Neuron-targeted Knockout of APE1 Forces Premature Cognitive Impairment and Synaptic Dysfunction in Adult Mice.

Adaptable and consistent neural function relies at least in part on the ongoing repair of oxidative damage that can accumulate in the brain over a lifespan. To determine whether forebrain neuron-targeted knockout of AP endonuclease 1 (APE1), a critical enzyme in the base excision DNA repair pathway, contributes to neuronal impairments, we generated APE1 conditional knockout mice under the control of the CamKIIα promotor (APE1 cKO). Spatial learning and memory were tested using the Morris water maze. Synaptic markers, including synapsin, vGLUT, GABA1, and GAD were immunostained and quantified. Dendritic morphology and number were characterized using Golgi staining. Long-term potentiation (LTP) was measured in slices from the 6-month-old brain. APE1 cKO mice did not significantly differ from WT mice in the learning phase of the Morris water maze, but performed significantly worse during the memory phase of the Morris water maze. vGLUT, GABA1, and GAD immunostaining was significantly decreased in APE1 cKO mice without concomitant changes in the number of synapsin-positive structures, suggesting that neural networks may be impaired but not at the level of total presynaptic structures. Dendrites were reduced both in number and length of spines in APE1 cKO mice. APE1 cKO brain slices exhibited decreased LTP induction compared to WT brain slices. Together, these data indicate that the conditional loss of APE1 in forebrain neurons leads to a phenotype consistent with expedited brain aging.

A triple-source CT system for micro-scale investigation of geological materials: A simulation study.

A triple-source CT system is proposed for micro-scale testing of geological materials. This study aims at reducing the projection acquisition time by two-thirds compared to a conventional single-source CT system. The proposed system with different positioning errors in the source-to-object distance (SOD) was simulated and tested using the Shepp-Logan phantom model, as well as slices of sand, glass beads, and concrete samples. Furthermore, the imaging quality of a single-source and the triple-source CT system with different dead detector pixels was compared. The results showed that within the maximum allowable positioning error, the pixel differences between the simulated and the original images are close to zero, and the structural similarities are greater than 0.96. In the presence of dead detector pixels, the quality of the simulated images in the triple-source CT system is superior to that of a single-source CT system. The presented triple-source CT system performs well in high-quality image reconstruction.

Distal hereditary neuropathy associated with a novel mutation in alanyl-aminoacyl-tRNA synthetase.

To report a new genetic cause of distal hereditary motor neuropathy (dHMN), which is likely associated with worsening during pregnancy. We collected the clinical data of a patient with severe weakness of the lower limbs induced by repeated pregnancy and performed relevant experimental examinations, including neuromuscular electrophysiological examination, neuromuscular biopsy, and genetic testing. The patient reported weakness of the right lower extremity after delivery of the first child. Initially, the right foot was weak during lifting, and symptoms gradually progressed to weakness when landing on the toe during walking. She then developed weakness of the right lower extremity and thinning of the right leg. After an interval of 2.5 years, after delivery of the second child, her left lower extremity developed asthenia, with the same symptoms as previously reported for the right lower extremity. Subsequently, weakness of both lower extremities became progressively worse, and she developed difficulty sitting up, getting out of bed, and walking. Physical examination showed that both upper limb vertebral tracts were damaged and both lower extremity motor nerves were damaged. Electrophysiology suggested motor axonal neurogenic damage. Brain magnetic resonance imaging demonstrated leukodystrophy. Sural nerve biopsy suggested mild axonal damage. Skeletal muscle biopsy suggested neurogenic skeletal muscle damage. Genetic testing suggested that there was a heterozygous mutation at the shear site of the AARS gene. An AARS mutation may cause dHMN associated with pyramidal tract signs.

Features of hyperintense white matter lesions and clinical relevance in systemic lupus erythematosus.

BACKGROUND: Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease characterized by complex and various clinical manifestations. The study aimed to analyze clinical features and cerebral magnetic resonance imaging (MRI) changes of hyperintense white matter (WM) lesions in SLE patients. METHODS: This was a retrospective study based on a consecutive cohort of 1191 SLE patients; 273 patients for whom cerebral MRI data were available were enrolled to assess hyperintense WM lesions associated with SLE. Patients were assigned to two groups, i.e., with or without hyperintense WM lesions. The MRI assessment showed that the hyperintense WM lesions could be classified into three categories: type A, periventricular hyperintense WM lesions; type B, subcortical hyperintense WM lesions; and type C, multiple discrete hyperintense WM lesions. The clinical and MRI characteristics were analyzed. Factors related to hyperintense WM lesions were identified by multivariate logistic regression analysis. RESULTS: Among the 273 SLE patients with available cerebral MRI scans, 35.9% (98/273) had hyperintense WM lesions associated with SLE. The proportions of types A, B, and C were 54.1% (53/98), 11.2% (11/98), and 92.9% (91/98), respectively. Fifty-one percents of the patients showed an overlap of two or three types. Type C was the most common subgroup to be combined with other types. Compared with those without hyperintense WM lesions, the patients with hyperintense WM lesions were associated with neuropsychiatric SLE (NPSLE), lupus nephritis (LN), hypertension, and hyperuricemia (P = 0.002, P = 0.018, P = 0.045, and P = 0.036, respectively). Significantly higher rates of polyserous effusions and cardiac involvement were found in the patients with hyperintense WM lesions (P = 0.029 and P = 0.027, respectively), and these patients were more likely to present with disease damage (P < 0.001). In addition, the patients with hyperintense WM lesions exhibited a higher frequency of proteinuria (P = 0.009) and higher levels of CD8+ T cells (P = 0.005). In the multivariate logistic analysis, hyperuricemia and higher CD8+ T cells percentages were significantly correlated with hyperintense WM lesions in SLE patients (P = 0.019; OR 2.129, 95% confidence interval [CI] 1.313-4.006 and P < 0.001; OR 1.056, 95% CI 1.023-1.098, respectively). CONCLUSIONS: Hyperintense WM lesions are common in SLE patients and significantly associated with systemic involvement, including NPSLE, LN, polyserous effusions, cardiac involvement, and disease damage. Hyperuricemia and a higher number of CD8+ T cells were independent factors associated with hyperintense WM lesions in SLE.

Impaired expression of BCAT1 relates to muscle atrophy of mouse model of sarcopenia.

BACKGROUND: The underlying mechanism of muscle atrophy in sarcopenia is still not fully understood; branched chain aminotransferase 1(BCAT1) isocitrate dehydrogenase-1 encodes an evolutionarily conserved cytoplasmic aminotransferase for glutamate and branched-chain amino acids (BCAAs), thus constituting a regulatory component of cytoplasmic amino and keto acid metabolism. In human gliomas carrying wild-type isocitrate dehydrogenase-1, BCAT1 promotes cell proliferation through amino acid catabolism. Hence, the goals of this study were to unravel the potential role of BCAT1 expression in muscle atrophy and to explore the mechanisms underlying this process. METHODS: We first measured Bcat1 expression by RT-qPCR and western blotting in murine and cellular models of muscle atrophy. To understand how the Bcat1-driven changes sustained muscle cell growth, we analyzed reactive oxygen species (ROS) levels and activation of the mTORC1/S6K1 pathway in muscle cells. Furthermore, we performed Cell Counting Kit-8(CCK8) assays and fluorescence staining to evaluate growth rate of cells and ROS levels. Finally, we verified that depletion of Bcat1 impairs the growth rate of muscle cells and increases ROS levels, indicating that muscle atrophy resulted from the downregulation of the mTORC1/S6K1 pathway. Data were analyzed by two-tailed unpaired Student's t-test or Mann-Whitney U test for two groups to determine statistical significance. Statistical analyses were performed using GraphPad Prism version 6.0 and SPSS 16.0 software. RESULTS: Bcat1 expression level in skeletal muscles was lower in murine and cellular models of sarcopenia than in the control groups. Bcat1 knockdown not only suppressed the growth of muscle cells but also increased the production of ROS. Impaired cell growth and increased ROS production was rescued by co-introduction of an shRNA-resistant Bcat1 cDNA or addition of the mTORC1 stimulator MYH1485. Muscle cells with Bcat1 knockdown featured lower mTORC1 and S6K1 phosphorylation (pS6K1) than NT muscle cells. Addition of either shRNA-resistant Bcat1 cDNA or MYH1485 rescued the suppression of cell growth, increase in ROS production, and decrease in pS6K1. CONCLUSIONS: The branched chain amino acids catabolic enzyme BCAT1 is essential for the growth of muscle cells. BCAT1 expression contributes to sustained growth of muscle cells by activating mTOR signaling and reducing ROS production.

Total Cerebral Small Vessel Disease Burden on MRI Correlates With Medial Temporal Lobe Atrophy and Cognitive Performance in Patients of a Memory Clinic.

Background: Cerebral small vessel disease (cSVD) and neurodegeneration are the two main causes of dementia and are considered distinct pathological processes, while studies have shown overlaps and interactions between the two pathological pathways. Medial temporal atrophy (MTA) is considered a classic marker of neurodegeneration. We aimed to investigate the relationship of total cSVD burden and MTA on MRI using a total cSVD score and to explore the impact of the two MRI features on cognition. Methods: Patients in a memory clinic were enrolled, who underwent brain MRI scan and cognitive evaluation within 7 days after the first visit. MTA and total cSVD score were rated using validated visual scales. Cognitive function was assessed by using Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA) scales. Spearman's correlation and regression models were used to test (i) the association between MTA and total cSVD score as well as each cSVD marker and (ii) the correlation of the MRI features and cognitive status. Results: A total of 312 patients were finally enrolled, with a median age of 75.0 (66.0-80.0) years and 40.7% (127/312) males. All of them finished MRI and MMSE, and 293 subjects finished MoCA. Of note, 71.8% (224/312) of the patients had at least one of the cSVD markers, and 48.7% (152/312) of them had moderate-severe MTA. The total cSVD score was independently associated with MTA levels, after adjusting for age, gender, years of education, and other vascular risk factors (OR 1.191, 95% CI 1.071-1.324, P = 0.001). In regard to individual markers, a significant association existed only between white matter hyperintensities and MTA after adjusting for the factors mentioned above (OR 1.338, 95% CI 1.050-1.704, P = 0.018). Both MTA and total cSVD score were independent risk factors for MMSE ≤ 26 (MTA: OR 1.877, 95% CI 1.407-2.503, P < 0.001; total cSVD score: OR 1.474, 95% CI 1.132-1.921, P = 0.004), and MoCA < 26 (MTA: OR 1.629, 95% CI 1.112-2.388, P = 0.012; total cSVD score: OR 1.520, 95% CI 1.068-2.162, P = 0.020). Among all the cSVD markers, microbleed was found significantly associated with MMSE ≤ 26, while no marker was demonstrated a relationship with MoCA < 26. Conclusion: Cerebral small vessel disease was related to MTA in patients of a memory clinic, and both the MRI features had a significant association with cognitive impairment.

The Cardiovascular and Cerebrovascular Health in North China From 2006 to 2011: Results From the KaiLuan Study.

Background: The American Heart Association (AHA) defined cardiovascular health in terms of four behaviors (smoking, diet, physical activity, body weight) and three factors (plasma glucose, cholesterol, blood pressure). By this definition, the prevalence of ideal cardiovascular health behaviors and factors is negatively correlated with all-cause mortality and risks of cardiovascular and cerebrovascular diseases and malignancy. We analyzed the trends in cardiovascular and cerebrovascular health behaviors and factors in the population of the KaiLuan study for 2006-2011, reported the results, and provided evidence for prevention. Methods and Results: We calculated the prevalence of cardiovascular and cerebrovascular health behaviors and factors from KaiLuan data for 2006-2007, 2008-2009, and 2010-2011. The prevalence of ideal cardiovascular and cerebrovascular health behaviors and factors is low in the KaiLuan population. Conclusions: The prevalence of ideal cardiovascular and cerebrovascular health behaviors and factors is low in the KaiLuan population. Clinical Trial Registration: http://www.chictr.org/cn/proj/show.aspx?proj=1441, unique identifier: ChiCTR-TNC-11001489.

Symptom measures in pediatric narcolepsy patients: a review.

PURPOSE: This study aimed to provide a summary of the measures to assess narcoleptic symptoms or complications in pediatric narcolepsy patients. METHODS: We searched in the National Center for Biotechnology Information (NCBI) for measures of narcoleptic symptoms for pediatric patients. Further review was conducted if relevant questionnaires or information were mentioned. RESULTS: There were only two narcolepsy-specific questionnaires, the narcolepsy severity scale and Ullanlinna Narcolepsy Scale, neither of them was developed or validated in the pediatric population. For cataplexy, all the measures were study-specific diaries and were not validated questionnaires. For excessive daytime sleepiness, the Epworth Sleepiness Scale was most frequently used to measure excessive daytime sleepiness in children. For nighttime sleep, the Children's Sleep Habits Questionnaire was most frequently used. For depression, the Children Depression Inventory was the most frequently used. For attention-deficit/hyperactivity disorder, the Child Behavior Checklist was the most frequently used. For quality of life, KIDSCREEN was most frequently used. CONCLUSIONS: At present, there is a lack of disease-specific and validated questionnaires for pediatric narcoleptic patients. This need can be met by modifying and adjusting the existing adult questionnaires and developing new questionnaires for pediatric narcoleptic patients.

Twenty-Four-Hour Ambulatory Blood Pressure Variability Associated With Cerebral Small Vessel Disease MRI Burden and Its Progression in Inpatients With Cerebrovascular Disease.

Background: Lacunar infarcts, white matter lesions, cerebral microbleed, enlarged perivascular space and brain atrophy are regarded as magnetic resonance imaging (MRI) manifestations of cerebral small vessel disease (cSVD). 24-hour blood pressure variability (BPV) has been reported to relate with cerebral small vessel disease, but the impact of 24-h BPV on the total MRI cSVD burden and its progression in inpatients with cerebrovascular disease has not been investigated yet. Methods: We enrolled inpatients with cerebrovascular disease, who underwent the 24-h ambulatory blood pressure monitoring (ABPM) and the brain MRI scan at baseline and had the follow-up brain MRI images stored in the clinical information system of our hospital. BPV was quantified by the calculation of standard deviation (SD), coefficient of variation (CV), weighted standard deviation (wSD) of blood pressure record. We evaluated the total cSVD score on baseline MRI and the MRI followed-up to obtain the total burden of cSVD. The cSVD burden progression was estimated through the comparison of the total cSVD score on the two MRIs. Results: A total of 140 patients with an average age of 65.6 years were finally enrolled, 82.9% (116/140) of whom had one or more cSVD markers. After a median of 4.4 years follow-up, cSVD score progression were found in 50.7% (71/140) of the patients. Both SD and CV of SBP and DBP during 24-h and daytime as well as the SBP wSD differed significantly among different total cSVD score groups. The SBP SD and CV during 24-h and daytime, the SBP SD in nighttime, the DBP SD and CV during the daytime were significantly higher in the cSVD progression group than those in the cSVD no-progression group. The SBP wSD and the DBP wSD were significantly higher in the cSVD progression group than those in the cSVD no-progression group. Logistic regression analyses revealed that daytime SBP SD and SBP wSD were independent risk factors for total cSVD burden [daytime SBP SD: OR = 1.628, 95% CI = 1.105-2.398 (per 5 mmHg increase in SD), P = 0.014; SBP wSD: OR = 2.248, 95% CI = 1.564-3.230 (per 5 mmHg increase in wSD), P < 0.001)] and SBP wSD was a significant predictor for cSVD progression [OR = 2.990, 95% CI = 1.053-8.496 (per 5 mmHg increase in wSD), P = 0.040]. Conclusion: Higher BPV were significantly related with total cSVD burden in inpatients with cerebrovascular disease. SBP SD during daytime and SBP wSD were independent risk factor for total cSVD burden and SBP wSD was an predictive factor for cSVD progression.

Tianzhi granule improves cognition and BPSD of vascular dementia: a randomized controlled trial.

BACKGROUND AND PURPOSE: Tianzhi granule (TZ) is usually used for patients with vascular dementia (VaD) in China. The aim was to assess the effect of TZ by a randomized clinical trial (RCT). METHODS: A 24-week RCT was conducted in 16 centres. Participants were grouped into TZ, donepezil or placebo. The co-primary outcomes were the Vascular Dementia Assessment Scale-cognitive subscale (VADAS-cog) and Clinician's Interview-based Impression of Change-plus caregiver information (CIBIC-plus). RESULTS: A total of 543 patients with mild to moderate VaD were enrolled, of whom 242 took TZ granules, 241 took donepezil, and 60 took placebo. The least-squares mean changes from baseline and 95% CI were 6.20 (5.31, 7.09) (TZ group), 6.53 (5.63, 7.42) (donepezil group) and 3.47 (1.76, 5.19) (placebo group), both TZ and donepezil showed small but significantly improvement compared with placebo group. The percent of improvement on the global impression which was measured by CIBIC-plus was 73.71% in TZ and 58.18% in placebo, there was significant different between TZ and placebo group (P = 0.004). No significant differences were observed between TZ and donepezil. No significant differences of adverse events were found. CONCLUSIONS: TZ and donepezil could bring symptomatic benefit for mild to moderate VaD. Trial registration The protocol had retrospectively registered at clinical trial.gov, Unique identifier: NCT02453932, date of registration: May 27, 2015; https://www.clinicaltrials.gov/ct2/show/NCT02453932?term=NCT02453932&rank=1.

Efficacy and Safety of Toutongning Capsule in Patients with Migraine: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial.

Objective: Toutongning (TTN) capsule, a Chinese patent medicine, is used as a prophylactic treatment for migraine. The present study was conducted as a postmarketing evaluation of the efficacy and safety of TTN capsule. Design: A randomized, double-blind, placebo-controlled trial. Location: Patients recruited from 14 medical centers in China from May 2014 to August 2015. Subjects: Patients between 18 and 65 years of age with a diagnosis of migraine. Interventions: The patients were randomly assigned to receive either TTN (1200 mg, three times daily) or a matched placebo (1:1) for 4 weeks. Outcome measures: The primary outcome measured was a minimum 50% reduction in the frequency of headaches from the 4-week baseline period to the last 4 weeks of the 12-week trial. Secondary outcomes included duration, days, and visual analog score of headache attack, interval between headache attacks, usage of acute analgesics, and score on the Headache Impact Test-6. In addition, all patients were evaluated for adverse events (AEs). Results: This study initially enrolled 400 patients; a total of 378 participants completed the experiment while fulfilling all study requirements. TTN had a superior effect compared with the placebo on both the primary and secondary outcome measures without any serious AEs or unexpected side effects. Conclusion: TTN can effectively prevent the occurrence of migraine headaches and is well-tolerated and safe. TTN may exhibit a persistent therapeutic effect even after cessation of use. Trial Registration number: ChiCTR-IPR-15007058.

Variants in MME are associated with autosomal-recessive distal hereditary motor neuropathy.

OBJECTIVE: To identify a new genetic cause in patients segregating distal hereditary motor neuropathy (dHMN) with an autosomal recessive pattern. METHODS: Whole-exome sequencing was conducted in two siblings and was combined with segregation analysis. Additionally, 83 unrelated dHMN patients with unknown genetic cause were screened. RNA analysis was performed using blood lymphocytes and HEK293 cells transfected with mutant plasmids. Immunohistochemistry and Western blot analysis was applied to the nerve tissue. The enzymatic activities of mutant proteins were measured in the cultured cells to verify the pathogenicity of variants. RESULTS: The clinical features of the patients showed late-onset phenotype of distal motor neuropathy without sensory involvement. We identified that compound heterozygous variants of c.1342C>T and c.2071_2072delGCinsTT in the membrane metalloendopeptidase (MME) gene co-segregated with the phenotype in a dHMN family. In an additional group of 83 patients with dHMN, compound heterozygous variants of c.1416+2T>C and c.2027C>T in MME were identified in one patient. The splice site variant c.1416+2T>C results in skipping of exon 13. The stop variant c.1342C>T induces mRNA degradation via nonsense-mediated mRNA decay. Transcript levels of MME in the lymphocytes showed no significant differences between the patients and controls. We also identified that MME variants were associated with mild decrease in protein expression in the sural nerve and significant impairments of enzymatic activity. INTERPRETATION: Variants in the MME gene were associated with not only a Charcot-Marie-Tooth neuropathy phenotype but also with an autosomal-recessive dHMN phenotype. Loss of function may play a role in the pathogenesis of dHMN.

Distinctive functional deficiencies in axonal conduction associated with two forms of cerebral white matter injury.

AIMS: This study determines whether assessment with compound action potentials (CAPs) can distinguish two different forms of cerebral white matter injury at the functional levels. METHODS: A pure demyelination model was induced in C57/BL6 adult mice by dietary supplementation of cuprizone (0.2%) for 6 weeks. Callosal L-N5-(1-Iminoethyl) ornithine (L-NIO) hydrochloride (27 mg/mL) was injected into the corpus callosum (CC) to induce a focal white matter stroke (WMS), resulting in both demyelination and axonal injury. White matter integrity was assessed by performing CAP recording, electron microscopy, and immunohistological and luxol fast blue (LFB) staining. RESULTS: Immunohistological and electron microscopic analyses confirmed the induction of robust demyelination in CC with cuprizone, and mixed demyelination and axonal damage with L-NIO. Electrophysiologically, cuprizone-induced demyelination significantly reduced the amplitude of negative peak 1 (N1), but increased the amplitude of negative peak 2 (N2), of the CAPs compared to the sham controls. However, cuprizone did not affect the axonal conduction velocity. In contrast, the amplitude and area of both N1 and N2 along with N1 axonal conduction velocity were dramatically decreased in L-NIO-induced WMS. CONCLUSIONS: Concertedly, parameters of the CAPs offer a novel functional assessment strategy for cerebral white matter injury in rodent models.

Efficacy and Safety of Chinese Herbs for the Prevention of the Risk of Renal Damage in Henoch-Schonlein Purpura in Children: Meta-Analysis of Randomized Controlled Trials and GRADE Evaluation.

Objective. To evaluate the efficacy and safety of traditional Chinese medicine in preventing kidney damage caused by Henoch-Schonlein Purpura (HSP) in Children by meta-analysis. Methods. We systematically searched the main Chinese and English electronic databases and collected randomized controlled trials of Chinese herbs in children with HSP until July 2018. Then we used the bias risk assessment tool in Cochrane Handbook 5. 1. 0 to complete the risk assessment of the included studies. We utilized STATA12.0 and RevMan 5.3 for meta-analysis and GRADE pro. for quality evaluation of evidence. Result. (1) Meta-analysis: data from 39 studies, representing 3643 individuals, were included in the analysis. Thirty-seven studies were treated with traditional Chinese medicine for clearing away heat and cooling blood, which were combined. On this basis, subgroup analysis was conducted according to the bias risk of the original study. It showed that Chinese herbs can significantly improve the treatment effect (OR: 4.31, 95% CI [3.34, 5.57], P < 0.01) and reduce the risk of renal damage (RR: 0.36; 95% CI [0.21, 0.61], P < 0.01) and the risk of recurrence (RR: 0.43, 95% CI [0.34, 0.54], P<0.01). (2) Side effect: a total of 7 studies described adverse reactions, and 12 of 319 patients in therapy group had adverse events and 20 of 263 patients in control group. (3) Publication bias: the bias risk Egger's test for the incidence of kidney injury was P=0.572, the relapse rate Egger's test was P=0.175, the efficiency was combined with the low-risk original study, and the bias risk Egger's test was P=0.175. There was not any significant publication bias based on the funnel plot and Egger's test. (4) GRADE evaluation: GRADE evaluation showed that the quality of evidence in the risk of renal damage and recurrence rate was moderate. Conclusion. Chinese medicine treatment can prevent the occurrence of renal damage in children with HSP and can reduce the recurrence rate, the incidence of adverse reactions, and the effect in terms of efficiency. However, the quality of the included studies in the meta-analysis and the quality of the evidence of outcomes were not high; the clinical use of the evidence needs to be cautious.

Bilateral striatal necrosis due to homoplasmic mitochondrial 3697G>A mutation presents with incomplete penetrance and sex bias.

BACKGROUND: Heteroplasmic mitochondrial 3697G>A mutation has been associated with leber hereditary optic neuropathy (LHON), mitochondrial encephalopathy, lactic acidosis and stroke-like episodes (MELAS), and LHON/MELAS overlap syndrome. However, homoplasmic m.3697G>A mutation was only found in a family with Leigh syndrome, and the phenotype and pathogenicity of this homoplasmic mutation still need to be investigated in new patients. METHODS: The clinical interviews were conducted in 12 individuals from a multiple-generation inherited family. Mutations were screened through exome next-generation sequencing and subsequently confirmed by PCR-restriction fragment length polymorphism. Mitochondrial complex activities and ATP production rate were measured by biochemical analysis. RESULTS: The male offspring with bilateral striatal necrosis (BSN) were characterized by severe spastic dystonia and complete penetrance, while the female offspring presented with mild symptom and low penetrance. All offspring carried homoplasmic mutation of NC_012920.1: m.3697G>A, p.(Gly131Ser). Biochemical analysis revealed an isolated defect of complex I, but the magnitude of the defect was higher in the male patients than that in the female ones. The ATP production rate also exhibited a similar pattern. However, no possible modifier genes on the X chromosome were identified. CONCLUSION: Homoplasmic m.3697G>A mutation could be associated with BSN, which expanded the clinical spectrum of m.3697G>A. Our preliminary investigations had not found the underlying modifiers to support the double hit hypothesis, while the high level of estrogens in the female patients might exert a potential compensatory effect on mutant cell metabolism.

Clonazepam improves the symptoms of two siblings with novel variants in the SYNJ1 gene.

BACKGROUND: Mutations in the SYNJ1 gene have been associated with early-onset of atypical Parkinson's disease or severe neurodegeneration with intractable seizures. Due to the rarity of the disease, there were limitations in the quality of available treatment options for SYNJ1-related diseases. METHODS: Two affected siblings from a non-consanguineous family were evaluated through a set of clinical and laboratory tests. The genetic screening was performed through exome next generation sequencing. SYNJ1 mutant transcripts were purified and cloned into the vectors for Sanger sequence of single-stranded DNA. Relative level of the SYNJ1 transcript was measured by quantitative PCR. RESULTS: The clinical features were characterized by a triad of symptomatic progression including diplopia, dystonia, and Parkinsonism. The dystonic symptoms were outstanding in the siblings, which preceded the Parkinsonism symptoms and became the main symptoms. Clonazepam resolved the clinical symptoms, especially the severe trunk dystonia and dystonic postures of limbs. Compound heterozygous variants (c.2579-2A > G; p.A860Gfs*5 and c.3845C > A; p.P1282L) were identified in the SYNJ1 gene co-segregating in this family. The proline residue is highly conserved across species and predicted to be damaging by several in silico tools. The splice site variant caused a skip of exon 20 and a significant reduction of the SYNJ1 transcript expression. CONCLUSIONS: Our study expanded the clinical and genetic spectrums of the SYNJ1-related diseases. Although our study was a preliminary observation, it indicated that clonazepam could improve the dystonic symptoms caused by mutations in the SYNJ1 gene.

Preconditioning with partial caloric restriction confers long-term protection against grey and white matter injury after transient focal ischemia.

Caloric restriction (CR) has been extensively examined as a preventative strategy against aging and various diseases, but CR effects on cerebral ischemia are largely unknown. We subjected C57BL6/J mice to ad libitum food access (LF) or a diet restricted to 70% of ad libitum food access (RF) for two to four weeks followed by 60 min of transient focal ischemia (tFCI). RF for four weeks protected against subsequent tFCI-induced infarct. RF improved sensorimotor function after stroke in the foot fault and corner tests, as well as performance in the Morris water maze test. In addition, RF preserved ischemic white matter tract integrity assessed by histology and compound action potential. Sirt1 and Sirt3 were both upregulated in RF ischemic brain, but heterozygous deletion of Sirt1 or knockout of Sirt3 did not alter the protection induced by RF against ischemic injury. RF induced significant release of adiponectin, a hormone related to glucose metabolism. Knockout of adiponectin decreased RF-induced protection after tFCI. These data demonstrate the novel finding that white matter, as well as neurons, benefit from CR prior to cerebral ischemic injury, and that adiponectin may contribute to these protective effects.

A novel KIF5A gene variant causes spastic paraplegia and cerebellar ataxia.

Mutations in the kinesin family member 5A (KIF5A) gene are mainly associated with autosomal dominant spastic paraplegia 10 (SPG10). The additional complicated symptoms of SPG10 commonly include a wide spectrum. However, cerebellar ataxia is only noticed in a very few patients. Herein, we described a large autosomal dominant family, in which the affected individuals presented with progressive spastic paraparesis and marked cerebellar ataxia. Exome sequencing revealed that a novel variant in the KIF5A gene might be responsible for the phenotype. The obvious cerebellar ataxia indicated that the KIF5A gene should be included in the expanding gene list for spasticity-ataxia spectrum.

Diabetes Mellitus Impairs White Matter Repair and Long-Term Functional Deficits After Cerebral Ischemia.

Background and Purpose- Type 2 diabetes mellitus (T2DM) is a major comorbidity that exacerbates ischemic brain injury and worsens functional outcome after stroke. T2DM is known to aggravate white matter (WM) impairment, but the underlying mechanism is not completely understood. This study was designed to test the hypothesis that T2DM impedes poststroke WM recovery by suppressing both oligodendrogenesis and beneficial microglia/macrophage responses. Methods- Permanent distal middle cerebral artery occlusion was performed in wild-type, homozygous diabetic db/db, and heterozygous db/+ mice. The adhesive removal, open field, and Morris water maze tests were used to assess neurobehavioral outcomes. Neuronal tissue loss, WM damage, oligodendrogenesis, and microglia/macrophage responses were evaluated up to 35 days after stroke. The functional integrity of WM was measured by electrophysiology. Primary microglia-oligodendrocyte cocultures were used for additional mechanistic studies. Results- T2DM exacerbated structural damage and impaired conduction of compound action potentials in WM 35 days after stroke. The deterioration in WM integrity correlated with poor sensorimotor performance. Furthermore, T2DM impaired the proliferation of oligodendrocyte precursor cells and the generation of new myelinating oligodendrocytes. T2DM also promoted a shift of microglia/macrophage phenotype toward the proinflammatory modality. Coculture studies confirmed that microglia/macrophage polarization toward the proinflammatory phenotype under high glucose conditions suppressed oligodendrocyte precursor cell differentiation. Conclusions- Deterioration of WM integrity and impairments in oligodendrogenesis after stroke are associated with poor long-term functional outcomes in experimental diabetes mellitus. High glucose concentrations may shift microglia/macrophage polarization toward a proinflammatory phenotype, significantly impairing oligodendrocyte precursor cell differentiation and WM repair.