VX-509 attenuates the stemness characteristics of colorectal cancer stem-like cells by regulating the epithelial-mesenchymal transition through Nodal/Smad2/3 signaling

BACKGROUND Colorectal cancer stem cells(CCSCs)are heterogeneous cells that can self-renew and undergo multidirectional differentiation in colorectal cancer(CRC)patients.CCSCs are generally accepted to be important sources of CRC and are responsible for the progression,metastasis,and therapeutic resistance of CRC.Therefore,targeting this specific subpopulation has been recognized as a promising strategy for overcoming CRC.AIM To investigate the effect of VX-509 on CCSCs and elucidate the underlying mechanism.METHODS CCSCs were enriched from CRC cell lines by in conditioned serum-free medium.Western blot,Aldefluor,transwell and tumorigenesis assays were performed to verify the phenotypic characteristics of the CCSCs.The anticancer efficacy of VX-509 was assessed in HCT116 CCSCs and HT29 CCSCs by performing cell viability analysis,colony formation,sphere formation,flow cytometry,and western blotting assessments in vitro and tumor growth,immunohistochemistry and immunofluorescence assessments in vivo.RESULTS Compared with parental cells,sphere cells derived from HCT116 and HT29 cells presented increased expression of stem cell transcription factors and stem cell markers and were more potent at promoting migration and tumori-genesis,demonstrating that the CRC sphere cells displayed CSC features.VX-509 inhibited the tumor malignant biological behavior of CRC-stem-like cells,as indicated by their proliferation,migration and clonality in vitro,and suppressed the tumor of CCSC-derived xenograft tumors in vivo.Besides,VX-509 suppressed the CSC character-istics of CRC-stem-like cells and inhibited the progression of epithelial-mesenchymal transition(EMT)signaling in vitro.Nodal was identified as the regulatory factor of VX-509 on CRC stem-like cells through analyses of differen-tially expressed genes and CSC-related database information.VX-509 markedly downregulated the expression of Nodal and its downstream phosphorylated Smad2/3 to inhibit EMT progression.Moreover,VX-509 reversed the dedifferentiation of CCSCs and inhibited the progression of EMT induced by Nodal overexpression.CONCLUSION VX-509 prevents the EMT process in CCSCs by inhibiting the transcription and protein expression of Nodal,and inhibits the dedifferentiated self-renewal of CCSCs.

1例利培酮致高泌乳素血症患者的药学监护

目的分析服用利培酮导致高泌乳素血症的病例,为临床安全、合理用药提供参考。方法对1例服用利培酮导致高泌乳素血症进行个体化治疗方案调整、药学监护、用药宣教,并结合相关文献,总结高泌乳素血症的临床表现、产生机制、不良结果、治疗方案及药学监护要点。结果本例为伴有精神病性症状的重度抑郁发作患者,服用利培酮治疗精神疾病的第17天出现溢乳、月经紊乱、血清泌乳素水平升高;通过联用阿立哌唑治疗,患者的血清泌乳素水平逐渐下降,溢乳消失。结论抗精神病药物导致的高泌乳血症不良反应存在羞耻感和隐蔽性,用药期间应加强患者的监护、用药宣教,定期检查血清泌乳素水平,做到早识别、早调整治疗方案。

莫西沙星致患者QT间期延长的药物不良反应分析

目的:分析莫西沙星致患者QT间期延长的发生和处置过程,为临床莫西沙星的用药安全提供参考。方法与结果:患者(男,76岁)因咳嗽、咳痰多日且有加重而入院治疗,入院时其胸部CT、肺部听诊和感染指标提示其存在肺部感染,遂予莫西沙星+头孢哌酮-舒巴坦钠抗感染治疗;第2天开始,行心电监测,并提示正常(QT/QTc388/439 ms);第3天,患者诉胸闷,再查心电图,提示QT间期延长(QT/QTc 467/529 ms);14 d后,停用莫西沙星;又2 d后,患者心电图检查提示正常(QT/QTc 358/421 ms);事后,诺氏评估量表提示莫西沙星与QT间期延长的关联性为“很可能”。结论:QT间期延长是莫西沙星较为常见的药物不良反应,临床在使用莫西沙星时应做好相应的监测,以便风险发生时进行及时的处置,从而保证患者的用药安全。

T2 Mapping and Fat Quantification of Thigh Muscles in Children with Duchenne Muscular Dystrophy

Quantitative magnetic resonance image(MRI)in individual muscles may be useful for monitoring disease progression in Duchenne muscular dystrophy(DMD).The purpose of this study w批to measure丁2 relaxation time of thigh muscles in children with DMD and healthy boys,and to correlate the T2 relaxation time of muscles with the fat fraction(FF)at quantitative magnetic resonance and results of clinical assessment.Thirty-two boys with DMD and 18 healthy boys were evaluated with T2 mapping and three-point Dixon MRI.Age,body mass index(BMI),muscle strength assessment,timed functional tests(time to walk or run 10 metres,rise from the floor and ascend four stairs),and the North Star Ambulatory Assessment(NSAA)were evaluated.Spearman’s correlation was used to assess the relationships between FF and clinical assessments and T2 relaxation time.The mean T2 relaxation time of thigh muscles in DMD was significantly longer than that in the control group(P<0.05),except for the gracilis(P=0.952).The gracilis,sartorius and adductor longus were relatively spared by fatty infiltration in DMD patients.The T2 relaxation time was correlated significantly with the mean FF in all muscles.Age,BMI,total muscle strength score,timed functional tests and NSAA were significantly correlated with the overall mean T2 relaxation time.T2 mapping may prove clinically useful in monitoring muscle changes as a result of the disease process and in predicting the outcome of DMD patients.

Simulations on the multi-shell target ignition driven by radiation pulse in Z-pinch dynamic hohlraum

We present the first simulation results of a multi-shell target ignition driven by Z-pinch dynamic hohlraum radiation pulse.The radiation pulse is produced with a special Z-pinch dynamic hohlraum configuration,where the hohlraum is composed of a single metal liner,a low-Z plastic foam,and a high-Z metallic foam.The implosion dynamics of a hohlraum and a multi-shell target are investigated separately by the one-dimensional code MULTI-IFE.When the peak drive current is 50 MA,simulations suggest that an x-ray pulse with nearly constant radiation temperature(-310 eV)and a duration about 9 ns can be obtained.A small multi-shell target with a radius of 1.35 mm driven by this radiation pulse is able to achieve volumetric ignition with an energy gain(G)about 6.19,where G is the ratio of the yield to the absorbed radiation.Through this research,we better understand the effects of non-uniformities and hydrodynamics instabilities in Z-pinch dynamic hohlraum.

Comparison and analysis of snow cover data based on dif-ferent definitions of snow cover days

In order to analyze the differences between the two snow cover data, the snow cover data of 884 meteorological stations in China from 1951 to 2005 are counted. The data include days of visual snow observation, snow depth, and snow cover durations, which vary according to different definitions of snow cover days. Two series of data, as defined by ＂snow depth＂ and by ＂weather obser- vation,＂ are investigated here. Our results show that there is no apparent difference between them in east China and the Xinjiang region, but in northeast China and the Tibetan Plateau the ＂weather observation＂ data vary by more than 10 days and the ＂snow depth＂ data vary by 0.4 cm. Especially in the Tibetan Plateau, there are at least 15 more days of＂weather observation＂ snow in most areas （sometimes more than 30 days）. There is an obvious difference in the snow cover data due to bimodal snowfall data in the Tibetan Plateau, which has peak snowfalls from September to October and from .April to May. At those times the temperature is too high for snow cover fol：mation mad only a few days have trace snow cover. Also, the characteristics and changing trends of snow cover are analyzed here based on the snow cover data of nine weather stations iri the northeast region of the Tibetan Plateau, by the Mann-KendaU test. The results show significantly fewer days of snow cover and shorter snow dtwations as defined by ＂snow depth＂ compared to that as defined by ＂weather observation.＂ Mann-Kendall tests of both series of snow cover durations show an abrupt change in 1987.

Effective extraction of photoneutron cross-section distribution using gamma activation and reaction yield ratio method

Photoneutron cross-section(PNCS)data are important in various current and emerging applications.Although a few sophis-ticated methods have been developed,there is still an urgent need to study the PNCS data.In this study,we propose the extraction of PNCS distributions using a combination of gamma activation and reaction yield ratio methods.To verify the validity of the proposed extraction method,experiments for generating^(62,64)Cu and^(85m,87m)Sr isotopes via laser-induced pho-toneutron reactions were performed,and the reaction yields of these isotopes were obtained.Using the proposed extraction method,the PNCS distributions of^(63)Cu and^(86)Sr isotopes(leading to^(85m)Sr isotope production)were successfully extracted.These extracted PNCS distributions were benchmarked against available PNCS data or TALYS calculations,demonstrating the validity of the proposed extraction method.Potential applications for predicting the PNCS distributions of the 30 iso-topes are further introduced.We conclude that the proposed extraction method is an effective complement to the available sophisticated methods for measuring and evaluating PNCS data.

Influence of stationary driven helical current on the m=2/n=1 resistive tearing mode

The influence of stationary driven helical current on tearing mode instability in the m=2/n=1 rational surface is explored numerically using resistive magnetohydrodynamic simulation in cylindrical geometry.The results indicate that the flip instabilities result from the sustained injection of the sufficiently strong helical current driven in the island O-point.The driven helical current induces high order harmonics of instabilities due to the delay of suppressing timing and the increase of its current intensity.With the appropriate current density values,the development of the perturbed kinetic energy can be limited and the occurrence of the flip instabilities can be delayed for a long time.The radial deviation of the current deposition can lead to poor inhibition effect,and the effect of current bias on the boundary is greater than that on the axis.

Neurofilament 200 expression in a rat model of complete spinal cord injury following growth-associated protein-43 treatment

BACKGROUND： Growth-associated protein-43 （GAP-43） expression in the nervous system has been demonstrated to promote neural regeneration, neuronal growth and development, as well as synaptic reconstruction. Neurofilament 200 （NF200） expression could reflect degree of injury and repair in injured spinal axons. OBJECTIVE： To observe NF200 expression changes in a rat model of complete spinal cord injury following GAP-43 treatment and to explore the effects of GAP-43 following spinal cord injury. DESIGN, TIME AND SETTING： A randomized, controlled, animal experiment was performed at the Laboratory of Histology and Embryology of Kunming Medical University between March 2007 and October 2008. MATERIALS： GAP-43 and GAP-43 antibody were provided by Beijing Boao Biology, China; mouse anti-rat NF200 antibody was purchased from Chemicon, USA. METHODS： Female, 8-week-old, Sprague Dawley rats were randomly assigned into three groups following complete spinal cord injury, with 20 animals in each group： GAP-43 antibody, GAP-43, and model groups. In addition, each group was subdivided into four subgroups according to sampling time after modeling, Le., 3-, 5-, 9-, and 15-day groups, with 5 rats in each group. GAP-43 antibody or GAP-43 was injected into injury sites of the spinal cord, 5 μg/0.2 mL, respectively, twice daily for three consecutive days, followed by three additional days of injection, once daily. The model group did not receive any treatment following injury. MAIN OUTCOME MEASURES： NF200 expression in the damaged spinal area at different stages was detected by immunohistochemistry; lower limb motion function following injury was evaluated using the Basso, Beattie and Bresnahan （BBB） locomotor rating scale. RESULTS： NF200 expression was significantly reduced in the GAP-43 antibody group, compared with GAP-43 and model groups, at 3 and 5 days after spinal cord injury （P 〈 0.05）. In addition, the model group expressed significantly less NF200 than the GAP-43 group （P 〈 0.05）. BBB scores from the GAP-43 antibody and model groups were remarkably less than the GAP-43 group （P 〈 0.05）. At 9 and 15 days of injury after drug withdrawal, NF200 expression was increased in the GAP-43 antibody group, and NF200 expression and BBB scores in the GAP-43 antibody and GAP-43 groups were significantly greater than in the model group （P 〈 0.05）. In particular, the GAP-43 group exhibited greater BBB scores than the GAP-43 antibody group at day 9 （P 〈 0.05）. CONCLUSION： GAP-43 promoted NF200 expression and recovery of lower limb function. Early administration of GAP-43 antibody produced reversible nerve inhibition, which was rapidly restored following withdrawal.

Gene Therapy Activates Retinal Pigment Epithelium Cell Proliferation for Age-related Macular Degeneration in a Mouse Model

Objective Age-related macular degeneration(AMD)is a degenerative retinal disease.The degeneration or death of retinal pigment epithelium(RPE)cells is implicated in the pathogenesis of AMD.This study aimed to activate the proliferation of RPE cells in vivo by using an adeno-associated virus(AAV)vector encodingβ-catenin to treat AMD in a mouse model.Methods Mice were intravitreally injected with AAV2/8-Y733F-VMD2-β-catenin for 2 or 4 weeks,andβ-catenin expression was measured using immunofluorescence staining,real-time quantitative reverse transcription polymerase chain reaction(PCR),and Western blotting.The function ofβ-catenin was determined using retinal flat mounts and laser-induced damage models.Finally,the safety of AAV2/8-Y733F-VMD2-β-catenin was evaluated by multiple intravitreal injections.Results AAV2/8-Y733F-VMD2-β-catenin induced the expression ofβ-catenin in RPE cells.It activated the proliferation of RPE cells and increased cyclin D1 expression.It was beneficial to the recovery of laser-induced damage by activating the proliferation of RPE cells.Furthermore,it could induce apoptosis of RPE cells by increasing the expression of Trp53,Bax and caspase3 while decreasing the expression of Bcl-2.Conclusion AAV2/8-Y733F-VMD2-β-catenin increasedβ-catenin expression in RPE cells,activated RPE cell proliferation,and helped mice heal from laser-induced eye injury.Furthermore,it could induce the apoptosis of RPE cells.Therefore,it may be a safe approach for AMD treatment.

生物启发和生物工程核酸药物载体

核酸药物具有直接作用于致病基因的优势,在治疗各种疾病方面具有巨大潜力.然而,由于核酸药物需要克服多重生理障碍才能到达靶点,因此在实际应用中面临诸多困难和挑战.为了提高核酸药物的稳定性和递送效率,研究人员开始利用生物工程化和生物启发材料所具有的内源性递送生物大分子的能力来递送核酸药物.本文重点介绍核酸药物递送过程中需要克服的生物障碍,以及生物工程和生物启发材料在核酸药物递送中的优势和应用.通过利用这些先进的生物材料,研究人员有望提高核酸药物的疗效,为疾病治疗提供新的解决方案.

四川锦屏隧道细菌群落特征及其组装过程

深地生物圈微生物群落组成及其潜在功能研究对于探索生命生存极限,安全开发利用地下空间具有重大意义。锦屏隧道位于四川省凉山彝族自治州,上覆地层为三叠纪的大理岩和灰岩,其最大埋深可达2525 m,该隧道的开挖为研究陆地深地生物圈微生物群落提供了宝贵的机会。为了探究锦屏隧道细菌群落组成、潜在功能及群落组装机制,分别采集锦屏隧道内松散的表层岩壁和沉积物样本进行16S rRNA扩增子的高通量测序分析。结果表明锦屏隧道细菌群落具有较高的多样性,香农威纳指数变化范围为5.19~8.71。群落组成上变形菌门(Proteobacteria)在所有样本中占主导地位,其次为放线菌门(Actinobacteria)和浮霉菌门(Planctomycetes)。纲水平上,γ-变形菌纲(Gammaproteobacteria)占绝对主导,在大部分样本中的相对丰度超过61.4%,α-变形菌纲(Alphaproteobacteria)和β-变形菌纲(Betaproteobacteria)也有较高的相对丰度。代谢功能上,锦屏隧道中化能异养细菌类群在锦屏隧道中占绝对主导,而以H2和CH_(4)为能源进行代谢的细菌类群相对丰度极低,经岩溶裂隙进入隧道内的地表有机质是这些异养细菌类群的潜在物质和能量来源。此外,与深地基岩和地表土壤环境研究结果对比发现,锦屏隧道内动物寄生及人类潜在病原体细菌类群的相对丰度较高(分别达到6.4%和6.3%),这表明深地生物圈潜在的生物安全隐患及人类活动对深地生物圈的扰动不可忽视。锦屏隧道细菌群落的共发生网络具有良好的模块性,Ralstonia、Planctomyces和Woodsholea是维持网络结构稳定的关键类群。群落构建分析表明锦屏隧道细菌群落构建以确定性过程为主导,其中异质性选择贡献最大,在岩壁微生物群落构建中占52.8%,对沉积物微生物群落构建以及对所有样本微生物群落构建的贡献分别为61.1%和61.4%,这可能是由锦屏隧道黑暗无光且寡营养的极端环境特点所决定。该研究结果揭示了四川锦屏隧道深地生物圈细菌的群落组成以及化能异养为主的生态功能特征,明确了环境条件对细菌群落构建的决定性作用,也为更好地开发利用锦屏地下空间提供了重要的生物安全参考。

Modeling CADASIL vascular pathologies with patient-derived induced pluripotent stem cells

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy(CADASIL)is a rare hereditary cerebrovascular disease caused by a NOTCH3 mutation.However,the underlying cellular and molecular mechanisms remain unidentified.Here,we generated non-integrative induced pluripotent stem cells(iPSCs)from fibroblasts of a CADASIL patient harboring a heterozygous NOTCH3 mutation(c.3226C>T,p.R1076C).Vascular smooth muscle cells(VSMCs)differentiated from CADASIL-specific iPSCs showed gene expression changes associated with disease phenotypes,including activation of the NOTCH and NF-kB signaling pathway,cytoskeleton disorganization,and excessive cell proliferation.In comparison,these abnormalities were not observed in vascular endothelial cells(VECs)derived from the patients iPSCs.Importantly,the abnormal upregulation of NF-kB target genes in CADASIL VSMCs was diminished by a NOTCH pathway inhibitor,providing a potential therapeutic strategy for CADASIL.Overall,using this iPSCbased disease model,our study identified clues for studying the pathogenic mechanisms of CADASIL and developing treatment strategies for this disease.

Modeling xeroderma pigmentosum associated neurological pathologies with patients-derived iPSCs

Xeroderma pigmentosum （XP） is a group of genetic disorders caused by mutations of XP-associated genes, resulting in impairment of DNA repair. XP patients frequently exhibit neurological degeneration, but the underlying mechanism is unknown, in part due to lack of proper disease models. Here, we generated patientspecific induced pluripotent stem cells （iPSCs） harboring mutations in five different XP genes including XPA, XPB, XPC, XPG, and XPV. These iPSCs were further differentiated to neural cells, and their susceptibility to DNA damage stress was investigated. Mutation of XPA in either neural stem cells （NSCs） or neurons resulted in severe DNA damage repair defects, and these neural cells with mutant XPA were hyper-sensitive to DNA damage-induced apoptosis. Thus, XP-mutant neural cells represent valuable tools to clari the molecular mechanisms of neurological abnormalities in the XP patients.

Muscle Magnetic Resonance Imaging for the Differentiation of Multiple AcyI-CoA Dehydrogenase Deficiency and Immune-mediated Necrotizing Myopathy

Background： Clinically, it is difficult to differentiate multiple acyl-CoA dehydrogenase deficiency （MADD） from immune-mediated necrotizing myopathy （IMNM） because they display similar symptoms. This study aimed to determine whether muscle magnetic resonance imaging （MRI） could be used for differential diagnosis between MADD and IMNM. Methods： The study evaluated 25 MADD patients, confirmed by muscle biopsy and ETFDH gene testing, and 30 IMNM patients, confirmed by muscle biopsy. Muscles were assessed for edema and fatty replacement using thigh MRI （tMRI）. Degrees and distribution patterns of fatty infiltration and edema in gluteus maximus and thigh muscles were compared. Results： Total fatty infiltration and edema scores （median, [Q 1, Q3]） were 4.00 （1.00, 15.00） and 0 （0, 4.00） in MADD and 14.50 （8.00, 20.75） and 22.00 （16.75, 32.00） in IMNM, respectively, which were significantly more severe in IMNM than that in MADD （P = 0.000 and P = 0.004~ respectively）. Edema scores tbr gluteus maximus, long head of biceps femoris, and semimembranosus were significantly higher in IMNM than in MADD （all P = 0.000）. Fatty infiltration scores for anterior and medial compartments were significantly more severe in IMNM than that in MADD （all P = 0.000）. Conclusion： Different patterns of muscle involvement on tMRI can contribute to differential diagnosis between MADD and IMNM when clinical suspicions alone are insufficient, thereby reducing the need for muscle biopsy.

CRISPR/Cas9-mediated targeted gene correction in amyotrophic lateral sclerosis patient iPSCs

Amyotrophic lateral sclerosis （ALS） is a complex neu- rodegenerative disease with cellular and molecular mechanisms yet to be fully described. Mutations in a number of genes including SOD1 and FUS are associated with familial ALS. Here we report the generation of induced pluripotent stem cells （iPSCs） from fibroblasts of familial ALS patients bearing SOD1＋1A27~c and FUS＋/GISe6A mutations, respectively. We further gener- ated gene corrected ALS iPSCs using CRISPR/Cas9 system. Genome-wide RNA sequencing （RNA-seq） analysis of motor neurons derived from SOD1＋~A272c and corrected iPSCs revealed 899 aberrant transcripts. Our work may shed light on discovery of early biomarkers and pathways dysregulated in ALS, as well as provide a basis for novel therapeutic strategies to treat ALS.

Levetiracetam administration is correlated with lower mortality in patients with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes: a retrospective study

Background:Studies on the relationship between antiepileptic drug (AED) administration and clinical outcomes in patients with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) remain scarce. Levetiracetam (LEV) is an AED that is neuroprotective in various neurologic disorders. This study aimed to determine the impact of LEV on the outcome of MELAS.Methods:A retrospective, single-center study was performed based on a large cohort of patients with MELAS with a history of seizures (n=102). Decisions on antiepileptic therapies were made empirically. Patients were followed up for 1 to 8 years (median, 4 years) and divided into 2 groups based on whether LEV was administered (LEV or non-LEV). The modified Rankin scale (mRS) scores and mortality risks were analyzed in all patients.Results:LEV, carbamazepine, benzodiazepines, topiramate, oxcarbazepine, valproate, and lamotrigine were administered in 48, 37, 18, 13, 11, 9, and 9 patients, singly or in combination, respectively. The mean mRS score of the LEV group (n=48) was lower than that of the non-LEV group (n=54;mean±standard deviation, 2.79±1.47 vs. 3.83±1.93, P=0.006) up to the end of the study. Nevertheless, there was no difference in the proportion of subjects without disability (mRS ranging 0-1) between the groups (P=0.37). The multivariate regressions revealed that LEV treatment was associated with lower mRS scores (odds ratio 0.32, 95% confidence interval [CI] 0.15-0.68, P=0.003) and mortality rates (hazard ratio 0.24, 95% CI 0.08-0.74, P=0.013). There was a significant difference in the Kaplan-Meier survival curves between the groups (χ^2=4.29, P=0.04).Conclusions:The LEV administration is associated with lower mortality in patients with MELAS in this retrospective study. Further laboratory research and prospective cohort studies are needed to confirm whether LEV has neuroprotective effects on patients with mitochondrial diseases.

Dysferlin Gene Mutation Spectrum in a Large Cohort of Chinese Patients with Dysferlinopathy

Background：Dysferlinopathy is caused by mutations in the dysferlin （DYSF） gene.Here,we described the genetic features of a large cohort of Chinese patients with this disease.Methods：Eighty-nine index patients were included in the study.DYSF gene analysis was performed by Sanger sequencing in 41 patients and targeted next generation sequencing （NGS） in 48 patients.Multiplex ligation-dependent probe amplification （MLPA） was performed to detect exon duplication/deletion in patients with only one pathogenic mutation.Results：Among the 89 index patients,79 patients were demonstrated to carry two disease-causing （73 cases） or possibly disease-causing mutations （6 cases）,including 26 patients with homozygous mutations.We identified 105 different mutations,including 59 novel ones.Notably,in 13 patients in whom only one pathogenic mutation was initially found by Sanger sequencing or NGS,3 were further identified to carry exon deletions by MLPA.The mutations identified in this study appeared to cluster in the N-terminal region.Mutation types included missense mutations （30.06%）,nonsense mutations （1 7.18%）,frameshift mutations （30.67%）,in-frame deletions （2.45%）,intronic mutations （17.79%）,and exonic rearrangement （1.84%）.No genotype-phenotype correlation was identified.Conclusions：DYSF mutations in Chinese patients clustered in the N-terminal region of the gene.Exonic rearrangements were found in 23% of patients with only one pathogenic mutation identified by Sanger sequencing or NGS.The novel mutations found in this study greatly expanded the mutational spectrum of dysferlinopathy.

“Target” and “Sandwich” Signs in Thigh Muscles have High Diagnostic Values for Collagen VI-related Myopathies

Background： Collagen Vl-related myopathies are autosomal dominant and recessive hereditary myopathies, mainly including Ullrich congenital muscular dystrophy （UCMD） and Bethlem myopathy （BM）. Muscle magnetic resonance imaging （MRI） has been widely used to diagnosis muscular disorders. The purpose of this study was to evaluate the diagnostic value of thigh muscles MRI for collagen VI-related myopathies. Methods： Eleven patients with collagen VI gene mutation-related myopathies were enrolled in this study. MRI of the thigh muscles was performed in all patients with collagen VI gene mutation-related myopathies and in 361 patients with other neuromuscular disorders （disease controls）. Tl-weighted images were used to assess fatty infiltration of the muscles using a modified Mercuri＇s scale. We assessed the sensitivity and specificity of the MRI features of collagen Vl-related myopathies. The relationship between fatty infiltration of muscles and specific collagen VI gene mutations was also investigated. Results： Eleven patients with collagen VI gene mutation-related rnyopathies included six UCMD patients and five BM patients. There was no significant difference between UCMD and BM patients in the fatty infiltration of each thigh muscle except sartorius （P = 0.033）： theretbre, we combined the UCMD and BM data. Mean fatty infiltration scores were 3.1 and 3.0 in adductor magnus and gluteus maximus, while the scores were 1.3, 1.3, and 1.5 in gracilis, adductor longus, and sartorius, respectively. A “target” sign in rectus femoris （RF） was present in seven cases, and a “sandwich” sign in vastus lateralis （VL） was present in ten cases. The “target” and “sandwich” signs had sensitivities of 63.6% and 90.9% and specificities of 97.3% and 96,9% for the diagnosis of collagen Vl-related myopathies, respectively. Fatty infiltration scores were 2.0-3.0 in seven patients with mutations in the triple-helical domain, and 1.0-1.5 in three of four patients with mutations in the N- or C-domain of the collagen VI genes. Conclusions： The “target” sign in RF and “sandwich” sign in VL are common MRI features and are useful for the diagnosis of collagen VI-related myopathies. The severity of fatty infiltration of muscles may have a relationship with the mutation location of collagen VI gene.

Muscle Magnetic Resonance Imaging in Patients with Various Clinical Subtypes of LMNA-Related Muscular Dystrophy

Background： LMNA-related muscular dystrophy can manifest in a wide variety of disorders, including Emery-Dreifuss muscular dystrophy （EDMD）, limb-girdle muscular dystrophy （LGMD）, and LMNA-associated congenital muscular dystrophy （L-CMD）. Muscle magnetic resonance imaging （MRI） has become a useful tool in the diagnostic workup of patients with muscle dystrophies. This study aimed to investigate whether there is a consistent pattern of MRl changes in patients with LMNA mutations in various muscle subtypes. Methods： Twenty-two patients with LMNA-related muscular dystrophies were enrolled in this study. M RI of the thigh and/or calf muscles was performed in them. The muscle MRI features of the three subtypes were compared by the Mann-Whitney U-test. The relationship between the clinical and MRI findings was also investigated by Spearman＇s rank analyses. Results： The present study included five EDMD, nine LGMD, and eight L-CMD patients. The thigh muscle MRI revealed that the fatty infiltration of the adductor magnus, semimembranosus, long and short heads of the biceps femoris, and vasti lnuscles, with relative sparing of the rectus femoris, was the predominant change observed in the EDMD, LGMD, and advanced-stage L-CMD phenotypes, ahhough the involvement of the vasti muscles was not prominent in the early stage of L-CMD. At the level of the call; six patients （one EDMD, four LGMD, and one L-CMD） also showed a similar pattern, in which the soleus and the medial and lateral gastrocnemius muscles were most frequently observed to have fatty infiltration. The fatty infiltration severity demonstrated higher scores associated with disease progression. with a corresponding rate of 1.483 ＋ 0.075 × disease dnration （X） （r = 0.444, P - 0.026）. It was noteworthy that in six L-CMD patients with massive inflammatory cell infiltration in muscle pathology, no remarkable edema-like signals were observed in muscle MRI. Conclusions： EDMD, LGMD and advanced-staged L-CMD subtypes showed similar pattern of muscle MRI changes, while early-staged L-CMD showed somewhat different changes. Muscle MRI of L-CMD with a nluscular dystrophy pattern in MRI provided important clues for differentiating it from childhood inflammatory myopathy. The fatty infiltration score could be used as a reliable biomarker for outcome measure of disease progression.