20 results on '"Cavestro C"'
Search Results
2. High prolactin levels as a worsening factor for migraine
- Author
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Cavestro, C., Rosatello, A., Marino, M. P., Micca, G., and Asteggiano, G.
- Published
- 2006
- Full Text
- View/download PDF
3. Psychiatric events in epilepsy
- Author
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Cornaggia, Cesare Maria, Beghi, Massimiliano, Beghi, Ettore, Cornaggia, C. M., Airoldi, L., Beghi, M., Bogliun, G., Brambilla, E., Fiordelli, E., Mascarini, A., Moltrasio, L., Primati, C., Hauser, W. A., Loeber, J. N., De Boer, H., Thorbecke, R., Steuernagel, E., Wolf, P., Sonnen, A. E. H., Severi, S., Zolo, P., Specchio, L. M., Specchio, N., Pasolini, M. P., Antonini, L., Aguglia, U., Russo, C., Gambardella, A., Giubergia, S., Zagnoni, P. G., Cosottini, Mirco, Zaccara, G., Trio, R., Pisani, F., Russo, M., Oteri, G., Cavestro, C. E., Tonini, C., Avanzini, G., Arienti, F., Defanti, C. A., Tartara, A., Manni, R., Castelnuovo, G., Murelli, R., Galimberti, C. A., Zanotta, N., Di Viesti, P., Zarrelli, M., Apollo, F., Runge, U., de Krom, M. C. T. F. M., van Heijden, C., Griet, J., Brown, S. W., Coyle, H., Lopez Lima, J. M., Beleza, P., Ferreira, E., Talvik, T., Beilmann, A., Belousova, E., Levart, T., Zupancic, N., Gromov, S., Lipatova, L. V., Mikhailov, V., Cornaggia, C, Beghi, M, Beghi, E, and Rest, 1
- Subjects
Adult ,Male ,medicine.medical_specialty ,Neurology ,Adolescent ,Referral ,Population ,Clinical Neurology ,Comorbidity ,Anxiety ,Epilepsy ,medicine ,Humans ,epilepsy, psychiatry ,Occupations ,Psychiatry ,Prospective cohort study ,education ,Depression (differential diagnoses) ,education.field_of_study ,Depression ,business.industry ,Mental Disorders ,Case-control study ,General Medicine ,Case-control ,medicine.disease ,Psychiatric ,Case-Control Studies ,Female ,Follow-Up Studies ,Hospitalization ,Socioeconomic Factors ,Neurology (clinical) ,MED/25 - PSICHIATRIA ,Case–control ,business - Abstract
Psychiatric events are thought to be more frequent in people with epileptic seizures than in the general population. However, inter-ictal psychiatric events attributable to epilepsy remain controversial. The aim of the present study was to evaluate the occurrence of psychiatric events in a population of fairly unselected patients with epilepsy and in the general population, and the correlation between psychiatric complaints and selected demographic and disease characteristics. The survey was part of a multicentre prospective cohort study of everyday life risks conducted in eight European countries and comparing referral children and adults with epilepsy referred to secondary/tertiary centers to age- and sex-matched non-epileptic controls. Nine hundred and fifty-one patients with epilepsy and 909 controls were studied. Each patient and his/her control received a diary to record any accident or illness, with severity, circumstances, causes, consequences, and (for the cases) the possible relation to a seizure. The follow-up period ranged between 1 and 2 years. Fifty-eight psychiatric events occurred in 25 patients (2.6%) and 88 in 19 controls (2.1%). Housewives (9.3%) and unemployed persons (4.1%) were mostly affected. No correlation was found between psychiatric events, demographic and disease characteristics. Our results suggest that people with epilepsy if unselected are not at higher risk for psychiatric disorders than the general population. © 2007 British Epilepsy Association.
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- 2007
4. Accidents in Patients with Epilepsy: Types, Circumstances, and Complications: A European Cohort Study
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van den Broek, Mariska, Beghi, Ettore, Cornaggia, C. M., Beghi, M., Bogliun, G., Fiordelli, E., Airoldi, L., Frigeni, B., Mascarini, A., Mapelli, L., Moltrasio, L., Biagi, E., Hauser, W. A., Loeber, J. N., Thorbecke, R., Di Viesti, P., Zarrelli, M., Apollo, F., Giovanni Rotondo, S., Steuernagel, E., Wolf, P., Sonnen, A. E. H., Specchio, L. M., Specchio, N., Boati, E., Defanti, C. A., Pinto, P., Breviario, E., Pasolini, M. P., Antonini, L., Aguglia, U., Russo, C., Gambardella, A., Giubergia, S., Zagnoni, P., Cosottini, Mirco, Zaccara, G., Pisani, F., Oteri, G., Cavestro, C. E., David, A., Tonini, C., Avanzini, G., Arienti, F., Tartara, A., Manni, R., Castelnovo, G., Murelli, R., Galimberti, C. A., Zanotta, N., Runge, U., Dekrom, M. C. T. F. M., Vanheijden, C., Griet, J., van denBroek, M. W. C., Brown, S. W., Coyle, H., Edge, Nr Alderley, Lopes Lima, J. M., Beleza, P., Ferreira, E., Talvik, T., Beilmann, A., Belousova, E., Nikanorowa, M., Ravnik, I. M., Levart, T., Zupancic, N., Gromov, S., Lipatova, L. V., Mikhailov, V., Van den Broek, M, Beghi, E, and Cornaggia, C
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Adult ,Male ,Pediatrics ,medicine.medical_specialty ,Adolescent ,Poison control ,Cohort Studies ,Epilepsy ,Risk Factors ,Injury prevention ,Accidents, Occupational ,Humans ,Medicine ,Prospective Studies ,Preschool ,Child ,Prospective cohort study ,Injuries ,business.industry ,epilepsy, complications, types, circumstances ,Accidents ,Accidents, Home ,Child, Preschool ,Europe ,Female ,Follow-Up Studies ,Hospitalization ,Patient Acceptance of Health Care ,Wounds and Injuries ,Neurology ,Neurology (clinical) ,medicine.disease ,Occupational ,Relative risk ,Cohort ,Home ,business ,Risk assessment ,Cohort study - Abstract
Purpose: To investigate the risk of accidents in a cohort of patients with epilepsy and in matched nonepilepsy controls. by type, circumstances, and complications. Methods: A total of 95 1 children and adults with idiopathic, cryptogenic, or remote symptomatic epilepsy and 904 matched controls seen in secondary and tertiary centers in eight European Countries (England. Estonia, Germany, Italy, the Netherlands, Portugal. Russia. and Slovenia) were followed Lip prospectively for 17,484 and 17.206 person-months and asked to report any accident requiring medical attention. its site, and complications. Risk assessment was done by using actuarial methods, relative risks (RRs). and 95% confidence intervals (CIs). Results: During the study period, 199 (21%) patients and 123 (14%) controls reported all accident (p < 0.0001); 24% were seizure related. The Cumulative probability of accidents at 12 and 24 months was 17 and 27% in the cases and 12 and 17% in the controls. The risk was highest for concussions (RR, 2.6; 95% Cl, 1.2-5.8), abrasions (RR, 2.1; 95% Cl, 1.1-4.0), and Wounds (RR, 1.9; Cl, 1.2-3.1). Domestic accidents prevailed in both groups, followed by street and work accidents, and were more common among cases. Compared with controls, patients with epilepsy reported more hospitalization, complications, and medical action. Disease characteristics associated with an increased risk of accidents included generalized epilepsy (conclusions), active epilepsy, and at least monthly seizures (abrasions). Most risks decreased, becoming nonsignificant after excluding, seizure-related events. Conclusions: Patients with epilepsy are at higher risk of accidents and their complications. However, the risk was substantially lower after exclusion of seizure-related events
- Published
- 2004
5. Accidents in patients with epilepsy: types, circumstances, and complications: a European cohort study
- Author
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van den Broek, M, Beghi, E, Cornaggia, C, Beghi, M, Bogliun, G, Fiordelli, E, Airoldi, L, Frigeni, B, Mascarini, A, Mapelli, L, Moltrasio, L, Biagi, E, Hauser, W, Loeber, J, Thorbecke, R, Di Viesti, P, Zarrelli, M, Apollo, F, Giovanni Rotondo, S, Steuernagel, E, Wolf, P, Sonnen, A, Specchio, L, Specchio, N, Boati, E, Defanti, C, Pinto, P, Breviario, E, Pasolini, M, Antonini, L, Aguglia, U, Russo, C, Gambardella, A, Giubergia, S, Zagnoni, P, Cosottini, M, Zaccara, G, Pisani, F, Oteri, G, Cavestro, C, David, A, Tonini, C, Avanzini, G, Arienti, F, Tartara, A, Manni, R, Castelnovo, G, Murelli, R, Galimberti, C, Zanotta, N, Runge, U, Dekrom, M, Vanheijden, C, Griet, J, van denBroek, M, Brown, S, Coyle, H, Edge, N, Lopes-Lima, J, Beleza, P, Ferreira, E, Talvik, T, Beilmann, A, Belousova, E, Nikanorowa, M, Ravnik, I, Levart, T, Zupancic, N, Gromov, S, Lipatova, L, Mikhailov, V, van den Broek M., Beghi E., Cornaggia C. M., Beghi M., Bogliun G., Fiordelli E., Airoldi L., Frigeni B., Mascarini A., Mapelli L., Moltrasio L., Biagi E., Hauser W. A., Loeber J. N., Thorbecke R., Di Viesti P., Zarrelli M., Apollo F., Giovanni Rotondo S., Steuernagel E., Wolf P., Sonnen A. E. H., Specchio L. M., Specchio N., Boati E., Defanti C. A., Pinto P., Breviario E., Pasolini M. P., Antonini L., Aguglia U., Russo C., Gambardella A., Giubergia S., Zagnoni P., Cosottini M., Zaccara G., Pisani F., Oteri G., Cavestro C. E., David A., Tonini C., Avanzini G., Arienti F., Tartara A., Manni R., Castelnovo G., Murelli R., Galimberti C. A., Zanotta N., Runge U., deKrom M. C. T. F. M., vanHeijden C., Griet J., van denBroek M. W. C., Brown S. W., Coyle H., Edge N. A., Lopes-Lima J. M., Beleza P., Ferreira E., Talvik T., Beilmann A., Belousova E., Nikanorowa M., Ravnik I. M., Levart T., Zupancic N., Gromov S., Lipatova L. V., Mikhailov V., van den Broek, M, Beghi, E, Cornaggia, C, Beghi, M, Bogliun, G, Fiordelli, E, Airoldi, L, Frigeni, B, Mascarini, A, Mapelli, L, Moltrasio, L, Biagi, E, Hauser, W, Loeber, J, Thorbecke, R, Di Viesti, P, Zarrelli, M, Apollo, F, Giovanni Rotondo, S, Steuernagel, E, Wolf, P, Sonnen, A, Specchio, L, Specchio, N, Boati, E, Defanti, C, Pinto, P, Breviario, E, Pasolini, M, Antonini, L, Aguglia, U, Russo, C, Gambardella, A, Giubergia, S, Zagnoni, P, Cosottini, M, Zaccara, G, Pisani, F, Oteri, G, Cavestro, C, David, A, Tonini, C, Avanzini, G, Arienti, F, Tartara, A, Manni, R, Castelnovo, G, Murelli, R, Galimberti, C, Zanotta, N, Runge, U, Dekrom, M, Vanheijden, C, Griet, J, van denBroek, M, Brown, S, Coyle, H, Edge, N, Lopes-Lima, J, Beleza, P, Ferreira, E, Talvik, T, Beilmann, A, Belousova, E, Nikanorowa, M, Ravnik, I, Levart, T, Zupancic, N, Gromov, S, Lipatova, L, Mikhailov, V, van den Broek M., Beghi E., Cornaggia C. M., Beghi M., Bogliun G., Fiordelli E., Airoldi L., Frigeni B., Mascarini A., Mapelli L., Moltrasio L., Biagi E., Hauser W. A., Loeber J. N., Thorbecke R., Di Viesti P., Zarrelli M., Apollo F., Giovanni Rotondo S., Steuernagel E., Wolf P., Sonnen A. E. H., Specchio L. M., Specchio N., Boati E., Defanti C. A., Pinto P., Breviario E., Pasolini M. P., Antonini L., Aguglia U., Russo C., Gambardella A., Giubergia S., Zagnoni P., Cosottini M., Zaccara G., Pisani F., Oteri G., Cavestro C. E., David A., Tonini C., Avanzini G., Arienti F., Tartara A., Manni R., Castelnovo G., Murelli R., Galimberti C. A., Zanotta N., Runge U., deKrom M. C. T. F. M., vanHeijden C., Griet J., van denBroek M. W. C., Brown S. W., Coyle H., Edge N. A., Lopes-Lima J. M., Beleza P., Ferreira E., Talvik T., Beilmann A., Belousova E., Nikanorowa M., Ravnik I. M., Levart T., Zupancic N., Gromov S., Lipatova L. V., and Mikhailov V.
- Abstract
Purpose: To investigate the risk of accidents in a cohort of patients with epilepsy and in matched nonepilepsy controls, by type, circumstances, and complications. Methods: A total of 951 children and adults with idiopathic, cryptogenic, or remote symptomatic epilepsy and 904 matched controls seen in secondary and tertiary centers in eight European countries (England, Estonia, Germany, Italy, the Netherlands, Portugal, Russia, and Slovenia) were followed up prospectively for 17,484 and 17,206 person-months and asked to report any accident requiring medical attention, its site, and complications. Risk assessment was done by using actuarial methods, relative risks (RRs), and 95% confidence intervals (CIs). Results: During the study period, 199 (21%) patients and 123 (14%) controls reported an accident (p < 0.0001); 24% were seizure related. The cumulative probability of accidents at 12 and 24 months was 17 and 27% in the cases and 12 and 17% in the controls. The risk was highest for concussions (RR, 2.6; 9.5% CI, 1.2-5.8), abrasions (RR, 2.1; 95% CI, 1.1-4.0), and wounds (RR, 1.9; CI, 1.2-3.1). Domestic accidents prevailed in both groups, followed by street and work accidents, and were more common among cases. Compared with controls, patients with epilepsy reported more hospitalization, complications, and medical action. Disease characteristics associated with an increased risk of accidents included generalized epilepsy (concussions), active epilepsy, and at least monthly seizures (abrasions). Most risks decreased, becoming nonsignificant after excluding seizure-related events. Conclusions: Patients with epilepsy are at higher risk of accidents and their complications. However, the risk was substantially lower after exclusion of seizure-related events.
- Published
- 2004
6. Treatment of first tonic-clonic seizure does not affect mortality: long-term follow-up of a randomised clinical trial
- Author
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Leone, Ma, Vallalta, R, Solari, A, Beghi, E, Hauser, Wa, Fratiglioni, L, Bogliun, G, DEL FELICE, Alessandra, Aloisi, P, Marelli, A, Porto, C, Fusi, L, Francesconi, C, Gambaro, P, Basso, P, Freschi, R, Meregalli, S, Boati, E, Mamoli, A, Gavalotti, B, Camerlingo, M, Rottoli, Mr, Bottacchi, E, Carenini, L, Sironi, L, Casara, Gl, Vecchi, M, Covezzi, E, Tortorici, G, Franzoni, E, Marchiani, V, Moscano, F, Giuliani, G, Angeleri, Va, Polonara, S, Terziani, S, Quattrini, A, Ortenzi, A, Paggi, A, Iemolo, F, Geda, C, Ferrari, Gf, Binetti, Ma, Martini, A, Perenchio, Mt, Malvezzi, L, Tabladon, G, Severi, S, Zolo, P, Montano, V, Fassio, F, Vignolo, L, Pasolini, Mp, Antonini, L, De Maria, G, Rossi, G, Tonini, C, Cittani, D, Zagnoni, Pg, Clerici, D, Romeo, A, Viri, M, Lodi, M, Mazza, S, Vaccario, Ml, De Mattei, M, Cremo, R, Zaina, P, Gentile, S, Lovera, N, Piazza, D, Ravetti, C, Cavestro, C, Rosettani, P., Leone MA, Vallalta R, Solari A, Beghi E, FIRST Group [.., Franzoni E, and ]
- Subjects
Male ,Time Factors ,long-term follow-up ,Electroencephalography ,law.invention ,Epilepsy ,Randomized controlled trial ,law ,Recurrence ,Risk Factors ,Young adult ,Family history ,Child ,first tonic-clonic seizure ,medicine.diagnostic_test ,treatment ,clinical trial ,Middle Aged ,Magnetic Resonance Imaging ,first tonic–clonic seizure ,seizure ,Settore MED/26 - NEUROLOGIA ,Psychiatry and Mental health ,Treatment Outcome ,Child, Preschool ,Anticonvulsants ,Female ,Adult ,medicine.medical_specialty ,Adolescent ,antiepileptic treatment ,Neurological examination ,Young Adult ,Seizures ,Internal medicine ,medicine ,Humans ,business.industry ,medicine.disease ,mortality ,Surgery ,Clinical trial ,tonic-clonic seizure ,Etiology ,Neurology (clinical) ,business ,Tomography, X-Ray Computed ,Follow-Up Studies - Abstract
Information on the effects of early treatment of seizures on mortality is scarce. The authors assessed the survival of patients with a first generalised tonic-clonic seizure, randomised to immediate treatment (treated) versus treatment only in the event of seizure recurrence (untreated), over a 20-year period. METHODS: The authors followed 419 patients. The median follow-up was 19.7 years (range 0.2-21.5) for a total of 7867 person-years. RESULTS: 40 persons (9.6%) died during follow-up, 19 (8.9%) treated and 21 (10.3.%) untreated. The probability of surviving was 100% at 1 year, 97% (95% CI 95% to 99%) at 5 years, 94% (91-97) at 10 years and 91% (87-95) at 20 years in treated patients and 100%, 98% (95-100), 97% (94-99) and 89% (85-94), respectively, in untreated patients (p=0.7). After adjustment for treatment of first seizure and putative risk factors (gender, age, seizure type, previous uncertain seizures, family history of seizures, pre-, peri- and postnatal risk factors, remote aetiological factors for epilepsy, abnormal neurological examination, CT or MRI abnormalities, EEG abnormalities and acute treatment), only the presence of aetiological factors for epilepsy predicted a higher mortality (HR 3.4, 95% CI 2.5 to 4.3%; p
- Published
- 2011
7. Studio prospettico multicentrico dei rischi della vita quotidiana nei pazienti con epilessia
- Author
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Cavestro, C, Beghi, E, Cornaggia, C, CORNAGGIA, CESARE MARIA, Cavestro, C, Beghi, E, Cornaggia, C, and CORNAGGIA, CESARE MARIA
- Published
- 1993
8. Sneddon's syndrome presenting with severe disabling bilateral headache.
- Author
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Cavestro C, Richetta L, Pedemonte E, and Asteggiano G
- Abstract
Sneddon's syndrome is a rare vascular disease affecting mainly skin and brain arterioles leading to their occlusion due to excessive endothelial proliferation. The two main features of this syndrome are livedo reticularis and lacunar subcortical infarcts. Here, we describe the case of a 64-year-old woman presenting with a 4-year history of a throbbing, bilateral, parieto-occipital headache associated with facial pain, but without any other accompanying symptom. The pain, initially misdiagnosed as atypical trigeminal neuralgia, worsened up to chronic daily and such severely disabling headache that she was constrained to bed. She presented with reduced cognitive functions, diffuse and severe livedo reticularis, severe myalgias and mild stiffness. All diagnostic test for different diseases were performed and other diseases excluded except for Sneddon's syndrome. Her symptoms were reduced firstly using acetylsalicylic acid, then ticlopidine 250 mg bid was begun and then Pentoxyphillin, resulting in a significant improvement of symptoms with the disappearance of headache. Her worsening in the first year was characterized by obsessive-compulsive behaviours, body-image misperceptions and panic attacks, improved for a period using olanzapine. Considering this case, we remark the importance of using headache classification to avoid diagnostic errors, secondly, we describe an atypical manifestation of Sneddon's syndrome and therapeutic efficacy of using ticlopidine and pentoxyphillin. [ABSTRACT FROM AUTHOR]
- Published
- 2009
- Full Text
- View/download PDF
9. Massive iron accumulation in PKAN-derived neurons and astrocytes: light on the human pathological phenotype
- Author
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Paolo Santambrogio, Maddalena Ripamonti, Anna Cozzi, Marzia Raimondi, Chiara Cavestro, Ivano Di Meo, Alicia Rubio, Stefano Taverna, Valeria Tiranti, Sonia Levi, Santambrogio, P., Ripamonti, M., Cozzi, A., Raimondi, M., Cavestro, C., Di Meo, I., Rubio, A., Taverna, S., Tiranti, V., and Levi, S.
- Subjects
Neurons ,Phosphotransferases (Alcohol Group Acceptor) ,Cancer Research ,Cellular and Molecular Neuroscience ,Phenotype ,Astrocytes ,Iron ,Immunology ,Humans ,Coenzyme A ,Cell Biology ,Pantothenate Kinase-Associated Neurodegeneration - Abstract
Neurodegeneration associated with defective pantothenate kinase-2 (PKAN) is an early-onset monogenic autosomal-recessive disorder. The hallmark of the disease is the massive accumulation of iron in the globus pallidus brain region of patients. PKAN is caused by mutations in the PANK2 gene encoding the mitochondrial enzyme pantothenate kinase-2, whose function is to catalyze the first reaction of the CoA biosynthetic pathway. To date, the way in which this alteration leads to brain iron accumulation has not been elucidated. Starting from previously obtained hiPS clones, we set up a differentiation protocol able to generate inhibitory neurons. We obtained striatal-like medium spiny neurons composed of approximately 70–80% GABAergic neurons and 10–20% glial cells. Within this mixed population, we detected iron deposition in both PKAN cell types, however, the viability of PKAN GABAergic neurons was strongly affected. CoA treatment was able to reduce cell death and, notably, iron overload. Further differentiation of hiPS clones in a pure population of astrocytes showed particularly evident iron accumulation, with approximately 50% of cells positive for Perls staining. The analysis of these PKAN astrocytes indicated alterations in iron metabolism, mitochondrial morphology, respiratory activity, and oxidative status. Moreover, PKAN astrocytes showed signs of ferroptosis and were prone to developing a stellate phenotype, thus gaining neurotoxic features. This characteristic was confirmed in iPS-derived astrocyte and glutamatergic neuron cocultures, in which PKAN glutamatergic neurons were less viable in the presence of PKAN astrocytes. This newly generated astrocyte model is the first in vitro disease model recapitulating the human phenotype and can be exploited to deeply clarify the pathogenetic mechanisms underlying the disease.
- Published
- 2022
10. CoA synthase plays a critical role in neurodevelopment and neurodegeneration.
- Author
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Cavestro C, D'Amato M, Colombo MN, Cascone F, Moro AS, Levi S, Tiranti V, and Di Meo I
- Abstract
Coenzyme A (CoA), which is widely distributed and vital for cellular metabolism, is a critical molecule essential in both synthesizing and breaking down key energy sources in the body. Inborn errors of metabolism in the cellular de novo biosynthetic pathway of CoA have been linked to human genetic disorders, emphasizing the importance of this pathway. The COASY gene encodes the bifunctional enzyme CoA synthase, which catalyzes the last two reactions of the CoA biosynthetic pathway and serves as one of the rate-limiting components of the pathway. Recessive variants of this gene cause an exceptionally rare and devastating disease called COASY protein-associated neurodegeneration (CoPAN) while complete loss-of-function variants in COASY have been identified in fetuses/neonates with Pontocerebellar Hypoplasia type 12 (PCH 12). Understanding why the different symptoms emerge in these disorders and what determines the development of one syndrome over the other is still not achieved. To shed light on the pathogenesis, we generated a new conditional animal model in which Coasy was deleted under the control of the human GFAP promoter. We used this mouse model to investigate how defects in the CoA biosynthetic pathway affect brain development. This model showed a broad spectrum of severity of the in vivo phenotype, ranging from very short survival (less than 2 weeks) to normal life expectancy in some animals. Surviving mice displayed a behavioral phenotype with sensorimotor defects. Ex vivo histological analysis revealed variable but consistent cerebral and cerebellar cortical hypoplasia, in parallel with a broad astrocytic hyper-proliferation in the cerebral cortex. In addition, primary astrocytes derived from this model exhibited lipid peroxidation, iron dyshomeostasis, and impaired mitochondrial respiration. Notably, Coasy ablation in radial glia and astrocytic lineage triggers abnormal neuronal development and chronic neuroinflammation, offering new insights into disease mechanisms., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Cavestro, D’Amato, Colombo, Cascone, Moro, Levi, Tiranti and Di Meo.)
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- 2024
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11. Emerging variants, unique phenotypes, and transcriptomic signatures: an integrated study of COASY-associated diseases.
- Author
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Cavestro C, Morra F, Legati A, D'Amato M, Nasca A, Iuso A, Lubarr N, Morrison JL, Wheeler PG, Serra-Juhé C, Rodríguez-Santiago B, Turón-Viñas E, Prouteau C, Barth M, Hayflick SJ, Ghezzi D, Tiranti V, and Di Meo I
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- Humans, Male, Female, Child, Child, Preschool, Epilepsy genetics, Fibroblasts metabolism, Adolescent, Autism Spectrum Disorder genetics, Adult, Transferases, Phenotype, Transcriptome
- Abstract
Objective: COASY, the gene encoding the bifunctional enzyme CoA synthase, which catalyzes the last two reactions of cellular de novo coenzyme A (CoA) biosynthesis, has been linked to two exceedingly rare autosomal recessive disorders, such as COASY protein-associated neurodegeneration (CoPAN), a form of neurodegeneration with brain iron accumulation (NBIA), and pontocerebellar hypoplasia type 12 (PCH12). We aimed to expand the phenotypic spectrum and gain insights into the pathogenesis of COASY-related disorders., Methods: Patients were identified through targeted or exome sequencing. To unravel the molecular mechanisms of disease, RNA sequencing, bioenergetic analysis, and quantification of critical proteins were performed on fibroblasts., Results: We identified five new individuals harboring novel COASY variants. While one case exhibited classical CoPAN features, the others displayed atypical symptoms such as deafness, language and autism spectrum disorders, brain atrophy, and microcephaly. All patients experienced epilepsy, highlighting its potential frequency in COASY-related disorders. Fibroblast transcriptomic profiling unveiled dysregulated expression in genes associated with mitochondrial respiration, responses to oxidative stress, transmembrane transport, various cellular signaling pathways, and protein translation, modification, and trafficking. Bioenergetic analysis revealed impaired mitochondrial oxygen consumption in COASY fibroblasts. Despite comparable total CoA levels to control cells, the amounts of mitochondrial 4'-phosphopantetheinylated proteins were significantly reduced in COASY patients., Interpretation: These results not only extend the clinical phenotype associated with COASY variants but also suggest a continuum between CoPAN and PCH12. The intricate interplay of altered cellular processes and signaling pathways provides valuable insights for further research into the pathogenesis of COASY-associated diseases., (© 2024 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)
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- 2024
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12. Inherited Disorders of Coenzyme A Biosynthesis: Models, Mechanisms, and Treatments.
- Author
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Cavestro C, Diodato D, Tiranti V, and Di Meo I
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- Humans, Iron metabolism, Biosynthetic Pathways genetics, Coenzyme A metabolism, Phosphotransferases (Alcohol Group Acceptor) metabolism, Pantothenate Kinase-Associated Neurodegeneration drug therapy, Cardiomyopathy, Dilated
- Abstract
Coenzyme A (CoA) is a vital and ubiquitous cofactor required in a vast number of enzymatic reactions and cellular processes. To date, four rare human inborn errors of CoA biosynthesis have been described. These disorders have distinct symptoms, although all stem from variants in genes that encode enzymes involved in the same metabolic process. The first and last enzymes catalyzing the CoA biosynthetic pathway are associated with two neurological conditions, namely pantothenate kinase-associated neurodegeneration (PKAN) and COASY protein-associated neurodegeneration (CoPAN), which belong to the heterogeneous group of neurodegenerations with brain iron accumulation (NBIA), while the second and third enzymes are linked to a rapidly fatal dilated cardiomyopathy. There is still limited information about the pathogenesis of these diseases, and the knowledge gaps need to be resolved in order to develop potential therapeutic approaches. This review aims to provide a summary of CoA metabolism and functions, and a comprehensive overview of what is currently known about disorders associated with its biosynthesis, including available preclinical models, proposed pathomechanisms, and potential therapeutic approaches.
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- 2023
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13. Identification of Autophagy as a Functional Target Suitable for the Pharmacological Treatment of Mitochondrial Membrane Protein-Associated Neurodegeneration (MPAN) In Vitro.
- Author
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Zanuttigh E, Derderian K, Güra MA, Geerlof A, Di Meo I, Cavestro C, Hempfling S, Ortiz-Collazos S, Mauthe M, Kmieć T, Cammarota E, Panzeri MC, Klopstock T, Sattler M, Winkelmann J, Messias AC, and Iuso A
- Abstract
Mitochondrial membrane protein-associated neurodegeneration (MPAN) is a relentlessly progressive neurodegenerative disorder caused by mutations in the C19orf12 gene. C19orf12 has been implicated in playing a role in lipid metabolism, mitochondrial function, and autophagy, however, the precise functions remain unknown. To identify new robust cellular targets for small compound treatments, we evaluated reported mitochondrial function alterations, cellular signaling, and autophagy in a large cohort of MPAN patients and control fibroblasts. We found no consistent alteration of mitochondrial functions or cellular signaling messengers in MPAN fibroblasts. In contrast, we found that autophagy initiation is consistently impaired in MPAN fibroblasts and show that C19orf12 expression correlates with the amount of LC3 puncta, an autophagy marker. Finally, we screened 14 different autophagy modulators to test which can restore this autophagy defect. Amongst these compounds, carbamazepine, ABT-737, LY294002, oridonin, and paroxetine could restore LC3 puncta in the MPAN fibroblasts, identifying them as novel potential therapeutic compounds to treat MPAN. In summary, our study confirms a role for C19orf12 in autophagy, proposes LC3 puncta as a functionally robust and consistent readout for testing compounds, and pinpoints potential therapeutic compounds for MPAN.
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- 2023
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14. PPAR Gamma Agonist Leriglitazone Recovers Alterations Due to Pank2-Deficiency in hiPS-Derived Astrocytes.
- Author
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Santambrogio P, Cozzi A, Di Meo I, Cavestro C, Vergara C, Rodríguez-Pascau L, Martinell M, Pizcueta P, Tiranti V, and Levi S
- Abstract
The novel brain-penetrant peroxisome proliferator-activated receptor gamma agonist leriglitazone, previously validated for other rare neurodegenerative diseases, is a small molecule that acts as a regulator of mitochondrial function and exerts neuroprotective, anti-oxidative and anti-inflammatory effects. Herein, we tested whether leriglitazone can be effective in ameliorating the mitochondrial defects that characterize an hiPS-derived model of Pantothenate kinase-2 associated Neurodegeneration (PKAN). PKAN is caused by a genetic alteration in the mitochondrial enzyme pantothenate kinase-2, whose function is to catalyze the first reaction of the CoA biosynthetic pathway, and for which no effective cure is available. The PKAN hiPS-derived astrocytes are characterized by mitochondrial dysfunction, cytosolic iron deposition, oxidative stress and neurotoxicity. We monitored the effect of leriglitazone in comparison with CoA on hiPS-derived astrocytes from three healthy subjects and three PKAN patients. The treatment with leriglitazone did not affect the differentiation of the neuronal precursor cells into astrocytes, and it improved the viability of PKAN cells and their respiratory activity, while diminishing the iron accumulation similarly or even better than CoA. The data suggest that leriglitazone is well tolerated in this cellular model and could be considered a beneficial therapeutic approach in the treatment of PKAN.
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- 2023
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15. Encephalitis in Patients with COVID-19: A Systematic Evidence-Based Analysis.
- Author
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Islam MA, Cavestro C, Alam SS, Kundu S, Kamal MA, and Reza F
- Subjects
- Adult, Brain diagnostic imaging, Child, Female, Humans, Male, SARS-CoV-2, COVID-19, Encephalitis complications, Mental Disorders
- Abstract
Although severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) predominantly infects the respiratory system, several investigations have shown the involvement of the central nervous system (CNS) along the course of the illness, with encephalitis being one of the symptoms. The objective of this systematic review was to evaluate the characteristics (clinical, neuro-radiological aspects, and laboratory features) and outcomes of encephalitis in COVID-19 patients. PubMed, Scopus, and Google Scholar databases were searched from 1 December 2019 until 21 July 2022 to identify case reports and case series published on COVID-19 associated with encephalitis. The quality of the included studies was assessed by the Joanna Briggs Institute critical appraisal checklists. This systematic review included 79 studies, including 91 COVID-19 patients (52.7% male) experiencing encephalitis, where 85.6% were adults (49.3 ± 20.2 years), and 14.4% were children (11.2 ± 7.6 years). RT-PCR was used to confirm 92.2% of the COVID-19 patients. Encephalitis-related symptoms were present in 78.0% of COVID-19 patients at the time of diagnosis. In these encephalitis patients, seizure (29.5%), confusion (23.2%), headache (20.5%), disorientation (15.2%), and altered mental status (11.6%) were the most frequently reported neurologic manifestations. Looking at the MRI, EEG, and CSF findings, 77.6%, 75.5%, and 64.1% of the patients represented abnormal results. SARS-CoV-2-associated or -mediated encephalitis were the most common type observed (59.3%), followed by autoimmune encephalitis (18.7%). Among the included patients, 66.7% were discharged (37.8% improved and 28.9% fully recovered), whereas 20.0% of the reported COVID-19-positive encephalitis patients died. Based on the quality assessment, 87.4% of the studies were of high quality. Although in COVID-19, encephalitis is not a typical phenomenon, SARS-CoV-2 seems like a neuropathogen affecting the brain even when there are no signs of respiratory illness, causing a high rate of disability and fatality.
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- 2022
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16. Massive iron accumulation in PKAN-derived neurons and astrocytes: light on the human pathological phenotype.
- Author
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Santambrogio P, Ripamonti M, Cozzi A, Raimondi M, Cavestro C, Di Meo I, Rubio A, Taverna S, Tiranti V, and Levi S
- Subjects
- Coenzyme A genetics, Coenzyme A metabolism, Humans, Iron metabolism, Neurons metabolism, Phenotype, Phosphotransferases (Alcohol Group Acceptor) metabolism, Astrocytes metabolism, Pantothenate Kinase-Associated Neurodegeneration genetics, Pantothenate Kinase-Associated Neurodegeneration metabolism, Pantothenate Kinase-Associated Neurodegeneration pathology
- Abstract
Neurodegeneration associated with defective pantothenate kinase-2 (PKAN) is an early-onset monogenic autosomal-recessive disorder. The hallmark of the disease is the massive accumulation of iron in the globus pallidus brain region of patients. PKAN is caused by mutations in the PANK2 gene encoding the mitochondrial enzyme pantothenate kinase-2, whose function is to catalyze the first reaction of the CoA biosynthetic pathway. To date, the way in which this alteration leads to brain iron accumulation has not been elucidated. Starting from previously obtained hiPS clones, we set up a differentiation protocol able to generate inhibitory neurons. We obtained striatal-like medium spiny neurons composed of approximately 70-80% GABAergic neurons and 10-20% glial cells. Within this mixed population, we detected iron deposition in both PKAN cell types, however, the viability of PKAN GABAergic neurons was strongly affected. CoA treatment was able to reduce cell death and, notably, iron overload. Further differentiation of hiPS clones in a pure population of astrocytes showed particularly evident iron accumulation, with approximately 50% of cells positive for Perls staining. The analysis of these PKAN astrocytes indicated alterations in iron metabolism, mitochondrial morphology, respiratory activity, and oxidative status. Moreover, PKAN astrocytes showed signs of ferroptosis and were prone to developing a stellate phenotype, thus gaining neurotoxic features. This characteristic was confirmed in iPS-derived astrocyte and glutamatergic neuron cocultures, in which PKAN glutamatergic neurons were less viable in the presence of PKAN astrocytes. This newly generated astrocyte model is the first in vitro disease model recapitulating the human phenotype and can be exploited to deeply clarify the pathogenetic mechanisms underlying the disease., (© 2022. The Author(s).)
- Published
- 2022
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17. Neuronal Ablation of CoA Synthase Causes Motor Deficits, Iron Dyshomeostasis, and Mitochondrial Dysfunctions in a CoPAN Mouse Model.
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Di Meo I, Cavestro C, Pedretti S, Fu T, Ligorio S, Manocchio A, Lavermicocca L, Santambrogio P, Ripamonti M, Levi S, Ayciriex S, Mitro N, and Tiranti V
- Subjects
- Animals, Coenzyme A metabolism, Female, Hemochromatosis etiology, Homeostasis, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Mitochondria genetics, Mitochondria metabolism, Mitochondria pathology, Mitochondrial Diseases etiology, Mitochondrial Diseases metabolism, Motor Disorders etiology, Motor Disorders metabolism, Coenzyme A Ligases physiology, Hemochromatosis pathology, Iron metabolism, Mitochondrial Diseases pathology, Motor Disorders pathology, Pantothenate Kinase-Associated Neurodegeneration complications, Synapsins physiology
- Abstract
COASY protein-associated neurodegeneration (CoPAN) is a rare but devastating genetic autosomal recessive disorder of inborn error of CoA metabolism, which shares with pantothenate kinase-associated neurodegeneration (PKAN) similar features, such as dystonia, parkinsonian traits, cognitive impairment, axonal neuropathy, and brain iron accumulation. These two disorders are part of the big group of neurodegenerations with brain iron accumulation (NBIA) for which no effective treatment is available at the moment. To date, the lack of a mammalian model, fully recapitulating the human disorder, has prevented the elucidation of pathogenesis and the development of therapeutic approaches. To gain new insights into the mechanisms linking CoA metabolism, iron dyshomeostasis, and neurodegeneration, we generated and characterized the first CoPAN disease mammalian model. Since CoA is a crucial metabolite, constitutive ablation of the Coasy gene is incompatible with life. On the contrary, a conditional neuronal-specific Coasy knock-out mouse model consistently developed a severe early onset neurological phenotype characterized by sensorimotor defects and dystonia-like movements, leading to premature death. For the first time, we highlighted defective brain iron homeostasis, elevation of iron, calcium, and magnesium, together with mitochondrial dysfunction. Surprisingly, total brain CoA levels were unchanged, and no signs of neurodegeneration were present.
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- 2020
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18. Prevalence of Headache in Patients With Coronavirus Disease 2019 (COVID-19): A Systematic Review and Meta-Analysis of 14,275 Patients.
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Islam MA, Alam SS, Kundu S, Hossan T, Kamal MA, and Cavestro C
- Abstract
Background: Coronavirus disease 2019 (COVID-19) started to spread globally since December 2019 from Wuhan, China. Headache has been observed as one of the clinical manifestations in COVID-19 patients. We aimed to conduct a comprehensive systematic review and meta-analysis to estimate the overall pooled prevalence of headache in COVID-19 patients. Methods: PubMed, Scopus, ScienceDirect, and Google Scholar databases were searched to identify studies published between December 2019 and March 2020. Adult (≥18 years) COVID-19 patients were considered eligible. We used random-effects model to estimate the pooled prevalence with 95% confidence intervals (CIs). Quality assessment was done using the Joanna Briggs Institute critical appraisal tools. This study is registered with PROSPERO (CRD42020182529). Results: We identified 2,055 studies, of which 86 studies ( n = 14,275, 49.4% female) were included in the meta-analysis. Overall, the pooled prevalence of headache in COVID-19 patients was 10.1% [95% CI: 8.76-11.49]. There was no significant difference of headache prevalence in severe or critical vs. non-severe (RR: 1.05, p = 0.78), survived (recovered or discharged) vs. non-survived (RR: 1.36, p = 0.23), and ICU vs. non-ICU (RR: 1.06, p = 0.87) COVID-19 patients. We detected 64.0, 34.9, and 1.1% of the included studies as high, moderate, and low quality, respectively. Conclusions: From the first 4-month data of the outbreak, headache was detected in 10.1% of the adult COVID-19 patients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2020 Islam, Alam, Kundu, Hossan, Kamal and Cavestro.)
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- 2020
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19. Alpha-Lipoic Acid Shows Promise to Improve Migraine in Patients with Insulin Resistance: A 6-Month Exploratory Study.
- Author
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Cavestro C, Bedogni G, Molinari F, Mandrino S, Rota E, and Frigeri MC
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- Adult, Biomarkers blood, Blood Glucose analysis, Cohort Studies, Combined Modality Therapy, Female, Follow-Up Studies, Glucose Tolerance Test, Humans, Hyperinsulinism blood, Hyperinsulinism complications, Hyperinsulinism metabolism, Insulin blood, Male, Middle Aged, Migraine with Aura complications, Migraine with Aura physiopathology, Migraine with Aura therapy, Migraine without Aura complications, Migraine without Aura physiopathology, Migraine without Aura therapy, Outpatient Clinics, Hospital, Severity of Illness Index, Antioxidants therapeutic use, Hyperinsulinism diet therapy, Insulin Resistance, Migraine with Aura diet therapy, Migraine without Aura diet therapy, Thioctic Acid therapeutic use
- Abstract
Alpha-lipoic acid (ALA) is known to lower insulin resistance (IR), which is common among migraineurs. To assess the effect of ALA on headache in migraineurs with IR, we performed an exploratory study on a cohort of patients with migraine, followed at our Headache Center. The 32 patients took ALA 400 mg b.i.d. for 6 months in addition to their on-going treatment. The percentage of patients with a reduction of at least 50% of the attacks was 0.53 (confidence interval [95% CI] 0.36-0.70) at 2 months, 0.56 (0.39-0.73) at 4 months, and 0.69 (0.53-0.85) at 6 months. The incidence rate ratio of attacks at 6 months versus baseline was 0.48 (0.43-0.53, P < .001), corresponding to a mean (95% CI) number of attacks of 5 (4-6) versus 11 (10-12). The number of days of treatment in the previous month was 7.7 (6.8-8.7) at baseline, 5.4 (4.6-6.2) at 2 months, 5.3 (4.5-6.1) at 4 months, and 4.3 (3.6-5.0) at 6 months. Baseline and 120-min glucose and insulin and quantitative insulin sensitivity check index (QUICKI) and the Stumvoll index did not change at 6 months versus baseline. This exploratory study shows that the administration of ALA may be associated with a reduction in the number of attacks and the days of treatment in migraineurs with IR. A randomized controlled trial is needed to test this possibility.
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- 2018
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20. Thrombophilic disorders in migraine.
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Cavestro C and Mandrino S
- Published
- 2014
- Full Text
- View/download PDF
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