TMEM151A Variants Cause Paroxysmal Kinesigenic Dyskinesia: A Large-Sample Study.

BACKGROUND: Paroxysmal kinesigenic dyskinesia (PKD) is the most common type of paroxysmal dyskinesias. Only one-third of PKD patients are attributed to proline-rich transmembrane protein 2 (PRRT2) mutations. OBJECTIVE: We aimed to explore the potential causative gene for PKD. METHODS: A cohort of 196 PRRT2-negative PKD probands were enrolled for whole-exome sequencing (WES). Gene Ranking, Identification and Prediction Tool, a method of case-control analysis, was applied to identify the candidate genes. Another 325 PRRT2-negative PKD probands were subsequently screened with Sanger sequencing. RESULTS: Transmembrane Protein 151 (TMEM151A) variants were mainly clustered in PKD patients compared with the control groups. 24 heterozygous variants were detected in 25 of 521 probands (frequency = 4.80%), including 18 missense and 6 nonsense mutations. In 29 patients with TMEM151A variants, the ratio of male to female was 2.63:1 and the mean age of onset was 12.93 ± 3.15 years. Compared with PRRT2 mutation carriers, TMEM151A-related PKD were more common in sporadic PKD patients with pure phenotype. There was no significant difference in types of attack and treatment outcome between TMEM151A-positive and PRRT2-positive groups. CONCLUSIONS: We consolidated mutations in TMEM151A causing PKD with the aid of case-control analysis of a large-scale WES data, which broadens the genotypic spectrum of PKD. TMEM151A-related PKD were more common in sporadic cases and tended to present as pure phenotype with a late onset. Extensive functional studies are needed to enhance our understanding of the pathogenesis of TMEM151A-related PKD. © 2021 International Parkinson and Movement Disorder Society.

Antibiotics prescription for targeted therapy of pediatric invasive pneumococcal diseases in China: a multicenter retrospective study.

BACKGROUND: Streptococcus pneumoniae (S. pneumoniae) is a major cause of bacterial meningitis, septicemia and pneumonia in children. Inappropriate choice of antibiotic can have important adverse consequences for both the individual and the community. Here, we focused on penicillin/cefotaxime non-susceptibility of S. pneumoniae and evaluated appropriateness of targeted antibiotic therapy for children with IPD (invasive pneumococcal diseases) in China. METHODS: A multicenter retrospective study was conducted in 14 hospitals from 13 provinces in China. Antibiotics prescription, clinical features and resistance patterns of IPD cases from January 2012 to December 2017 were collected. Appropriateness of targeted antibiotics therapy was assessed. RESULTS: 806 IPD cases were collected. The non-susceptibility rates of S. pneumoniae to penicillin and cefotaxime were 40.9% and 20.7% respectively in 492 non-meningitis cases, whereas those were 73.2% and 43.0% respectively in 314 meningitis cases. Carbapenems were used in 21.3% of non-meningitis cases and 42.0% of meningitis cases for targeted therapy. For 390 non-meningitis cases with isolates susceptible to cefotaxime, vancomycin and linezolid were used in 17.9% and 8.7% of cases respectively for targeted therapy. For 179 meningitis cases with isolates susceptible to cefotaxime, vancomycin and linezolid were prescribed in 55.3% and 15.6% of cases respectively. Overall, inappropriate targeted therapies were identified in 361 (44.8%) of 806 IPD cases, including 232 (28.8%) cases with inappropriate use of carbapenems, 169 (21.0%) cases with inappropriate use of vancomycin and 62 (7.7%) cases with inappropriate use of linezolid. CONCLUSIONS: Antibiotic regimens for IPD definite therapy were often excessive with extensive prescription of carbapenems, vancomycin or linezolid in China. Antimicrobial stewardship programs should be implemented to improve antimicrobial use.

Serum soluble lymphocyte activation gene-3 as a diagnostic biomarker in Parkinson's disease: A pilot multicenter study.

OBJECTIVE: Lymphocyte activation gene-3 (LAG-3) could mediate pathological α-synuclein transmission in neurodegeneration and may be involved in the pathogenesis of Parkinson's disease (PD). The aim of the present study was to explore soluble LAG-3 (sLAG-3) as a potential diagnostic biomarker for PD. METHODS: Serum sLAG-3 concentrations were measured by a quantitative ELISA for patients with PD, essential tremor (ET) and age- and sex-matched controls. The relationships between sLAG-3 and clinical phenotype were assessed via correlation analysis and logistic regression. RESULTS: Serum sLAG-3 levels in patients with PD were significantly higher than those in ET patients and age- and sex-matched controls. The area under the curve of serum sLAG-3 in differentiating PD from age- and sex-matched controls was 0.82. Serum sLAG-3 was associated with non-motor symptoms and excessive daytime sleep. CONCLUSION: sLAG-3 is a candidate novel biomarker for PD. © 2018 International Parkinson and Movement Disorder Society.

Case report: Muscular tuberculosis with lower-extremity muscular masses as the initial presentation: Clinicopathological analysis of two cases and review of the literature.

Background: Tuberculosis (TB) is a threat to public health that mostly affects people in developing countries. TB presenting as a soft tissue mass is rare and is usually seen in patients with muscular tuberculosis (MT). Case presentation: In this study, we present the clinical, radiographic, and pathological features of two cases and retrospective evaluations of an additional 28 patients who were diagnosed with MT. More patients were men (60.9%) than women (39.1%), with a male-to-female ratio of 1.6:1. The average age among male and female patients was 38.9 and 30.1 years, respectively. MT usually presents with painful or painless muscular nodules on the lower limbs. Imaging findings, including ultrasound, CT, and MRI, can be used to identify lesions and sites for biopsy. The most typical histopathological feature of MT is granulomatous inflammation with caseous necrosis and epithelioid granulomata. Acid-fast bacilli stain and polymerase chain reaction (PCR) assays are helpful in identifying tubercle bacillus. Conclusion: We describe two MT cases with lower-extremity muscular masses as the initial presentation. The results suggest that muscle biopsy and pathological analysis remain necessary for diagnosis. Most of the patients could be cured with standard antituberculosis therapy.

[Analysis on work related fatigue among prison police and mental medical staffs].

OBJECTIVE: To investigate the work related fatigue among prison police and mental medical staffs; to compare the social support between two groups; to develop specific intervention strategies in the future. METHODS: The Chinese Maslach Burnout Inventory (CMBI) and the Social Support Rating Scale (SSRS) were applied to 100 prison police and 100 mental medical staffs respectively. Their status of work related fatigue and relevant social support were analyzed accordingly. RESULTS: 1) The level of fatigue among prison police was higher than mental medical staffs (P < 0.05); 2) The factor scores of "emotional burnout" and "depersonalization" among prison police were higher than that among mental medical staffs (P < 0.05). There was no significant difference between the two groups on the "decreased sense of achievement" (P > 0.05); 3) The level of social support in the prison police was higher than that in the mental medical staffs (P < 0.05). CONCLUSION: Both prison police and mental medical staffs were vulnerable to suffering from fatigue. However, the details and relevant social support between these two groups were different. Active intervention should be taken for different occupation.

Clinicopathologic characterization and abnormal autophagy of CSF1R-related leukoencephalopathy.

BACKGROUND: CSF1R-related leukoencephalopathy, also known as hereditary diffuse leukoencephalopathy with spheroids (HDLS), is a rare white-matter encephalopathy characterized by motor and neuropsychiatric symptoms due to colony-stimulating factor 1 receptor (CSF1R) gene mutation. Few of CSF1R mutations have been functionally testified and the pathogenesis remains unknown. METHODS: In order to investigate clinical and pathological characteristics of patients with CSF1R-related leukoencephalopathy and explore the potential impact of CSF1R mutations, we analyzed clinical manifestations of 15 patients from 10 unrelated families and performed brain biopsy in 2 cases. Next generation sequencing was conducted for 10 probands to confirm the diagnosis. Sanger sequencing, segregation analysis and phenotypic reevaluation were utilized to substantiate findings. Functional examination of identified mutations was further explored. RESULTS: Clinical and neuroimaging characteristics were summarized. The average age at onset was 35.9 ± 6.4 years (range 24-46 years old). Younger age of onset was observed in female than male (34.2 vs. 39.2 years). The most common initial symptoms were speech dysfunction, cognitive decline and parkinsonian symptoms. One patient also had marked peripheral neuropathy. Brain biopsy of two cases showed typical pathological changes, including myelin loss, axonal spheroids, phosphorylated neurofilament and activated macrophages. Electron microscopy disclosed increased mitochondrial vacuolation and disorganized neurofilaments in ballooned axons. A total of 7 pathogenic variants (4 novel, 3 documented) were identified with autophosphorylation deficiency, among which c.2342C > T remained partial function of autophosphorylation. Western blotting disclosed the significantly lower level of c.2026C > T (p.R676*) than wild type. The level of microtubule associated protein 1 light chain 3-II (LC3-II), a classical marker of autophagy, was significantly lower in mutants expressed cells than wild type group by western blotting and immunofluorescence staining. CONCLUSIONS: Our findings support the loss-of-function and haploinsufficiency hypothesis in pathogenesis. Autophagy abnormality may play a role in the disease. Repairing or promoting the phosphorylation level of mutant CSF1R may shed light on therapeutic targets in the future. However, whether peripheral polyneuropathy potentially belongs to CSF1R-related spectrum deserves further study with longer follow-up and more patients enrolled. TRIAL REGISTRATION: ChiCTR, ChiCTR1800015295. Registered 21 March 2018.

Synthesis, characterization, and study on HeLa cells activity of a dinuclear complex [Cu4(phen)4(H2O)2]·(pyri)·3H2O.

The complex [Cu4(phen)4(H2O)2]·(pyri)·3H2O(where phen=1,10-phenanthroline and pyri=3,5-pyridine dicarboxylic acid)has been synthesized and characterized. IR spectra, elemental analysis and X-ray single-crystal diffraction were carried out to determine the composition and crystal structure of the complex. The binding of the complex with HC-DNA (HeLa cells DNA, which was extracted by ourselves) was investigated by fluorescence spectrum. Gel electrophoresis assay demonstrates the ability of the complex to cleave the extracted HC-DNA. Additionally, the complex exhibited a significant cytotoxic specificity and cancer cell inhibitory rate. The apoptotic tests indicate that the complex have an apoptotic effect on HeLa cells.

[The expression of periphery blood leucocyte CCR3 and CCR5 in the children with Epstein-Barr virus associated infectious mononucleosis].

OBJECTIVE: To explore the expression of periphery blood leucocyte CCR3 and CCR5 and to comprehend T helper cell in the Children with Epstein-Barr virus associated infectious mononucleosis. METHODS: We defined the children according to the diagnosis criterion through Paul-Bunnell test inspecting the children's periphery blood unusual lymphocyte and detecting their anti-EBV-CA-IgM, anti-EBV-CA-IgG and anti-EBV-NA-IgG by ELISA and counted the ratio of CCR3 + and CCR5 + cells in lymphocytes with flow cytometry. RESULTS: The ratio of unusual lymphocyte in IM was higher than that of the healthy control group (P < 0.05). The ratio of CCR3 + cells in IM group was higher than that of the healthy control group (P < 0.05). The ratio of CCR5 + cells in IM group was significantly lower than that of the healthy control group. CCR3 + had direct interrelation with fever continued time and the ratio of unusual lymphocyte. There was a negative interrelation between CCR5 and fever continued time (P < 0.05). CONCLUSIONS: Children infectious of IM expressed higher level of CCR3 + and lower level of CCR5 + and there was a tendency of Th2 polarization with over production of T helper cell divide imbalance. CCR3 + and CCR5 + may be important targets to judge the degree of seriousness of IM.

Synthesis, characterization, interaction with DNA and cytotoxicity in vitro of novel pyridine complexes with Zn(II).

Four novel Zn(II) complexes [Zn(L(1))(bipy)(H(2)O)(2)].4H(2)O(1), [Zn(L(1))(phen)(H(2)O)(2)].4H(2)O(2), [Zn(L(2))(bipy)(H(2)O)(2)].4H(2)O(3) and [Zn(L(2))(phen)(H(2)O)(2)].4H(2)O (4), where bipy=2,2'-bipyridine, phen=1,10-phenanthroline, L(1)=2,2'-bipyridine 5,5'-dicarboxylic acid, L(2)=2,2'-bipyridine-4,4'-dicarboxylic acid, have been synthesized and characterized using IR, (1)H NMR, element analysis and single-crystal X-ray diffractometry. The unit cell parameters for the title complex (1), a=7.9621(10)A, b=12.6853(17)A, c=13.3714(17)A, alpha=68.549(2) degrees , beta=79.065(2) degrees , gamma=88.723(2) degrees , V=1232.5(3)A(3), Z=15, space group,P-1(2).complex (4) a=9.5710(5)A, b=14.1140(7)A, c=19.0045(9)A, alpha=90 degrees , beta=99.9920(10) degrees , gamma=90 degrees , V=2528.3(2)A(3), Z=32, space group, P121/n 1(14). The binding of the complexes with fish sperm DNA (FS-DNA) was investigated by electronic absorption spectra and fluorescence spectroscopy, showing that the complexes have the ability of interaction with DNA of intercalative mode. The intrinsic binding constant K of the complexes with FS-DNA is 0.37 x 10(5)M(-1) (1) 0.73 x 10(5)M(-1) (2), 0.98 x 10(5)M(-1) (3), and 1.05 x 10(5)M(-1) (4). The results indicate that the four complexes bound to DNA with different binding affinity, in the order complex 4>3>2>1. Gel electrophoresis assay demonstrates the ability of the complexes to cleave the pBR322 plasmid DNA. The cytotoxic activity of the complexes was tested against four different cancer cell lines. The four complexes exhibited cytotoxic specificity and significant cancer cell inhibitory rate.