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Objective:To investigate the clinical, genetic, and pathological features of nemaline myopathy type 8 (NEM8) caused by KLHL40 gene variation. Methods:The clinical data, gene sequencing results, and musculoskeletal pathophysiology of two cases (a pair of twins) with NEM8 admitted to our hospital in July 2022 were collected. CNKI, VIP, Wanfang, Yiigle, PubMed, Embase, and Web of Science Database were searched with the English and Chinese terms "nemaline myopathy type 8", "nemaline body myopathy type 8", and " KLHL40" from January 2007 to February 2023. The clinical, genetic, and musculoskeletal characteristics of the NEM8 cases were summarized using the descriptive statistical analysis method. Results:(1) Case report: The mother (G2P2) of the twins (Ⅳ-2 and Ⅳ-3) was conceived by IVF-embryo transfer and delivered at 37 +1 gestational weeks. The two cases were dizygotic twins whose maternal grandmother had lip and palate cleft. The first baby (Ⅳ-1) of the woman exhibited absent left pinna, contracture at the end of both fingers, talipes equinovarus in both feet and died of respiratory failure two hours after birth. Fetal edema and fetal movement delay in the twins and varus right foot in one twin were found during pregnancy. Both cases developed intrapartum asphyxia with the clinical manifestations of generalized muscle weakness, respiratory failure, dysphagia, multiple joint contractures, and fractures. The families withdrew the treatment and the twins died after maintaining life with ventilators for 53 days after birth. Whole exome sequencing of the pedigree found c.1779G>T (p.W593C) homozygous variants of the KLHL40 gene in the twins and c.1779G>T (p.W593C) heterozygous variants of the KLHL40 gene in the parents, both were de novo. Musculoskeletal pathophysiology indicated that muscle fibers are thin and round with a fetal shape and absent rod. (2) Literature review: Among the 29 cases of NEM8, including two current cases and 27 cases retrieved from 15 papers, eight cases terminated the pregnancies, and 21 were live births; seven cases (24.1%) with positive family history; 19 cases (65.5%) were found with abnormalities during pregnancy, including abnormal fetal movements, polyhydramnios, joint contracture, and fetal edema. Of the 21 live births, 20 cases had intrapartum asphyxia, 21 had postnatal respiratory failure, 20 had generalized muscle weakness, and 19 had dysphagia. Among the 29 cases, 17 cases (58.6%) were homozygous variants of the KLHL40 gene, and 12 cases (41.4%) were compound heterozygous variants. The detection rate of c.1516A>C(p.Thr506Pro) was the highest [72.4% (21/29)], followed by c.602G>A(p.Trp201*) [17.2% (5/29)]. Out of the 15 cases who underwent musculoskeletal pathological examination, all had abnormal muscle fiber size and morphology; 10 cases had rods. Conclusions:NEM8 should be considered for those with abnormal fetal movements, polyhydramnios, joint malformation, fetal edema during the fetal period and failure to establish respiration at birth as well as postnatal generalized muscle weakness, respiratory failure, dysphagia, multiple joint contractures, and fracture. Moreover, genetic detection should be performed as soon as possible. NEM8 can be diagnosed in ones with KLHL40 gene homozygous or compound heterozygous variants and musculoskeletal pathological results of abnormal size and shape of muscle fibers, regardless of the presence of rods.
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Objective:To explore the effect of adhesion molecule nectin-1 expression on epileptic seizure and mossy fiber sprouting.Methods:(1) Adult male SD rats were randomly divided into control group ( n=6), empty vector group ( n=6) and lentivirus interfered group ( n=24), and rats in the lentivirus interfered group were further divided into 4 subgroups ( n=6) according to the time points of lentivirus injection (3, 7, 14 and 30 d after injection). The protein expression of nectin-1 in the hippocampus of rats was detected by Western blotting. (2) Another 12 male SD rats were randomly selected and divided into lentivirus epilepsy group ( n=6) and empty vector epilepsy group ( n=6). Lentivirus and empty lentivirus vector were injected into the hippocampus of the above two groups respectively, and then, pilocarpine epilepsy models were kindled; the behavior changes of these rats were recorded, and changes of mossy fiber sprouting in the hippocampus were observed by Timm staining. Results:(1) There were significant differences in hippocampal nectin-1 protein expressions in each group ( F=76.120, P=0.000); the nectin-1 expression in the 7, 14, and 30 d subgroups was significantly decreased as compared with that in the control group and empty vector group ( P<0.05). (2) The results of behavior changes showed that the times required for the lentivirus epilepsy group to be kindled successfully ([34.33±2.38] min) were significantly longer than those for the empty vector epilepsy group ([24.50±2.06] min, t=7.650, P=0.000). In terms of seizure level, the seizure level of rats in the lentivirus epilepsy group was significantly lower at each time point within one h modeling than that of rats in the empty vector epilepsy group ( P<0.05). After kindling, the time of spontaneous seizure appeared in the lentivirus epilepsy group was significantly longer than that in the empty vector epilepsy group, and the frequencies of spontaneous seizure in the lentivirus epilepsy group were significantly decreased as compared with those in the empty vector epilepsy group ( P<0.05). Timm staining scores in the lentivirus epilepsy group (3.500±0.224) were significantly lower than those in the empty vector epilepsy group (4.667±0.211, t=9.289, P=0.000). Conclusion:Inhibition of nectin-1 expression in hippocampal area of epileptic rats can delay the occurrence of epilepsy and reduce the frequencies of spontaneous seizures of epileptic rats, whose mechanism may be related to the reduction of nectin-1 in the formation of mossy fiber sprouting in abnormal neural circuits of hippocampal area.
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BACKGROUND@#Mesenchymal stem cell (MSC)-based cell transplantation is an effective means of treating chronic liver injury, fibrosis and end-stage liver disease. However, extensive studies have found that only a small number of transplanted cells migrate to the site of injury or lesion, and repair efficacy is very limited. @*METHODS@#Bone marrow-derived MSCs (BM-MSCs) were generated that overexpressed the erythropoietin (EPO) gene using a lentivirus. Cell Counting Kit-8 was used to detect the viability of BM-MSCs after overexpressing EPO. Cell migration and apoptosis were verified using Boyden chamber and flow cytometry, respectively. Finally, the anti-fibrosis efficacy of EPO-MSCs was evaluated in vivo using immunohistochemical analysis. @*RESULTS@#EPO overexpression promoted cell viability and migration of BM-MSCs without inducing apoptosis, and EPO-MSC treatment significantly alleviated liver fibrosis in a carbon tetrachloride (CCl4 ) induced mouse liver fibrosis model. @*CONCLUSION@#EPO-MSCs enhance anti-fibrotic efficacy, with higher cell viability and stronger migration ability compared with treatment with BM-MSCs only. These findings support improving the efficiency of MSCs transplantation as a potential therapeutic strategy for liver fibrosis.
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BACKGROUND@#Mesenchymal stem cell (MSC)-based cell transplantation is an effective means of treating chronic liver injury, fibrosis and end-stage liver disease. However, extensive studies have found that only a small number of transplanted cells migrate to the site of injury or lesion, and repair efficacy is very limited. @*METHODS@#Bone marrow-derived MSCs (BM-MSCs) were generated that overexpressed the erythropoietin (EPO) gene using a lentivirus. Cell Counting Kit-8 was used to detect the viability of BM-MSCs after overexpressing EPO. Cell migration and apoptosis were verified using Boyden chamber and flow cytometry, respectively. Finally, the anti-fibrosis efficacy of EPO-MSCs was evaluated in vivo using immunohistochemical analysis. @*RESULTS@#EPO overexpression promoted cell viability and migration of BM-MSCs without inducing apoptosis, and EPO-MSC treatment significantly alleviated liver fibrosis in a carbon tetrachloride (CCl4 ) induced mouse liver fibrosis model. @*CONCLUSION@#EPO-MSCs enhance anti-fibrotic efficacy, with higher cell viability and stronger migration ability compared with treatment with BM-MSCs only. These findings support improving the efficiency of MSCs transplantation as a potential therapeutic strategy for liver fibrosis.
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Aim To study the therapeutic effect of CpG-ODN, an agonist of Toll-like receptor 9 (TLR9), on hypoxic/ischemic encephapathy in neonatal rats and investigate the mechanisms.Methods Fifty healthy 7-day-old neonatal Wistar rats (in either gender, weighing 12~17g) were randomly divided into sham operation group, HIBD group, and CpG-ODN low group(0.35 mL·kg-1), CpG-ODN middle group(1.40 mL·kg-1), CpG-ODN high group(5.60 mL·kg-1).The neurological function was scored after 48h operation;ten rats of each group was executed respectively and brains tissue was taken;HE staining was used to observe the brain pathological changes.Western blot assay was used to detect the expressions of TLR9 and phosphor-p38 mitogen-activated protein kinases(p-p38 MAPK), and enzyme linked immunosorbent assay (ELISA) method was adopted to detect TNF-α expression.Results The CpG-ODN low, middle group were improved in impairment significantly compared with the HIBD group, and the brain pathological change was lessened, while the CpG-ODN high group was impaired significantly compared with the HIBD group (P<0.05), and brain pathological change was sharpened.Western blot showed the up-regulation in TLR9 and p-p38 MAPK and a significant increase of the expression of TNF-α in the brain tissue in CpG-ODN group with statistical difference in HIBD group and sham operation group(P<0.05).Conclusions The neuro-behavioral score and nervous system function can be improved and the hypoxic/ischemic brain damage can be reduced in neonatal rats in the CpG-ODN low, middle group.The protective mechanisms may be suitably via activating p38 MAPK signaling pathway to promote p38 MAPK phosphory1ation and up-regulation of the expression of TNF-α in the brain tissue of rats.
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Objective To investigate the association of single nucleotide polymorphisms (SNPs) in COX-2 with aspirin resistance in Chinese cerebral infarction patients. Methods A total of 150 Chinese cerebral infarction patients were recruited. Platelet aggregation response was measured by light transmission aggregometry method and four SNPs located in COX2 gene were genotyped by sequencing method. Results Sixty patients of the total were classified as aspirin non-responders. For clinical variables , concentrations of high homocysteine and the frequency of recurrence cerebral infarction were significantly higher in aspirin non-responders when compared with aspirin responders. Univariate analysis of SNPs showed that rs20417 , rs689465 and rs689466 were significantly associated with aspirin resistance. Multivariate analysis indicated that after adjusting other SNPs and clinical risk factors, rs20417 and rs689466 were still significantly associated with aspirin resistance. Conclusions Rs689466 is significantly associated with aspirin resistance in Chinese cerebral infarction patients even after the adjustment of rs20417. By combining rs689466 , rs20417 and other clinical risk factors , we may better classify the aspirin non-responders from aspirin responders.
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Objective To investigate the effect of phosphatidylinesitol-3 kinase/serine threonine kinase (PI3K/Akt) signaling pathway on expression of beta-site amyloid precursor protein cleaving enzyme-1 (BACE1) in the hippocampus neurons of rat brain. Methods Forty SD rats were randomly divided into 4 groups: blank control group, sham-operated group, insulin group and wortmannin group. Insulin or the specific inhibitor of PI3K, wortmannin was injected into hippocampus neurons to activate or inhibit the signaling pathway in insulin group or wortmannin group, respectively. Immunoprecipitation and Western blot were used to analyze the proteins levels of PI3K/Akt and BACE1. Results In insulin treatment group,among the proteins downstream of signaling pathway, expression of Akt increased (0. 952±0.060 vs 0.835±0.029,t=4.9150, P=0.0001), phospho-Akt set473 increased (0.800±0.075 vs 0.657± 0.025,t=4.5598, P=0.0002), phospho-GSK-3α decreased (0.604±0.062 vs 0.726±0.041, t= 3.5871, P=0.0018 ), and the expression of mature BACE1 and β-CTF significantly decreased. In wortmannin group, the expression of Akt and phospho-Akt ser473 were inhibited; phospho-GSK-3α increased ; mature BACEI (1.004±0.096) and β-CTF (1.031±0.048) increased (t=11.5980, P= 0.0000 and t =4.2194, P =0.0004, respectively). Conclusions PI3K/Akt signaling pathway might effect the expression of BACE1, in which impaired signaling pathway may cause the amyloid precursor protein to be easily processed by BACE1, and thus involves the pathology of Alzheimer' s disease.
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OBJECTIVE: To introduce the research progression of fMRI in brain functional localization in China or abroad in the recent 15 years, so as to further comprehend the effect and value of fMRI.DATA SOURCES: A computer-based online search of Medline database was undertaken to identify English articles about fMRI published from 1990 to 2005 with the keywords "functional magnetic resonance imaging (fMRI), brain".STUDY SELECTION: The articles about experimental studies of fMRI articles irrelative to motor function, sensory function, hearing function, visuEnglish title.DATA EXTRACTION: Totally 6 144 relevant articles were collected, 18 articles were involved according to the inclusive criteria, and the others were excluded. cles about sensory function, including 1 about simple tactile stimulation,ry function, including 2 about simple visual stimulation, and 1 about binoction, including about hearing stimulation by various methods, and 1 about comparison between normal and abnormal subjects by the same stimulation.language function, 1 about visual language function, and 1 about listening basic principle.CONCLUSION: fMRI was more accurate, convenient and direct than other methods. It can not only show localization, size and dimension of the activated areas in different cerebral regions, but also show accurate anatomical position. Many aspects still need to be consummated, for example, exploration of the stimulating method, design of advanced hardware, post processing of the image and the effect of visualization. With the development of hardware, software and the endless endeavor of scientists, fMRI dooms to play an important role in illustrating the function of human brain.
