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1.
Nat Commun ; 12(1): 4488, 2021 07 23.
Artigo em Inglês | MEDLINE | ID: mdl-34301944

RESUMO

Opn7b is a non-visual G protein-coupled receptor expressed in zebrafish. Here we find that Opn7b expressed in HEK cells constitutively activates the Gi/o pathway and illumination with blue/green light inactivates G protein-coupled inwardly rectifying potassium channels. This suggests that light acts as an inverse agonist for Opn7b and can be used as an optogenetic tool to inhibit neuronal networks in the dark and interrupt constitutive inhibition in the light. Consistent with this prediction, illumination of recombinant expressed Opn7b in cortical pyramidal cells results in increased neuronal activity. In awake mice, light stimulation of Opn7b expressed in pyramidal cells of somatosensory cortex reliably induces generalized epileptiform activity within a short (<10 s) delay after onset of stimulation. Our study demonstrates a reversed mechanism for G protein-coupled receptor control and Opn7b as a tool for controlling neural circuit properties.


Assuntos
Proteínas de Ligação ao GTP/metabolismo , Neurônios/metabolismo , Opsinas/metabolismo , Optogenética/métodos , Proteínas de Peixe-Zebra/metabolismo , Peixe-Zebra/metabolismo , Animais , Proteínas de Ligação ao GTP/genética , Células HEK293 , Humanos , Camundongos Endogâmicos C57BL , Neurônios/fisiologia , Opsinas/genética , Células Piramidais/metabolismo , Células Piramidais/fisiologia , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo , Transdução de Sinais/genética , Córtex Somatossensorial/citologia , Córtex Somatossensorial/metabolismo , Sinapses/genética , Sinapses/fisiologia , Peixe-Zebra/genética , Proteínas de Peixe-Zebra/genética
2.
J Neurochem ; 156(5): 589-603, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-32083308

RESUMO

Reelin is a protein that is best known for its role in controlling neuronal layer formation in the developing cortex. Here, we studied its role for post-natal cortical network function, which is poorly explored. To preclude early cortical migration defects caused by Reelin deficiency, we used a conditional Reelin knock-out (RelncKO ) mouse, and induced Reelin deficiency post-natally. Induced Reelin deficiency caused hyperexcitability of the neocortical network in vitro and ex vivo. Blocking Reelin binding to its receptors ApoER2 and VLDLR resulted in a similar effect. Hyperexcitability in RelncKO organotypic slice cultures could be rescued by co-culture with wild-type organotypic slice cultures. Moreover, the GABAB receptor (GABAB R) agonist baclofen failed to activate and the antagonist CGP35348 failed to block GABAB Rs in RelncKO mice. Immunolabeling of RelncKO cortical slices revealed a reduction in GABAB R1 and GABAB R2 surface expression at the plasma membrane and western blot of RelncKO cortical tissue revealed decreased phosphorylation of the GABAB R2 subunit at serine 892 and increased phosphorylation at serine 783, reflecting receptor deactivation and proteolysis. These data show a role of Reelin in controlling early network activity, by modulating GABAB R function. Cover Image for this issue: https://doi.org/10.1111/jnc.15054.


Assuntos
Moléculas de Adesão Celular Neuronais/deficiência , Proteínas da Matriz Extracelular/deficiência , Neocórtex/metabolismo , Proteínas do Tecido Nervoso/deficiência , Receptores de GABA-B/fisiologia , Serina Endopeptidases/deficiência , Transdução de Sinais/fisiologia , Animais , Animais Recém-Nascidos , Moléculas de Adesão Celular Neuronais/genética , Proteínas da Matriz Extracelular/genética , Feminino , Agonistas dos Receptores de GABA-B/farmacologia , Masculino , Camundongos , Camundongos Knockout , Proteínas do Tecido Nervoso/genética , Técnicas de Cultura de Órgãos , Serina Endopeptidases/genética , Transdução de Sinais/efeitos dos fármacos
3.
Microcirculation ; 27(5): e12616, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32108981

RESUMO

OBJECTIVE: In Europe, MMA is a very rare non-inflammatory vasculopathy. MMA is an important differential diagnosis of cerebral vasculitis. Systemic manifestations, such as livedo racemosa or renal artery stenosis, associated with Moyamoya variants suggest the involvement also of non-cerebral vessels. Hypothetically, capillary microscopy could be a promising non-invasive screening method to visualize microcirculation, for example prior to cerebral angiography. METHODS: Standardized capillary microscopic images were taken in European patients with MMA and subsequently evaluated in a blinded analysis, using data obtained from a large NP cohort and a large SLE cohort by the same blinded Investigator as controls. RESULTS: Twenty-four European MMD patients and 14 healthy accompanying controls were included in this study. The results were compared to 116 SLE patients and 754 NP subjects. In MMD patients, no capillary morphological differences were found in comparison with NP, in particular no density reduction or increased neoangiogenesis. The pattern observed in the SLE cohort was clearly distinct from NP and MMD with regard to vascular density, vascular damage, and neoangiogenesis. CONCLUSIONS: MMD is not associated with microvascular changes of the nailfold capillaries. In this respect, it is clearly distinct from SLE.

4.
Chembiochem ; 21(5): 612-617, 2020 03 02.
Artigo em Inglês | MEDLINE | ID: mdl-31468691

RESUMO

Optogenetics uses light-sensitive proteins, so-called optogenetic tools, for highly precise spatiotemporal control of cellular states and signals. The major limitations of such tools include the overlap of excitation spectra, phototoxicity, and lack of sensitivity. The protein characterized in this study, the Japanese lamprey parapinopsin, which we named UVLamP, is a promising optogenetic tool to overcome these limitations. Using a hybrid strategy combining molecular, cellular, electrophysiological, and computational methods we elucidated a structural model of the dark state and probed the optogenetic potential of UVLamP. Interestingly, it is the first described bistable vertebrate opsin that has a charged amino acid interacting with the Schiff base in the dark state, that has no relevance for its photoreaction. UVLamP is a bistable UV-sensitive opsin that allows for precise and sustained optogenetic control of G protein-coupled receptor (GPCR) pathways and can be switched on, but more importantly also off within milliseconds via lowintensity short light pulses. UVLamP exhibits an extremely narrow excitation spectrum in the UV range allowing for sustained activation of the Gi/o pathway with a millisecond UV light pulse. Its sustained pathway activation can be switched off, surprisingly also with a millisecond blue light pulse, minimizing phototoxicity. Thus, UVLamP serves as a minimally invasive, narrow-bandwidth probe for controlling the Gi/o pathway, allowing for combinatorial use with multiple optogenetic tools or sensors. Because UVLamP activated Gi/o signals are generally inhibitory and decrease cellular activity, it has tremendous potential for health-related applications such as relieving pain, blocking seizures, and delaying neurodegeneration.


Assuntos
Proteínas de Peixes/metabolismo , Lampreias/metabolismo , Optogenética/métodos , Receptores Acoplados a Proteínas G/metabolismo , Opsinas de Bastonetes/metabolismo , Animais , Células HEK293 , Humanos , Raios Ultravioleta
5.
Childs Nerv Syst ; 35(7): 1231-1237, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31037424

RESUMO

Moyamoya angiopathy is a rare vasculopathy with stenosis and/or occlusion of bilateral intracranial parts of internal carotid arteries and/or proximal parts of middle and anterior cerebral arteries. PHACE syndrome is characterized by large segmental hemangiomas in the cervical-facial region. Both conditions are known to be associated in rare cases. Recently, it was discussed in the literature that RNF213 variants could be etiologically involved in this association. Here, we describe a childhood case with this rare co-occurrence in which we did not identify any rare RNF213 variant. The clinical and genetic backgrounds are discussed.


Assuntos
Adenosina Trifosfatases/genética , Coartação Aórtica/complicações , Anormalidades do Olho/complicações , Doença de Moyamoya/complicações , Síndromes Neurocutâneas/complicações , Ubiquitina-Proteína Ligases/genética , Adulto , Coartação Aórtica/diagnóstico por imagem , Coartação Aórtica/genética , Encéfalo/diagnóstico por imagem , Anormalidades do Olho/diagnóstico por imagem , Anormalidades do Olho/genética , Feminino , Humanos , Imageamento por Ressonância Magnética , Doença de Moyamoya/diagnóstico por imagem , Doença de Moyamoya/genética , Síndromes Neurocutâneas/diagnóstico por imagem , Síndromes Neurocutâneas/genética
6.
J Neurol ; 266(6): 1421-1428, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30868219

RESUMO

INTRODUCTION: Moyamoya angiopathy (MMA) is a rare vasopathy, especially among European Caucasians. Data about demographics, clinical presentation, comorbid conditions, radiological findings as well as laboratory and cerebral spinal fluid (CSF) data are sparse. METHODS: Patients with MMA treated in the Alfried Krupp Hospital, Essen, Germany, between 2010 and 2017 with focus on demographic, clinical, radiological and laboratory as well as CSF data were evaluated retrospectively. Patients with non-Caucasian family background were excluded from this study. RESULTS: Altogether 200 European Caucasian patients with MMA were identified. There was a female predominance of 3.2:1. The mean age at first presentation was 32.9 years and the mean age of diagnosis was 36.0 years. Eleven of 194 index patients (5.7%) showed a familial presentation. In 11.6% posterior cerebral artery was additionally involved, in 4% additionally cerebral aneurysm and in 2.5% dysgenesis of corpus callosum was found. Most patients suffered from transient ischemic attacks (71.5%) and stroke (82%). Cerebral hemorrhage was found in 9.5%. Livedo racemosa was an associated symptom in 12.8% of patients and thyroid diseases were found in 23.8%. CONCLUSIONS: Compared with Asian data, cerebral hemorrhages are infrequent and female predominance is accentuated among European Caucasians. Some former unknown rare features like associated livedo racemosa, dysgenesis of corpus callosum and associated syncope have been discovered systematically for the first time in this huge European Caucasian cohort.


Assuntos
Grupo com Ancestrais do Continente Europeu/estatística & dados numéricos , Doença de Moyamoya/epidemiologia , Doença de Moyamoya/fisiopatologia , Adolescente , Adulto , Idoso , Agenesia do Corpo Caloso/epidemiologia , Criança , Pré-Escolar , Comorbidade , Feminino , Alemanha/epidemiologia , Humanos , Masculino , Pessoa de Meia-Idade , Doença de Moyamoya/complicações , Estudos Retrospectivos , Fatores Sexuais , Dermatopatias Vasculares/epidemiologia , Dermatopatias Vasculares/etiologia , Síncope/epidemiologia , Síncope/etiologia , Adulto Jovem
7.
Stroke ; 50(4): 789-796, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30908154

RESUMO

Background and Purpose Moyamoya angiopathy (MMA) is a rare cerebral vasculopathy outside of Asia. In Japanese patients, a vast majority of patients carry the founder p.R4810K variant in the RNF213 gene, and familial cases are around 10%. In European patients, data about familial occurrence are limited. The aim of this study was to characterize the clinical and molecular features of several European families with a parent-to-child transmission of MMA. Methods Out of 126 MMA probands referred, we identified 113 sporadic probands and 13 familial probands. Segregation analysis showed a vertical parent-to-child pattern of inheritance in the families of 5 of these probands. All 5 families were of German or Dutch ancestry. We investigated the clinical features of affected members and used whole-exome sequencing to screen RNF213 and 13 genes involved in Mendelian MMA and to identify genes recurrently mutated in these families. Results Twelve affected MMA patients were identified, including 9 females and 3 males. Age at clinical onset ranged from 11 to 65 years. In 3 of 5 families, associated livedo racemosa was found. We did not detect any deleterious variants in the 13 known MMA genes. RNF213 rare missense variants predicted to be pathogenic were detected in all affected members of 2 of these families, as well as 2 candidate variants of the PALD1 gene. Conclusions Nonsyndromic MMA was identified in 5 European families, including 2 to 3 clinically affected cases segregating with a parent-to-child pattern of inheritance in each family. Molecular screening detected rare deleterious variants within RNF213 and PALD1 in all affected members of 2 of these 5 families, as well as in some clinically unaffected members. Altogether these data raise the difficult and, to date unanswered, question of the medical indication of presymptomatic screening.


Assuntos
Adenosina Trifosfatases/genética , Predisposição Genética para Doença , Doença de Moyamoya/diagnóstico , Mutação , Ubiquitina-Proteína Ligases/genética , Adolescente , Adulto , Idade de Início , Idoso , Alelos , Criança , Europa (Continente) , Feminino , Frequência do Gene , Estudos de Associação Genética , Humanos , Masculino , Pessoa de Meia-Idade , Doença de Moyamoya/genética , Linhagem , Fosfoproteínas Fosfatases/genética , Sequenciamento Completo do Exoma , Adulto Jovem
8.
J Neurol ; 266(5): 1153-1159, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30805794

RESUMO

BACKGROUND: The lacking awareness of healthcare providers bears the risk of delayed or false diagnoses in rare diseases. No systematic data about misdiagnoses of Moyamoya angiopathy (MMA) are available. OBJECTIVE: To evaluate the rate and pattern of missed diagnoses in MMA. METHODS: Retrospective analysis of a consecutive case series from a single German referral center. Rates of missed or delayed diagnoses in Caucasian MMA patients were calculated based on discharge letters from other hospitals and systematic chart review. RESULTS: Out of 192 Caucasian patients eventually diagnosed with MMA at our center, an initial misdiagnosis was identified in 119 patients (62%). The time between onset and diagnosis was 1 year in 24 patients, 2 years in 23 patients, 3 years in 10 patients, and > 3 years in 49 patients (mean 5.28, median 3, standard deviation 5.11, and range 4-26 years). The most common misdiagnoses were cerebral vasculitis (31%), etiologically ill-defined stroke diagnoses (30.2%), and MS (3.6%). CONCLUSIONS: This is the first systematic report which shows that patients with MMA are at high risk to be falsely diagnosed and treated. Depiction of typical vascular abnormalities in angiopathy is essential. Normal CSF cell counts, negative oligoclonal bands, and lack of infratentorial lesions as well as gadolinium-positive T1 lesions on MRI may be red flags differentiating this vasculopathy from vasculitis and MS.


Assuntos
Diagnóstico Tardio , Erros de Diagnóstico , Doença de Moyamoya/diagnóstico , Adolescente , Adulto , Angiografia , Criança , Pré-Escolar , Grupo com Ancestrais do Continente Europeu , Feminino , Humanos , Lactente , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Doença de Moyamoya/etnologia , Estudos Retrospectivos , Vasculite/diagnóstico , Adulto Jovem
9.
J Neurol ; 265(10): 2370-2378, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30120561

RESUMO

BACKGROUND: Despite the consensus on the necessity of revascularizing surgery in Moyamoya angiopathy in Asia, the indication in Caucasian Moyamoya patients is discussed controversially. OBJECTIVE: The safety of revascularizing surgery in Europe should be clarified. METHODS: This study retrospectively analyzed the rate of complications as well as clinical symptoms within the first 3 months after bypass surgery between superficial temporal artery and middle cerebral artery (STA-MCA). RESULTS: 64 direct bypass procedures in 45 patients (95.5% Caucasians) were analyzed. The magnetic resonance imaging at day 6 showed subdural hematoma in 60.3%. The mean diameter of these hematomas on magnetic resonance imaging was 5.1 mm (SD 3.4 mm) and increased in 25% at follow-up. No difference was found between those patients with early (day 1) or late (day 7) restarts of antiplatelet therapy. Magnetic resonance imaging at day 6 revealed hyperperfusion syndrome after six of 64 procedures (9.3%). Three of these six had clinical symptoms; two-thirds were transient within seconds. Magnetic resonance imaging depicted stroke after seven procedures (10.9%). Five of these seven patients had no new symptoms. Altogether, after ten procedures (15%), patients complained about clinical symptoms. These were all transient. No new transient ischemic attacks occurred during the 3 month follow-up and no new lesions were detected in magnetic resonance imaging. Only two patients underwent surgery for asymptomatic subdural hematoma. All other subdural hematomas resolved spontaneously. CONCLUSION: Revasculating surgery is a safe procedure in Caucasian patients with Moyamoya angiopathy. The observed complications have a good prognosis.


Assuntos
Revascularização Cerebral , Artéria Cerebral Média/cirurgia , Doença de Moyamoya/cirurgia , Artérias Temporais/cirurgia , Adolescente , Adulto , Europa (Continente) , Grupo com Ancestrais do Continente Europeu , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Artéria Cerebral Média/diagnóstico por imagem , Doença de Moyamoya/diagnóstico por imagem , Doença de Moyamoya/fisiopatologia , Inibidores da Agregação Plaquetária/uso terapêutico , Complicações Pós-Operatórias , Prognóstico , Estudos Retrospectivos , Artérias Temporais/diagnóstico por imagem , Adulto Jovem
10.
PLoS One ; 13(7): e0200446, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30001348

RESUMO

BACKGROUND AND PURPOSE: Moyamoya angiopathy is a progressive cerebral vasculopathy. The p.R4810K substitution in RNF213 has previously been linked to moyamoya disease in Asian populations. When associated with other medical conditions, such as neurofibromatosis type 1, this vasculopathy is frequently reported as moyamoya syndrome. Intriguingly, most cases of moyamoya-complicated neurofibromatosis type 1 have been described in Caucasians, inverting the population ratio observed in Asians, although prevalence of neurofibromatosis type 1 is constant worldwide. Our aim was to investigate whether, among Caucasians, additive genetic factors may contribute to the occurrence of moyamoya in neurofibromatosis type 1. METHODS: Whole exome sequencing was carried out on an Italian family with moyamoya-complicated neurofibromatosis type 1 to identify putative genetic modifiers independent of the NF1 locus and potentially involved in moyamoya pathogenesis. Results were validated in an unrelated family of German ancestry. RESULTS: We identified the p.P186S substitution (rs35857561) in MRVI1 that segregated with moyamoya syndrome in both the Italian and German family. CONCLUSIONS: The rs35857561 polymorphism in MRVI1 may be a genetic susceptibility factor for moyamoya in European patients with neurofibromatosis type 1. MRVI1 is a functional partner of ITPR1, PRKG1 and GUCY1A3, which are involved in response to nitric oxide. Mutations in GUCY1A3 have been recently linked to a recessive syndromic form of moyamoya with esophageal achalasia.


Assuntos
Predisposição Genética para Doença , Proteínas de Membrana/genética , Doença de Moyamoya/complicações , Doença de Moyamoya/genética , Neurofibromatose 1/complicações , Neurofibromatose 1/genética , Fosfoproteínas/genética , Adolescente , Adulto , Criança , Pré-Escolar , Estudos de Coortes , Grupo com Ancestrais do Continente Europeu/genética , Família , Feminino , Estudos de Associação Genética , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Doença de Moyamoya/diagnóstico por imagem , Neurofibromatose 1/diagnóstico por imagem , Polimorfismo de Nucleotídeo Único , Sequenciamento Completo do Exoma , Adulto Jovem
11.
Clin Neurol Neurosurg ; 160: 137-141, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28734234

RESUMO

OBJECTIVES: The etiology and genetic susceptibility of primary central nervous system vasculitis (PCNSV) are still unclear. PATIENTS AND METHODS: We analyzed the DNA of 25 Caucasian patients with PCNSV for human leucocyte antigen genes HLA-A, HLA-B, HLA-DRB1, and HLA-DQB1, respectively. HLA-frequencies of the 25 patients with PCNSV were compared with HLA-frequencies of matched Caucasian controls. RESULTS: No statistically significant associations were found for HLA-B, HLA-DR1 and HLA-DQB1 variant. In the PCNSV group, only the HLA-A*69 variant was found more often than expected statistically. CONCLUSION: The results of this study indicate a potential association of HLA marker with PCNSV in Caucasian patients. Further studies are needed to elucidate the role of genes within the human major histocompatibility complex in the pathogenesis of this angiopathy.


Assuntos
Antígenos HLA-A/genética , Antígenos de Histocompatibilidade Classe I/genética , Vasculite do Sistema Nervoso Central/genética , Adolescente , Adulto , Idoso , Criança , Feminino , Alemanha , Humanos , Masculino , Pessoa de Meia-Idade , Vasculite do Sistema Nervoso Central/diagnóstico por imagem , Adulto Jovem
12.
Eur J Hum Genet ; 25(8): 995-1003, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28635953

RESUMO

Moyamoya angiopathy (MMA) is a cerebral angiopathy affecting the terminal part of internal carotid arteries. Its prevalence is 10 times higher in Japan and Korea than in Europe. In East Asian countries, moyamoya is strongly associated to the R4810K variant in the RNF213 gene that encodes for a protein containing a RING-finger and two AAA+ domains. This variant has never been detected in Caucasian MMA patients, but several rare RNF213 variants have been reported in Caucasian cases. Using a collapsing test based on exome data from 68 European MMA probands and 573 ethnically matched controls, we showed a significant association between rare missense RNF213 variants and MMA in European patients (odds ratio (OR)=2.24, 95% confidence interval (CI)=(1.19-4.11), P=0.01). Variants specific to cases had higher pathogenicity predictive scores (median of 24.2 in cases versus 9.4 in controls, P=0.029) and preferentially clustered in a C-terminal hotspot encompassing the RING-finger domain of RNF213 (P<10-3). This association was even stronger when restricting the analysis to childhood-onset and familial cases (OR=4.54, 95% CI=(1.80-11.34), P=1.1 × 10-3). All clinically affected relatives who were genotyped were carriers. However, the need for additional factors to develop MMA is strongly suggested by the fact that only 25% of mutation carrier relatives were clinically affected.


Assuntos
Adenosina Trifosfatases/genética , Doença de Moyamoya/genética , Mutação de Sentido Incorreto , Ubiquitina-Proteína Ligases/genética , Adenosina Trifosfatases/química , Adolescente , Adulto , Estudos de Casos e Controles , Criança , Pré-Escolar , Grupo com Ancestrais do Continente Europeu/genética , Exoma , Feminino , Heterozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Doença de Moyamoya/etnologia , Domínios RING Finger/genética , Ubiquitina-Proteína Ligases/química
13.
Biochem Biophys Res Commun ; 483(4): 1040-1050, 2017 02 19.
Artigo em Inglês | MEDLINE | ID: mdl-27392710

RESUMO

Calcium is a key signaling molecule and ion involved in a variety of diverse processes in our central nervous system (CNS) which include gene expression, synaptic transmission and plasticity, neuronal excitability and cell maintenance. Proper control of calcium signaling is not only vital for neuronal physiology but also cell survival. Mutations in fundamental channels, transporters and second messenger proteins involved in orchestrating the balance of our calcium homeostasis can lead to severe neurodegenerative disorders, such as Spinocerebellar (SCA) and Episodic (EA) ataxias. Hereditary ataxias make up a remarkably diverse group of neurological disorders clinically characterized by gait ataxia, nystagmus, dysarthria, trunk and limb ataxia and often atrophy of the cerebellum. The largest family of hereditary ataxias is SCAs which consists of a growing family of 42 members. A relatively smaller family of 8 members compose the EAs. The gene mutations responsible for half of the EA members and over 35 of the SCA subtypes have been identified, and several have been found to be responsible for cerebellar atrophy, abnormal intracellular calcium levels, dysregulation of Purkinje cell pacemaking, altered cerebellar synaptic transmission and/or ataxia in mouse models. Although the genetic diversity and affected cellular pathways of hereditary ataxias are broad, one common theme amongst these genes is their effects on maintaining calcium balance in primarily the cerebellum. There is emerging evidence that the pathogenesis of hereditary ataxias may be caused by imbalances in intracellular calcium due to genetic mutations in calcium-mediating proteins. In this review we will discuss the current evidence supporting the role of deranged calcium as the culprit to neurodegenerative diseases with a primary focus on SCAs and EAs.


Assuntos
Cálcio/metabolismo , Homeostase , Animais , Sinalização do Cálcio , Humanos , Camundongos , Mutação , Ataxias Espinocerebelares/genética , Ataxias Espinocerebelares/metabolismo
14.
Cephalalgia ; 37(5): 496-500, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-27112705

RESUMO

Background Headache is common in patients with Moyanoya angiopathy (MMA), but usually underestimated in its management and not well characterized. Methods A validated self-administered headache screening questionnaire and a telephone interview were used in order to investigate headache characteristics, frequency and pain intensity in a large cohort of 55 German patients with MMA. Results Thirty-seven patients (67.3%) had suffered from headache in the past year. Headache intensity was rated 3.2 ± 1.3 on a verbal rating scale from 0 to 10. Seventeen patients (47.9%) reported migraine-like headache, 10 patients (27.0%) reported tension type-like headache and 10 patients (27.0%) had a combination of both. The majority of patients with migraine-like headache ( n = 10, 58.8%) described migrainous aura. Headache frequency and intensity improved significantly after revascularization surgery; however, nine patients developed new-onset headache postoperatively. Conclusion Headache is very common in MMA, often with a migraine-like phenotype. Tension type-like headache was also found in 27% of patients, which is a new finding that has not been reported before.


Assuntos
Grupo com Ancestrais do Continente Europeu , Cefaleia/diagnóstico , Cefaleia/epidemiologia , Doença de Moyamoya/diagnóstico , Doença de Moyamoya/epidemiologia , Adolescente , Adulto , Idoso , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Adulto Jovem
15.
Clin Neurol Neurosurg ; 152: 52-56, 2017 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-27898361

RESUMO

OBJECTIVE: Movement disorders are a rare manifestation of Moyamoya angiopathy (MMA). Data on prevalence and clinical presentation are warranted. Possible involuntary movements include focal motor seizures, tremor, limb-shaking transient ischemic attacks, choreiform and spastic or dystonic movement disorders. PATIENTS AND METHODS: We developed a questionnaire to systematically assess movement disorders in MMA. Patients' history of involuntary movements and their clinical presentation were assessed systematically by interview. Additionally, demographic data were assessed as well as localization of movements, possible trigger factors and the presence of other symptoms. RESULTS: The questionnaire was administered to 63 European patients with MMA. The response rate was high with 93.6% participating patients. Twenty-eight patients (47.4%) reported involuntary movement disorders including periodic tremor, irregular jerks, involuntary movements with loopy or pranced character, stiffness and muscle cramps. From those patients, 16 (57.1%) individuals had the symptoms prior to the diagnosis of MMA. The most common involuntary movements were irregular jerks witnessed by 17 (60.7%) patients, followed by stiffness and muscle cramps in 10 (35.7%). Eight (28.6%) Patients suffered from unintended loopy and pranced character, while 4 individuals (14.3%) remembered periodic tremor. Of the 28 patients who witnessed movement disorders, 23 had undergone revascularization surgery (82.1%). From the latter subgroup, movement disorders were reversed in 7 out of 12 patients (58.3%) with irregular jerks and 4 out of 7 patients (57.1%) with unintended loopy and pranced character. CONCLUSIONS: Our study elucidates the high incidence of movement disorders in an unselected consecutively recruited cohort of European MMA patients.


Assuntos
Transtornos dos Movimentos/etiologia , Doença de Moyamoya/complicações , Adulto , Estudos Epidemiológicos , Feminino , Alemanha/epidemiologia , Humanos , Masculino , Pessoa de Meia-Idade , Transtornos dos Movimentos/diagnóstico , Transtornos dos Movimentos/epidemiologia , Doença de Moyamoya/diagnóstico , Doença de Moyamoya/epidemiologia , Inquéritos e Questionários
16.
Neurobiol Learn Mem ; 133: 129-135, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27311758

RESUMO

Conditioned responses gradually weaken and eventually disappear when subjects are repeatedly exposed to the conditioned stimulus (CS) in the absence of the unconditioned stimulus (US), a process called extinction. Studies have demonstrated that extinction of conditioned taste aversion (CTA) can be prevented by interfering with protein synthesis in the insular cortex (IC). However, it remained unknown whether it is possible to pharmacologically stabilize the taste aversive memory trace over longer periods of time. Thus, the present study aimed at investigating the time frame during which extinction of CTA can be efficiently prevented by blocking protein synthesis in the IC. Employing an established conditioning paradigm in rats with saccharin as CS, and the immunosuppressant cyclosporine A (CsA) as US, we show here that daily bilateral intra-insular injections of the protein synthesis inhibitor anisomycin (120µg/µl) immediately after retrieval significantly diminished CTA extinction over a period of five retrieval days and subsequently reached levels of saline-infused controls. These findings demonstrate that it is possible to efficiently delay but not to fully prevent CTA extinction during repeated retrieval trials by blocking protein translation with daily bilateral infusions of anisomycin in the IC. These data confirm and extent earlier reports indicating that the role of protein synthesis in CTA extinction learning is not limited to gastrointestinal malaise-inducing drugs such as lithium chloride (LiCl).


Assuntos
Anisomicina/farmacologia , Comportamento Animal/efeitos dos fármacos , Córtex Cerebral/efeitos dos fármacos , Condicionamento Clássico/efeitos dos fármacos , Ciclosporina/farmacologia , Extinção Psicológica/efeitos dos fármacos , Imunossupressores/farmacologia , Rememoração Mental/efeitos dos fármacos , Biossíntese de Proteínas/efeitos dos fármacos , Inibidores da Síntese de Proteínas/farmacologia , Animais , Anisomicina/administração & dosagem , Ciclosporina/administração & dosagem , Imunossupressores/administração & dosagem , Masculino , Inibidores da Síntese de Proteínas/administração & dosagem , Ratos , Fatores de Tempo
17.
Brain Behav Immun ; 51: 252-257, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26365026

RESUMO

In order to analyze the effects of pre-exposure to either the unconditioned (US) or conditioned stimulus (CS) on learned immunosuppression, we employed an established conditioned taste aversion (CTA) paradigm in rats. In our model, a sweet-tasting drinking solution (saccharin) serves as CS and injection of the immunosuppressive drug cyclosporine A (CsA) is used as US. The conditioned response is reflected by a pronounced CTA and diminished cytokine production by anti-CD3 stimulated splenic T cells. In the present study, experimental animals were exposed either to the US or the CS three times prior to the acquisition phase. On the behavioral level, we found a significantly diminished CTA when animals were pre-exposed to the US or the CS before acquisition. In contrast, US or CS pre-exposure did not affect the behaviorally conditioned suppression of interleukin (IL)-2 production. From the clinical perspective, our data may suggest that conditioning paradigms could be systemically integrated as supportive therapeutic interventions in patients that are already on immunosuppressive therapy or have had previous contact to the gustatory stimulus. Such supportive therapies to pharmacological regimens could not only help to reduce the amount of medication needed and, thus, unwanted toxic side effects, but may also maximize the therapeutic outcome.


Assuntos
Aprendizagem da Esquiva/fisiologia , Condicionamento Psicológico/efeitos dos fármacos , Ciclosporina/administração & dosagem , Imunossupressão , Imunossupressores/administração & dosagem , Animais , Aprendizagem da Esquiva/efeitos dos fármacos , Masculino , Ratos , Paladar/fisiologia
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