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A one-year and two-month old girl indicated large head circumference, widely spaced eyes, narrow palpebral fissures, strabismus on the right eye, broad and low nasal bridge and low-set ears. She had knee over extension and foot eversion on both sides while standing with help. She also had hypotonia and was not able to stand or walk independently. She can say "ma ma" unconsciously. In the neuropsychological developmental assessment, delayed development was shown on gross motor function, fine movement, adaptive capacity, speech and social behavior function. A de novo heterozygous mutation, c.3872G>A(p.G1291D), likely pathogenic, was detected in the CHD3 gene via the next generation sequencing. Snijders Blok-Campeau syndrome was confirmed. It is an extremely rare disease with only 60 cases reported globally. This case expands the CHD3 gene mutation sites and suggests that rare diseases need to be considered and genetic tests should be performed in children with intellectual developmental delay and abnormal facial features, so as to help early diagnosis. Citation.
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ADN Helicasas/genética , Complejo Desacetilasa y Remodelación del Nucleosoma Mi-2/genética , Hipotonía Muscular , Conducta Social , Femenino , Heterocigoto , Humanos , Lactante , Hipotonía Muscular/genética , MutaciónRESUMEN
Malignant mesothelioma (MM) is an almost invariably fatal cancer caused by asbestos exposure. The toxicity of asbestos fibers is related to their physicochemical properties and the generation of free radicals. We set up a pilot study to investigate the potential of the zeolite clinoptilolite to counteract the asbestos carcinogenesis by preventing the generation of reactive nitrogen and oxygen radicals. In cell culture experiments, clinoptilolite prevented asbestos-induced cell death, reactive oxygen species production, DNA degradation, and overexpression of genes known to be up-regulated by asbestos. In an asbestos-induced transgenic mouse model of MM, mice were injected intraperitoneal injections with blue asbestos, with or without clinoptilolite, and monitored for 30 weeks. By the end of the trial all 13 mice injected with asbestos alone had reached humane end points, whereas only 7 of 29 mice receiving crocidolite and clinoptilolite reached a similar stage of disease. Post-mortem examination revealed pinpoint mesothelioma-like tumors in affected mice, and the absence of tumor formation in surviving mice. Interestingly, the macrophage clearance system, which was largely suppressed in asbestos-treated mice, exhibited evidence of increased phagocytosis in mice treated with asbestos and clinoptilolite. Our study suggests that inhibiting the asbestos-induced generation of reactive oxygen species and stimulating the macrophage system may represent a pathway to amelioration of asbestos-induced toxicity. Additional studies are warranted to explore the underlying mechanisms responsible for our observations.
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For centuries, zeolites have been used for their utility in binding metals, and they feature in a multitude of agricultural and industrial applications in which the honeycombed zeolite structures form ideal ion exchangers, catalysts and binding agents. Zeolites are currently in a transition period, moving towards implementation in human ailments and diseases. Here, we postulated that zeolites may be able to counter the effects of excess iron and conducted a mouse model trial to gauge the utility of this notion. We used the transgenic mouse strain MexTAg299 for a thirty-week pilot trial in which iron polymaltose and/or the zeolite clinoptilolite was injected into the peritoneum twice weekly. Mice were sacrificed at the end of the trial period and examined by postmortem and histology for significant physiological differences between mouse subgroups. In this study, we demonstrated that a common zeolite, clinoptilolite, is able to maintain the general health and well-being of mice and prevent iron-induced deleterious effects following iron overload. When zeolites are given with iron biweekly as intraperitoneal injections, mice showed far less macroscopic visual organ discoloration, along with near normal histology, under iron overload conditions when compared to mice injected with iron only. The purpose of the present pilot study was to examine potential alternatives to current iron chelation treatments, and the results indicate an advantage to using zeolites in conditions of iron excess. Zeolites may have translational potential for use in cases of human iron overload.
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BACKGROUND AND PURPOSE: To determine the optimal dose of 2-iminobiotin (2-IB) for the treatment of moderate to severe asphyxia in a neonatal piglet model of hypoxia-ischemia. METHODS: Newborn piglets were subjected to a 30-minute hypoxia-ischemia insult and randomly treated with vehicle or 2-IB (0.1 mg/kg, 0.2 mg/kg, or 1.0 mg/kg). aEEG background and seizure activity were scored after hypoxia-ischemia every 4 h until 24 h and at 48 h and neurobehavioral scores were obtained. Brain tissue was collected and processed for analysis of caspase-3 activity, histology, and tyrosine nitration. RESULTS: A dose range of 0.1 to 1.0 mg/kg/dose of 2-IB improved short-term outcome as demonstrated by an increased survival with a normal aEEG and decreased nitrotyrosine staining in the 2-IB-treated animals, indicating decreased cellular damage. Neurobehavior, caspase-3 activity in thalamus, and histology scores were not significantly different. CONCLUSIONS: Based on survival with a normal aEEG, 0.2 mg/kg 2-IB is likely to be the most appropriate dose for use in future clinical trials in neonates with perinatal hypoxia-ischemia.
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Asfixia/tratamiento farmacológico , Asfixia/etiología , Biotina/análogos & derivados , Hipoxia-Isquemia Encefálica/complicaciones , Óxido Nítrico Sintasa/antagonistas & inhibidores , Animales , Biotina/uso terapéutico , Encéfalo/metabolismo , Encéfalo/patología , Caspasa 3/metabolismo , Relación Dosis-Respuesta a Droga , Electroencefalografía , Modelos Animales , Porcinos , Factores de Tiempo , Resultado del TratamientoRESUMEN
BACKGROUND: Both hypothermia and erythropoietin (EPO) are reported to have neuroprotective effects after perinatal hypoxia-ischemia (HI). We investigated a possible additive effect of the use of a combination of hypothermia-EPO in a rat model of neonatal HI. METHODS: At postnatal day 7, rats were subjected to HI and then randomized to 3 h of hypothermia, EPO, or both. Sensorimotor function was assessed by the cylinder-rearing test (CRT) at 2 and 5 wk after HI. Brain lesion volume and white matter loss were determined by hematoxylin-eosin and luxol fast blue staining, respectively. RESULTS: Multivariable analysis using general linear modeling showed that hypothermia, EPO, and the interaction hypothermia × gender were determinants of sensorimotor function, both at 2 and 5 wk after HI. Neuroprotective effects of hypothermia at 5 wk were more pronounced in females, showing 52% improvement in the CRT. Maximal improvement in males was 26% after combined treatment with hypothermia and EPO. Histological outcome was improved by hypothermia only with no additional effect of EPO or gender. CONCLUSION: Hypothermia after HI improved sensorimotor function in females more than in males. There was a borderline additive effect of EPO when combined with hypothermia. Histology of brain lesion volume and white matter damage was improved only by hypothermia.
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Eritropoyetina/uso terapéutico , Hipotermia Inducida/métodos , Hipoxia-Isquemia Encefálica/tratamiento farmacológico , Hipoxia-Isquemia Encefálica/terapia , Fármacos Neuroprotectores/uso terapéutico , Animales , Animales Recién Nacidos , Glucemia , Temperatura Corporal , Femenino , Técnicas Histológicas , Hipoxia-Isquemia Encefálica/patología , Modelos Lineales , Masculino , Ratas , Factores SexualesRESUMEN
There are mixed reports on the neuroprotective properties of erythropoietin (EPO) in animal models of birth asphyxia. We investigated the effect of EPO on short- and long-term outcome after neonatal hypoxic-ischemic (HI) brain injury in mice and compared the effect of two different dose regimens of EPO. Nine-day-old mice were subjected to HI, and EPO was injected i.p. at 0, 24, and 48 h after HI in a dose of either 5 or 20 kU/kg. Paw preference in the cylinder rearing test (CRT) was used as a measure of sensorimotor function. Only in female mice, administration of EPO at 5 kU/kg but not 20 kU/kg improved sensorimotor function, reduced striatum atrophy and hippocampal lesion volume, and enhanced myelin basic protein (MBP) staining as determined at 4 and 9 wk after HI. In addition, at 72 h after HI, more Ki 67 cells were found in the subventricular zone and dentate gyrus after EPO 5 kU/kg treatment, indicating an increase in progenitor cell proliferation. In conclusion, EPO improves sensorimotor function after neonatal HI and protects against striatum atrophy, hippocampus injury, and white matter loss. The protective effect of EPO is dose-dependent and only present in females.
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Eritropoyetina/farmacología , Eritropoyetina/uso terapéutico , Hipocampo/citología , Hipoxia-Isquemia Encefálica/tratamiento farmacológico , Hipoxia-Isquemia Encefálica/patología , Vaina de Mielina/efectos de los fármacos , Desempeño Psicomotor/efectos de los fármacos , Animales , Apoptosis/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Eritropoyetina/administración & dosificación , Femenino , Hipocampo/efectos de los fármacos , Humanos , Recién Nacido , Masculino , Ratones , Proteína Básica de Mielina/metabolismo , Neurogénesis/efectos de los fármacos , Factores Sexuales , Factores de TiempoRESUMEN
Recent progress has provided us with several promising neuroprotective compounds to reduce perinatal hypoxic-ischemic (HI) brain injury. In the early post HI phase, therapies can be concentrated on ion channel blockage (Xenon), anti-oxidation (allopurinol, 2-iminobiotin, and indomethacin), anti-inflammation (erythropoietin [EPO], melatonin), and anti-apoptosis (nuclear factor kappa B [NF-κB]and c-jun N-terminal kinase [JNK] inhibitors); in the later phase, therapies should be targeted to promote neuronal regeneration by stimulation of neurotrophic properties of the neonatal brain (EPO, growth factors, stem cells transplantation). Combination of pharmacological interventions with moderate hypothermia, which is the only established therapy for post HI brain injury, is probably the next step to fight HI brain damage in the clinical setting. Further studies should be concentrated on more rational pharmacological strategies by determining the optimal time and dose to inhibit the various potentially destructive molecular pathways and/or to enhance endogenous repair meanwhile avoiding the adverse effects.
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Asfixia Neonatal/tratamiento farmacológico , Citoprotección/efectos de los fármacos , Neonatología/tendencias , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/uso terapéutico , Asfixia Neonatal/fisiopatología , Terapia Combinada , Humanos , Recién Nacido , Cuidado Intensivo Neonatal/métodos , Cuidado Intensivo Neonatal/tendencias , Neonatología/métodos , Fármacos Neuroprotectores/efectos adversosRESUMEN
Perinatal hypoxia-ischemia (HI) is an important cause of neonatal brain injury. Recent progress in the search for neuroprotective compounds has provided us with several promising drugs to reduce perinatal HI-induced brain injury. In the early stage (first 6 hours after birth) therapies are concentrated on prevention of the production of reactive oxygen species or free radicals (xanthine-oxidase-, nitric oxide synthase-, and prostaglandin inhibition), anti-inflammatory effects (erythropoietin, melatonin, Xenon) and anti-apoptotic interventions (nuclear factor kappa B- and c-jun N-terminal kinase inhibition); in a later stage stimulation of neurotrophic properties in the neonatal brain (erythropoietin, growth factors) can be targeted to promote neuronal and oligodendrocyte regeneration. Combination of pharmacological means of treatment with moderate hypothermia, which is accepted now as a meaningful therapy, is probably the next step in clinical treatment to fight post-asphyxial brain damage. Further studies should be directed at a more rational use of therapies by determining the optimal time and dose to inhibit the different potentially destructive molecular pathways or to enhance endogenous repair while at the same time avoiding adverse effects of the drugs used.
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During neonatal hypoxic-ischemic brain injury, activation of transcription of a series of genes is induced to stimulate erythropoiesis, anti-apoptosis, apoptosis, necrosis and angiogenesis. A key factor mediating these gene transcriptions is hypoxia-inducible factor-1alpha (HIF-1alpha). During hypoxia, HIF-1alpha protein is stabilized and heterodimerizes with HIF-1beta to form HIF-1, subsequently regulating the expression of target genes. HIF-1alpha participates in early brain development and proliferation of neuronal precursor cells. Under pathological conditions, HIF-1alpha is known to play an important role in neonatal hypoxic-ischemic brain injury: on the one hand, HIF-1alpha has neuroprotective effects whereas it can also have neurotoxic effects. HIF-1alpha regulates the transcription of erythropoietin (EPO), which induces several pathways associated with neuroprotection. HIF-1alpha also promotes the expression of vascular endothelial cell growth factor (VEGF), which is related to neovascularization in hypoxic-ischemic brain areas. In addition, HIF-1alpha has an anti-apoptotic effect by increasing the expression of anti-apoptotic factors such as EPO during mild hypoxia. The neurotoxic effects of HIF-1alpha are represented by its participation in the apoptotic process by increasing the stability of the tumor suppressor protein p53 during severe hypoxia. Moreover, HIF-1alpha plays a role in cell necrosis, by interacting with calcium and calpain. HIF-1alpha can also exacerbate brain edema via increasing the permeability of the blood-brain barrier (BBB). Given these properties, HIF-1alpha has both neuroprotective and neurotoxic effects after hypoxia-ischemia. These events are cell type specific and related to the severity of hypoxia. Unravelling of the complex functions of HIF-1alpha may be important when designing neuroprotective therapies for hypoxic-ischemic brain injury.