RESUMEN
Pitt-Hopkins syndrome (PTHS) is a neurodevelopmental disorder caused by haploinsufficiency of transcription factor 4 (TCF4). In this work, we focused on the cerebral cortex and investigated in detail the progenitor cell dynamics and the outcome of neurogenesis in a PTHS mouse model. Labeling and quantification of progenitors and newly generated neurons at various time points during embryonic development revealed alterations affecting the dynamic of cortical progenitors since the earliest stages of cortex formation in PTHS mice. Consequently, establishment of neuronal populations and layering of the cortex were found to be altered in heterozygotes subjects at birth. Interestingly, defective layering process of pyramidal neurons was partially rescued by reintroducing TCF4 expression using focal in utero electroporation in the cerebral cortex. Coincidentally with a defective dorsal neurogenesis, we found that ventral generation of interneurons was also defective in this model, which may lead to an excitation/inhibition imbalance in PTHS. Overall, sex-dependent differences were detected with more marked effects evidenced in males compared with females. All of this contributes to expand our understanding of PTHS, paralleling the advances of research in autism spectrum disorder and further validating the PTHS mouse model as an important tool to advance preclinical studies.
Asunto(s)
Corteza Cerebral , Modelos Animales de Enfermedad , Hiperventilación , Discapacidad Intelectual , Neurogénesis , Factor de Transcripción 4 , Animales , Factor de Transcripción 4/metabolismo , Factor de Transcripción 4/genética , Femenino , Masculino , Ratones , Hiperventilación/metabolismo , Hiperventilación/genética , Hiperventilación/patología , Discapacidad Intelectual/genética , Discapacidad Intelectual/patología , Discapacidad Intelectual/metabolismo , Corteza Cerebral/metabolismo , Corteza Cerebral/patología , Facies , Caracteres Sexuales , Interneuronas/metabolismo , Interneuronas/patología , Células Piramidales/metabolismo , Células Piramidales/patología , HaploinsuficienciaRESUMEN
OTUB1 is one of the most highly expressed deubiquitinases, counter-regulating the two most abundant ubiquitin chain types. OTUB1 expression is linked to the development and progression of lung cancer and idiopathic pulmonary fibrosis in humans. However, the physiological function of OTUB1 is unknown. Here, we show that constitutive whole-body Otub1 deletion in mice leads to perinatal lethality by asphyxiation. Analysis of (single-cell) RNA sequencing and proteome data demonstrated that OTUB1 is expressed in all lung cell types with a particularly high expression during late-stage lung development (E16.5, E18.5). At E18.5, the lungs of animals with Otub1 deletion presented with increased cell proliferation that decreased saccular air space and prevented inhalation. Flow cytometry-based analysis of E18.5 lung tissue revealed that Otub1 deletion increased proliferation of major lung parenchymal and mesenchymal/other non-hematopoietic cell types. Adult mice with conditional whole-body Otub1 deletion (wbOtub1del/del ) also displayed increased lung cell proliferation in addition to hyperventilation and failure to adapt the respiratory pattern to hypoxia. On the molecular level, Otub1 deletion enhanced mTOR signaling in embryonic and adult lung tissues. Based on these results, we propose that OTUB1 is a negative regulator of mTOR signaling with essential functions for lung cell proliferation, lung development, adult lung tissue homeostasis, and respiratory regulation.
Asunto(s)
Proliferación Celular , Cisteína Endopeptidasas/fisiología , Homeostasis , Hiperventilación/patología , Enfermedades Pulmonares/patología , Insuficiencia Respiratoria/patología , Serina-Treonina Quinasas TOR/metabolismo , Animales , Femenino , Hiperventilación/etiología , Enfermedades Pulmonares/etiología , Enfermedades Pulmonares/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Insuficiencia Respiratoria/etiología , Serina-Treonina Quinasas TOR/genéticaRESUMEN
Pitt-Hopkins syndrome (PTHS) is a rare autism spectrum-like disorder characterized by intellectual disability, developmental delays, and breathing problems involving episodes of hyperventilation followed by apnea. PTHS is caused by functional haploinsufficiency of the gene encoding transcription factor 4 (Tcf4). Despite the severity of this disease, mechanisms contributing to PTHS behavioral abnormalities are not well understood. Here, we show that a Tcf4 truncation (Tcf4tr/+) mouse model of PTHS exhibits breathing problems similar to PTHS patients. This behavioral deficit is associated with selective loss of putative expiratory parafacial neurons and compromised function of neurons in the retrotrapezoid nucleus that regulate breathing in response to tissue CO2/H+. We also show that central Nav1.8 channels can be targeted pharmacologically to improve respiratory function at the cellular and behavioral levels in Tcf4tr/+ mice, thus establishing Nav1.8 as a high priority target with therapeutic potential in PTHS.
Asunto(s)
Haploinsuficiencia , Proteínas de Homeodominio/genética , Hiperventilación/genética , Discapacidad Intelectual/genética , Canal de Sodio Activado por Voltaje NAV1.8/genética , Neuronas/metabolismo , Factor de Transcripción 4/genética , Factores de Transcripción/genética , Animales , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Bencimidazoles/farmacología , Tronco Encefálico/efectos de los fármacos , Tronco Encefálico/metabolismo , Tronco Encefálico/patología , Dióxido de Carbono/metabolismo , Dióxido de Carbono/farmacología , Modelos Animales de Enfermedad , Facies , Regulación de la Expresión Génica , Proteínas de Homeodominio/metabolismo , Humanos , Hiperventilación/tratamiento farmacológico , Hiperventilación/metabolismo , Hiperventilación/patología , Discapacidad Intelectual/tratamiento farmacológico , Discapacidad Intelectual/metabolismo , Discapacidad Intelectual/patología , Masculino , Ratones , Ratones Noqueados , Canal de Sodio Activado por Voltaje NAV1.8/metabolismo , Neuronas/efectos de los fármacos , Neuronas/patología , Desempeño Psicomotor/efectos de los fármacos , Desempeño Psicomotor/fisiología , Pirazoles/farmacología , Respiración/efectos de los fármacos , Factor de Transcripción 4/deficiencia , Factores de Transcripción/metabolismoRESUMEN
BACKGROUND: There are few cohort studies describing the adaptive functioning profile for Pitt-Hopkins syndrome (PTHS). In this study we examine the adaptive functioning profile for PTHS and compare it to Angelman syndrome (AS). METHOD: Caregivers of 14 individuals with PTHS, 33 with deletion AS and 23 with non-deletion AS, completed the Vineland Adaptive Behavior Scales-II. RESULTS: The profile of adaptive functioning in PTHS was characterised by strengths in socialisation, followed by motor skills, communication then daily living skills. The PTHS group scored significantly lower than the non-deletion AS group on all domains except socialisation and significantly lower than the deletion AS group, for motor skills only. CONCLUSIONS: An uneven adaptive behavior profile for individuals with PTHS mirrors that of AS, with implications for assessment and intervention.
Asunto(s)
Adaptación Fisiológica , Hiperventilación/patología , Discapacidad Intelectual/patología , Fenotipo , Actividades Cotidianas , Adolescente , Adulto , Síndrome de Angelman/patología , Niño , Facies , Humanos , Destreza Motora , Conducta SocialRESUMEN
Hyperventilation changes the extracellular pH modulating many central pathologies, such as tremor. The questions that remain unanswered are the following: (1) Hyperventilation modulates which aspects of the oscillations? (2) Whether the effects of hyperventilation are instantaneous and the recovery is rapid and complete? Here we study the effects of hyperventilation on eye oscillations in the syndrome of oculopalatal tremor (OPT), a disease model affecting the inferior olive and cerebellar system. These regions are commonly involved in the pathogenesis of many movement disorders. The focus on the ocular motor system also allows access to the well-known physiology and precise measurement techniques. We found that hyperventilation causes modest but insignificant changes in the intensity of oscillation displacement (i.e., how large the eye excursions are) and velocity (i.e., how fast do the eyes move during oscillations). We found the robust increase in the randomness of the oscillatory waveform during hyperventilation and it instantaneously reverts to the baseline after hyperventilation. The subsequent analysis classified the oscillations according to their waveform shape and randomness into different clusters. The hyperventilation substantially changed the cluster type in 60% of the subjects, but it reverted to the pre-hyperventilation cluster at the conclusion of the hyperventilation. In summary, hyperventilation instantaneously affects the randomness of the oscillatory waveforms but there are less substantial effects on the intensity. The deficits reverse immediately at the end of the hyperventilation.
Asunto(s)
Hiperventilación , Temblor , Movimientos Oculares , Humanos , Hiperventilación/patología , Núcleo Olivar/fisiología , Temblor/patología , Visión OcularRESUMEN
Pitt-Hopkins syndrome is a rare neurodevelopment disorder caused by haploinsufficiency of the transcription factor 4 (TCF4). The main clinical symptoms of Pitt-Hopkins syndrome are severe development delay, intellectual disability, characteristic facial phenotype, and breathing abnormalities, including episodic hyperventilation. Different pathogenic variants can lead to Pitt-Hopkins syndrome. The most common are large deletions at 18q21 encompassing the TCF4 gene and frameshifting/nonsense single nucleotide variants. However, variants in noncoding regions can also lead to Pitt-Hopkins syndrome by disrupting the normal pre-mRNA splicing machinery. Here we describe three patients with Pitt-Hopkins syndrome caused by a large deletion in chromosome 18, a nonsense variant, and a novel variant located in intron 11 of TCF4 c.922+5G > A. Using RT-PCR analysis and minigene splicing assay we showed that this intronic variant leads to exon 11 skipping resulting in a formation of a premature stop codon. To our knowledge, this is the first functional annotation of a splicing variant in Pitt-Hopkins syndrome.
Asunto(s)
Haploinsuficiencia , Hiperventilación/genética , Discapacidad Intelectual/genética , Factor de Transcripción 4/genética , Preescolar , Deleción Cromosómica , Cromosomas Humanos Par 18/genética , Codón sin Sentido , Facies , Femenino , Células HEK293 , Humanos , Hiperventilación/patología , Lactante , Discapacidad Intelectual/patología , Factor de Transcripción 4/metabolismoRESUMEN
The psychiatric risk-associated transcription factor 4 (TCF4) is linked to schizophrenia. Rare TCF4 coding variants are found in individuals with Pitt-Hopkins syndrome-an intellectual disability and autism spectrum disorder. TCF4 contains a C-terminal basic-helix-loop-helix (bHLH) DNA binding domain which recognizes the enhancer-box (E-box) element 5'-CANNTG-3' (where N = any nucleotide). A subset of the TCF4-occupancy sites have the expanded consensus binding specificity 5'-C(A/G)-CANNTG-3', with an added outer Cp(A/G) dinucleotide; for example in the promoter for CNIH3, a gene involved in opioid dependence. In mammalian genomes, particularly brain, the CpG and CpA dinucleotides can be methylated at the 5-position of cytosine (5mC), and then may undergo successive oxidations to the 5-hydroxymethyl (5hmC), 5-formyl (5fC), and 5-carboxyl (5caC) forms. We find that, in the context of 5'-0CG-1CA-2CG-3TG-3'(where the numbers indicate successive dinucleotides), modification of the central E-box 2CG has very little effect on TCF4 binding, E-box 1CA modification has a negative influence on binding, while modification of the flanking 0CG, particularly carboxylation, has a strong positive impact on TCF4 binding to DNA. Crystallization of TCF4 in complex with unmodified or 5caC-modified oligonucleotides revealed that the basic region of bHLH domain adopts multiple conformations, including an extended loop going through the DNA minor groove, or the N-terminal portion of a long helix binding in the DNA major groove. The different protein conformations enable arginine 576 (R576) to interact, respectively, with a thymine in the minor groove, a phosphate group of DNA backbone, or 5caC in the major groove. The Pitt-Hopkins syndrome mutations affect five arginine residues in the basic region, two of them (R569 and R576) involved in 5caC recognition. Our analyses indicate, and suggest a structural basis for, the preferential recognition of 5caC by a transcription factor centrally important in brain development.
Asunto(s)
Arginina/química , Citosina/análogos & derivados , ADN/química , Timina/química , Factor de Transcripción 4/química , Secuencia de Aminoácidos , Arginina/metabolismo , Sitios de Unión , Clonación Molecular , Citosina/química , Citosina/metabolismo , ADN/genética , ADN/metabolismo , Ensayo de Cambio de Movilidad Electroforética , Escherichia coli/genética , Escherichia coli/metabolismo , Facies , Expresión Génica , Humanos , Hiperventilación/genética , Hiperventilación/metabolismo , Hiperventilación/patología , Discapacidad Intelectual/genética , Discapacidad Intelectual/metabolismo , Discapacidad Intelectual/patología , Modelos Moleculares , Mutación , Motivos de Nucleótidos , Unión Proteica , Conformación Proteica en Hélice alfa , Dominios y Motivos de Interacción de Proteínas , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Alineación de Secuencia , Homología de Secuencia de Aminoácido , Timina/metabolismo , Factor de Transcripción 4/genética , Factor de Transcripción 4/metabolismoAsunto(s)
Neoplasias del Tronco Encefálico/genética , Hiperventilación/genética , Discapacidad Intelectual/genética , Meduloblastoma/genética , Adulto , Neoplasias del Tronco Encefálico/patología , Facies , Femenino , Humanos , Hiperventilación/patología , Discapacidad Intelectual/patología , Meduloblastoma/patologíaRESUMEN
The TCF4 gene encodes for the basic helix-loop-helix transcription factor 4 (TCF4), which plays an important role in the development of the central nervous system (CNS). Haploinsufficiency of TCF4 was found to cause Pitt-Hopkins syndrome (PTHS), a severe neurodevelopmental disorder. Recently, the screening of a large cohort of medulloblastoma (MB), a highly aggressive embryonal brain tumor, revealed almost 20% of adult patients with MB of the Sonic hedgehog (SHH) subtype carrying somatic TCF4 mutations. Interestingly, many of these mutations have previously been detected as germline mutations in patients with PTHS. We show here that overexpression of wild-type TCF4 in vitro significantly suppresses cell proliferation in MB cells, whereas mutant TCF4 proteins do not to the same extent. Furthermore, RNA sequencing revealed significant upregulation of multiple well-known tumor suppressors upon expression of wild-type TCF4. In vivo, a prenatal knockout of Tcf4 in mice caused a significant increase in apoptosis accompanied by a decreased proliferation and failed migration of cerebellar granule neuron precursor cells (CGNP), which are thought to be the cells of origin for SHH MB. In contrast, postnatal in vitro and in vivo knockouts of Tcf4 with and without an additional constitutive activation of the SHH pathway led to significantly increased proliferation of CGNP or MB cells. Finally, publicly available data from human MB show that relatively low expression levels of TCF4 significantly correlate with a worse clinical outcome. These results not only point to time-specific roles of Tcf4 during cerebellar development but also suggest a functional linkage between TCF4 mutations and the formation of SHH MB, proposing that TCF4 acts as a tumor suppressor during postnatal stages of cerebellar development.
Asunto(s)
Proteínas Hedgehog/genética , Meduloblastoma/genética , Mutación , Factor de Transcripción 4/genética , Animales , Apoptosis/genética , Línea Celular Tumoral , Movimiento Celular/genética , Proliferación Celular/genética , Facies , Proteínas Hedgehog/metabolismo , Humanos , Hiperventilación/genética , Hiperventilación/metabolismo , Hiperventilación/patología , Discapacidad Intelectual/genética , Discapacidad Intelectual/metabolismo , Discapacidad Intelectual/patología , Meduloblastoma/metabolismo , Meduloblastoma/patología , Ratones , Ratones Noqueados , Factor de Transcripción 4/metabolismoRESUMEN
High-throughput sequencing (HTS) of human genome coding regions allows the simultaneous screen of a large number of genes, significantly improving the diagnosis of non-syndromic intellectual disabilities (ID). HTS studies permit the redefinition of the phenotypical spectrum of known disease-causing genes, escaping the clinical inclusion bias of gene-by-gene Sanger sequencing. We studied a cohort of 903 patients with ID not reminiscent of a well-known syndrome, using an ID-targeted HTS of several hundred genes and found de novo heterozygous variants in TCF4 (transcription factor 4) in eight novel patients. Piecing together the patients from this study and those from previous large-scale unbiased HTS studies, we estimated the rate of individuals with ID carrying a disease-causing TCF4 mutation to 0.7%. So far, TCF4 molecular abnormalities were known to cause a syndromic form of ID, Pitt-Hopkins syndrome (PTHS), which combines severe ID, developmental delay, absence of speech, behavioral and ventilation disorders, and a distinctive facial gestalt. Therefore, we reevaluated ten patients carrying a pathogenic or likely pathogenic variant in TCF4 (eight patients included in this study and two from our previous ID-HTS study) for PTHS criteria defined by Whalen and Marangi. A posteriori, five patients had a score highly evocative of PTHS, three were possibly consistent with this diagnosis, and two had a score below the defined PTHS threshold. In conclusion, these results highlight TCF4 as a frequent cause of moderate to profound ID and broaden the clinical spectrum associated to TCF4 mutations to nonspecific ID.
Asunto(s)
Secuenciación de Nucleótidos de Alto Rendimiento , Hiperventilación/genética , Discapacidad Intelectual/genética , Factor de Transcripción 4/genética , Adolescente , Adulto , Niño , Preescolar , Facies , Femenino , Humanos , Hiperventilación/diagnóstico , Hiperventilación/patología , Discapacidad Intelectual/diagnóstico , Discapacidad Intelectual/patología , Masculino , Mutación , Fenotipo , Adulto JovenRESUMEN
Pitt-Hopkins syndrome (PTHS) is a rare, genetic disorder caused by a molecular variant of TCF4 which is involved in embryologic neuronal differentiation. PTHS is characterized by syndromic facies, psychomotor delay, and intellectual disability. Other associated features include early-onset myopia, seizures, constipation, and hyperventilation-apneic spells. Many also meet criteria for autism spectrum disorder. Here the authors present a series of 23 PTHS patients with molecularly confirmed TCF4 variants and describe 3 unique individuals. The first carries a small deletion but does not exhibit the typical facial features nor the typical pattern of developmental delay. The second exhibits typical facial features, but has attained more advanced motor and verbal skills than other reported cases to date. The third displays typical features of PTHS, however inherited a large chromosomal duplication involving TCF4 from his unaffected father with somatic mosaicism. To the authors' knowledge, this is the first chromosomal duplication case reported to date.
Asunto(s)
Hiperventilación/terapia , Discapacidad Intelectual/terapia , Adolescente , Adulto , Niño , Preescolar , Diagnóstico Diferencial , Facies , Variación Genética , Humanos , Hiperventilación/genética , Hiperventilación/patología , Hiperventilación/psicología , Lactante , Discapacidad Intelectual/genética , Discapacidad Intelectual/patología , Discapacidad Intelectual/psicología , Fenotipo , Estudios Retrospectivos , Factor de Transcripción 4/genéticaRESUMEN
Human haploinsufficiency of the transcription factor Tcf4 leads to a rare autism spectrum disorder called Pitt-Hopkins syndrome (PTHS), which is associated with severe language impairment and development delay. Here, we demonstrate that Tcf4 haploinsufficient mice have deficits in social interaction, ultrasonic vocalization, prepulse inhibition, and spatial and associative learning and memory. Despite learning deficits, Tcf4(+/-) mice have enhanced long-term potentiation in the CA1 area of the hippocampus. In translationally oriented studies, we found that small-molecule HDAC inhibitors normalized hippocampal LTP and memory recall. A comprehensive set of next-generation sequencing experiments of hippocampal mRNA and methylated DNA isolated from Tcf4-deficient and WT mice before or shortly after experiential learning, with or without administration of vorinostat, identified "memory-associated" genes modulated by HDAC inhibition and dysregulated by Tcf4 haploinsufficiency. Finally, we observed that Hdac2 isoform-selective knockdown was sufficient to rescue memory deficits in Tcf4(+/-) mice.
Asunto(s)
Metilación de ADN/genética , Memoria , Plasticidad Neuronal/genética , Proteína 2 Similar al Factor de Transcripción 7/metabolismo , Animales , Trastorno Autístico/complicaciones , Trastorno Autístico/patología , Trastorno Autístico/fisiopatología , Islas de CpG/genética , Metilación de ADN/efectos de los fármacos , Modelos Animales de Enfermedad , Facies , Perfilación de la Expresión Génica , Técnicas de Silenciamiento del Gen , Hipocampo/metabolismo , Histona Desacetilasa 2/metabolismo , Inhibidores de Histona Desacetilasas/farmacología , Ácidos Hidroxámicos/farmacología , Hiperventilación/complicaciones , Hiperventilación/genética , Hiperventilación/patología , Hiperventilación/fisiopatología , Discapacidad Intelectual/complicaciones , Discapacidad Intelectual/genética , Discapacidad Intelectual/patología , Discapacidad Intelectual/fisiopatología , Potenciación a Largo Plazo/efectos de los fármacos , Masculino , Memoria/efectos de los fármacos , Ratones , Actividad Motora/efectos de los fármacos , Plasticidad Neuronal/efectos de los fármacos , Inhibición Prepulso/efectos de los fármacos , Proteína 2 Similar al Factor de Transcripción 7/genética , Transcripción Genética/efectos de los fármacos , VorinostatRESUMEN
Mutations in TCF4 (basic helix-loop-helix transcription factor 4), a gene with complex organization and multiple transcription initiation sites, are usually associated with Pitt-Hopkins syndrome (PTHS). However, a translocation encompassing the 5' end of TCF4 and several point mutations have been linked to non-syndromic intellectual disability (NSID). Here we describe a family with autosomal dominantly inherited NSID in seven relatives with a partial deletion of TCF4, disrupting the 5' end of the gene, predicted to result in the reduction of the number of mRNAs that can be produced by alternative transcription initiation. Functional studies indicate that it leads to reduced levels of transcripts coding for TCF4 protein isoforms with a nuclear localization signal, which may be relevant to the phenotype. The findings in our family support the notion that the position of the mutation in TCF4 is relevant to the phenotype, with those mutations in the 5' region, cassette exons and regions not affecting the important functional domains being linked to NSID rather than PTHS. We suggest that screening for mutations in TCF4 could be considered in the investigation of NSID.
Asunto(s)
Factores de Transcripción Básicos con Cremalleras de Leucinas y Motivos Hélice-Asa-Hélice/genética , Discapacidad Intelectual/genética , Factores de Transcripción/genética , Transcripción Genética , Regiones no Traducidas 5' , Exones/genética , Facies , Femenino , Humanos , Hiperventilación/genética , Hiperventilación/patología , Discapacidad Intelectual/patología , Masculino , Linaje , Fenotipo , Mutación Puntual/genética , Factor de Transcripción 4RESUMEN
No disponible
Asunto(s)
Adulto , Humanos , Masculino , Informes de Casos , Hiperventilación/metabolismo , Hiperventilación/patología , Encefalomielitis/genética , Encefalomielitis/metabolismo , Encefalomielitis Aguda Diseminada/metabolismo , Encefalomielitis Aguda Diseminada/patología , Coma/patología , Taquipnea/metabolismo , Terapéutica/métodos , Hiperventilación/complicaciones , Hiperventilación/diagnóstico , Inflamación Neurogénica/complicaciones , Encefalomielitis/complicaciones , Encefalomielitis/patología , Encefalomielitis Aguda Diseminada/complicaciones , Encefalomielitis Aguda Diseminada/genética , Coma/complicaciones , Taquipnea/diagnóstico , Terapéutica/normasAsunto(s)
Encefalopatías/complicaciones , Encefalopatías/patología , Hiperventilación/etiología , Hiperventilación/patología , Anciano , Análisis de los Gases de la Sangre , Tronco Encefálico/patología , Cerebelo/patología , Femenino , Humanos , Inflamación , Imagen por Resonancia Magnética , Grabación en VideoRESUMEN
Calpains are a family of cytoplasmic calcium-dependent proteinases with papain-like activity. They participate in a variety of processes in the body: age changes, functioning of endothelium and pulmonary system, regulation of apoptosis and necrosis, development of various hypometabolic states, arterial hypertension, diabetes and chronic kidney disease, tumor growth. It is concluded that calpains, causing limited proteolysis of substrates, play an important role in a wide range of biological phenomena. Their activity is associated with the response to the calcium-dependent signaling and the effects of aging. Inhibition of calpains activity contributes to inhibition of endothelial dysfunction, cardiovascular disease, formation of structural and functional changes in the kidney tissue, has neuroprotective effect, preventing sarcopenia, reduces inflammatory reactions caused by hyperventilation of the lungs.
Asunto(s)
Envejecimiento/metabolismo , Calpaína/metabolismo , Apoptosis , Calcio/metabolismo , Señalización del Calcio , Calpaína/antagonistas & inhibidores , Calpaína/química , Calpaína/genética , Enfermedades Cardiovasculares/metabolismo , Enfermedades Cardiovasculares/patología , Enfermedades Cardiovasculares/prevención & control , Diabetes Mellitus/tratamiento farmacológico , Diabetes Mellitus/metabolismo , Diabetes Mellitus/patología , Inhibidores Enzimáticos/uso terapéutico , Humanos , Hipertensión/tratamiento farmacológico , Hipertensión/metabolismo , Hipertensión/patología , Hiperventilación/metabolismo , Hiperventilación/patología , Hiperventilación/prevención & control , Isoenzimas/antagonistas & inhibidores , Isoenzimas/química , Isoenzimas/genética , Isoenzimas/metabolismo , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismo , Neoplasias/patología , Insuficiencia Renal Crónica/tratamiento farmacológico , Insuficiencia Renal Crónica/metabolismo , Insuficiencia Renal Crónica/patología , Sarcopenia/metabolismo , Sarcopenia/patología , Sarcopenia/prevención & controlRESUMEN
BACKGROUND AND PURPOSE: Cerebrovascular oxygenation changes during respiratory challenges have clinically important implications for brain function, including cerebral autoregulation and the rate of brain metabolism. SWI is sensitive to venous oxygenation level by exploitation of the magnetic susceptibility of deoxygenated blood. We assessed cerebral venous blood oxygenation changes during simple voluntary breath-holding (apnea) and hyperventilation by use of SWI at 3T. MATERIALS AND METHODS: We performed SWI scans (3T; acquisition time of 1 minute, 28 seconds; centered on the anterior commissure and the posterior commissure) on 10 healthy male volunteers during baseline breathing as well as during simple voluntary hyperventilation and apnea challenges. The hyperventilation and apnea tasks were separated by a 5-minute resting period. SWI venograms were generated, and the signal changes on SWI before and after the respiratory stress tasks were compared by means of a paired Student t test. RESULTS: Changes in venous vasculature visibility caused by the respiratory challenges were directly visualized on the SWI venograms. The venogram segmentation results showed that voluntary apnea decreased the mean venous blood voxel number by 1.6% (P < .0001), and hyperventilation increased the mean venous blood voxel number by 2.7% (P < .0001). These results can be explained by blood CO2 changes secondary to the respiratory challenges, which can alter cerebrovascular tone and cerebral blood flow and ultimately affect venous oxygen levels. CONCLUSIONS: These results highlight the sensitivity of SWI to simple and noninvasive respiratory challenges and its potential utility in assessing cerebral hemodynamics and vasomotor responses.
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Apnea/metabolismo , Contencion de la Respiración , Venas Cerebrales/metabolismo , Hiperventilación/metabolismo , Interpretación de Imagen Asistida por Computador/métodos , Angiografía por Resonancia Magnética/métodos , Oxígeno/sangre , Adulto , Apnea/patología , Venas Cerebrales/patología , Humanos , Hiperventilación/patología , Masculino , Reproducibilidad de los Resultados , Sensibilidad y Especificidad , VoliciónRESUMEN
Modulation in ventilatory settings is one of the approaches and interventions used to treat and prevent secondary brain damage after traumatic brain injury (TBI). Here we investigate the effect of hyperoxia in combination with hypoventilation on brain oxygenation, metabolism and intracranial pressure. Twelve pigs were divided into three groups; group1-100% hyperoxia (n=4), group 2-100% hyperoxia and 20% decrease in minute volume (MV) (n=4) and group 3-100% hyperoxia and 50% decrease in MV (n=4). Neither of the ventilator settings affected the lactate/pyruvate ratio significantly. However, there was a significant decrease of brain lactate (2.6±1.7 to 1.8±1.6mM) and a rapid and marked increase in brain oxygenation (7.9±0.7 to 61.3±17.6mmHg) in group 3. Intracranial pressure (ICP) was not significantly affected in this group, however, the ICP increased significantly in group 2 with 100% hyperoxia plus 20% reduction in minute volume. We conclude that hyperoxia in combination with 50% decrease in MV showed pronounced increase in partial brain oxygen tension (pbrO2) and decrease in brain lactate. The ventilatory modification, used in this study should be considered for further investigation as a possible therapeutic intervention for TBI patients.
Asunto(s)
Encéfalo/metabolismo , Hiperventilación/patología , Hipoventilación/patología , Ácido Láctico/metabolismo , Consumo de Oxígeno/fisiología , Animales , Análisis de los Gases de la Sangre , Presión Sanguínea/fisiología , Frecuencia Cardíaca/fisiología , Hiperventilación/fisiopatología , Hipoventilación/fisiopatología , Presión Intracraneal/fisiología , Masculino , Microdiálisis , Oxígeno/metabolismo , PorcinosRESUMEN
TCF4 (transcription factor 4; E2-2, ITF2) is a transcription factor that when haplo-insufficient causes Pitt-Hopkins Syndrome (PTHS), an autism-spectrum disorder that is associated with pervasive developmental delay and severe intellectual disability. The TCF4 gene is also a risk factor with highly significant linkage to schizophrenia, presumably via overexpression of the TCF4 gene product in the central nervous system. This review will present an overview of the clinical manifestations of PTHS and relate those clinical attributes to the underlying molecular genetics of TCF4. In order to provide a molecular biological context for the loss of function of TCF4 in PTHS, the review will also present a brief overview of the basic biochemistry of TCF4-mediated regulation of cellular and neuronal gene expression. In the final section of this review, I will discuss and speculate upon possible roles for the TCF4 transcription factor in neuronal function and comment upon how understanding these roles may give new insights into the molecular neurobiology of human cognition.