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1.
Parasitol Res ; 123(9): 316, 2024 Sep 04.
Article in English | MEDLINE | ID: mdl-39230789

ABSTRACT

Schistosomiasis remains a formidable challenge to global public health. This study aims to predict the spatial distribution of schistosomiasis seropositive rates in Hunan Province, pinpointing high-risk transmission areas and advocating for tailored control measures in low-endemic regions. Six machine learning models and their corresponding hybrid machine learning-Kriging models were employed to predict the seropositive rate. The optimal model was selected through internal and external validations to simulate the spatial distribution of seropositive rates. Our results showed that the hybrid machine learning-Kriging model demonstrated superior predictive performance compared to basic machine learning model and the Cubist-Kriging model emerged as the most optimal model for this study. The predictive map revealed elevated seropositive rates around Dongting Lake and its waterways with significant clustering, notably in the central and northern regions of Yiyang City and the northeastern areas of Changde City. The model identified gross domestic product, annual average wind speed and the nearest distance from the river as the top three predictors of seropositive rates, with annual average daytime surface temperature contributing the least. In conclusion, our research has revealed that integrating the Kriging method significantly enhances the predictive performance of machine learning models. We developed a Cubist-Kriging model with high predictive performance to forecast the spatial distribution of schistosomiasis seropositive rates. These findings provide valuable guidance for the precise prevention and control of schistosomiasis.


Subject(s)
Machine Learning , Schistosomiasis , China/epidemiology , Humans , Schistosomiasis/epidemiology , Schistosomiasis/prevention & control , Seroepidemiologic Studies , Spatial Analysis , Models, Statistical , Animals
2.
Diabetes Metab Res Rev ; 39(4): e3614, 2023 05.
Article in English | MEDLINE | ID: mdl-36670050

ABSTRACT

AIMS: To investigate whether intermittently scanned continuous glucose monitoring without alarms (intermittently scanned CGM (isCGM)) improves glycaemic control over capillary blood glucose monitoring (BGM) among adult type 1 diabetes mellitus (T1DM) patients with suboptimal control. MATERIALS AND METHODS: Adults with T1DM and HbA1c between 7% and 10% were 1:1 randomized to use isCGM or BGM for 24 weeks. The primary outcome was the change in HbA1c levels after intervention. The secondary outcomes were the changes in sensor-derived metrics. RESULTS: A total of 104 adults with T1DM (34.2 ± 12.2 years; M/F, 38/66) were randomized to the isCGM group (n = 54) and the BGM group (n = 50). After 24 weeks, HbA1c significantly decreased in the isCGM group (8.1 ± 0.7% to 7.5 ± 1.0%) and the BGM group (8.0 ± 0.8% to 7.7 ± 1.0%) with between-group differences of 0.3% (95% coefficient intervals, 0.0%-0.6%; P = 0.04). The percentage of HbA1c reduction over 1.0% and 1.5% was significantly higher in the isCGM group with adjusted odds ratios of 2.5 (95% CI: 1.1-5.5; P = 0.03) and 3.2 (95% CI: 1.1-9.0; P = 0.03). Mean time-in-range 70-180 mg/dl (TIR) in the isCGM group significantly increased (from 58.5 ± 13.0% to 63.0 ± 12.6%), whereas mean TIR was similar in the BGM group (from 58.0 ± 14.6% to 57.5 ± 14.5%). Time spent in hyperglycemia reduced more in the isCGM group and time spent in hypoglycemia did not change significantly in both groups. CONCLUSIONS: Among adult T1DM patients with suboptimal glycaemic control, compared with BGM, isCGM use resulted in a statistically significant improvement in glycaemic control after 24-week intervention. TRIAL REGISTRATION: Clinicaltrials.gov Identifier (NCT03522870).


Subject(s)
Diabetes Mellitus, Type 1 , Hypoglycemia , Humans , Adult , Diabetes Mellitus, Type 1/drug therapy , Blood Glucose , Blood Glucose Self-Monitoring/methods , Glycated Hemoglobin , Hypoglycemia/prevention & control , Hypoglycemic Agents/therapeutic use
3.
Mol Biol Rep ; 50(8): 6643-6654, 2023 Aug.
Article in English | MEDLINE | ID: mdl-37358763

ABSTRACT

BACKGROUND: Sepsis is a life-threatening disease with a limited effectiveness and the potential mechanism remains unclear. LncRNA NEAT-2 is reported to be involved in the regulation of cardiovascular disease. This study aimed to investigate the function of NEAT-2 in sepsis. METHODS: We built sepsis animal model with Male Balb/C mice induced by cecal ligation and puncture (CLP). A total of 54 mice were randomly assigned into eight groups: sham operation group (n = 18), CLP group (n = 18), CLP plus si-control group (n = 3), CLP plus si-NEAT2 group (n = 3), CLP plus mimic control group (n = 3), CLP plus miR-320 group (n = 3), CLP plus normal saline group (n = 3), and normal control group (n = 3). The number of peripheral endothelial progenitor cells (EPCs), the expression level of NEAT-2 and miR-320 were detected during progression of sepsis, as well as the number of peripheral EPCs and level of TNF-α, IL-6, VEGF, ALT, AST and Cr. In addition, the function of EPCs was evaluated after NEAT-2 knockdown and miR-320 overexpression in vitro. RESULTS: The number of circulating EPCs increased significantly in sepsis. NEAT-2 expression was significantly increased in the progress of sepsis, accompanied with miR-320 downregulated. NEAT-2 knockdown and miR-320 overexpression attenuated hepatorenal function and increased cytokines in sepsis. Moreover, NEAT-2 knockdown and miR-320 overexpression decreased the proliferation, migration and angiogenesis of endothelial progenitor cells in vitro. CONCLUSIONS: LncRNA-NEAT2 regulated the number and function of endothelial progenitor cells via miR-320 in sepsis, which may contribute to the development of novel potential clinical therapy for sepsis.


Subject(s)
Endothelial Progenitor Cells , MicroRNAs , RNA, Long Noncoding , Sepsis , Mice , Male , Animals , RNA, Long Noncoding/genetics , Liver/metabolism , Sepsis/genetics , Sepsis/metabolism , MicroRNAs/genetics , MicroRNAs/metabolism , Disease Models, Animal
4.
Chemotherapy ; 68(1): 48-54, 2023.
Article in English | MEDLINE | ID: mdl-35810737

ABSTRACT

Fusidic acid (FA) had excellent antimicrobial effects due to its unique mechanism of action. Since 1962, FA has been widely used in the systemic and topical treatment of staphylococcal infections and exhibits a well-characterized potency against methicillin-susceptible Staphylococcus aureus, methicillin-resistant Staphylococcus aureus, and methicillin-resistant coagulase-negative Staphylococci. In view of the spectrum of activity, no cross-resistance with other clinically used antibiotics, and potential penetration into brain tissue, FA was used to treat possible gra-positive bacteria in 3 patients with intracranial infections in the present report. FA and its active metabolite (3-keto FA) were measured in plasma and cerebrospinal fluid (CSF) to assess the treatment of FA, and the results indicated that 1,500 mg per day of FA was sufficient to achieve therapeutic concentrations in both plasma and CSF in intracranial infection patients, while the dosage did not experience unexpected regimen-related toxicity.


Subject(s)
Methicillin-Resistant Staphylococcus aureus , Staphylococcal Infections , Humans , Fusidic Acid/therapeutic use , Fusidic Acid/pharmacology , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/therapeutic use , Staphylococcal Infections/drug therapy , Staphylococcal Infections/microbiology , Staphylococcus aureus , Microbial Sensitivity Tests
5.
Pak J Med Sci ; 39(5): 1492-1495, 2023.
Article in English | MEDLINE | ID: mdl-37680811

ABSTRACT

Objective: To investigate the effects of morphine hydrochloride sustained-release tablets and oxycodone hydrochloride sustained-release tablets on T-cell levels in advanced lung squamous cell carcinoma(LUSC) with moderate to severe cancer pain. Methods: A retrospective study was used, ninety-eight patients who were admitted to The First Affiliated Hospital of Hebei North University for treatment of advanced LUSC with moderate to severe cancer pain between January 2021 and December 2021 were randomized into two groups(n=49 each) using the sealed envelope system. The reference group was treated with morphine hydrochloride sustained-release tablets, while the experimental group received oxycodone hydrochloride sustained-release tablets to compare pain relief rates(PRRs), levels of T cells, pain intensity, et al. Blood samples were collected for lymphocyte levels by flow cytometry. Results: The experimental group had significantly higher level than the reference group(P<0.05). Before administration, the two groups did not differ greatly in levels of T-cell subsets or pain scores on the visual analog scale(P>0.05, respectively). At 15 days of administration, the Treg level in the experimental group was higher than in the reference group; T helper 17 and 22 cells were reduced in both groups, and the decrease was more pronounced in the experimental group. At seven and 15 days of administration, the experimental group had a VAS score significantly lower than the reference group(P<0.05). The total adverse reaction rate was significantly lower in the experimental group as compared with the reference group(P<0.05). Conclusions: Oxycodone hydrochloride sustained-release tablets demonstrate desirable efficacy and safety in advanced LUSC with moderate to severe cancer pain by modulating T-cells in the body and improving the PRR.

6.
Am J Hum Genet ; 105(1): 166-176, 2019 07 03.
Article in English | MEDLINE | ID: mdl-31178126

ABSTRACT

Neuronal intranuclear inclusion disease (NIID) is a slowly progressing neurodegenerative disease characterized by eosinophilic intranuclear inclusions in the nervous system and multiple visceral organs. The clinical manifestation of NIID varies widely, and both familial and sporadic cases have been reported. Here we have performed genetic linkage analysis and mapped the disease locus to 1p13.3-q23.1; however, whole-exome sequencing revealed no potential disease-causing mutations. We then performed long-read genome sequencing and identified a large GGC repeat expansion within human-specific NOTCH2NLC. Expanded GGC repeats as the cause of NIID was further confirmed in an additional three NIID-affected families as well as five sporadic NIID-affected case subjects. Moreover, given the clinical heterogeneity of NIID, we examined the size of the GGC repeat among 456 families with a variety of neurological conditions with the known pathogenic genes excluded. Surprisingly, GGC repeat expansion was observed in two Alzheimer disease (AD)-affected families and three parkinsonism-affected families, implicating that the GGC repeat expansions in NOTCH2NLC could also contribute to the pathogenesis of both AD and PD. Therefore, we suggest defining a term NIID-related disorders (NIIDRD), which will include NIID and other related neurodegenerative diseases caused by the expanded GGC repeat within human-specific NOTCH2NLC.


Subject(s)
Intranuclear Inclusion Bodies/pathology , Neurodegenerative Diseases/pathology , Receptors, Notch/genetics , Trinucleotide Repeat Expansion/genetics , Adult , Aged , Female , Humans , Intranuclear Inclusion Bodies/genetics , Male , Middle Aged , Neurodegenerative Diseases/genetics , Pedigree , Exome Sequencing
7.
Cerebellum ; 21(3): 358-367, 2022 Jun.
Article in English | MEDLINE | ID: mdl-34264505

ABSTRACT

Spinocerebellar ataxias (SCAs) are a large group of hereditary neurodegenerative diseases characterized by ataxia and dysarthria. Due to high clinical and genetic heterogeneity, many SCA families are undiagnosed. Herein, using linkage analysis, WES, and RP-PCR, we identified the largest SCA36 pedigree in Asia. This pedigree showed some distinct clinical characteristics. Cognitive impairment and gaze palsy are common and severe in SCA36 patients, especially long-course patients. Although no patients complained of hearing loss, most of them presented with hearing impairment in objective auxiliary examination. Voxel-based morphometry (VBM) demonstrated a reduction of volumes in cerebellum, brainstem, and thalamus (corrected P < 0.05). Reduced volumes in cerebellum were also found in presymptomatic carriers. Resting-state functional MRI (R-fMRI) found reduced ReHo values in left cerebellar posterior lobule (corrected P < 0.05). Diffusion tensor imaging (DTI) demonstrated a reduction of FA values in cerebellum, midbrain, superior and inferior cerebellar peduncle (corrected P < 0.05). MRS found reduced NAA/Cr values in cerebellar vermis and hemisphere (corrected P < 0.05). Our findings could provide new insights into management of SCA36 patients. Detailed auxiliary examination are recommended to assess hearing or peripheral nerve impairment, and we should pay more attention to eye movement and cognitive changes in patients. Furthermore, for the first time, our multimodel neuroimaging evaluation generate a full perspective of brain function and structure in SCA36 patients.


Subject(s)
Diffusion Tensor Imaging , Spinocerebellar Ataxias , Cerebellum , Humans , Magnetic Resonance Imaging , Pedigree , Spinocerebellar Ataxias/diagnostic imaging , Spinocerebellar Ataxias/genetics
8.
Arch Microbiol ; 204(7): 441, 2022 Jun 30.
Article in English | MEDLINE | ID: mdl-35773566

ABSTRACT

Mycoplasma pneumoniae (MPP) induced pneumonia is a common disease of children. Sinomenine (SIN) is an isoquinoline mainly sequestered from Sinomenium acutum. It is a promising drug for treating arthritis, lung, colon, liver and gastric cancer. Hence, the present study investigated the role and mechanism of SIN treatment in MPP induced pneumonia in experimental in-vivo mice model. The BALB/c male mice were separated into four groups (n = 6 mice/group): normal, MPP, MPP + SIN (20 mg/kg bw), and SIN (20 mg/kg bw) alone. Results were expressed as mean ± SD. Data were analyzed using one way Analysis of Variance (ANOVA) with the Dunnett's post hoc test using SPSS v 18.0. P value < 0.05 was considered significant. The total protein, cell count, inflammatory cytokines, MP-IgM, Monocyte chemo attractant protein-1 (MCP-1), and MP-DNA were measured. The protein expressions of Bax/Bcl-2, ERK, JNK, NF-κB were analyzed and histopathology of lungs was examined. SIN treatment significantly (p < 0.05) reduced the total proteins, cell counts in BALF, inflammatory cytokines, MP-IgM, MCP-1, MP-DNA and reversed the histological alterations. SIN attenuated the apoptotic pathway through the modulation of Bax/Bcl-2 expression. SIN alleviated pulmonary inflammatory mediators and apoptosis in MPP-infected mice via suppression of ERK/JNK/NF-κB signaling. SIN administration diminished inflammation and lung fibrosis by inhibiting apoptosis in MPP mice. Hence, SIN is a potential natural protective remedy for MPP.


Subject(s)
MAP Kinase Signaling System , Morphinans , Mycoplasma pneumoniae , NF-kappa B , Pneumonia, Mycoplasma , Animals , Cytokines/metabolism , Immunoglobulin M , Inflammation , MAP Kinase Signaling System/drug effects , Male , Mice , Mice, Inbred BALB C , Morphinans/pharmacology , Mycoplasma pneumoniae/drug effects , NF-kappa B/metabolism , Pneumonia, Mycoplasma/drug therapy , Pneumonia, Mycoplasma/metabolism , bcl-2-Associated X Protein/metabolism
9.
Endocr J ; 69(3): 243-251, 2022 Mar 28.
Article in English | MEDLINE | ID: mdl-34629336

ABSTRACT

Pancreatic neuroendocrine tumors (P-NETs) secreting ectopic adrenocorticotropic hormones (ACTH) are rare and often delayed in diagnosis due to their atypical clinical characteristics. Here, we describe a case of P-NET in the pancreatic tail. The tumor had metastasized to the liver and secreted gastrin and ACTH. A 60-year-old female patient was diagnosed with gastrinoma in the pancreatic tail with liver metastases in 2015. After 3 months, the patient presented refractory hypokalemia and thyroid dysfunction. The final diagnosis was P-NET with ectopic ACTH syndrome (EAS). After cytoreductive surgery and the use of long-acting somatostatin analogs, plasma potassium levels and thyroid function were effectively corrected. Although Sandostatin LAR® Depot and proton pump inhibitors (PPIs) were used throughout the follow-up period, the tumor relapsed 4 years later. After aggressive treatment, including right hepatectomy, microwave coagulation of the left liver, and cholecystectomy, the tumor returned 4 months later. Finally, the patient underwent three hepatic artery embolizations and 12 courses of CAPTEM regimen chemotherapy. The markers of disease were almost maintained in the normal ranges until now. We have followed up on this case for more than 5 years. A timely and comprehensive examination of hormones and immunohistochemistry is essential. The prognosis of P-NET is poor. Regular long-term follow-up and the application of combined therapies are helpful to control the disease and improve the prognosis.


Subject(s)
ACTH Syndrome, Ectopic , Neuroendocrine Tumors , Pancreatic Neoplasms , ACTH Syndrome, Ectopic/diagnosis , ACTH Syndrome, Ectopic/etiology , ACTH Syndrome, Ectopic/pathology , Adrenocorticotropic Hormone , Female , Follow-Up Studies , Humans , Middle Aged , Neuroendocrine Tumors/complications , Neuroendocrine Tumors/diagnosis , Neuroendocrine Tumors/therapy , Pancreatic Neoplasms/complications , Pancreatic Neoplasms/diagnosis , Pancreatic Neoplasms/therapy
10.
Microb Pathog ; 150: 104703, 2021 Jan.
Article in English | MEDLINE | ID: mdl-33347963

ABSTRACT

Contamination with the fungus Alternaria spp. is often considered to have originated from laboratory sources, which occasionally causes infection in immunocompromised patients, termed as phaeohyphomycosis. Here, we have reported a case of cutaneous alternariosis caused by Alternaria alternata. This diagnosis was based on microscopic examination and mycological culturing of patient's vesicular lesions, with the use of 5 molecular markers (namely, ITS, ATPase, Actin, rpb2, and tef1) for strain identification. We noted that Alternaria infection caused an increase in the serum level of (1-3)-ß-D-glucan (BG) in the patients. To the best of our knowledge, no such finding has been reported in previously in the literature.


Subject(s)
Alternariosis , beta-Glucans , Alternaria , Alternariosis/diagnosis , Alternariosis/drug therapy , Antifungal Agents/therapeutic use , Humans , Immunocompromised Host
11.
Brain ; 143(1): 222-233, 2020 01 01.
Article in English | MEDLINE | ID: mdl-31819945

ABSTRACT

Essential tremor is one of the most common movement disorders. Despite its high prevalence and heritability, the genetic aetiology of essential tremor remains elusive. Up to now, only a few genes/loci have been identified, but these genes have not been replicated in other essential tremor families or cohorts. Here we report a genetic study in a cohort of 197 Chinese pedigrees clinically diagnosed with essential tremor. Using a comprehensive strategy combining linkage analysis, whole-exome sequencing, long-read whole-genome sequencing, repeat-primed polymerase chain reaction and GC-rich polymerase chain reaction, we identified an abnormal GGC repeat expansion in the 5' region of the NOTCH2NLC gene that co-segregated with disease in 11 essential tremor families (5.58%) from our cohort. Clinically, probands that had an abnormal GGC repeat expansion were found to have more severe tremor phenotypes, lower activities of daily living ability. Obvious genetic anticipation was also detected in these 11 essential tremor-positive families. These results indicate that abnormal GGC repeat expansion in the 5' region of NOTCH2NLC gene is associated with essential tremor, and provide strong evidence that essential tremor is a family of diseases with high clinical and genetic heterogeneities.


Subject(s)
Asian People/genetics , Essential Tremor/genetics , Trinucleotide Repeat Expansion/genetics , Adult , Aged , Female , GC Rich Sequence , Genetic Linkage , Humans , Intranuclear Inclusion Bodies/genetics , Intranuclear Inclusion Bodies/ultrastructure , Male , Microscopy, Electron , Middle Aged , Neurodegenerative Diseases/genetics , Pedigree , Polymerase Chain Reaction , Skin/ultrastructure , Exome Sequencing , Whole Genome Sequencing
12.
Int J Clin Pract ; 75(12): e15007, 2021 Dec.
Article in English | MEDLINE | ID: mdl-34784092

ABSTRACT

OBJECTIVE: To apply the mini-clinical evaluation exercise (Mini-CEX) to orthopaedics and check its influence on clinical operational abilities and thinking abilities. METHODS: The original Mini-CEX was modified to fit orthopaedics, and another Mini-CEX was established to test interns' clinical operational abilities. A total of 39 interns had to complete two types of Mini-CEX twice, once at the beginning and once at the end of the internship. Clinical supervisors collected all the scores and analysed the differences in the average scores between the first and second assessments. The interns were divided into Qualified teacher group and Excellent teacher group according to their Mini-CEX scores. RESULTS: The results of the Mini-CEX examination of the two groups were compared. Researchers found a significant difference between the two assessments on seven domains (all P < 0.05). The scores at the end were higher than those at the beginning, which indicated that the interns' clinical thinking and operational abilities had improved. The average scores of the interns in the Excellent teacher group were significantly higher than those of interns in the Qualified teacher group. CONCLUSIONS: The modified Mini-CEX is suitable for orthopaedic education and could help cultivate interns' clinical thinking ability.


Subject(s)
Internship and Residency , Orthopedics , Clinical Competence , Humans , Physical Examination , Students
13.
Proc Natl Acad Sci U S A ; 115(45): 11567-11572, 2018 11 06.
Article in English | MEDLINE | ID: mdl-30348779

ABSTRACT

Whole-exome sequencing has been successful in identifying genetic factors contributing to familial or sporadic Parkinson's disease (PD). However, this approach has not been applied to explore the impact of de novo mutations on PD pathogenesis. Here, we sequenced the exomes of 39 early onset patients, their parents, and 20 unaffected siblings to investigate the effects of de novo mutations on PD. We identified 12 genes with de novo mutations (MAD1L1, NUP98, PPP2CB, PKMYT1, TRIM24, CEP131, CTTNBP2, NUS1, SMPD3, MGRN1, IFI35, and RUSC2), which could be functionally relevant to PD pathogenesis. Further analyses of two independent case-control cohorts (1,852 patients and 1,565 controls in one cohort and 3,237 patients and 2,858 controls in the other) revealed that NUS1 harbors significantly more rare nonsynonymous variants (P = 1.01E-5, odds ratio = 11.3) in PD patients than in controls. Functional studies in Drosophila demonstrated that the loss of NUS1 could reduce the climbing ability, dopamine level, and number of dopaminergic neurons in 30-day-old flies and could induce apoptosis in fly brain. Together, our data suggest that de novo mutations could contribute to early onset PD pathogenesis and identify NUS1 as a candidate gene for PD.


Subject(s)
Brain/metabolism , Dopaminergic Neurons/metabolism , Mutation , Nerve Tissue Proteins/genetics , Parkinson Disease/genetics , Receptors, Cell Surface/genetics , Adult , Age of Onset , Animals , Apoptosis/genetics , Aryl Hydrocarbon Receptor Nuclear Translocator/antagonists & inhibitors , Aryl Hydrocarbon Receptor Nuclear Translocator/genetics , Aryl Hydrocarbon Receptor Nuclear Translocator/metabolism , Base Sequence , Brain/pathology , Case-Control Studies , Cohort Studies , Disease Models, Animal , Dopamine/metabolism , Dopaminergic Neurons/pathology , Drosophila Proteins/antagonists & inhibitors , Drosophila Proteins/genetics , Drosophila Proteins/metabolism , Drosophila melanogaster/genetics , Drosophila melanogaster/metabolism , Early Diagnosis , Female , Gene Expression , Gene Regulatory Networks , Humans , Male , Nerve Tissue Proteins/metabolism , Parents , Parkinson Disease/diagnosis , Parkinson Disease/metabolism , Parkinson Disease/pathology , RNA, Small Interfering/genetics , RNA, Small Interfering/metabolism , Receptors, Cell Surface/metabolism , Siblings
14.
Hum Mol Genet ; 27(4): 625-637, 2018 02 15.
Article in English | MEDLINE | ID: mdl-29294000

ABSTRACT

Paroxysmal kinesigenic dyskinesia (PKD) is a heterogeneous movement disorder characterized by recurrent dyskinesia attacks triggered by sudden movement. PRRT2 has been identified as the first causative gene of PKD. However, it is only responsible for approximately half of affected individuals, indicating that other loci are most likely involved in the etiology of this disorder. To explore the underlying causative gene of PRRT2-negative PKD, we used a combination strategy including linkage analysis, whole-exome sequencing and copy number variations analysis to detect the genetic variants within a family with PKD. We identified a linkage locus on chromosome 12 (12p13.32-12p12.3) and detected a novel heterozygous mutation c.956 T>G (p.319 L>R) in the potassium voltage-gated channel subfamily A member 1, KCNA1. Whole-exome sequencing in another 58 Chinese patients with PKD who lacked mutations in PRRT2 revealed another novel mutation in the KCNA1 gene [c.765 C>A (p.255 N>K)] within another family. Biochemical analysis revealed that the L319R mutant accelerated protein degradation via the proteasome pathway and disrupted membrane expression of the Kv1.1 channel. Electrophysiological examinations in transfected HEK293 cells showed that both the L319R and N255K mutants resulted in reduced potassium currents and respective altered gating properties, with a dominant negative effect on the Kv1.1 wild-type channel. Our study suggests that these mutations in KCNA1 cause the Kv1.1 channel dysfunction, which leads to familial PKD. The current study further extended the genotypic spectrum of this disorder, indicating that Kv1.1 channel dysfunction maybe one of the underlying defects in PKD.


Subject(s)
Dystonia/genetics , Kv1.1 Potassium Channel/genetics , Adult , Asian People , DNA Copy Number Variations , Female , HEK293 Cells , Humans , Male , Middle Aged , Mutation/genetics , Pedigree
15.
Cytokine ; 133: 155146, 2020 09.
Article in English | MEDLINE | ID: mdl-32505094

ABSTRACT

Rheumatoid arthritis (RA) is a chronic, symmetric, systemic autoimmune disease. Because insufficient apoptosis of fibroblast-like synoviocytes (FLS) is an important characteristic of RA, promoting apoptosis is considered a potential therapeutic tool for treating RA. We have previously found that daphnetin (7,8-dihydroxycoumarin, DAP) has a pro-apoptotic effect on fibroblast-like synoviocytes from collagen-induced arthritis (CIA) rats. In the present study, we further investigated the mechanisms of DAP-induced apoptosis in CIA-FLS. CIA-FLS were incubated with DAP for 48 h in the presence or absence of caspase inhibitors, including inhibitors of caspase-3, caspase-8, or caspase-9 or a pan-caspase inhibitor; then, a series of experiments were performed to evaluate the mechanisms of DAP-induced apoptosis. Our results showed that DAP markedly decreased cell viability and induced the apoptosis of CIA-FLS along with typical morphological and ultrastructural changes; moreover, DAP increased FasL, cytochrome c (Cyt-c), Bax, caspase-3, caspase-8, and caspase-9 mRNA expression and Bax, caspase-3, caspase-8, and caspase-9 protein expression. In contrast, DAP decreased Bcl-2 mRNA and protein expression and promoted the release of Cyt-c from the mitochondria into the cytosol; these effects were attenuated to varying degrees by pre-treatment with caspase inhibitors, especially with caspase-3 or caspase-9 inhibitors or a pan-caspase inhibitor. In conclusion, the current findings demonstrate that the DAP-induced apoptosis of CIA-FLS occurred mainly via a caspase-dependent pathway, in particular the mitochondrial pathway, and that the Bax/Bcl-2 ratio was involved in this process. Thus, DAP may be a potential therapeutic agent for RA.


Subject(s)
Apoptosis/drug effects , Arthritis, Rheumatoid/drug therapy , Fibroblasts/drug effects , Mitochondria/drug effects , Synoviocytes/drug effects , Umbelliferones/pharmacology , Animals , Arthritis, Rheumatoid/chemically induced , Arthritis, Rheumatoid/metabolism , Caspases/metabolism , Cell Line , Collagen/pharmacology , Fibroblasts/metabolism , Mitochondria/metabolism , Rats , Signal Transduction/drug effects , Synovial Membrane/drug effects , Synovial Membrane/metabolism , Synoviocytes/metabolism
16.
Cytokine ; 127: 154952, 2020 03.
Article in English | MEDLINE | ID: mdl-31865066

ABSTRACT

Daphnetin (DAP), an active ingredient extracted from Daphne odora, has pharmacological effects such as anti-inflammatory, antioxidation and anti-tumor properties. The current study aims to investigate the relationship between the anti-rheumatoid effect of DAP and the inhibition of both the PI3K/AKT/mTOR and autophagy signaling pathways. DAP inhibited the proliferation of CIA-FLS in a dose-dependent manner and induce apoptosis, accelerated the G1/G0 phase and inhibited the S phase. DAP reduced the phosphorylation of AKT and mTOR and the expression of Atg5, Beclin-1 and LC3-II/LC3-I in CIA-FLS induced by TNF-α. DAP also reduced the inflammatory response in CIA-FLS induced by TNF-α by inhibiting the cytokine expression of TNF-α, IL-6, TGF-ß, IL-17, and INF-γ and promoting IL-10 expression. Overall, DAP inhibited the proliferation of CIA-FLS by down-regulating the PI3K/AKT/mTOR signaling pathway and inhibited autophagy in order to induces apoptosis, which may be potential therapeutic approach in treatment of RA.


Subject(s)
Arthritis, Experimental/drug therapy , Autophagy/drug effects , Fibroblasts/drug effects , Signal Transduction/drug effects , Synoviocytes/drug effects , Tumor Necrosis Factor-alpha/metabolism , Umbelliferones/pharmacology , Animals , Anti-Inflammatory Agents/pharmacology , Apoptosis/drug effects , Arthritis, Experimental/chemically induced , Arthritis, Experimental/metabolism , Arthritis, Rheumatoid/chemically induced , Arthritis, Rheumatoid/drug therapy , Arthritis, Rheumatoid/metabolism , Cell Cycle/drug effects , Cell Proliferation/drug effects , Cells, Cultured , Collagen/pharmacology , Disease Models, Animal , Fibroblasts/metabolism , Inflammation/drug therapy , Inflammation/metabolism , Phosphorylation/drug effects , Rats , Synoviocytes/metabolism
17.
J Med Genet ; 56(4): 265-270, 2019 04.
Article in English | MEDLINE | ID: mdl-30194086

ABSTRACT

BACKGROUND: The locus for familial cortical myoclonic tremor with epilepsy (FCMTE) has long been mapped to 8q24 in linkage studies, but the causative mutations remain unclear. Recently, expansions of intronic TTTCA and TTTTA repeat motifs within SAMD12 were found to be involved in the pathogenesis of FCMTE in Japanese pedigrees. We aim to identify the causative mutations of FCMTE in Chinese pedigrees. METHODS: We performed genetic linkage analysis by microsatellite markers in a five-generation Chinese pedigree with 55 members. We also used array-comparative genomic hybridisation (CGH) and next-generation sequencing (NGS) technologies (whole-exome sequencing, capture region deep sequencing and whole-genome sequencing) to identify the causative mutations in the disease locus. Recently, we used low-coverage (~10×) long-read genome sequencing (LRS) on the PacBio Sequel and Oxford Nanopore platforms to identify the causative mutations, and used repeat-primed PCR for validation of the repeat expansions. RESULTS: Linkage analysis mapped the disease locus to 8q23.3-24.23. Array-CGH and NGS failed to identify causative mutations in this locus. LRS identified the intronic TTTCA and TTTTA repeat expansions in SAMD12 as the causative mutations, thus corroborating the recently published results in Japanese pedigrees. CONCLUSIONS: We identified the pentanucleotide repeat expansion in SAMD12 as the causative mutation in Chinese FCMTE pedigrees. Our study also suggested that LRS is an effective tool for molecular diagnosis of genetic disorders, especially for neurological diseases that cannot be positively diagnosed by conventional clinical microarray and NGS technologies.


Subject(s)
Genetic Association Studies , Introns , Nerve Tissue Proteins/genetics , Pedigree , Phenotype , Tandem Repeat Sequences , Adult , Comparative Genomic Hybridization , Epilepsies, Myoclonic/diagnosis , Epilepsies, Myoclonic/genetics , Female , Genetic Association Studies/methods , Humans , Male , Sequence Analysis, DNA , Exome Sequencing , Whole Genome Sequencing
18.
World J Surg Oncol ; 18(1): 302, 2020 Nov 19.
Article in English | MEDLINE | ID: mdl-33213468

ABSTRACT

BACKGROUND: Analysis of the risk factors associated with functional delayed gastric emptying after distal gastric cancer surgery to provide a basis for further reduction of the incidence of this complication. METHODS: Total of 1382 patients with distal gastric cancer from January 2016 to October 2018 were enrolled. Correlation analysis was performed in 53 patients with FDGE by logistic regression. Subgroup risk analysis was performed in 114 patients with preoperative pyloric obstruction. A Pearson Chi-square analysis was used to compare categorical variables between normal distribution groups. Meanwhile, a t test was used to compare continuous variables between groups. Odds ratio (OR) was used for comparison of the two groups, and it was summarized with its 95% confidence interval (CI) and p value using logistic regression. RESULT: In multivariable analysis, age (OR 1.081, 95% CI, 1.047-1.117), BMI (OR 1.233, 95% CI, 1.116-1.363), preoperative pyloric obstruction (OR 3.831, 95% CI, 1.829-8.023), smaller volume of residual stomach (OR 1.838, 95% CI, 1.325-6.080), and anastomosis in greater curvature perpendicular (OR 3.385, 95% CI, 1.632-7.019) and in greater curvature parallel (OR 2.375, 95% CI, 0.963-5.861) were independent risk factors of FDGE. In the preoperative pyloric obstruction group, higher BMI (OR 1.309, 95% CI, 1.086-1.579) and preoperative obstruction time (OR 1.054, 95% CI, 1.003-1.108) were independent risk factors of FDGE and preoperative gastrointestinal decompression (OR 0.231, 95% CI, 0.068-0.785) was independent protective factor of FDGE. CONCLUSION: Adequate gastrointestinal decompression should be performed before the operation to reduce the incidence of postoperative gastroparesis in patients with preoperative pyloric obstruction. We also could improve the surgical methods to reduce the occurrence of FDGE, such as controlling the size of the residual stomach, ensuring blood supply. Especially selecting an appropriate stapler and anastomosis during the anastomosis process, the occurrence of FDGE can be reduced.


Subject(s)
Gastroparesis , Stomach Neoplasms , Humans , Postoperative Complications/epidemiology , Postoperative Complications/prevention & control , Prognosis , Retrospective Studies , Risk Factors , Stomach Neoplasms/surgery
19.
World J Surg Oncol ; 18(1): 2, 2020 Jan 02.
Article in English | MEDLINE | ID: mdl-31898548

ABSTRACT

BACKGROUND: The status of lymph nodes in early gastric cancer is critical to make further clinical treatment decision, but the prediction of lymph node metastasis remains difficult before operation. This study aimed to develop a nomogram that contained preoperative factors to predict lymph node metastasis in early gastric cancer patients. METHODS: This study analyzed the clinicopathologic features of 823 early gastric cancer patients who underwent gastrectomy retrospectively, among which 596 patients were recruited in the training cohort and 227 patients in the independent validation cohort. Significant risk factors in univariate analysis were further identified to be independent variables in multivariable logistic regression analysis, which were then incorporated in and presented with a nomogram. And internal and external validation curves were plotted to evaluate the discrimination of the nomogram. RESULTS: Totally, six independent predictors, including the tumor size, macroscopic features, histology differentiation, P53, carbohydrate antigen 19-9, and computed tomography-reported lymph node status, were enrolled in the nomogram. Both the internal validation in the training cohort and the external validation in the validation cohort showed the nomogram had good discriminations, with a C-index of 0.82 (95%CI, 0.78 to 0.86) and 0.77 (95%CI, 0.60 to 0.94) respectively. CONCLUSIONS: Our study developed a new nomogram which contained the most common and significant preoperative risk factors for lymph node metastasis in patients with early gastric cancer. The nomogram can identify early gastric cancer patients with the high probability of lymph node metastasis and help clinicians make more appropriate decisions in clinical practice.


Subject(s)
Lymph Nodes/pathology , Nomograms , Stomach Neoplasms/pathology , CA-19-9 Antigen/metabolism , Early Detection of Cancer , Female , Follow-Up Studies , Gastrectomy/methods , Gastroscopy/methods , Humans , Lymphatic Metastasis , Male , Middle Aged , Predictive Value of Tests , Preoperative Care/methods , Prognosis , ROC Curve , Retrospective Studies , Stomach Neoplasms/diagnostic imaging , Stomach Neoplasms/metabolism , Stomach Neoplasms/surgery , Tomography, X-Ray Computed
20.
J Org Chem ; 84(4): 1797-1807, 2019 02 15.
Article in English | MEDLINE | ID: mdl-30664353

ABSTRACT

A new strategy for the construction of two kinds of fully substituted pyrroles, including 2-aminopyrroles and bicyclic pyrroles from Morita-Baylis-Hillman (MBH) acetates with 1,1-enediamines (EDAMs), or heterocyclic ketene aminals (HKAs) via base-promoted tandem Michael addition, elimination, and aromatization sequence has been developed, affording the expected products in moderate to excellent yields. This methodology is a highly efficient, concise way to access 2-aminopyrroles or bicyclic pyrroles with diversity in molecular structures from accessible building blocks under moderate reaction conditions.

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