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1.
Hum Genet ; 139(4): 545-555, 2020 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-32020363

RESUMEN

Secretory carrier membrane proteins (SCAMPs) play an important role in exocytosis in animals, but the precise function of SCAMPs in human disease is unknown. In this study, we identified a homozygous mutation, SCAMP5 R91W, in a Chinese consanguineous family with pediatric epilepsy and juvenile Parkinson's disease. Scamp5 R91W mutant knock-in mice showed typical early-onset epilepsy similar to that in humans. Single-neuron electrophysiological recordings showed that the R91W mutation significantly increased the frequency of miniature excitatory postsynaptic currents (mEPSCs) at a resting state and also increased the amplitude of evoked EPSCs. The R91W mutation affected the interaction between SCAMP5 and synaptotagmin 1 and may affect the function of the SNARE complex, the machinery required for vesicular trafficking and neurotransmitter release. Our work shows that dysfunction of SCAMP5 shifted the excitation/inhibition balance of the neuronal network in the brain, and the deficiency of SCAMP5 leads to pediatric epilepsy.


Asunto(s)
Potenciales de Acción , Encéfalo , Epilepsia , Proteínas de la Membrana , Mutación Missense , Red Nerviosa , Neurotransmisores/metabolismo , Potenciales Sinápticos , Animales , Encéfalo/metabolismo , Encéfalo/patología , Epilepsia/genética , Epilepsia/metabolismo , Epilepsia/patología , Técnicas de Sustitución del Gen , Células HEK293 , Humanos , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Ratones , Ratones Transgénicos , Red Nerviosa/metabolismo , Red Nerviosa/patología
2.
Life Sci ; 246: 117400, 2020 Apr 01.
Artículo en Inglés | MEDLINE | ID: mdl-32032645

RESUMEN

AIMS: Comparative sub-acute toxicity, including tolerance and dependence potential of fentanyl and its three novel and potent analogues was determined in mice. MAIN METHODS: Comparative sub-acute (21 d, intraperitoneal; 1/10 LD50) toxicity of fentanyl and its three novel analogues viz., N-(1-(2-phenoxyethyl)-4-piperidinyl) propionanilide (2), N-isopropyl-3-(4-(N-phenylpropionamido)piperidin-1-yl)propanamide (5), and N-t-butyl-3-(4-(N-phenylpropionamido)piperidin-1-yl)propanamide (6) was determined in mice. Animals were observed for additional seven days to assess the recovery. The brain, liver and kidney toxicity was assessed on the basis of various biochemical, oxidative, histological, and neuroadaptive markers. The expression levels of key neuronal markers associated with drug tolerance and dependence were investigated by western blot and immunohistochemistry. KEY FINDINGS: Fentanyl and its analogues caused abnormal levels of liver and kidney specific biomarkers in plasma. Brain malondialdehyde (MDA) levels were raised by all the treatments and kidney MDA level by analogue 6 (21 d). Reduced glutathione levels in brain, liver, and kidney were diminished by all the treatments (21 & 28 d) and a significant change in the levels of antioxidant enzymes was also produced mainly after 21 d. The deleterious effects of fentanyl and its analogues were further substantiated by corresponding histopathological changes in brain, liver and kidney (21 & 28 d). These compounds were also found to produce neuroadaptive changes as evidenced by the increased expression levels of c-Fos, glucocorticoid receptor, N-methyl-d-aspartate receptor1 and µ-opioid receptor (21 & 28 d). SIGNIFICANCE: Three novel analogues of fentanyl were envisaged to have alternative therapeutic potentials. However, their comparative sub-acute toxicity revealed undesirable side effects, thereby masking their therapeutic ability.


Asunto(s)
Fentanilo/toxicidad , Animales , Biomarcadores/análisis , Western Blotting , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Daño del ADN/efectos de los fármacos , Fentanilo/análogos & derivados , Glutatión/análisis , Riñón/efectos de los fármacos , Riñón/metabolismo , Hígado/efectos de los fármacos , Hígado/metabolismo , Masculino , Malondialdehído/análisis , Ratones , Estrés Oxidativo/efectos de los fármacos
3.
Life Sci ; 246: 117430, 2020 Apr 01.
Artículo en Inglés | MEDLINE | ID: mdl-32061671

RESUMEN

Angiopoietin-1 (Ang-1), a regulatory angiogenesis protein and it has been found to be involved in the occurrence and progression of Alzheimer's disease. However, it was still to be addressed the distinctly role and the molecular mechanisms of Ang-1 affects Alzheimer's disease. Our data suggest that Ang-1 aggravated the accumulation of Aß42 and cognitive decline in APP/PS1 mice. The upregulation of APPß is essential for Aß42 production in N2a cells overexpressing the mutational human APP gene (N2a/APP695 cells), while downregulation of PEN2 could reduce APP expression. Silencing of FOXA2 lead to inhibition of APP expression, as well as decrease of Aß42 contents. In conclusion, Ang-1 has an accelerative effect on Alzheimer's disease by increasing the secretion of Aß42 via FOXA2/PEN2/APP pathway.


Asunto(s)
Enfermedad de Alzheimer/etiología , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Angiopoyetina 1/fisiología , Factor Nuclear 3-beta del Hepatocito/metabolismo , Transducción de Señal , Enfermedad de Alzheimer/metabolismo , Secretasas de la Proteína Precursora del Amiloide/fisiología , Precursor de Proteína beta-Amiloide/fisiología , Animales , Western Blotting , Encéfalo/metabolismo , Ensayo de Inmunoadsorción Enzimática , Técnica del Anticuerpo Fluorescente , Factor Nuclear 3-beta del Hepatocito/fisiología , Aprendizaje por Laberinto , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Reacción en Cadena en Tiempo Real de la Polimerasa
6.
Zhongguo Zhen Jiu ; 40(2): 173-8, 2020 Feb 12.
Artículo en Chino | MEDLINE | ID: mdl-32100504

RESUMEN

OBJECTIVE: To observe the expression of GABAA receptor mRNA in different brain regions of the central nervous system in chronic inflammatory pain rats and the intervention effect of electroacupuncture (EA). METHODS: A total of 48 SPF male SD rats were randomly divided into a blank control group, a model control group, an EA group and a sham EA group, 12 rats in each group. The model of chronic inflammatory pain was established by injecting Freund's complete adjuvant into the foot. The EA group was treated with EA 28 days after the model establishment. The "Housanli" (ST 36) and "Kunlun" (BL 60) were selected and treated with dilatational wave, 2 Hz/100 Hz in frequency, 0.5-1.5 mA for 30 min; EA was given only once. In the sham EA group, the same acupoints were selected but the needles were only inserted into subcutaneous area; EA was connected for 30 min without electrical stimulation. The behavior changes of mechanical pain threshold and thermal pain threshold before model establishment, 1 day, 3 days, 7 days, 14 days, 21 days and 28 days after the model establishment as well as emotional behavior 29 days after the model establishment were observed; the relative expressions of GABAA receptor mRNA in anterior cingulate cortex, amygdala and hypothalamus were observed. RESULTS: Compared with the blank control group, the change rates of mechanical pain threshold and thermal pain threshold in the model control group were decreased significantly 1 day, 3 days, 7 days, 14 days, 21 days, 28 days after model establishment (P<0.01); 29 days after model establishment, the movement distance and staying time in the central area of open field test in the model control group were decreased significantly (P<0.05). After EA intervention, compared with the model control group and the sham EA group, the change rates of mechanical pain threshold and thermal pain threshold, as well as the movement distance and the staying time of central area were significantly increased in the EA group (P<0.01, P<0.05). Twenty-nine days after model establishment, the expression of GABAA receptor mRNA in anterior cingulate cortex and hypothalamus was not significantly different among all groups (P>0.05). Compared with the blank control group, the expression of GABAA receptor mRNA in the amygdala was decreased significantly in the model control group (P<0.01); compared with the model control group and the sham EA group, the expression of GABAA receptor mRNA in amygdala was increased after intervention in the EA group (P<0.01). CONCLUSION: Single treatment of EA could significantly increase the mechanical pain threshold and thermal pain threshold, improve abnormal emotional behavior in rats with chronic inflammatory pain, which may be related to the increasing of expression of GABAA receptor mRNA in the amygdala.


Asunto(s)
Encéfalo/metabolismo , Electroacupuntura , Inflamación/terapia , Dolor , Receptores de GABA-A/metabolismo , Puntos de Acupuntura , Amígdala del Cerebelo , Animales , Masculino , ARN Mensajero/metabolismo , Distribución Aleatoria , Ratas , Ratas Sprague-Dawley
8.
Zoolog Sci ; 37(1): 42-49, 2020 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-32068373

RESUMEN

For seasonal adaptation, the brown-winged green bug Plautia stali (Hemiptera: Pentatomidae) enters reproductive diapause by suppressing juvenile hormone biosynthesis. Plautia stali myoinhibitory peptides (Plast-MIPs) are known to have allatostatic effects and to suppress juvenile hormone biosynthesis. We examined Plast-MIP-producing neurons in the brain with immunohistochemistry and Fourier transform ion cyclotron resonance mass spectrometry. Rabbit polyclonal antiserum against Plast-MIP revealed immunoreactive cells in seven regions of the brain, including the posterior antennal lobe, basal optic lobe, dorsal anterior protocerebrum, ventrolateral protocerebrum, pars intercerebralis, posterior protocerebrum, and dorsal posterior region to the calyx of the mushroom body, aside from the gnathal ganglion. Anatomical locations of the immunoreactive cells in the pars intercerebralis and dorsal posterior region to the mushroom body calyx partly overlapped with the cell body location stained by retrograde dye fills from the corpus allatum and corpus cardiacum complex. Direct mass spectrometry revealed the molecular ion peaks corresponding to the predictive mass of Plast-MIPs in the pars intercerebralis and the corpus allatum-corpus cardiacum complex. Plast-MIP immunoreactivity in different cell types suggests that Plast-MIPs have different functions in the cephalic ganglia. Considering the anatomical location of neurons projecting to the corpus allatum-corpus cardiacum and results of mass spectrometry, Plast-MIP immunoreactive cells in the pars intercerebralis may play a role in suppressing juvenile hormone biosynthesis.


Asunto(s)
Encéfalo/metabolismo , Hemípteros/fisiología , Proteínas de Insectos/metabolismo , Neuropéptidos/metabolismo , Animales , Diapausa de Insecto/fisiología , Femenino , Hemípteros/metabolismo , Inmunohistoquímica , Hormonas Juveniles/biosíntesis , Neuronas/metabolismo
9.
Adv Exp Med Biol ; 1202: 1-12, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32034706

RESUMEN

ATP is a cotransmitter with glutamate, noradrenaline, GABA, acetylcholine and dopamine in the brain. There is a widespread presence of both adenosine (P1) and P2 nucleotide receptors in the brain on both neurons and glial cells. Adenosine receptors play a major role in presynaptic neuromodulation, while P2X ionotropic receptors are involved in fast synaptic transmission and synaptic plasticity. P2Y G protein-coupled receptors are largely involved in presynaptic activities, as well as mediating long-term (trophic) signalling in cell proliferation, differentiation and death during development and regeneration. Both P1 and P2 receptors participate in neuron-glial interactions. Purinergic signalling is involved in control of cerebral vascular tone and remodelling and has been implicated in learning and memory, locomotor and feeding behaviour and sleep. There is increasing interest in the involvement of purinergic signalling in the pathophysiology of the CNS, including trauma, ischaemia, epilepsy, neurodegenerative diseases, neuropsychiatric and mood disorders, and cancer, including gliomas.


Asunto(s)
Encéfalo/metabolismo , Receptores Purinérgicos/metabolismo , Transducción de Señal , Transmisión Sináptica , Adenosina Trifosfato/metabolismo , Animales , Humanos
10.
Adv Exp Med Biol ; 1226: 97-109, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32030679

RESUMEN

Intramedullary spinal cord tumors (IMSCT) are rare entities for which there currently exist no standardized treatment paradigms. Consequently, patients usually receive treatment modalities that were established for intracerebral tumors; these approaches, however, typically result in functional impairment, recurrent tumor growth, and short overall survival. There is a distinct lack of promising research efforts in this field, which raises questions about whether spinal cord tumor microenvironment (TME) might promote the development, progression, and treatment resistance of IMSCT. In this review, we aim to examine spinal cord biology, compare spinal cord and brain microenvironments, and discuss mutual interactions between IMSCT and TME. Manipulating these pathways may provide new treatment approaches for future patient groups.


Asunto(s)
Neoplasias de la Médula Espinal , Microambiente Tumoral , Encéfalo/metabolismo , Humanos , Médula Espinal/metabolismo , Neoplasias de la Médula Espinal/metabolismo , Neoplasias de la Médula Espinal/patología , Neoplasias de la Médula Espinal/terapia
11.
J Neurosci ; 40(5): 944-954, 2020 Jan 29.
Artículo en Inglés | MEDLINE | ID: mdl-31996470

RESUMEN

The brilliant and often prescient hypotheses of Ramon y Cajal have proven foundational for modern neuroscience, but his statement that "In adult centers the nerve paths are something fixed, ended, immutable … " is an exception that did not stand the test of empirical study. Mechanisms of cellular and circuit-level plasticity continue to shape and reshape many regions of the adult nervous system long after the neurodevelopmental period. Initially focused on neurons alone, the field has followed a meteoric trajectory in understanding of activity-regulated neurodevelopment and ongoing neuroplasticity with an arc toward appreciating neuron-glial interactions and the role that each neural cell type plays in shaping adaptable neural circuity. In this review, as part of a celebration of the 50th anniversary of Society for Neuroscience, we provide a historical perspective, following this arc of inquiry from neuronal to neuron-glial mechanisms by which activity and experience modulate circuit structure and function. The scope of this consideration is broad, and it will not be possible to cover the wealth of knowledge about all aspects of activity-dependent circuit development and plasticity in depth.


Asunto(s)
Encéfalo/metabolismo , Red Nerviosa/metabolismo , Plasticidad Neuronal/fisiología , Neuronas/metabolismo , Animales , Encéfalo/citología , Humanos , Red Nerviosa/citología
12.
J Exp Biol ; 223(Pt 2)2020 Jan 29.
Artículo en Inglés | MEDLINE | ID: mdl-31900346

RESUMEN

Social isolation strongly modulates behavior across the animal kingdom. We utilized the fruit fly Drosophila melanogaster to study social isolation-driven changes in animal behavior and gene expression in the brain. RNA-seq identified several head-expressed genes strongly responding to social isolation or enrichment. Of particular interest, social isolation downregulated expression of the gene encoding the neuropeptide Drosulfakinin (Dsk), the homologue of vertebrate cholecystokinin (CCK), which is critical for many mammalian social behaviors. Dsk knockdown significantly increased social isolation-induced aggression. Genetic activation or silencing of Dsk neurons each similarly increased isolation-driven aggression. Our results suggest a U-shaped dependence of social isolation-induced aggressive behavior on Dsk signaling, similar to the actions of many neuromodulators in other contexts.


Asunto(s)
Agresión , Drosophila melanogaster/fisiología , Neuropéptidos/metabolismo , Oligopéptidos/metabolismo , Aislamiento Social , Animales , Conducta Animal/fisiología , Encéfalo/metabolismo , Drosophila melanogaster/genética , Masculino , Neuropéptidos/genética , Oligopéptidos/genética , Análisis de Secuencia de ARN
13.
Cell Prolif ; 53(2): e12759, 2020 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-31922310

RESUMEN

OBJECTIVE: Low levels of adiponectin (APN), a biomarker of diabetes mellitus, have been implicated in the poor outcome of intracerebral haemorrhage (ICH). Herein, we aimed to demonstrate the neuroprotective effects of a blood-brain barrier-permeable APN peptide (APNp) on ICH injury in diabetic mice and explore the underlying mechanisms. MATERIALS AND METHODS: Recombinant APNp was administrated intraperitoneally to mice with collagenase-induced ICH. Neurological deficits, brain water content and neural apoptosis were assessed. Western blotting, immunofluorescence staining, quantitative RT-PCR and transmission electron microscopy were used to determine the signalling pathways affected by APNp. RESULTS: Adiponectin peptide significantly alleviated neural apoptosis, neurological deficits and brain oedema following ICH in diabetic mice. Mechanistically, APNp promoted the restoration of peroxisome proliferator-activated receptor gamma coactivator (PGC)-1α related mitochondrial function and suppressed activating transcription factor 4 (ATF4)-CCAAT-enhancer-binding protein homologous protein (CHOP)-induced neural apoptosis. Furthermore, Smad3 signalling was found to play a regulatory role in this process by transcriptionally regulating the expression of PGC-1α and ATF4. APNp significantly suppressed the elevated phosphorylation and nuclear translocation of Smad3 after ICH in diabetic mice, while the protective effects of APNp on mitochondrial and ATF4-CHOP apoptosis pathways were counteracted when Smad3 was activated by exogenous transforming growth factor (TGF)-ß1 treatment. CONCLUSIONS: Our study provided the first evidence that APNp promoted neural survival following ICH injury in the diabetic setting and revealed a novel mechanism by which APNp suppressed mitochondrial and ATF4-CHOP apoptosis pathways in a Smad3 dependent manner.


Asunto(s)
Adiponectina/metabolismo , Apoptosis/fisiología , Hemorragia Cerebral/metabolismo , Diabetes Mellitus Experimental/metabolismo , Mitocondrias/metabolismo , Neuronas/metabolismo , Transducción de Señal/fisiología , Factor de Transcripción Activador 4/metabolismo , Animales , Encéfalo/metabolismo , Núcleo Celular/metabolismo , Células Cultivadas , Masculino , Ratones , Ratones Endogámicos C57BL , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/metabolismo , Transporte de Proteínas/fisiología , Proteínas Recombinantes/metabolismo , Proteína smad3/metabolismo , Factor de Transcripción CHOP/metabolismo , Factor de Crecimiento Transformador beta1/metabolismo
14.
J Photochem Photobiol B ; 204: 111775, 2020 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-31935591

RESUMEN

Wogonin (5,7-dihydroxy-8-methoxy flavone), an active component isolated from the root of Scutellaria baicalensis Georgi. Neurotoxic effects of γ irradiation have been established in humans and animals. The current study was designed to evaluate whether wogonin could restrain γ irradiation-induced neurotoxicity in rats and to explore the underlying mechanisms. Rats were divided into five groups, 10 rats each. Group 1 was orally administered distilled water and served as control. Group 2 received an oral daily dose of wogonin (30 mg/kg). Rats in group 3 were exposed to a whole-body single dose of γ-irradiation. Animals in group 4 received an oral daily dose of wogonin (30 mg/kg) for 15 days then exposed to a whole-body single dose of γ-irradiation. In group 5, rats were exposed to a whole-body single dose of γ-irradiation then were orally administered a daily dose of wogonin (30 mg/kg) for 15 days. There were significant increases in malondialdehyde (MDA), tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß) and Interleukin 6 (IL-6) levels and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) mRNA and protein expression. Whereas significant decreases in reduced glutathione (GSH), superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPX) level as well as nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) mRNA and protein expression in the irradiated group when compared with the relevant control. The cerebral cortex of irradiated rats showed vacuolization and nuclear pyknosis in the neuronal cells and focal gliosis. Wogonin administration pre- or post-irradiation significantly ameliorated all these previous effects. Wogonin had antioxidant and anti-inflammatory effects and ameliorated the histopathological changes in the brain.


Asunto(s)
Encéfalo/efectos de los fármacos , Flavanonas/farmacología , Rayos gamma , Fármacos Neuroprotectores/farmacología , Administración Oral , Animales , Encéfalo/metabolismo , Encéfalo/efectos de la radiación , Medicamentos Herbarios Chinos/farmacología , Glutatión/metabolismo , Glutatión Peroxidasa/genética , Glutatión Peroxidasa/metabolismo , Hemo-Oxigenasa 1/genética , Hemo-Oxigenasa 1/metabolismo , Interleucina-6/genética , Interleucina-6/metabolismo , Masculino , Malondialdehído/metabolismo , Factor 2 Relacionado con NF-E2/genética , Factor 2 Relacionado con NF-E2/metabolismo , FN-kappa B/genética , FN-kappa B/metabolismo , Ratas , Ratas Wistar , Superóxido Dismutasa/genética , Superóxido Dismutasa/metabolismo , Factor de Necrosis Tumoral alfa/genética , Factor de Necrosis Tumoral alfa/metabolismo
15.
J Agric Food Chem ; 68(8): 2547-2553, 2020 Feb 26.
Artículo en Inglés | MEDLINE | ID: mdl-31995978

RESUMEN

Anticholinergic organophosphate (OP) agents act on the diverse serine hydrolases, thereby revealing unexpected biological effects. Epidemiological studies indicate a relationship between the OP exposure and development of attention-deficit/hyperactivity disorder (ADHD)-like symptoms, whereas no plausible mechanism for the OP-induced ADHD has been established. The present investigation employs ethyl octylphosphonofluoridate (EOPF) as an OP-probe, which is an extremely potent inhibitor of endocannabinoid (EC, anandamide and 2-arachidonoylglycerol)-hydrolyzing enzymes: that is, fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL). An ex vivo experiment shows that EOPF treatment decreases FAAH and MAGL activities and conversely increases EC levels in the rat brain. Subsequently, EOPF (treated intraperitoneally once at 0, 1, 2, or 3 mg/kg) clearly induces ADHD-like behaviors (in elevated plus-maze test) in both Wistar and spontaneously hypertensive rats. The EOPF-induced behaviors are reduced by a concomitant administration of cannabinoid receptor inverse agonist SLV-319. Accordingly, the EC system is a feasible target for OP-caused ADHD-like behaviors in adolescent rats.


Asunto(s)
Amidohidrolasas/antagonistas & inhibidores , Trastorno por Déficit de Atención con Hiperactividad/enzimología , Encéfalo/enzimología , Endocannabinoides/metabolismo , Inhibidores Enzimáticos/efectos adversos , Monoacilglicerol Lipasas/antagonistas & inhibidores , Compuestos Organofosforados/efectos adversos , Amidohidrolasas/metabolismo , Animales , Trastorno por Déficit de Atención con Hiperactividad/inducido químicamente , Trastorno por Déficit de Atención con Hiperactividad/metabolismo , Trastorno por Déficit de Atención con Hiperactividad/psicología , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Humanos , Masculino , Monoacilglicerol Lipasas/metabolismo , Ratas , Ratas Wistar
17.
BMC Med Genet ; 21(1): 10, 2020 01 08.
Artículo en Inglés | MEDLINE | ID: mdl-31914951

RESUMEN

BACKGROUND: The role of deleterious copy number variations in schizophrenia is well established while data regarding pathogenic variations remain scarce. We report for the first time a case of schizophrenia in a child with a pathogenic mutation of the chromodomain helicase DNA binding protein 2 (CHD2) gene. CASE PRESENTATION: The proband was the second child of unrelated parents. Anxiety and sleep disorders appeared at the age of 10 months. He presented febrile seizures and, at the age of 8, two generalized tonic-clonic seizures. At the age of 10, emotional withdrawal emerged, along with a flat affect, disorganization and paranoid ideation, without seizures. He began to talk and giggle with self. Eventually, the patient presented daily auditory and visual hallucinations. The diagnosis of childhood onset schizophrenia (DSM V) was then evoked. Brain imaging was unremarkable. Wakefulness electroencephalography showed a normal background and some bilateral spike-wave discharges that did not explain the psychosis features. A comparative genomic hybridization array (180 K, Agilent, Santa Clara, CA, USA) revealed an 867-kb 16p13.3 duplication, interpreted as a variant of unknown significance confirmed by a quantitative PCR that also showed its maternal inheritance. Risperidone (1,5 mg per day), led to clinical improvement. At the age of 11, an explosive relapse of epilepsy occurred with daily seizures of various types. The sequencing of a panel for monogenic epileptic disorders and Sanger sequencing revealed a de novo pathogenic heterozygous transition in CHD2 (NM_001271.3: c.4003G > T). CONCLUSIONS: This case underlines that schizophrenia may be, sometimes, underpinned by a Mendelian disease. It addresses the question of systematic genetic investigations in the presence of warning signs such as a childhood onset of the schizophrenia or a resistant epilepsy. It points that, in the absence of pathogenic copy number variation, the investigations should also include a search for pathogenic variations, which means that some of the patients with schizophrenia should benefit from Next Generation Sequencing tools. Last but not least, CHD2 encodes a member of the chromodomain helicase DNA-binding (CHD) family involved in chromatin remodeling. This observation adds schizophrenia to the phenotypic spectrum of chromodomain remodeling disorders, which may lead to innovative therapeutic approaches.


Asunto(s)
Variaciones en el Número de Copia de ADN/genética , Proteínas de Unión al ADN/genética , Esquizofrenia/genética , Encéfalo/metabolismo , Encéfalo/patología , Niño , Cromatina/genética , Ensamble y Desensamble de Cromatina/genética , Electroencefalografía , Femenino , Heterocigoto , Humanos , Masculino , Mutación , Fenotipo , Esquizofrenia/fisiopatología , Convulsiones Febriles/genética , Convulsiones Febriles/patología
18.
Adv Exp Med Biol ; 1232: 25-31, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-31893390

RESUMEN

Hypoxic ischemic encephalopathy (HIE) leads to significant mortality and morbidity, and therapeutic hypothermia (TH) has become a standard of care following HIE. After TH, the body temperature is brought back to 37 °C. Early electroencephalography (EEG) is a reliable outcome biomarker following HIE. We hypothesized that changes in cerebral oxidative metabolism, measured as Δ[oxCCO], in relation to changes in brain tissue oxygenation (measured as Δ[HbD]) during rewarming will correlate with injury severity as evidenced on amplitude integrated EEG/EEG at initial presentation. Broadband near-infrared spectroscopy (NIRS) and systemic data were collected during rewarming from 14 infants following HIE over a mean period of 12.5 h. All infants were monitored with video EEG telemetry using a standard neonatal montage. aEEG and EEG background was classified into mild, moderate and severely abnormal groups based on the background pattern. Two infants had mild, 6 infants had moderate and another 6 infants had severe abnormality at presentation. The relationship between [oxCCO] and [HbD] was evaluated between two groups of infants with abnormal electrical activity (mild vs moderate to severe). A significant difference was noted between the groups in the relationship between [oxCCO] and [HbD] (as r2) (p = 0.02). This result indicates that the mitochondrial injury and deranged oxidative metabolism persists in the moderate to severely abnormal group during rewarming.


Asunto(s)
Electroencefalografía , Hipotermia Inducida , Hipoxia-Isquemia Encefálica , Biomarcadores/análisis , Encéfalo/metabolismo , Humanos , Hipoxia-Isquemia Encefálica/diagnóstico , Lactante , Recién Nacido , Recalentamiento
19.
Adv Exp Med Biol ; 1232: 33-38, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-31893391

RESUMEN

Monitoring of cerebral tissue oxygen saturation (StO2) by near-infrared spectroscopy (NIRS oximetry) has great potential to reduce the incidence of hypoxic and hyperoxic events and thus prevent long-term disabilities in preterm neonates. Since the light has to penetrate superficial layers (bone, skin and cerebrospinal fluid) before it reaches the brain, the question arises whether these layers influence cerebral StO2 measurement. We assessed this influence on the accuracy of cerebral StO2 values. For that purpose, we simulated light propagation with 'N-layered medium' software. It was found that with a superficial layer thickness of ≤6 mm, typical for term and preterm neonates, StO2 accurately reflects cerebral tissue oxygenation.


Asunto(s)
Oximetría , Oxígeno , Cráneo , Encéfalo/metabolismo , Humanos , Hipoxia/diagnóstico , Recién Nacido , Oximetría/normas , Cráneo/anatomía & histología , Espectroscopía Infrarroja Corta
20.
Adv Exp Med Biol ; 1232: 339-345, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-31893429

RESUMEN

We used a miniature broadband NIRS system to monitor concentration changes in brain oxygenation (oxy- and deoxy- haemoglobin [HbO2], [HHb]) and oxidised cytochrome-c-oxidase ([oxCCO]) during a high +Gz acceleration, induced by a human centrifuge, on two healthy experienced volunteers (2 male, 34 and 37 years). We performed a sequence of several +Gz exposures that were terminated at the onset of visual symptoms (loss of peripheral vision). Systemic parameters were recorded (i.e. heart rate, blood pressure and arterial saturation), and brain tissue blood volume changes ([HbT] = [HbO2] + [HHb]) and oxygen delivery ([HbDiff] = [HbO2] - [HHb]) were calculated. Volunteer 1 demonstrated a decrease in [HbT] of -3.49 ± 0.02 µMol and [HbDiff] of -3.23 ± 0.44 µMol, and an increase of [oxCCO] of 0.42 ± 0.01µMol. Volunteer 2 demonstrated a decrease in [HbDiff] of -4.37 ± 0.23 µMol, and no significant change in [HbT] (0.53 ± 0.06 µMol) and [oxCCO] (0.09 ± 0.06 µMol). The variability of the brain metabolic response was related to the level of ischaemia, suggesting that suppression of metabolism was due to lack of glucose substrate delivery rather than oxygen availability.


Asunto(s)
Aceleración , Complejo IV de Transporte de Electrones , Hemodinámica , Espectroscopía Infrarroja Corta , Adulto , Encéfalo/enzimología , Encéfalo/metabolismo , Complejo IV de Transporte de Electrones/metabolismo , Voluntarios Sanos , Humanos , Masculino , Estrés Oxidativo , Oximetría/instrumentación , Oxígeno/metabolismo
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