical fMRI studies based on unconditioned fear methods may provide a valuable translational approach to better characterize etiological and pathological processes underlying anxiety disorders., (Copyright © 2011 Elsevier B.V. and ECNP. All rights reserved.)
- Published
- 2012
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41. Validation of cerebral blood perfusion imaging as a modality for quantitative pharmacological MRI in rats.
- Author
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Bruns A, Künnecke B, Risterucci C, Moreau JL, and von Kienlin M
- Subjects
- Animals, Blood Flow Velocity drug effects, Cerebrovascular Circulation drug effects, Male, Rats, Rats, Wistar, Reproducibility of Results, Sensitivity and Specificity, Amphetamine pharmacology, Blood Flow Velocity physiology, Cerebrovascular Circulation physiology, Magnetic Resonance Angiography methods, Magnetic Resonance Angiography veterinary, Perfusion Imaging methods, Perfusion Imaging veterinary
- Abstract
The aim of this study was to validate continuous arterial spin labeling (CASL) as a quantitative imaging modality for pharmacological MRI (phMRI) based on local cerebral blood perfusion. Specifically, the capability of CASL to assess brain-activity signatures of pharmacological interventions in animal models was evaluated with respect to drug discovery in diseases of the central nervous system (CNS). Perfusion as a surrogate for neuronal activity was measured in various brain areas of the rat. The validation approach was threefold. First, perfusion was shown to reliably reflect differential effects of anesthesia on striatal activation. Different baseline levels and different temporal response profiles after amphetamine challenges under isoflurane, propofol, ketamine, and alpha-chloralose anesthesia were consistent with known properties of these anesthetics. Second, remarkable consistency of multi-area baseline perfusion patterns between independent groups of animals confirmed the notion that CASL is highly reproducible and thus particularly suitable for long-term longitudinal studies. Third, administration of the well-characterized psychotomimetic compounds amphetamine and phencyclidine (PCP) elicited dose-dependent activation patterns that were related to the drugs' particular interactions with the dopaminergic and glutamatergic systems, respectively. In conclusion, perfusion-based phMRI is a robust, reliable and valid quantitative technique suitable for evaluating brain-activation patterns in animal models of CNS diseases.
- Published
- 2009
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42. Functional magnetic resonance imaging reveals similar brain activity changes in two different animal models of schizophrenia.
- Author
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Risterucci C, Jeanneau K, Schöppenthau S, Bielser T, Künnecke B, von Kienlin M, and Moreau JL
- Subjects
- Acoustic Stimulation methods, Analysis of Variance, Animals, Animals, Newborn, Brain Mapping, Dose-Response Relationship, Radiation, Image Processing, Computer-Assisted methods, Inhibition, Psychological, Male, Models, Neurological, Oxygen blood, Rats, Rats, Sprague-Dawley, Rats, Wistar, Reflex, Startle physiology, Brain blood supply, Brain physiopathology, Disease Models, Animal, Magnetic Resonance Imaging, Phencyclidine, Schizophrenia chemically induced, Schizophrenia metabolism, Schizophrenia physiopathology
- Abstract
Rationale and Objectives: In schizophrenia research, most of the functional imaging studies have been performed in psychotic patients, but little is known about brain areas involved in the expression of psychotic-like symptoms in animal models. The objective of this study was to visualize and compare brain activity abnormalities in a neurodevelopmental and a pharmacological animal model of schizophrenia., Methods: Blood perfusion of specific brain areas, taken as indirect measure of brain activity, was investigated in adult rats following either neonatal ventral hippocampal lesion or acute administration of phencyclidine. Quantitative perfusion magnetic resonance imaging was performed on five frontal brain slices using the continuous arterial spin labeling technique. The mean perfusion was calculated in several brain structures, which were identified on anatomical images., Results: Lesioned animals exhibiting deficits in prepulse inhibition of the startle reflex showed a significant blood perfusion increase in the nucleus accumbens, basolateral amygdala, ventral pallidum, entorhinal-piriform cortex, orbital prefrontal cortex, and in the bed nucleus of the stria terminalis, and a decrease of perfusion in the temporal cortex. Similar effects were seen following acute phencyclidine administration in naïve animals., Conclusion: Our data point out specific cortical and subcortical brain areas involved in the development of psychotic-like symptoms in two different animal models of schizophrenia. The observed brain activity abnormalities are reminiscent of classical neuroimaging findings described in schizophrenic patients.
- Published
- 2005
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43. Excitotoxic lesions of the prelimbic-infralimbic areas of the rodent prefrontal cortex disrupt motor preparatory processes.
- Author
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Risterucci C, Terramorsi D, Nieoullon A, and Amalric M
- Subjects
- Animals, Behavior, Animal, Brain Mapping, Cues, Discrimination Learning, Light, Limbic System drug effects, Male, Memory, Short-Term, Motor Activity drug effects, Photic Stimulation, Prefrontal Cortex drug effects, Psychomotor Performance drug effects, Rats, Rats, Wistar, Reaction Time, Time Factors, Limbic System physiology, Neurotoxins toxicity, Prefrontal Cortex physiology, Psychomotor Performance physiology
- Abstract
The medial prefrontal cortex (mPFC) is involved in a variety of cognitive and emotional processes; in rodents its implication in motor planning is less known, however. We therefore investigated how the mPFC contributes to the information processes involved in the execution of a reaction time task in rats. Subjects were trained to rapidly release a lever at the onset of a cue light, which was presented after an unpredictable period of variable duration (500, 750, 1000 and 1250 ms). Excitotoxic lesions of the whole mPFC or two mPFC subregions [e.g. the dorsal anterior cingulate and the prelimbic-infralimbic (PL-IL) areas] were achieved by intracerebral infusions of ibotenic acid (9.4 micro g/ micro L) at different volumes. Extensive mPFC lesions produced increased premature responding and disrupted motor readiness, e.g. the distribution of preparatory patterns during the variable preparatory periods. The deficits lasted for 3 weeks and could be reinstated 2 months after the lesion by varying the duration of the preparatory periods to increase time uncertainty. Furthermore, lesions restricted to the PL-IL cortex areas reproduced all the deficits of mPFC lesions, whereas pregenual anterior cingulate cortex lesions had no effect. The results emphasize a critical role of the rat PL-IL region in motor preparatory processes. Hence, discrete lesions of this area reproduce some deficits such as impairment of time estimation and disinhibitory behaviours observed in humans with frontal hypoactivity.
- Published
- 2003
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44. D1 and D2 dopamine receptors contribute to the locomotor response induced by Group II mGluRs activation in the rat nucleus accumbens.
- Author
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Breysse N, Risterucci C, and Amalric M
- Subjects
- Amino Acids, Dicarboxylic pharmacology, Animals, Benzazepines pharmacology, Dopamine Antagonists pharmacology, Drug Interactions, Excitatory Amino Acid Agonists administration & dosage, Excitatory Amino Acid Agonists pharmacology, Excitatory Amino Acid Antagonists pharmacology, Glycine pharmacology, Male, Microinjections, Nucleus Accumbens anatomy & histology, Raclopride pharmacology, Rats, Rats, Wistar, Receptors, Metabotropic Glutamate agonists, Receptors, Metabotropic Glutamate antagonists & inhibitors, Resorcinols pharmacology, Stimulation, Chemical, Glycine analogs & derivatives, Motor Activity drug effects, Nucleus Accumbens drug effects, Receptors, Dopamine D1 drug effects, Receptors, Dopamine D2 drug effects, Receptors, Metabotropic Glutamate drug effects
- Abstract
Whereas the involvement of ionotropic glutamate receptors (iGluRs) in the functional interaction between glutamate and dopamine (DA) systems in the nucleus accumbens (N. Acc.) is well established, the role of metabotropic glutamate receptors (mGluRs) is less clear. This study was thus aimed to investigate the mechanisms involving DA and glutamate systems via mGluRs in the generation of motor activity in rats. Intra-accumbens infusion of the Group II agonist (2S,3S,4S)-2-(carboxycyclopropyl)glycine (L-CCG-I; 25, 50, 100 nmol) increased locomotor activity, whereas the Group I agonist (S)-3,5-dihydroxyphenylglycine (S-3,5-DHPG) at the same doses had no effect. The effects of L-CCG-I were blocked by a selective Group II mGluRs antagonist (2S,3S,4S)-2-methyl-2-(carboxypropyl)glycine (MCCG; 50 nmol). The locomotor stimulant effect induced by L-CCG-I might be partly DA mediated, as it is abolished by a pretreatment with the DA receptor antagonist haloperidol (0.1 mg/kg ip) and potentiated by D-amphetamine systemic injection (0.5 mg/kg sc). Furthermore, selective D1 (SCH 23390; 0.005, 0.01 and 0.02 mg/kg) or D2 (raclopride; 0.05, 0.1 and 0.2 mg/kg) antagonists injected systemically were also effective in decreasing L-CCG-I induced hyperactivity. Taken together, these results demonstrate that stimulation of Group II but not Group I mGluRs contributes to the regulation of motor behavior in the N. Acc. and that this increased activity requires the activation of both D1 and D2 DA receptors.
- Published
- 2002
- Full Text
- View/download PDF
45. [Minor functional digestive disorders in the infant].
- Author
-
Crow M, Risterucci C, Jernité M, and Sarda P
- Subjects
- Digestive System Diseases diet therapy, Humans, Infant, Newborn, Digestive System Diseases prevention & control, Infant Food
- Published
- 1990
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