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.

Noninvasive tools based on immune biomarkers for the diagnosis of central nervous system graft-vs-host disease:Two case reports and a review of the literature

BACKGROUND Central nervous system graft-vs-host disease(CNS-GVHD)is a rare cause of CNS disorders after allogeneic hematopoietic stem cell transplantation.Currently,establishing a diagnosis of CNS-GVHD is challenging because the diagnostic criteria and diagnostic methods are not well defined and many confounding factors need to be ruled out.CASE SUMMARY Here,we present two patients with CNS-GVHD.Both patients with a history of acute GVHD or chronic GVHD developed neurological symptoms that could not be explained by other causes,and had abnormal cerebrospinal fluid(CSF)studies as determined by CSF and blood immune biomarker examinations,suggestive of suspected CNS-GVHD.Due to the lack of specific magnetic resonance imaging abnormalities and the rapid clinical deterioration of the patients,we did not attempt to perform a brain biopsy,but prompted the initiation of empirical immunosuppressive therapy.In view of the rapid and favorable response to local and systematic immunosuppressive treatment and the aforementioned neurologic manifestations together with CSF abnormalities and other negative findings,a final diagnosis of CNS-GVHD was made.CONCLUSION CSF and blood immune biomarker examinations facilitated the diagnosis of CNSGVHD,which are particularly suitable for patients who are critically ill and require urgent treatment and for those who are unsuitable for invasive diagnostic procedures.

Varicella-zoster virus meningitis with hypoglycorrhachia: A case report

BACKGROUND Varicella-zoster virus(VZV)is a common viral infection,but meningitis is a rare complication of VZV infection.The cerebrospinal fluid glucose of viral meningitis is usually within the normal range,which is different from bacteria,fungi,and cancerous meningitis.This paper reports a case of VZV meningitis with hypoglycorrhachia and the relevant literature was reviewed.CASE SUMMARY We report a case of an immunocompetent 39-year-old male,presenting with severe headache and fevers,without meningeal signs or exanthem,found to have VZV meningitis by the metagenomic next-generation sequencing of cerebrospinal fluid.The cerebrospinal fluid analysis revealed hypoglycorrhachia(cerebrospinal fluid glucose of 2.16)and he was treated successfully with intravenous acyclovir.Our literature review identified only ten cases diagnosed with VZV meningitis with hypoglycorrhachia previously reported to date in the English literature whose cerebrospinal fluid glucose was from 1.6 to 2.7mmol/L,with a ratio of cerebrospinal fluid to serum glucose from 0.30 to 0.49.CONCLUSION Although rare,the cerebrospinal fluid of patients with VZV meningitis may have hypoglycorrhachia,which broadens the understanding of the disease.

Prehospital Identification of Stroke Subtypes in Chinese Rural Areas

Background： Differentiating intracerebral hemorrhage （ICH） from cerebral infarction as early as possible is vital tbr the timely initiation of different treatments. This study developed an applicable model for the ambulance system to differentiate stroke subtypes. Methods： From 26,163 patients initially screened over 4 years, this study comprised 1989 consecutive patients with potential first-ever acute stroke with sudden onset of the focal neurological deficit, conscious or not, and given ambulance transport for admission to two county hospitals in Yutian County of Hebei Province. All the patients underwent cranial computed tomography （CT） or magnetic resonance imaging to confirm the final diagnosis based on stroke criteria. Correlation with stroke subtype clinical features was calculated and Bayes＇ discriminant model was applied to discriminate stroke subtypes. Results： Among the 1989 patients, 797,689, 109, and 394 received diagnoses of cerebral infarction, ICH, subarachnoid hemorrhage, and other forms of nonstroke, respectively. A history of atrial fibrillation, vomiting, and diabetes mellitus were associated with cerebral infarction, while vomiting, systolic blood pressure _〉180 mmHg, and age 〈65 years were more typical of ICH. For noncomatose stroke patients, Bayes＇ discriminant model for stroke subtype yielded a combination of multiple items that provided 72.3% agreement in the test model and 79.3% in the validation model; for comatose patients, corresponding agreement rates were 75.4% and 73.5%. Conclusions： The model herein presented, with multiple parameters, can predict stroke subtypes with acceptable sensitivity and specificity before CT scanning, either in alert or comatose patients. This may facilitate prehospital management for patients with stroke.

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.

Clinical and laboratory survey of 65 Chinese patients with Leigh syndrome

Background Leigh syndrome is an inherited neurodegenerative disease that emerges in infancy and childhood and presents with a clinically heterogeneous variety of neuromuscular and non-neuromuscular disorders. It can result from the inheritance of mutations in either nuclear or mitochondrial DNA. In the current study, we performed a retrospective study in 65 patients in order to investigate the clinical and genetic characteristics of Leigh syndrome in Chinese patients. Methods Sixty-five unrelated cases （35 men and 30 women） who were hospitalized in the past 12 years were reviewed. Diagnosis was based on both the clinical presentation and the characteristic neuropathologic findings of bilateral symmetric necrotizing lesions in the basal ganglia and brain stem as detected using cranial computed tomography （CT） scan or magnetic resonance imaging （MRI）. The differential diagnosis of organic acidurias and fatty acid IS-oxidation defects were performed. Specific point mutations and deletions in mitochondrial DNA （T8993G, T8993C, T9176C, A8344G, A3243G） were screened by PCR-restriction analysis and Southern blot. The SURF1 gene was sequenced. Skeletal muscle biopsies were performed in 17 （26.2%） of the patients. The diagnosis was confirmed by autopsy in 6 （9.2%） patients. Results The patients had various forms of metabolic encephalomyopathy. Filly-nine （90.8%） of the patients had the typical neuroradiological features of Leigh syndrome, including symmetrical necrotizing lesions scattered within the basal ganglia, thalamus and brain stem. Twenty （30.8%） patients were confirmed by genetic, biochemical analysis and autopsy. Specific point mutations in mitochondrial DNA were found in 5 cases （7.7%）. Of these, the A8344G mutation was detected in 2 patients. The T8993G T8993C, and A3243G point mutations were identified in 3 other patients, respectively. SURF1 mutations associated with cytochrome c oxidase deficiency were identified in 8 （12.3%） families by DNA sequencing. A G604C mutation was identified in 6 （9.2%） patients. The genotypes of 52 patients remained unknown. Conclusions Leigh syndrome presents as a diverse array of clinical features and can result from specific mutations in nuclear or mitochondrial DNA. In this study, SURF1 mutations associated with cytochrome c oxidase deficiency were identified in 8 （12.3%） out of 65 patients with Leigh syndrome. It indicates that SURF1 mutations might be a common cause of Leigh syndrome in China. The etiology of Leigh syndrome in Chinese patients represents a persistent challenge to clinicians.

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.

Detection of multiple antibodies in myasthenia gravis and its clinical significance

Background Antibodies against acetylcholine receptor, acetylcholinesterase, ryanodine receptor and titin have been found in patients with myasthenia gravis. However, the relations between these antibodies and character of myasthenia gravis are unknown. This study aimed to detect multiple antibodies in myasthenia gravis and to investigate its clinical significance. Methods These antibodies were detected by enzyme-linked immunoabsorbent assay in 89 cases of myasthenia gravis, 66 cases of other neurological diseases and 66 healthy controls. The incidences of antibodies were compared using the chi-square test. Results Acetylcholine receptor, acetylcholinesterase, titin and ryanodine receptor antibodies were detected in 53.9%, 20.2%, 64.0% and 55.0% of myasthenia gravis patients respectively, higher than in patients of other neurological diseases and controls groups. The combination of the four antibodies assays provided 94.4% sensitivity and 84.0% specificity for the diagnosis of myasthenia gravis. Acetylcholinesterase antibody occurred more frequently in acetylcholine receptor antibody negative patients with adverse reactions to neostigmine test. Titin antibody provided 82.1% sensitivity and 52.5% specificity for myasthenia gravis with thymoma. Incidences of titin and of ryanodine receptor antibody were higher in late onset myasthenia gravis than in early onset myasthenia gravis. The proportion of titin antibody positive patients increased with the severity of myasthenia gravis as graded by a modified Osserman scale. Conclusions Testing for acetylcholine receptor, acetylcholinesterase, titin and ryanodine receptor antibodies can offer a better diagnostic method for myasthenia gravis than each antibody test alone. Titin antibody combined with computed tomography was better for the diagnosis of thymoma. Titin antibody occurred most frequently in severe myasthenia gravis.

Clinical features and management of postural tachycardia syndrome in children： a single-center experience

Background The incidence of postural tachycardia syndrome （POTS） has been increasing in children and adolescents,while clinical characteristics of POTS in the pediatric population are not fully understood.Methods An observational study was performed in 150 pediatric patients aged between 5 and 18 years who underwent head-up tilt test （HUTT） with the diagnosis of POTS at Peking University First Hospital from March 2008 to August 2013.Demographic data,clinical presentation,autonomic parameters,laboratory findings,and treatments were recorded.Results POTS in children commonly occurred in the age of 7-14 years.Dizziness （84.00％） was the most common symptom,followed by weakness （72.00％） and orthostatic syncope （62.67％）.Positive family history of orthostatic intolerance （Ol） was found in 24.64％ of children with POTS.And 33.09％ of them had preceding infection history as precipitating events.Ten percent of them suffered from orthostatic hypertension.Hyperadrenergic status was documented in 51.28％ of 39 patients who were tested for the standing norepinephrine levels.More than half of POTS patients,with 24-hour urinary sodium level ＜124 mmol/24 hours,were suitable for treatment of salt supplementation.At least 25.74％ of POTS patients were of positive acetylcholine receptor （AChR） antibody.Low iron storage in children with POTS was relatively rare.Most patients responded well to treatments,43.51％ of patients recovered,while 7.63％ of them had relapse after symptoms disappeared.Conclusions POTS is a relatively common condition with complex pathophysiology and heterogeneous clinical manifestation.A comprehensive therapeutic regimen is recommended for the treatment.

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.

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.

Clinical Analysis of Partial Epilepsy with Auras

Background： An aura is usually considered to be the initial clinical sign of a seizure. The types ofabnomlal neuron activities （i.e., localized and generalized firing） play an important role in the diagnosis of epilepsy. The goal of this study was to investigate the types of auras and its correlation with the localization and treatment of epilepsy. Methods： The 426 epileptic patients with auras from a single center were reviewed with reference to International League Against Epilepsy （ILAE, 1981） classification; the clinical manifestations and incidence of auras were analyzed in this retrospective study, as well as the restllts of electroencephalogram （EEG）, brain magnetic resonance imaging （M RI） and the treatment inethods. Results： Among the 426 epileptic patients, six different types of auras were defined, including autonomic auras, sensory auras, mental and affective auras, aura as vertigo, cognitive auras, and unspeakable feelings. Duration of auras ranged fi＇om 2 s to 7 rain; the median duration of auras was 64.2 s. Abnormal EEG was observed in 297 （69.72%） patients. Moreover, abnormal brain MRI was observed in 125 （29.34%） patients. Nineteen （4.46%） epilepsy patients with auras underwent both surgeries and antiepileptic drugs （AEDs） while others were treated only with AEDs. Conclusions： This study suggested that auras played an important role in the diagnosis, classification, and localization of epilepsy. Epileptic aura could help differentiate partial seizure from generalized seizure.

In vivo evaluation of urokinase-loaded hollow nanogels for sonothrombolysis on suture embolization-induced acute ischemic stroke rat model

The urokinase-type plasminogen activator(uPA)loaded hollow nanogels(nUK)were synthesized by a one-step reaction of glycol chitosan and aldehyde capped poly(ethylene oxide).The resultant formulation is sensitive to diagnostic ultrasound(US)of 2 MHz.Herein,we evaluated the in vivo sonothrombolysis performance of the nUK on acute ischemic stroke rat model which was established by suture embolization of middle cerebral artery(MCA).Via intravenous(i.v.)administration,the experimental data prove a controlled release of the therapeutic protein around the clots under ultrasound stimulation,leading to enhanced thrombolysis efficiency of the nUK,evidenced from smaller infarct volume and better clinical scores when compared to the i.v.dose of free uPA no matter with or without US intervention.Meanwhile,the preservation ability of the nanogels not only prolonged the circulation duration of the protein,but also resulted in the better blood-brain barrier protection of the nUK formulation,showing no increased risk on the hemorrhagic transformation than the controls.This work suggests that the nUK is a safe sonothrombolytic formulation for the treatment of acute ischemic stroke.

Clinical and Brain Magnetic Resonance Imaging Features in a Cohort of Chinese Patients with Kearns-Sayre Syndrome

Background： Kearns-Sayre syndrome （KSS） is a mitochondrial DNA （mtDNA） deletion disorder characterized by a triad of onset before 20 years of age, ophthalmoplegia, and pigmentary retinopathy. The heart and central nervous system are commonly involved. We summarized clinical and brain magnetic resonance imaging （M RI） features of a cohort of Chinese KSS patients. Methods： Nineteen patients confirmed by muscle biopsy and mtDNA analysis were enrolled. We examined clinical profiles, mainly focusing on changes in electrocardiogram （ECG） and brain MRI. The correlation between genotype and phenotype was statistically analyzed. Results： The mean age of onset was 9.6 ＋ 4.3 years, with all developing the classic triad at the time of diagnosis. Heart conduction block was detected in 63.2%, with four initially presenting as bundle branch block and developing into complete atrioventricular block over 3-72 months. Brain MRI showed symmetric high-T2 signals in 100% of cerebral and cerebellar white matter, as well as brainstem, 46.7% of basal ganglia, and 53.3% of thalamus. There were two patterns of cerebral white matter involvements, one with selective subcortical U-fibers and the other with periventricular white matter. The size of mtDNA deletion did not significantly correlate with age of onset or percentage of ragged blue fibers on muscle pathology. Conclusions： The clinical features of KSS evolve dynamically, affecting the cardiac conduction system predominantly, highlighting the significance of ECG monitoring. Brain MRI showed changes involving both the white matter and deep gray nuclei. Clinical presentation or severity of muscle pathological changes is not related to the size of mtDNA deletions.

Study of Enhanced Depth Imaging Optical Coherence Tomography in Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy

Background： Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy （CADASIL） is a hereditar5 small artery disease caused by NOTCH3 gene mutation. We performed enhanced depth imaging optical coherence tomography （EDI-OCT） to evaluate the retinal vessel changes in CADASIL patients and assessed their consonance with brain magnetic resonance imaging （MPRI） findings. Methods： Of 27 genetically confirmed patients and an equal number of controls were recruited at the Peking University First ttospital from January 2015 to August 2016. All patients underwent 7T-MRI of the brain. Fazekas score, number of small infarcts and microblecds were evaluated. All patients and controls underwent EDI-OCT to measure subtbveal choroidal thickness （SFCT）, inner and outer diameters as well as arterial and venous wall thickness, and arterial venous ratio of the inner （AVRin） and outer diameters （AVRout）. The relation between retinal vessel changes and Fazekas scores, numbers of small infarcts, or microbleeds was analyzed. Paired t-test was used to compare the SFCT and retinal vessel measurement data between patients and controls. Spearman＇s correlation was used to investigmc the correlation between retinal vessel changes and MRI lesions. Results： In CADASI L patients, mean SFCT （268.37 ± 46.50 μm） and mean arterial inner diameter （93.46 ± 9.70 gin） were signilicantly lower than that in controls （P 〈 0.00 ）, P = 0.048, respectively）. Mean arterial outer diameter （ 131.74 ± 10.87 μm）, venous inner （ 128.99 ± 13.62 μm） and outer diameter （ 164.82 ±14.77 μm）, and mean arterial （ 19.13 ±1.85 μm） and venous （ 17.91 ±2.76 μm） wall thickness were significantly higher than that in controls （P = 0.023, P 0.004, P 〈 0.001, P 〈 0.001, respectively）. Arterial inner diameter （r= - 0.39, P 0.044）] AVRin （r -0.65, P 〈 0.001）, and AVR,, （r =0.56, P - 0.002） showed a negative correlation with the number of small infarcts. Venous inner diameter （rs=0.46, P= 0.016） showed a positive correlation with the number of small infarcts. Venous inner diameter （r 0.59, P = 0.002）, outer diameter （rs=0.47, P= 0.017）, showed a positive correlation with the number of cerebral microbleeds （CM Bs）. AVRin （r =0.52, P = 0.007） and AVRout （r = -0.40, P =0.048） showed a negative correlation with the number of CMBs. Conclusions： Measurement of retinal vessels using EDI-OCT correlates moderately well with MRI parameters. EDI-OCT might bc a useful evaluation tool for CADASIL patients.

Compound Heterozygote Mutation of C12orf65 Causes Distal Motor Neuropathy and Optic Atrophy

The C12orf65 gene is a nuclear gene that encodes a mitochondrial matrix protein contributing to mitochondrial translation. C12orf65 gene-related diseases are rare and present with large heterophenotypes. Most of the reported patients have had optic atrophy with intellectual disability, encephalomyopathy, spastic paraplegia, and ophthalmoplegia. Peripheral neuropathy has been reported in one thmily. Here, we report a case of a Chinese patient with optic atrophy and distal motor neuropathy due to a novel compound heterozygous mutation in the C12orf65 gene.

Different Eukaryotic Initiation Factor 2Be Mutations Lead to Various Degrees of Intolerance to the Stress of Endoplasmic Reticulum in Oligodendrocytes

Vanishing white matter disease （VWM）, a human atitosomal recessive inherited leukoencephalopathy, is due to mutations in eukaryotic initiation factor 2B （elF2B）. elF2B is responsible for tile initiation of protein synthesis by its guanine nucleotide exchange lhctor （GEF） activity. Mutations ofelF2B impair GEF activity at different degree. Previous studies implied improperly activated unlblded protein response （UPR） and endoplasmic reticulum stress （ERS） participated in the pathogenesis ofVWM. Autophagy relieves endoplasmic reticulum load by eliminating the unfolded protein. It is still unknown the effects of genotypes on the pathogenesis. In this work, UPR and autophagy flux were analyzed with different mutational types. Methods： ERS tolerance, reflected by apoptosis and cell viability, was detected in human oligodendrocyte cell line transfected with the wild type, or different mutations of p. Argl 13 His, p. Arg269＊ or p. Ser610-Asp613del in el F2 Be. A representative U PR-PERK component of activating transcription lhctor 4 （ATF4） was measured under the basal condition and ERS induction. Autophagy was analyzed the flux in the presence of lysosomal inhibitors. Results： The degree of ERS tolerance varied in different genotypes. The truncated or deletion mutant showed prominent apoptosis cell viability declination after ERS induction. The most seriously damaged GEF activity ofp. Arg269＊ group underwent spontaneous apoptosis. The truncated or deletion mutant showed elevated ATF4 under basal as well as ERS condition. Decreased expression of LC3-1 and LC3-11 in the mutants reflected an impaired autophagy flux, which was more obvious in the truncated or deletion mutants alter ERS induction. Conclusions： GEF activities in dilt;erent genotypes could influence the cell ERS tolerance as well as compensatory pathways of UPR and autophagy. Oligodendrocytes with truncated or deletion inutants showed less tolerable to ERS.

Clinical and Genetic Features of Chinese X-linked Charcot-Marie-Tooth Type 1 Disease

Background： X-linked Charcot-Marie-Tooth type 1 （CMT1 X） disease is one of the most common forms of inherited neuropathy caused by mutations in the gap junction beta-1 protein （GJB1） gene （also known as connexin 32）. This study presented the clinical and genetic features of a series of Chinese patients with GJB1 gene mutations. Methods： A total of 22 patients from unrelated families, who were referred to Department of Neurology, Peking University First Hospital from January 2005 to January 2016, were identified with GJBI mutations. Their clinical records and laboratory findings were retrospectively collected and reviewed. Mutations in the GJB1 gene were analyzed by targeted next-generation sequencing （NGS）. Nucleotide alternations were confirnled with Sanger sequencing. Results： The CMT1X patients predominantly showed distal muscle weakness of lower limbs with mild sensory disturbance. The mean age of onset was 15.6 ± 8.7 years （ranging from 1 year to 42 years）. The sudden onset of cerebral symptoms appeared in four patients （ 18.2%）： two were initial symptoms. One case had constant central nervous system （CNS） signs. There were 19 different heterozygous mutations, including 15 known mutations and tbur novel mutations （c. II5G〉T, c.380T〉A, c.263C〉A, and c.818_819insGGGCT）. Among the 22 Chinese patients with CMT1X, the frequency of the GJB1 mutation was 4.5% in transmembrane domain 1 （TM1）, 4.5% in TM2, 27.7% in TM3, 9.1% in TM4, 4.5% in extracellular 1 （EC1）, 27.3% in EC2, 9.1% in intracellular loop, 13.6% in the N-terminal domain, and 4.5% in the C-ternlinal domain. CMTIX with CNS impairment appeared in five （22.7%） of these patients. Conclusions： This study indicated that CNS impairment was not rare in Chinese CMT1X patients. Mutations in the EC2 domain of the GJBI gene were hotspot in Chinese CMT1X patients.

Relationship of cerebral microbleeds to inflammatory marker levels

Aim: The purpose of this study is to investigate the incidence, distribution and risk factors of cerebral microbleeds (CMBs) and the relation between CMBs and inflammation in ischemic cerebrovascular disease. Methods: Two hundred and one patients without acute infarction or transient ischemic attack were enrolled. The presence and number of CMB were assessed on susceptibility-weighted imaging. The traditional risk factors of CMB were recorded. Levels of high-sensitivity C-reactive protein (hs-CRP), interleukin-6 (IL-6), and matrix metalloproteinase-9 (MMP-9) were tested. Logistic regression analyses were used for multiple-factor analysis of risk factors of CMB. Results: Of the 201 patients, 49 (24.38%) had CMB. Multivariate logistic regression analyses showed that the age, the prevalence of hypertension, silent lacunar infarction, white matter lesion, Montreal Cognitive Assessment Score, the using rate of antithrombotic drugs and levels of hs-CRP, IL-6, MMP-9 were the risk factors for CMB. After adjustments for traditional risk factors, inflammatory marker levels remained to be associated with CMBs. The adjusted odd ratios of hs-CRP, IL-6 and MMP-9 were 1.745 (1.342-2.270), 1.223 (1.018-1.533) and 1.284 (1.082-1.423), respectively. Furthermore, inflammatory marker levels were the risk factor for deep or infratentorial CMBs and lobar CMBs. Conclusion: The age, prevalence of hypertension, silent lacunar infarction, white matter lesion, MoCA Score, the using rate of antithrombotic drugs and serum hs-CRP, IL-6, and MMP-9 levels were the independent risk factors for CMBs.

Efficacy and Safety of Teriflunomide in Chinese Patients with Relapsing Forms of Multiple Sclerosis: A Subgroup Analysis of the Phase 3 TOWER Study

Background:Disease-modifying therapy is the standard treatment for patients with multiple sclerosis (MS)in remission.The primary objective of the current analysis was to assess the efficacy and safety of two teriflunomide doses (7mg and 14mg)in the subgroup of Chinese patients with relapsing MS included in the TOWER study. Methods:TOWER was a multicenter,multinational,randomized, double-blind,parallel-group (three groups),placebo-controlled study.This subgroup analysis includes 148 Chinese patients randomized to receive either teriflunomide 7mg (n =51), teriflunomide 14mg (n=43),or placebo (n=54). Results:Of the 148patients in the intent-to-treat population, adjusted annualized-relapse rates were 0.63(95% confidence interval [CI]:0.44,0.92)in the placebo group,0.48(95%CI:0.33, 0.70)in the teriflunomide 7mg group,and 0.18(95%CI:0.09,0.36)in the terifltmomide 14mg group;this corresponded to a significant relative risk reduction in the teriflunomide 14mg group versus placebo (-71.2%,P =0.0012).Terifiunomide 14mg also tended to reduce 12-week confirmed disability worsening by 68.1% compared with placebo (hazard ratio:0.319,P =0.1194).There were no differences across all treatment groups in the proportion of patients with treatment-emergent adverse events (TEAEs;72.2% in the placebo group,74.5%in the teriflunomide 7mg group,and 69.8% in the teriflunomide 14mg group);corresponding proportions for serious adverse events were 11.1%,3.9%,and 11.6%,respectively.The most frequently reported TEAEs with teriflunomide versus placebo were neutropenia,increased alanine aminotransferase,and hair thinning. Conclusions:Teriflunomide was as effective and safe in the Chinese subpopulation as it was in the overall population of patients in the TOWER trial.Teriflunomide has the potential to meet unmet medical needs for MS patients in China.