Consideraciones bioéticas en el manejo de la esclerosis lateral amiotrófica: Una aproximación al quehacer fonoaudiológico

Introducción: La esclerosis lateral amiotrófica (ELA) es la forma más común de enfermedad degenerativa de motoneurona en la edad adulta y es considerada una enfermedad terminal. Por lo mismo, el accionar del fonoaudiólogo debe considerar el respeto a los principios bioéticos básicos para garantizar una asistencia adecuada. Objetivo: Conocer aquellas consideraciones bioéticas relacionadas al manejo y estudio de personas con ELA para luego brindar una aproximación hacia el quehacer fonoaudiológico. Método: Se efectuó una búsqueda bibliográfica en las bases de datos PubMed, Scopus y SciELO. Se filtraron artículos publicados desde 2000 hasta junio de 2023 y fueron seleccionados aquellos que abordaban algún componente bioético en población con ELA. Resultados: Aspectos relacionados al uso del consentimiento informado y a la toma de decisiones compartidas destacaron como elementos esenciales para apoyar la autonomía de las personas. Conclusión: Una correcta comunicación y una toma de decisiones compartida son claves para respetar la autonomía de las personas. A su vez, la estandarización de procedimientos mediante la investigación clínica permitirá aportar al cumplimiento de los principios bioéticos de beneficencia y no maleficencia, indispensables para la práctica profesional.

Introduction: Amyotrophic lateral sclerosis (ALS) is the most common form of degenerative motor neuron disease in adulthood and is considered a terminal disease. For this reason, the actions of the speech therapist must consider respect for basic bioethical principles to guarantee adequate assistance. Objective: To know those bioethical considerations related to the management and study of people with ALS to then provide an approach to speech therapy. Methodology: A bibliographic search was carried out in the PubMed, Scopus, and SciELO databases. Articles published from 2000 to June 2023 were filtered and those that addressed a bioethical component in the population with ALS were selected. Results: Aspects related to the use of informed consent and shared decision-making stood out as essential elements to support people's autonomy. Conclusion: Proper communication and shared decision-making are key to respecting people's autonomy. In turn, the standardization of procedures through clinical research will contribute to compliance with the bioethical principles of beneficence and non-maleficence, essential for professional practice.

Consensus from the Brazilian Academy of Neurology for the diagnosis, genetic counseling, and use of disease-modifying therapies in 5q spinal muscular atrophy / Consenso da Academia Brasileira de Neurologia para diagnóstico, aconselhamento genético e uso de terapias modificadoras na atrofia muscular espinhal 5q

Abstract Spinal muscular atrophy linked to chromosome 5 (SMA-5q) is an autosomal recessive genetic disease caused by mutations in the SMN1. SMA-5q is characterized by progressive degeneration of the spinal cord and bulbar motor neurons, causing severe motor and respiratory impairment with reduced survival, especially in its more severe clinical forms. In recent years, highly effective disease-modifying therapies have emerged, either acting by regulating the splicing of exon 7 of the SMN2 gene or adding a copy of the SMN1 gene through gene therapy, providing a drastic change in the natural history of the disease. In this way, developing therapeutic guides and expert consensus becomes essential to direct the use of these therapies in clinical practice. This consensus, prepared by Brazilian experts, aimed to review the main available disease-modifying therapies, critically analyze the results of clinical studies, and provide recommendations for their use in clinical practice for patients with SMA-5q. This consensus also addresses aspects related to diagnosis, genetic counseling, and follow-up of patients under drug treatment. Thus, this consensus provides valuable information regarding the current management of SMA-5q, helping therapeutic decisions in clinical practice and promoting additional gains in outcomes.

Resumo Atrofia muscular espinhal ligada ao cromossomo 5 (AME-5q) é uma doença genética de herança autossômica recessiva causada por mutações no gene SMN1. A AME-5q cursa com degeneração progressiva dos motoneurônios medulares e bulbares, acarretando grave comprometimento motor e respiratório com redução da sobrevida, especialmente nas suas formas clínicas mais graves. Nos últimos anos, terapias modificadoras da doença altamente eficazes, ou que atuam regulando o splicing do exon 7 do gene SMN2 ou adicionando uma cópia do gene SMN1 via terapia gênica, têm surgido, proporcionando uma mudança drástica na história natural da doença. Dessa forma, o desenvolvimento de guias terapêuticos e de consensos de especialistas torna-se importante no sentido de direcionar o uso dessas terapias na prática clínica. Este consenso, preparado por especialistas brasileiros, teve como objetivos revisar as principais terapias modificadoras de doença disponíveis, analisar criticamente os resultados dos estudos clínicos dessas terapias e prover recomendações para seu uso na prática clínica para pacientes com AME-5q. Aspectos relativos ao diagnóstico, aconselhamento genético e seguimento dos pacientes em uso das terapias também são abordados nesse consenso. Assim, esse consenso promove valiosas informações a respeito do manejo atual da AME-5q auxiliando decisões terapêuticas na prática clínica e promovendo ganhos adicionais nos desfechos finais.

Noninvasive mechanical ventilation assistance in amyotrophic lateral sclerosis: a systematic review

ABSTRACT BACKGROUND: Respiratory failure is the most common cause of death in patients with amyotrophic lateral sclerosis (ALS), and morbidity is related to poor quality of life (QOL). Non-invasive ventilation (NIV) may be associated with prolonged survival and QOL in patients with ALS. OBJECTIVES: To assess whether NIV is effective and safe for patients with ALS in terms of survival and QOL, alerting the health system. DESIGN AND SETTING: Systematic review was conducted in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses reporting standards using population, intervention, comparison, and outcome strategies. METHODS: The Cochrane Library, CENTRAL, MEDLINE, LILACS, EMBASE, and CRD databases were searched based on the eligibility criteria for all types of studies on NIV use in patients with ALS published up to January 2022. Data were extracted from the included studies, and the findings were presented using a narrative synthesis. RESULTS: Of the 120 papers identified, only 14 were related to systematic reviews. After thorough reading, only one meta-analysis was considered eligible. In the second stage, 248 studies were included; however, only one systematic review was included. The results demonstrated that NIV provided relief from the symptoms of chronic hypoventilation, increased survival, and improved QOL compared to standard care. These results varied according to clinical phenotype. CONCLUSIONS: NIV in patients with ALS improves the outcome and can delay the indication for tracheostomy, reducing expenditure on hospitalization and occupancy of intensive care unit beds. SYSTEMATIC REVIEW REGISTRATION: PROSPERO database: CRD42021279910 — https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=279910.

Study of Cerebellar Tissue Following Induction of Aging in Mice By Di-Galactose / Estudio del Tejido Cerebeloso tras la Inducción del Envejecimiento en Ratones por D-Galactosa

SUMMARY: The cerebellum is a crucial area of the hindbrain that plays an essential role in balancing, excitement control, and subtle and accurate functions. Studies have shown that long-term use of D-galactose in mice, as with the symptoms of aging, causes morphological and functional disorders in the brain. This study was performed to evaluate the changes in the cerebellum cortex tissue and the measurement of reactive oxygen species (ROS) in the cerebellum following the induction of aging in mice by D-galactose. Accordingly, subjects were randomly assigned into two groups: Normal saline group and Aging group (D-galactose). To create an aging model, D- galactose, and saline solution (sodium chloride 0.9 %) were used. After completing the preparation and passage of the tissue, the cerebellum specimens were cut in 5 microns thickness and then stained with hematoxylin-eosin stain and finally examined under a Nikon microscope. Quantitative variables were analyzed by SPSS software using T-test. In the observations of cerebellum tissue samples, in the aged induced group by D-galactose, the most changes were observed in the Neuron purkinjense (Purkinje cells) layer. In the observations of the cerebellum tissue samples of aging group induced by D-galactose, the most changes were observed in the Neuron purkinjense, and the arrangement and placement of these cells were disorientated. The nucleus positioning was not central, and the Neuron purkinjense induced by aging were seen in different morphological forms. Necrosis, Chromatolysis, and Pyknosis were found. Based on the results, D-galactose (induction of aging) causes pathological changes in the cerebellar cortex, especially in the Neuron purkinjense layer.

El cerebelo es un área crucial del rombencéfalo que desempeña un papel esencial en el equilibrio, el control de la excitación y las funciones sutiles y precisas. Los estudios han demostrado que el uso a largo plazo de D-galactosa en ratones, al igual que con los síntomas del envejecimiento, provoca trastornos morfológicos y funcionales en el cerebro. Este estudio se realizó para evaluar los cambios en el tejido de la corteza del cerebelo y la medición de especies reactivas de oxígeno (ROS) en el cerebelo luego de la inducción del envejecimiento en ratones por D-galactosa. En consecuencia, los sujetos fueron asignados aleatoriamente a dos grupos: grupo de solución salina normal y grupo de envejecimiento (D-galactosa). Para crear un modelo de envejecimiento, se utilizaron D-galactosa y solución salina (cloruro de sodio al 0,9 %). Después de completar la preparación y el paso del tejido, las muestras de cerebelo se cortaron en un grosor de 5 µm y luego se tiñeron con tinción de hematoxilina-eosina y finalmente se examinaron bajo un microscopio Nikon. Las variables cuantitativas se analizaron mediante el software SPSS utilizando la prueba T. En las observaciones de muestras de tejido de cerebelo, en el grupo envejecido inducido por D-galactosa, la mayoría de los cambios se observaron en la capa de neuronas purkinjenses (células de Purkinje). En las observaciones de las muestras de tejido del cerebelo del grupo de envejecimiento inducidas por D-galactosa, la mayoría de los cambios se observaron en las neuronas purkinjenses, y la disposición y ubicación de estas células estaban desorientadas. El posicionamiento del núcleo no era central y las neuronas purkinjenses inducidas por el envejecimiento se observaban en diferentes formas morfológicas. Se encontró necrosis, cromatólisis y picnosis. Según los resultados, la D-galactosa (inducción del envejecimiento) provoca cambios patológicos en la corteza cerebelosa, especialmente en la capa de neuronas purkinjenses.

Telehealth for amyotrophic lateral sclerosis in a multidisciplinary service in a Brazilian reference center / Telessaúde para esclerose lateral amiotrófica em um serviço multidisciplinar em um centro de referência brasileiro

Abstract Background Telehealth has been used in the treatment of different diseases, and it has been shown to provide benefits for patients with amyotrophic lateral sclerosis (ALS). Due to the social distancing measures put into effect during the coronavirus disease 2019 (COVID-19) pandemic, there was an urgent need for telehealth to ensure the provision of healthcare. Objective To evaluate the feasibility of telehealth for the provision of multidisciplinary ALS care, and to assess its acceptability among patients and caregivers. Methods We conducted a retrospective cohort study in which multidisciplinary evaluations were performed using the Teleconsulta platform. The patients included had ALS and at least one in-person clinical evaluation. The patients and the caregivers answered satisfaction questionnaires. Results The sample was composed of 46 patients, 32 male and 14 female subjects. The average distance from their residences to the reference services was of 115 km. Respiratory adjustment was the most addressed topic. Conclusion The strategy is viable and well accepted in terms of satisfaction. It was even more positive for patients in advanced stages of the disease or for those living far from the referral center.

Resumo Antecedentes A telessaúde tem sido utilizada no tratamento de diferentes doenças, e demonstrou-se que ela traz benefícios para pacientes com esclerose lateral amiotrófica (ELA). Devido às medidas de distanciamento social postas em prática durante a pandemia de doença do coronavírus 2019 (coronavirus disease 2019, COVID-19, em inglês), houve uma necessidade urgente de se usar a telessaúde para garantir a provisão dos cuidados de saúde. Objetivo Avaliar a viabilidade da telessaúde para a prestação de cuidados multidisciplinares na ELA, e verificar a sua aceitabilidade entre os pacientes e os cuidadores. Métodos Realizou-se um estudo de coorte retrospectivo, com avaliações multidisciplinares realizadas por meio da plataforma Teleconsulta. Os pacientes incluídos apresentavam ELA, e já haviam passado por pelo menos uma avaliação clínica presencial. Os pacientes e os cuidadores responderam a questionários de satisfação. Resultados A amostra continha 46 pacientes, 32 do sexo masculino e 14 do sexo feminino. A distância média de suas residências ao serviço de referência era de 115 km. O ajuste respiratório foi o tema mais abordado. Conclusão A estratégia é viável e bem-aceita em termos de satisfação. Foi ainda mais positiva para os pacientes com doença avançada ou residentes em uma cidade distante do centro de referência.

Inhibition of histone methyltransferase PRMT5 attenuates cisplatin-induced hearing loss through the PI3K/Akt-mediated mitochondrial apoptotic pathway / 药物分析学报

This study aimed to evaluate the therapeutic potential of inhibiting protein arginine methyltransferase 5(PRMT5)in cisplatin-induced hearing loss.The effects of PRMT5 inhibition on cisplatin-induced auditory injury were determined using immunohistochemistry,apoptosis assays,and auditory brainstem response.The mechanism of PRMT5 inhibition on hair cell survival was assessed using RNA-seq and Cleavage Under Targets and Tagment-quantitative polymerase chain reaction(CUT&Tag-qPCR)analyses in the HEI-OC1 cell line.Pharmacological inhibition of PRMT5 significantly alleviated cisplatin-induced damage to hair cells and spiral ganglion neurons in the cochlea and decreased apoptosis by protecting mitochondrial function and preventing the accumulation of reactive oxygen species.CUT&Tag-qPCR analysis demonstrated that inhibition of PRMT5 in HEI-OC1 cells reduced the accumulation of H4R3me2s/H3R8me2s marks at the promoter region of the Pik3ca gene,thus activating the expression of Pik3ca.These findings suggest that PRMT5 inhibitors have strong potential as agents against cisplatin-induced ototoxicity and can lay the foundation for further research on treatment strategies of hearing loss.

Progress of major biomarkers for neonatal brain injury in clinical application / 国际儿科学杂志

With the continuous progress of monitoring and treatment skills, the mortality of neonates has gradually decreased, and the long-term neurodevelopmental outcome has become the primary concern of society and families.During the perinatal period, the developing brain is vulnerable to hypoxia, hemorrhage, infection and inflammation, which may cause varying degrees of brain cell damage.Studies have found that proteins released by damaged brain cells can be detected in the body fluid of neonates, which are related to the occurrence and prognosis of neonatal brain injury.This article mainly reviews the recently reported brain injury biomarkers such as S100B, neuron specific enolase(NSE)and glial fibrillary acidic protein(GFAP)in different biological samples and its clinical predictive value for the occurrence of brain injury and neurodevelopmental prognosis.

Expression changes of NaV channel subunits correlate with developmental maturation of electrophysiological characteristics of rat cerebellar Purkinje neurons / 南方医科大学学报

OBJECTIVE@#To investigate the variations in the expression of voltage-gated sodium (Nav) channel subunits during development of rat cerebellar Purkinje neurons and their correlation with maturation of electrophysiological characteristics of the neurons.@*METHODS@#We observed the changes in the expression levels of NaV1.1, 1.2, 1.3 and 1.6 during the development of Purkinje neurons using immunohistochemistry in neonatal (5-7 days after birth), juvenile (12-14 days), adolescent (21-24 days), and adult (42-60 days) SD rats. Using whole-cell patch-clamp technique, we recorded the spontaneous electrical activity of the neurons in ex vivo brain slices of rats of different ages to analyze the changes of electrophysiological characteristics of these neurons during development.@*RESULTS@#The expression of NaV subunits in rat cerebellar Purkinje neurons showed significant variations during development. NaV1.1 subunit was highly expressed throughout the developmental stages and increased progressively with age (P < 0.05). NaV1.2 expression was not detected in the neurons in any of the developmental stages (P > 0.05). The expression level of NaV1.3 decreased with development and became undetectable after adolescence (P < 0.05). NaV1.6 expression was not detected during infancy, but increased with further development (P < 0.05). NaV1.1 and NaV1.3 were mainly expressed in the early stages of development. With the maturation of the rats, NaV1.3 expression disappeared and NaV1.6 expression increased in the neurons. NaV1.1 and NaV1.6 were mainly expressed after adolescence. The total NaV protein level increased gradually with development (P < 0.05) and tended to stabilize after adolescence. The spontaneous frequency and excitability of the Purkinje neurons increased gradually with development and reached the mature levels in adolescence. The developmental expression of NaV subunits was positively correlated with discharge frequency (r=0.9942, P < 0.05) and negatively correlated with the excitatory threshold of the neurons (r=0.9891, P < 0.05).@*CONCLUSION@#The changes in the expression levels of NaV subunits are correlated with the maturation of high frequency electrophysiological properties of the neurons, suggesting thatmature NaV subunit expressions is the basis of maturation of electrophysiological characteristics of the neurons.

Effect of Astrocyte-neuron Coupling Imbalance in Development of Alzheimer's Disease and Intervention Mechanism of Kidney-tonifying and Marrow-filling TCM Prescriptions / 中国实验方剂学杂志

Astrocytes are important nerve cells in the central nervous system （CNS）， which mainly play a key role in nutrition and support. Astrocytes and neurons undergo close energy coupling and substance coupling， which are closely related and interact with each other. In recent years， many studies have shown that the astrocyte-neuron coupling imbalance plays a central role in the occurrence and progression of Alzheimer's disease （AD） and serves as an important therapeutic target receiving increasing attention. According to traditional Chinese medicine （TCM） theory， the main pathogenesis of AD is kidney deficiency and marrow inadequacy， and in clinical medication， kidney-tonifying and marrow-filling TCM prescriptions are often employed with satisfactory results achieved. As reported， many kidney-tonifying and marrow-filling prescriptions exhibit regulatory and protective effects on the imbalance of astrocyte-neuron coupling， suggesting that the effect of kidney-tonifying and marrow-filling prescriptions in treating AD may have some internal relationship with its regulation of the imbalance of astrocyte-neuron coupling. This article reviewed the underlying internal relationship between the imbalance of astrocyte-neuron coupling and the pathogenesis of kidney deficiency and marrow inadequacy in AD and the research progress in the intervention mechanism of TCM for tonifying the kidney and filling the marrow.

Cholinergic dysfunction-induced insufficient activation of alpha7 nicotinic acetylcholine receptor drives the development of rheumatoid arthritis through promoting protein citrullination via the SP3/PAD4 pathway

Both cholinergic dysfunction and protein citrullination are the hallmarks of rheumatoid arthritis (RA), but the relationship between the two phenomena remains unclear. We explored whether and how cholinergic dysfunction accelerates protein citrullination and consequently drives the development of RA. Cholinergic function and protein citrullination levels in patients with RA and collagen-induced arthritis (CIA) mice were collected. In both neuron-macrophage coculture system and CIA mice, the effect of cholinergic dysfunction on protein citrullination and expression of peptidylarginine deiminases (PADs) was assessed by immunofluorescence. The key transcription factors for PAD4 expression were predicted and validated. Cholinergic dysfunction in the patients with RA and CIA mice negatively correlated with the degree of protein citrullination in synovial tissues. The cholinergic or alpha7 nicotinic acetylcholine receptor (α7nAChR) deactivation and activation resulted in the promotion and reduction of protein citrullination in vitro and in vivo, respectively. Especially, the activation deficiency of α7nAChR induced the earlier onset and aggravation of CIA. Furthermore, deactivation of α7nAChR increased the expression of PAD4 and specificity protein-3 (SP3) in vitro and in vivo. Our results suggest that cholinergic dysfunction-induced deficient α7nAChR activation, which induces the expression of SP3 and its downstream molecule PAD4, accelerating protein citrullination and the development of RA.

Corticostriatal Neurons in the Anterior Auditory Field Regulate Frequency Discrimination Behavior / 神经科学通报·英文版

The anterior auditory field (AAF) is a core region of the auditory cortex and plays a vital role in discrimination tasks. However, the role of the AAF corticostriatal neurons in frequency discrimination remains unclear. Here, we used c-Fos staining, fiber photometry recording, and pharmacogenetic manipulation to investigate the function of the AAF corticostriatal neurons in a frequency discrimination task. c-Fos staining and fiber photometry recording revealed that the activity of AAF pyramidal neurons was significantly elevated during the frequency discrimination task. Pharmacogenetic inhibition of AAF pyramidal neurons significantly impaired frequency discrimination. In addition, histological results revealed that AAF pyramidal neurons send strong projections to the striatum. Moreover, pharmacogenetic suppression of the striatal projections from pyramidal neurons in the AAF significantly disrupted the frequency discrimination. Collectively, our findings show that AAF pyramidal neurons, particularly the AAF-striatum projections, play a crucial role in frequency discrimination behavior.

Functional Autapses Form in Striatal Parvalbumin Interneurons but not Medium Spiny Projection Neurons / 神经科学通报·英文版

Autapses selectively form in specific cell types in many brain regions. Previous studies have also found putative autapses in principal spiny projection neurons (SPNs) in the striatum. However, it remains unclear whether these neurons indeed form physiologically functional autapses. We applied whole-cell recording in striatal slices and identified autaptic cells by the occurrence of prolonged asynchronous release (AR) of neurotransmitters after bursts of high-frequency action potentials (APs). Surprisingly, we found no autaptic AR in SPNs, even in the presence of Sr2+. However, robust autaptic AR was recorded in parvalbumin (PV)-expressing neurons. The autaptic responses were mediated by GABAA receptors and their strength was dependent on AP frequency and number. Further computer simulations suggest that autapses regulate spiking activity in PV cells by providing self-inhibition and thus shape network oscillations. Together, our results indicate that PV neurons, but not SPNs, form functional autapses, which may play important roles in striatal functions.

MASH1 induces neuron transdifferentiation of adrenal medulla chromaffin cells / 中南大学学报(医学版)

OBJECTIVES@#Nerve growth factor (NGF) induces neuron transdifferentiation of adrenal medulla chromaffin cells (AMCCs) and consequently downregulates the secretion of epinephrine (EPI), which may be involved in the pathogenesis of bronchial asthma. Mammalian achaete scute-homologous 1 (MASH1), a key regulator of neurogenesis in the nervous system, has been proved to be elevated in AMCCs with neuron transdifferentiation in vivo. This study aims to explore the role of MASH1 in the process of neuron transdifferentiation of AMCCs and the mechanisms.@*METHODS@#Rat AMCCs were isolated and cultured. AMCCs were transfected with siMASH1 or MASH1 overexpression plasmid, then were stimulated with NGF and/or dexamethasone, PD98059 (a MAPK kinase-1 inhibitor) for 48 hours. Morphological changes were observed using light and electron microscope. Phenylethanolamine-N-methyltransferase (PNMT, the key enzyme for epinephrine synthesis) and tyrosine hydroxylase were detected by immunofluorescence. Western blotting was used to test the protein levels of PNMT, MASH1, peripherin (neuronal markers), extracellular regulated protein kinases (ERK), phosphorylated extracellular regulated protein kinases (pERK), and JMJD3. Real-time RT-PCR was applied to analyze the mRNA levels of MASH1 and JMJD3. EPI levels in the cellular supernatant were measured using ELISA.@*RESULTS@#Cells with both tyrosine hydroxylase and PNMT positive by immunofluorescence were proved to be AMCCs. Exposure to NGF, AMCCs exhibited neurite-like processes concomitant with increases in pERK/ERK, peripherin, and MASH1 levels (all P<0.05). Additionally, impairment of endocrine phenotype was proved by a signifcant decrease in the PNMT level and the secretion of EPI from AMCCs (all P<0.01). MASH1 interference reversed the effect of NGF, causing increases in the levels of PNMT and EPI, conversely reduced the peripherin level and cell processes (all P<0.01). MASH1 overexpression significantly increased the number of cell processes and peripherin level, while decreased the levels of PNMT and EPI (all P<0.01). Compared with the NGF group, the levels of MASH1, JMJD3 protein and mRNA in AMCCs in the NGF+PD98059 group were decreased (all P<0.05). After treatment with PD98059 and dexamethasone, the effect of NGF on promoting the transdifferentiation of AMCCs was inhibited, and the number of cell processes and EPI levels were decreased (both P<0.05). In addition, the activity of the pERK/MASH1 pathway activated by NGF was also inhibited.@*CONCLUSIONS@#MASH1 is the key factor in neuron transdifferentiation of AMCCs. NGF-induced neuron transdifferentiation is probably mediated via pERK/MASH1 signaling.

Neuroprotective effect of ginsenoside Re on drosophila model of Parkinson's disease / 中国中药杂志

This study aims to explore the neuroprotective mechanism of ginsenoside Re(GS-Re) on drosophila model of Parkinson's disease(PD) induced by rotenone(Rot). To be specific, Rot was used to induce PD in drosophilas. Then the drosophilas were grouped and respectively treated(GS-Re: 0.1, 0.4, 1.6 mmol·L~(-1); L-dopa: 80 μmol·L~(-1)). Life span and crawling ability of drosophilas were determined. The brain antioxidant activity [content of catalase(CAT), malondialdehyde(MDA), reactive oxygen species(ROS), superoxide dismutase(SOD)], dopamine(DA) content, and mitochondrial function [content of adenosine triphosphate(ATP), NADH:ubiquinone oxidoreductase subunit B8(NDUFB8) Ⅰ activity, succinate dehydrogenase complex, subunit B(SDHB) Ⅱ activity] were detected by enzyme-linked immunosorbent assay(ELISA). The number of DA neurons in the brains of drosophilas was measured with the immunofluorescence method. The levels of NDUFB8 Ⅰ, SDHB Ⅱ, cytochrome C(Cyt C), nuclear factor-E2-related factor 2(Nrf2), heme oxygenase-1(HO-1), B-cell lymphoma/leukemia 2(Bcl-2)/Bcl-2-assaciated X protein(Bax), and cleaved caspase-3/caspase-3 in the brain were detected by Western blot. The results showed that model group [475 μmol·L~(-1) Rot(IC_(50))] demonstrated significantly low survival rate, obvious dyskinesia, small number of neurons and low DA content in the brain, high ROS level and MDA content, low content of SOD and CAT, significantly low ATP content, NDUFB8 Ⅰ activity, and SDHB Ⅱ activity, significantly low expression of NDUFB8 Ⅰ, SDHB Ⅱ, and Bcl-2/Bax, large amount of Cyt C released from mitochondria to cytoplasm, low nuclear transfer of Nrf2, and significantly high expression of cleaved caspase-3/caspase-3 compared with the control group. GS-Re(0.1, 0.4, and 1.6 mmol·L~(-1)) significantly improved the survival rate of PD drosophilas, alleviated the dyskinesia, increased DA content, reduced the loss of DA neurons, ROS level, and MDA content in brain, improved content of SOD and CAT and antioxidant activity in brain, maintained mitochondrial homeostasis(significantly increased ATP content and activity of NDUFB8 Ⅰ and SDHB Ⅱ, significantly up-regulated expression of NDUFB8 Ⅰ, SDHB Ⅱ, and Bcl-2/Bax), significantly reduced the expression of Cyt C, increased the nuclear transfer of Nrf2, and down-regulated the expression of cleaved caspase-3/caspase-3. In conclusion, GS-Re can significantly relieve the Rot-induced cerebral neurotoxicity in drosophilas. The mechanism may be that GS-Re activates Keap1-Nrf2-ARE signaling pathway by maintaining mitochondrial homeostasis, improves antioxidant capacity of brain neurons, then inhibits mitochondria-mediated caspase-3 signaling pathway, and the apoptosis of neuronal cells, thereby exerting the neuroprotective effect.

Effect of transcranial direct current stimulation on neurological injury markers and prognosis in patients with acute and severe carbon monoxide poisoning / 中华劳动卫生职业病杂志

Objective: To observe the effects of transcranial direct current stimulation (tDCS) on nerve injury markers and prognosis in patients with acute severe carbon monoxide poisoning (ASCOP) . Methods: In May 2021, 103 ASCOP patients were treated in the emergency department of Harrison International Peace Hospital of Hebei Medical University from November 2020 to January 2021. The patients were divided into two groups according to whether they received tDCS treatment. The control group (50 cases) were given oxygen therapy (hyperbaric oxygen and oxygen inhalation) , reducing cranial pressure, improving brain circulation and cell metabolism, removing oxygen free radicals and symptomatic support, and the observation group (53 cases) was treated with 2 weeks of tDCS intensive treatment on the basis of conventional treatment. All patients underwent at least 24 h bispectral index (BIS) monitoring, BIS value was recorded at the hour and the 24 h mean value was calculated. Neuron-specific enolase (NSE) and serum S100B calcium-binding protein (S100B) were detected after admission, 3 d, 7 d and discharge. Follow-up for 60 days, the incidence and time of onset of delayed encephalopathy (DEACMP) with acute carbon monoxide poisoning in the two groups were recorded. Results: The NSE and S100B proteins of ASCOP patients were significantly increased at admission, but there was no significant difference between the two groups (P=0.711, 0.326) . The NSE and S100B proteins were further increased at 3 and 7 days after admission. The increase in the observation group was slower than that in the control group, and the difference was statistically significant (P(3 d)=0.045, 0.032, P(7 d)=0.021, 0.000) ; After 14 days, it gradually decreased, but the observation group decreased rapidly compared with the control group, with a statistically significant difference (P=0.009, 0.025) . The 60 day follow-up results showed that the incidence of DEACMP in the observation group was 18.87% (10/53) , compared with 38.00% (19/50) in the control group (P=0.048) ; The time of DEACMP in the observation group[ (16.79±5.28) d] was later than that in the control group[ (22.30±5.42) d], and the difference was statistically significant (P=0.013) . Conclusion: The early administration of tDCS in ASCOP patients can prevent the production of NSE and S100B proteins, which are markers of nerve damage. and can improve the incidence and time of DEACMP.

Expression changes and clinical significance of serum neuron-specific enolase and squamous cell carcinoma antigen in lung cancer patients after radiotherapy

Abstract Objective: To explore the changes and clinical significance of serum Neuron-Specific Enolase (NSE) and Squamous Cell Carcinoma antigen (SCC) in patients with lung cancer before and after radiotherapy. Methods: 82 patients with lung cancer were treated with radiotherapy, and effective clinical intervention was given during the radiotherapy process. The patients were followed up for 1 year after radiotherapy and were divided into a recurrence and metastasis group (n = 28) and a non-recurrence and metastasis group (n = 54) according to their prognosis. Another 54 healthy volunteers examined in the present study's hospital during the same period were selected as the control group. To compare the changes of NSE and SCC levels in serum in patients with lung cancer at admission and after radiotherapy, and to explore their clinical significance. Results: After intervention, NSE and SCC levels in the serum of the two groups of patients were significantly lower than those before intervention, and the levels of CD4+ and CD4+/CD8+ were significantly higher than those before intervention (p < 0.05); the level of CD8+ was not significantly different from that before intervention (p > 0.05). And NSE and SCC levels in the intervention group were significantly lower than those in the routine group, the levels of CD4+, CD4+/CD8+ were significantly higher than those in the routine group (p < 0.05). Conclusion: NSE and SCC in serum can preliminarily evaluate the effect of radiotherapy in patients with lung cancer and have a certain predictive effect on prognosis.

Protective effect and mechanism of baicalein on hypoxia-induced cortical neuron injury in rats / 中国药房

OBJECTIVE To explore the protective effect and possible mechanism of baicalein on hypoxia-induced cortical neuron injury in rats. METHODS The cortical neurons of rats （RN-C cells） were studied and cultured under hypoxic conditions （5%CO2， 94% N2， 1%O2） for 24 hours； the effects of different concentrations of baicalein （0.01， 0.1， 1， 10， 100 μmol/L） on the survival rate of hypoxic RN-C cells were investigated； the effects of baicalein （0.1 μmol/L） on the activities of lactate dehydrogenase （LDH） and superoxide dismutase （SOD）， the content of malondialdehyde （MDA）， migration rate， apoptotic rate， cell cycle and the expressions of cleaved caspase-3， B-cell lymphoma-2 （Bcl-2） and Bcl-2 X protein （Bax） were all detected. RESULTS Compared with control group， the survival rate of cells in the hypoxia group was significantly reduced （P＜0.01）； 0.01， 0.1 and 1 μmol/L baicalein could reverse survival rate of hypoxia-induced cortical neurons （P＜0.05 or P＜0.01）. Scratch experiments showed that baicalein significantly increased the migration rate of hypoxic RN-C cells （P＜0.01）. Compared with control group， the activity of LDH in the supernatant and the content of MDA in the cells， apoptotic rate and the proportion of cells in G1 phase， were significantly increased in the hypoxia group， while SOD activity and the proportion of cells in G2+S phase was decreased significantly （P＜0.01）. The protein expressions of cleaved caspase-3 were increased significantly， while the ratio of Bcl-2/Bax in cells was significantly reduced （P＜0.05 or P＜0.01）. Compared with hypoxia group， the above indexes were all reversed significantly in baicalein group （P＜0.01）. CONCLUSIONS Baicalein can promote the proliferation and migration of cortical neurons， improve hypoxia-induced cell apoptosis and cell cycle distribution， decrease the activity of LDH in supernatant and the level of cellular lipid peroxidation， and improve antioxidant levels. Its mechanism may be related to regulating the caspase- 3/Bax/Bcl-2 pathway.

Clinical profile of genetically confirmed Spinal Muscular Atrophy (SMA) Among Filipino children less than 18 years old

@#Spinal muscular atrophy (SMA) is the most common inherited lethal disease in children. Confirmatory diagnosis is based on molecular genetic testing of survival motor neuron (SMN) genes. We aimed to describe the phenotypic presentation of Filipino infants and children with SMA based on the copy number analysis of SMN genes. Medical records of 17 Filipino children were reviewed from January 2017 to December 2019. De-identified clinical data fulfilled the diagnostic criteria defined by the International SMA Consortium. Among Filipino children, the predominant SMA type by copy number was type I having two copies of SMN2 gene. The clinical severity based on symptom onset and highest functional motor capacity attained correlated with SMN2 copy number congruent with existing data. A significant time lag between symptom onset to confirmation of genetic diagnosis was noted. Nine out of the 17 (52%) children did not have a family history of the disease, raising the possibility of mutation carriers in these families since the incidence of de novo mutations in literature is about 2%. These data offered the first epidemiological pattern of genetically confirmed SMA among Filipino children; provided additional information for genetic counselling; and an avenue to consider pre-symptomatic newborn screening and carrier testing that would change proactive measures and opportunities for therapy. These measures unavoidably will decrease the incidence and prevalence of disease in the future.

Assessment of the upper motor neuron degeneration by detailed motor homunculus cortex thickness in amyotrophic lateral sclerosis / 西安交通大学学报(医学版)

【Objective】 The involvement of upper motor neuron (UMN) degeneration is crucial to the diagnosis of amyotrophic lateral sclerosis (ALS). This study aimed to determine objective and sensitive UMN degeneration markers for an accurate and early diagnosis. 【Methods】 A total of 108 ALS patients and 90 age- and gender-matched control subjects were recruited from ALS Clinic of The First Affiliated Hospital of Xi’an Jiaotong University. The motor homunculus cortex thickness data in MRI were collected from all the participants. The clinical characteristics and UMN clinical examination of bulbar, cervical, thoracic and lumbosacral regions were collected from the ALS patients. 【Results】 Cortical thickness was significantly thinner in the ALS group than in the control group in bilateral head-face-bulbar and upper-limb areas (P<0.05). The cortical thickness of the global UMN positive group was significantly thinner than that of control groups in bilateral head-face-bulbar and upper-limb areas (P<0.05). The cortical thickness of the UMN positive group in the corresponding region was significantly thinner than that of control groups in bilateral head-face-bulbar and upper-limb areas (P<0.05). 【Conclusion】 The thinning of the motor homunculus cortex can be used as an objective marker of UMN involvement in ALS patients in clinical practice.

Neuroimaging advances in patients with amyotrophic lateral sclerosis / 西安交通大学学报(医学版)

Amyotrophic lateral sclerosis (ALS) is a multi-system neurodegenerative disease characterized with degeneration of both motor and non-motor areas. Complicated clinical manifestations and lack of objective biomarkers for upper motor neuron deficits challenged the early diagnosis of ALS. Meanwhile, heterogeneous non-motor symptoms and conflicted treatment effects exacerbated the management and therapy of the disease. The multiparametric functional MRI has the potential to address all the needs for diagnosis, management, and disease modified therapy in ALS. The present paper summarizes the research progress in both motor and non-motor impairment in ALS, as well as their potential value in visualizing disease stages and drug effect evaluation. Focusing on the heterogeneity of the disease and combining with brain and spinal cord imaging may provide direct evidence for disease diagnosis and treatment and be the priority in the future for ALS.