Protective Effect of Tongxinluo Capsule on Cerebral Ischemia-reperfusion Injury and Its Mechanism of Action / 中国实验方剂学杂志

Objective:To study the protective effect of Tongxinluo capsule on cerebral ischemia-reperfusion injury, and explore the mechanism of Tongxinluo capsule in treating cerebral ischemia through network pharmacology. Method:The C57BL/6 mouse middle cerebral artery occlusion(MCAO) model was established by improved suture method and divided into sham operation group, model group, low, medium and high-dose Tongxinluo groups (crude drug 1,2,4 g·kg-1, intragastric administration), Aspirin group (2.055 g·L-1, intraperitoneal injection). Then, neurological function score and 2,3,5-triphenyltetrazole chloride(TTC) staining method were used to determine the infarct size of mice at 24, 48, 72 h by cerebral ischemia-reperfusion. First, chemical constituents of Tongxinluo capsule were screened from the BATMAN-TCM database, and the targets were analyzed. Then, gene ontology (GO) enrichment and Kyoto encyclopedia of genes and genomes (KEGG) enrichment analysis were performed, and traditional Chinese medicine(TCM)-active ingredient-target network was constructed. Finally, the multi-dimensional pharmacological mechanism of Tongxinluo capsule in the treatment of cerebral ischemia was predicted. Result:Longa score, HE staining and TTC staining all suggested that Tongxinluo capsule could alleviate brain injury in mice after cerebral ischemia and reperfusion, and the improvement degree of Tongxinluo capsule on brain injury was gradually enhanced with the increase of Tongxinluo capsule dose. A total of 132 active components and 240 intersection targets, including cyclic adenosine monophosphate(cAMP)-dependent protein kinase catalytic subunit alpha (PRKACA), adenylate cyclase 1(ADCY1), serine/threonine kinase 1 (Akt1), dopamine receptor D2 (DRD2) and discs large homolog 4 (DLG4) were screened from 12 TCM in Tongxinluo capsule. GO was enriched in cationic channel activity, ion gated channel activity, gate channel activity, neurotransmitter receptor activity, ion channel activity, etc. KEGG was enriched in cAMP signaling pathway, calcium signaling pathway, neuroactive ligand-receptor interaction, cyclic guanosine monophosphate(cGMP)/protein kinase G(PKG) signaling pathway and dopaminergic synaptic signaling pathway. Conclusion:Tongxinluo capsule can alleviate brain damage in mice with cerebral ischemia-reperfusion, and achieve brain protection through multiple targets and multiple links. Network pharmacology reveals effective components，targets and pathway of Tongxinluo capsule in the treatment of cerebral ischemia, which provides theoretical support for the mechanism of Tongxinluo capsule in the treatment of cerebral ischemia.

A clinical and genetic analysis of a child with supernumerary marker chromosome 15-caused mental retardation, intractable epilepsy, and central precocious puberty / 中国当代儿科杂志

Supernumerary marker chromosome 15 is a rare chromosome abnormality. This paper reports the clinical diagnosis and treatment, as well as genetic defects, of a child with supernumerary marker chromosome 15. The patient was a 9.5-year-old girl who had mental and motor retardation since infancy, breast development at the age of 7 years, and seizures at the age of 8.5 years. Seizures occurred with various features and could not be controlled by a variety of antiepileptic drugs. No abnormalities were found by brain magnetic resonance imaging. Electroencephalogram showed frequent epileptiform discharges. G-banding karyotype analysis, fluorescence in situ hybridization, methylation-specific multiplex ligation-dependent probe amplification, and array comparative genomic hybridization identified a de novo 15q duplication in the patient. The maternal copy number increased in the 15q11-13 region. The form of genome rearrangement was 47,XX,+inv dup(15)(pter to q13:q13 to pter). The increased copy number in the 15q11-13 region is closely related to mental retardation, intractable epilepsy, and central precocious puberty. High-resolution karyotype analysis is recommended for children with unexplained mental retardation and epilepsy.

Glucose transporter 1 deficiency syndrome: features of movement disorders, diagnosis and treatment / 中国当代儿科杂志

<p><b>OBJECTIVE</b>To investigate the clinical features, diagnosis and treatment of glucose transporter 1 deficiency syndrome (GLUT1-DS), as well as the diagnostic value of movement disorders.</p><p><b>METHODS</b>The clinical data of four children with GLUT1-DS were collected, and their clinical features, treatment, and follow-up results were analyzed.</p><p><b>RESULTS</b>There were two boys and two girls, with an age of onset of 2-15 months. Clinical manifestations included movement disorders, seizures, and developmental retardation. Seizures were the cause of the first consultation in all cases. The four children all had persistent ataxia, dystonia, and dysarthria; two had persistent tremor, two had paroxysmal limb paralysis, and two had eye movement disorders. Paroxysmal symptoms tended to occur in fatigue state. All four children had reductions in the level of cerebrospinal fluid glucose and its ratio to blood glucose, as well as SLC2A1 gene mutations. The four children were given a ketogenic diet, at a ketogenic ratio of 2:1 to 3:1, and achieved complete remission of paroxysmal symptoms within 5 weeks.</p><p><b>CONCLUSIONS</b>GLUT1-DS should be considered for epileptic children with mental retardation and motor developmental delay complicated by various types of movement disorders. The ketogenic diet is effective at a ketogenic ratio of 2:1 to 3:1 for the treatment of GLUT1-DS.</p>

Clinical and molecular genetic study of nonketotic hyperglycinemia in a Chinese family / 中国当代儿科杂志

Nonketotic hyperglycinemia (NKH) is a rare, inborn error of metabolism. In this case report, a Chinese male infant was diagnosed with NKH caused by GLDC gene mutation. The clinical characteristics and genetic diagnosis were reported. The infant presented with an onset of early metabolic encephalopathy and Ohtahara syndrome. Both blood and urinary levels of metabolites were in the normal range. Brain MRI images indicated a poor development of corpus callosum, and a burst suppression pattern was found in the EEG. Results of target gene sequencing technology combined with multiplex ligation-dependent probe amplification (MLPA) indicated a heterozygous missense mutation of c.1786 C>T (p.R596X) in maternal exon 15 and a loss of heterozygosity of 4-15 exon gross deletions in paternal GLDC gene. These definite pathogenic mutations confirmed the diagnosis of NKH. The infant's clinical condition was not improved after treatment with adreno-cortico-tropic-hormone, topiramate and dextromethorphan, and he finally died at 4 months of age. Patients with NKH often exhibit complicated clinical phenotypes and are lack of specific symptoms. NKH could be diagnosed by metabolic screening and molecular genetic analysis.

Episodic central nervous system symptoms with reversible white matter involvement in Chinese patients with X-linked Charcot-Marie-Tooth disease and literatures review / 中华儿科杂志

<p><b>OBJECTIVE</b>To analyze the phenotype and genotype of CMTX1 patients with episodic transient reversible white matter involvement, and delineate the features of brain MRI in the episode and the possible mechanisms.</p><p><b>METHOD</b>Three Chinese probands and their family members were sequenced in the coding regions of GJB1. With the other 16 reported CMTX1 patients with episodic transient reversible white matter involvement, the clinical feature of the episodic central nervous system symptoms and the genotypes were reviewed.</p><p><b>RESULT</b>Missense mutations in GJB1 were identified in all 3 probands. In 19 patients with transient reversible white matter involvement, the episodes were manifested as weakness of the limbs, dysarthria, and dysphagia, without disturbance of consciousness or seizures. The episodes lasted for 13 hours (10 min-72 hours) with complete remission in all patients; There were multiple episodes in 9 patients. During the episode, brain MRI showed symmetrical high signals in T2 weighted, Flair and DWI images in periventricular white matter, with predominance in posterior region including splenium of corpus callosum. These changes in imaging were most prominent during or within 1 week after the clinical episode.Significant improvements occurred within 1 month, with complete remission within 4-6 months.No specific locations of mutant amino acids in GJB1 protein were found in these patients with episodic transient reversible white matter involvement.</p><p><b>CONCLUSION</b>Episodic transient reversible white matter involvement may present in a small number of patients with CMTX1. Transient edema of oligodendrocytes due to the dysfunction of gap junction may be involved in the pathogenesis. There is no correlation between the location of the mutant amino acids in GJB1 and the occurrence of the episodes.</p>

Clinical and genetic study of twelve Chinese patients with Alexander disease / 中华儿科杂志

<p><b>OBJECTIVE</b>To delineate the phenotype and genotype characteristics in 12 Chinese children with Alexander disease (AD), which is helpful for the molecular diagnosis and genetic counseling in China.</p><p><b>METHODS</b>Clinical diagnosis of AD was based on MRI criteria proposed by van der Knaarp in 2001. Included AD patients were followed up for 0.50 - 3.67 years. Mutations in GFAP were detected by DNA sequencing.</p><p><b>RESULTS</b>The 12 cases of AD were clinically diagnosed. Age of first visit was 4.87 years (0.75 - 12.00 years), with 3 types of chief complaints: developmental delay in 3, recurrent seizures in 7, unable to walk after falling in 2. Average head circumference was 52.34 cm (44 - 58 cm), which larger than age-matched average by 6.45% (1.80% - 13.95%). On the first visit, scaling according to Gross motor functional classification system (GMFCS) was performed, with GMFCSI in 8, II in 3, V in 1. Mild to severe cognitive dysfunction were found in 8, and seizures in 11 cases. The 12 patients were followed up for 0.50 - 3.67 years, their motor and cognitive function remained stable. Episodic aggravations provoked by fever or falling were observed in 5 cases (41.67%). Heterozygous missense mutations of GFAP were detected in 12 patients. All mutations were de novo; 3 out of 10 mutations identified were novel. R79 and R239 were hot mutations, which was consistent with previous reports. Mutations were located in exon 1 in 8 cases.</p><p><b>CONCLUSIONS</b>The phenotype in these patients is characterized by slower progression compared with reports from other population and high incidence of seizures. And episodic aggravations provoked by fever or falling were more common. The genotype characteristics are consistent with previous reports. The results of this research expanded the number of patients with Alexander disease found to have GFAP coding mutations in China.</p>

Emotional and behavioral comorbidities and the impact on the quality of life in epilepsy children / 中华儿科杂志

<p><b>OBJECTIVE</b>To find out the rate of comorbidities of depression, anxiety disorder and attention deficit hyperactivity disorder (ADHD) symptoms in children with epilepsy and to analyze the relevant affecting factors and impacts on quality of life.</p><p><b>METHOD</b>Totally 142 children with various types of epilepsy underwent neuropsychological assessment with the Depression Self-rating Scale for Children, the Screen for Child Anxiety Related Emotional Disorders and the ADHD Rating Scale-IV, an 18-item parent-rated questionnaire based on the diagnostic criteria for ADHD, the quality of life was measured in 100 cases on antiepileptic medications by the Quality of Life in Epilepsy Inventory (QOLIE-31). The comorbidity rates were calculated using t-test, chi(2) test and multiple logistic analysis, the variables associated with psychiatric comorbidities were determined, and the impact on quality of life was analyzed.</p><p><b>RESULT</b>(1) The total rate of emotional and behavioral comorbidities was 57.7% (82/142), the frequency of depressive disorder, anxiety disorder and ADHD was 14.8%, 44.4% and 17.6%, respectively. The suicidal ideation occasionally occurred in 5.6% of the cases and 0.7% of cases often had the ideation, but no suicidal action was found in any case. (2) Risk factors for the emotional and behavioral disorders: multiple logistic analysis indicated that age, gender and epilepsy illness-related variables were not relative to the comorbidities, P > 0.05, there were interactions among the disorders. (3) The impact on the quality of life: The emotional and behavioral conditions were associated with the low quality of life, which was significantly lower in epileptic children with co-morbid disorder compared to non-comorbidities epilepsy group. Especially negative impact on the total score of quality of life and four sub-items such as overall quality, emotional well-being, cognitive and social function, P < 0.001. There were also significant differences between the two groups in the other three sub-items including fear for seizure attack, energy/fatigue and medication effects (P < 0.05).</p><p><b>CONCLUSIONS</b>The frequency of emotional and behavioral disorders including depress disorder, anxiety disorder and ADHD was considerably high in children with epilepsy. Age, gender and epilepsy illness-related variables are not associated with the emotional and behavioral comorbidities, which interfere with each other. Emotional and behavioral disorder is one of the negative factors to the quality of life in epileptic patients. Neuropsychological assessment and treatment are important for improvement of the quality of life in children with epilepsy.</p>

Follow-up study on levetiracetam monotherapy in children with epilepsy / 中国当代儿科杂志

<p><b>OBJECTIVE</b>To evaluate the efficacy and tolerability of levetiracetam (LEV) in the treatment of epilepsy as a monotherapy in children.</p><p><b>METHODS</b>Thirty-two children with epilepsy (age ranged from 8 months to 12 years) and who had received LEV monotherapy were investigated by a self-controlled and open-label research. LEV was administered at a dose of 10 mg/kg.d, and increased by 10 mg/kg.d per week till to the target dose (20-40 mg/kg.d), with a mean dose of 35 mg/kg.d.</p><p><b>RESULTS</b>Thirty-one patients were followed up for more than three months. Twenty-five patients (80.6%) had at least 50% reduction in seizures, 22 cases (70.9%) became seizure-free, and LEV therapy was discontinued in 5 patients (16.1%) due to either an inadequate seizure control or aggravated seizures. The therapy-related adverse events included mood and behavioral changes (6/31, 19.4%), asthenia (2/31, 6.5%), somnolence (2/31, 6.5%), and skin rashes (1/31, 3.2%). The adverse effects were spontaneously disappeared or disappeared after reducing the LEV dose.</p><p><b>CONCLUSIONS</b>LEV monotherapy is effective and safe for the control of partial and generalized tonic-clonic seizures in children with epilepsy. LEV appears to be a promising anti-epileptic drug for monotherapy in children with epilepsy.</p>

Effects of over-expressing resistin on glucose and lipid metabolism in mice / 浙江大学学报（英文版）（B辑：生物医学和生物技术）

Resistin, a newly discovered peptide hormone mainly secreted by adipose tissues, is present at high levels in serum of obese mice and may be a potential link between obesity and insulin resistance in rodents. However, some studies of rat and mouse models have associated insulin resistance and obesity with decreased resistin expression. In humans, no relationship between resistin level and insulin resistance or adiposity was observed. This suggests that additional studies are necessary to determine the specific role of resistin in the regulation of energy metabolism and adipogenesis. In the present study, we investigated the effect of resistin in vivo on glucose and lipid metabolism by over-expressing resistin in mice by intramuscular injection of a recombinant eukaryotic expression vector pcDNA3.1-Retn encoding porcine resistin gene. After injection, serum resistin and serum glucose (GLU) levels were significantly increased in the pcDNA3.1-Retn-treated mice; there was an obvious difference in total cholesterol (TC) level between the experiment and the control groups on Day 30. In pcDNA3.1-Retn-treated mice, both free fatty acid (FFA) and high density lipoprotein (HDL) cholesterol levels were markedly lower than those of control, whereas HDL cholesterol and triglyceride (TG) levels did not differ between the two groups. Furthermore, lipase activity was expressly lower on Day 20. Our data suggest that resistin over-expressed in mice might be responsible for insulin resistance and parameters related to glucose and lipid metabolism were changed accordingly.