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Background The pathogenesis of silicosis is complex and treatment methods are limited. SiO2-induced increase of transforming growth factor-β1 (TGF-β1) can activate fibroblasts to promote collagen deposition, ultimately leading to fibrosis. Previous studies have confirmed that lipid metabolism plays an important role in the progression of silicosis. Peroxisome proliferator-activated receptor γ coactivator 1α (PGC1α) mediates mitochondrial dysfunction and lipid metabolism pathways in diabetic models, but its role in silicosis has not been elucidated. Objective To investigate the effect of PGC1α on lipid metabolism disorder of macrophages induced by SiO2 and its effect on the progression of silicosis fibrosis. Methods (1) Macrophages were divided into four groups by transfecting and silencing PGC1α and its control sequence in macrophages and followed by SiO2 stimulation: negative control group (transfected with si-NC for 48 h), si-PGC1α group (transfected with si-PGC1α for 48 h), SiO2 stimulation group (stimulated with 50 μg·mL−1 SiO2 for 36 h after transfection with si-NC for 48 h), and si-PGC1α+SiO2 group (stimulated with 50 μg·mL−1 SiO2 for 36 h after transfection with si-PGC1α for 48 h). Western blot and cell immunofluorescence were used to test PGC1α expression, 4,4-difluoro-1,3,5,7,8-pentamethyl-4-bora-3a,4a-diaza-s-indacene (BODIPY 493/503) and total cholesterol (TC) and free cholesterol (FC) kits were used to test lipid accumulation, and the Oroboros2k-Oxygraph respiratory test system (O2K) was used to assess the effects of PGC1α on mitochondrial respiratory chain. ELISA kits were used to test TGF-β1 expressed in the macrophage supernatant. (2) Lung fibroblasts were divided into the same four groups as above, and stimulated with the supernatant of macrophages in the above groups. The expression of collagen Ι (COL Ι), E-cadherin (Eca), and fibronectin (FN) were detected by cell immunofluorescence and Western blot to further evaluate the effect of silencing PGC1α on fibrosis. Results The protein expression level of PGC1α stimulated by SiO2 was decreased, and the relative expression level of PGC1α was 0.78 times that of the control group (P<0.05). After transfection with si-PGC1α, the expression of PGC1α was decreased, and the relative protein expression level of the si-PGC1α group was 0.86 times that of the control group (P<0.05). Compared with the SiO2 stimulation group, the staining area of BODIPY 493/503 in the si-PGC1α+SiO2 group was enhanced, and the cholesterol-related indexes [TC, FC and cholesterol ester (CE)] were increased to 1.38, 1.10, and 2.26 times those in the SiO2 stimulation group (P<0.05). The activity of mitochondrial complex Ι was decreased, and the level of complex Ι in the si-PGC1α+SiO2 group was 0.63 times that in the SiO2 stimulation group (P<0.05). The secretion of TGF-β1 by macrophages increased, and the level of TGF-β1 in the si-PGC1α+SiO2 group was 1.15 times that of the SiO2 stimulation group (P<0.05). In addition, after stimulation of primary lung fibroblasts with macrophage supernatant, silencing PGC1α increased the expression levels of COL Ι and FN, while decreased the expression of Eca. The protein levels of COL Ι, FN, and Eca in the si-PGC1α+SiO2 group were 1.39, 1.18, and 0.82 times those in the SiO2 stimulation group, respectively (P<0.05). Conclusion Silencing PGC1α exacerbates SiO2-induced lipid metabolism disorder, inhibits mitochondrial respiratory chain, and aggravates the fibrosis induced by SiO2, suggesting that PGC1α may participate silicosis fibrosis by regulating mitochondrial respiratory chain and lipid metabolic disorder induced by SiO2.
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Objective:To summarize the clinical manifestations, gene variations, diagnosis and treatment of 3 cases with SLC35A2 variations characterized by congenital glycosylation disorder Ⅱm (CDG Ⅱm). Methods:A total of 3 patients admitted to the Department of Pediatrics of Xiangya Hospital of Central South University in China from 2018 to 2020 were examined in detail. The studies till January 2022 were searched with key words of "congenital disorders of glycosylation Ⅱm", " SLC35A2" and "CDG Ⅱm" in both English and Chinese in the databases of China National Knowledge Infrast Ructure (CNKI), Wanfang, Online Mendelian Inheritance in Man and PubMed, and the clinical manifestations, genetic variation, treatments and prognosis of patients with SLC35A2 mutation were summarized. Results:The patients all presented with intractable infantile spasm and global developmental delay, onset in infancy. A variety of antiepileptic treatments had temporary and partial efficacy. Otherwise, proband 2 and 3 presented with abnormal glutamic-pyruvic transaminase and increased platelets. Funduscopy showed dysplasia of the retinal pigment epithelium in both eyes, and they both received D-galactose treatment. A total of 22 relevant case reports, including 99 patients, were collected. The 99 patients all were heterozygous mutations, and a total of 75 different variation sites were reported. The clinical manifestations were characterized by global developmental delay or mental retardation ( n=89), epileptic seizure ( n=75), hypotonia ( n=57), facial deformity ( n=57), skeletal abnormality ( n=50), visual impairment ( n=42), elevated glutamic-pyruvic transaminase ( n=31), gastrointestinal symptoms ( n=28), skin deformity ( n=26), microcephaly ( n=23) and congenital heart disease ( n=12). Craniocerebral magnetic resonance imaging may be normal in the early stage. With age, magnetic resonance imaging may show abnormal white matter signals, brain atrophy, dysplasia of corpus callosum, delayed myelination, enlargement of lateral ventricle, brain stem atrophy and so on. Studies have shown that galactose treatment may be effective. Conclusions:SLC35A2 variants lead to CDG Ⅱm, whose clinical manifestations mainly include epileptic encephalopathy and global developmental delay. Multiple antiepileptic therapies can temporarily or partially control seizures, while oral galactose may improve the clinical symptoms, showing its prospect as a dietary therapy.
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Epilepsy is one of the most common chronic neurological diseases, which results from diverse etiologies, and its mechanism is very complicated.Ion channel gene mutation is a common genetic cause of epilepsy.Voltage-gated chloride channels (ClCs) can change the chloride ion concentration and electric potential difference across the plasma membrane, and thereby regulate the electrical excitability of neurons.CLCN-1, CLCN-2, CLCN-3, CLCN-4 and CLCN-6 are reported to be associated with epilepsy, which could increase susceptibility to epilepsy or cause seizures.This review is focused on recent advances in ClCs and epilepsy.
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OBJECTIVE@#To explore the prognostic factors of patients with unresectable liver metastasis colorectal cancer after failed conversion chemotherapy.@*METHODS@#A retrospective, case-controlled study was performed. Study subjects were 105 patients who were diagnosed with synchronous liver metastasis colorectal cancer after failed chemotherapy (metastasis evaluated as unresectable after the conversion chemotherapy) at Xinhua Hospital, Shanghai Jiaotong University from January 2012 to December 2015. Overall survival(OS) was retrospectively analyzed using Kaplan-Meier method. Log-rank test was used to compare survival among groups. Univariate and multivariate analysis was conducted for prognosis using Cox regression model.@*RESULTS@#Of 105 cases,70 were male and 35 were female with median age of 60 years old. Twenty-one patients had right colon cancer, 41 had left colon cancer, 42 had rectal cancer and 1 had synchronous cancers(sigmoid colon and rectum). One hundred and two (97.1%) patients were cT3-4 and 90 patients were cN+ (imaging diagnosis). Eighty-nine (84.8%) patients were loaded with 2 or more liver metastases with the median maximum diameter of 48.3 mm. The patients were followed up for 3 to 43 months from the day of diagnosis. The median OS was 11 months (interquartile range, 8-18). The median OS of patients with cN0, cN1 and cN2 stage was 17, 13 and 10 months, respectively(P=0.026). The median OS of patients with single lesion, 2-3 lesions, 4-10 lesions and more than 10 lesions was 15, 15, 17 and 9 months, respectively (P=0.002). OS of patients with maximum diameter of liver metastatic lesion ≤ 50 mm, 51-100 mm and >100 mm was 15, 10 and 8 months, respectively(P=0.003). The median OS of patients with chemotherapy response of partial response (PR), stable disease (SD) and progressive disease (PD) was 17, 14 and 8 months, respectively(P<0.001). OS was 17 months in patients receiving second line chemotherapy and was 10 months in those without second line chemotherapy (P<0.001). OS in patients undergoing primary tumor resection was 13 month and in those without primary tumor resection was 9 months; the difference was not significant (P=0.060). Multivariate analysis showed that cN2(HR=2.115, 95%CI:1.089-4.109, P=0.027), the maximum diameter of liver metastatic lesion more than 100 mm (HR=3.112, 95%CI:1.455-6.657, P=0.003), chemotherapy response of PD (HR=4.435, 95%CI:2.506-7.533,P<0.001) and without second line chemotherapy(HR=4.432,95%CI:2.186-8.986, P=0.010) were independent prognostic factors.@*CONCLUSIONS@#For patients with unresectable liver metastasis from colorectal cancer after failed conversion chemotherapy, prognostic factors include cN2, the maximum diameter of liver metastatic lesion, chemotherapy response and second line chemotherapy. Whether the resection of primary tumor can prolong OS further study.
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Female , Humans , Male , Middle Aged , Antineoplastic Agents , Therapeutic Uses , China , Colorectal Neoplasms , Drug Therapy , Pathology , Liver Neoplasms , Diagnosis , Prognosis , Retrospective Studies , Treatment FailureABSTRACT
Objective K93T point mutation exists in the quinoid dihydropteridine reductase ( QDPR) of OLEFT rats which catalyzes QDPR into tetrahydrobinopterin(BH4), while dihydrofolate reductase(DHFR) can reduce QDPR to BH4, which implies crosstalk between hydrobiopterin and folate metabolism.By investigating the influence of QDPR expression on DHFR expression of NRK-52E cells, the article aimed to find out the possible underlying mechanism of QDPR gene in diabetic nephropathy ( DN). Methods Western blot was performed to identify the expression level in NRK-52E cell under high glucose ambience and DHFR pro-tein expression of OLETF rats.NRK-52E cells were transfected by the lentivirus to establish no-load overexpression, overexpressed QDPR and knockdown QDPR models.Each group was given 5.4 mmol/L normal sugar medium and 30mmol/L in high glucose ambi-ence for 72 hours'cell cultivation to simulate DN model.Observation was made on the influence of QDPR gene expression levels on DHFR in high glucose ambience. Results The western blot analysis revealed that DHFR protein decreased in NHG group( [0.33 ± 0.16] vs [0.64 ±0.5], P<0.05) and OLETF rats cortex ([0.56 ±0.16] vs [1.03 ±0.12], P<0.01).In high glucose ambi-ence, compared with LV-OCON-HG group, the protein expression of DHFR was significantly decreased in LV-QDPR-HG group ([0.12 ±0.09] vs [0.63 ±0.08], P<0.01).No difference was found in the comparison of DHFR expression levels between LV-SHQDPR-HG and LV-SHCON-HG group. Conclusion DHFR protein expression decreases in NRK-52E cells of high glucose and LOLETF rat model, which suggests that DHFR protein plays an important role in the development of DN.QDPR overexpression leads to the decreased expression of DHFR, which implies that overexpressed QDPR influences the occurrence and process of DN by down-regulating DHFR expression level.
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ObjectiveTo investigate the diagnostic value of interferon gamma release assays (IGRAs) in children with tuberculous meningitis.MethodsThe prospective case-control study was applied. From January 2012 to March 2013, 32 children diagnosed with tuberculous meningitis (TBM group) and 30 children diagnosed with non-tuberculous meningitis (non-TBM group) were recruited. The positive rates of the interferon gamma release assays (IGRAs), tuberculin skin test (TST), mycobacterium tuberculosis antibody test (TB-IgG), cerebrospinal lfuid of mycobacterium tuberculosis DNA test (TB-DNA), and the sensitivity, speciifcity, negative and positive predictive value of all these tests were compared between TBM group and non-TBM group.Results The positive rate of IGRAs, TST, TB-IgG, and TB-DNA was 87.50%, 56.25%, 46.88% and 34.38%respectively in TBM group, and 6.67%, 23.33%, 20% and 0% respectively in non-TBM group. The differences were statistically signiifcant (P<0.05). The sensitivity of IGRAs, TST, TB-IgG, and TB-DNA was 87.5%, 56.25%, 6.88% and 34.38% respectively. The speciifcity of IGRAs, TST, TB-IgG, and TB-DNA was 93.33%, 76.67%, 80.00% and 100% respectively. The differences of sensitivity and speciifcity were statistically signiifcant (P<0.05). The sensitivity of IGRAs was higher than that of other tests (P<0.017). The positive predictive value of IGRAs, TST, TB-IgG, and TB-DNA was 93.33%, 72%, 71.43% and 100% respec-tively. The negative predictive value was 87.50%, 62.16%, 58.54% and 58.82% respectively.Conclusions IGRAs, TST, TB-IgG, and TB-DNA are valuable in the diagnosis of tuberculous meningitis. IGRAs has a relatively higher sensitivity and speciifcity.
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Objective To evaluate the therapeutic efficacy of atomoxetine hydrochloride for attention deficit hyperactivity disorder (ADHID) combined with Tourette syndrome (TS).Methods Twenty-six cases of children with ADHD combined with TS were firstly diagnosed American Psychiatric Association Diagnostic and Statistical Manual of Mental Disorders fourth edition (DSM-Ⅳ) of ADHD and TS were treated with atomoxetine.The symptoms were improved and conditions were assessed based on the fourth version of ADHD parent rating scale and the severity of Yale comprehensive pumping quantity during pre-treatment,the 2nd,4th,6th and the 8 week of therapeutic courses,respectively.The adverse reaction was observed.Results 1.Compared with pre-treatment,attention deficit scores after treatment were statistically different (t =8.41,9.97,all P ＜ 0.05) in the 6th,8th week of therapeutic courses;hyperactivity /imnpulsivity scores were statistically different (Z =-4.39,-4.47,-4.46,all P ＜0.05) in the 4th,6th,8th week; Motor tics scores were statistically different (t =18.30,18.67,20.32,all P ＜ 0.05) in the 4th,6th,8th week; The vocal tic score:the second weeks already had statistically different(t =5.45,P ＜ 0.05); And the impaired function score were statistical significance (Z =-3.95,-3.94,all P ＜ 0.05) at the 6th and 8th week.2.The effective rate of ADHD and TS was 7.69％ and 15.38％,respectively in the 2td week.The curative effect had no statistical significance (x2 =0.188,P ＞0.05).But at the tourth week of assessment,and the rates of curative effect were respectively 19.23％ and 46.15 ％.It had statistical significance (x2 =3.923,P ＜ 0.05).In the 6th,8th weeks,there was no significant difference between the 2 efficiency (x2 =0.083,0.103,all P ＞0.05).3.During the treatment,no severe adverse reaction had appeared.Conclusions Atomoxetine in ADHD comorbid TS had exact curative effect and no obvious adverse reactions.In the treatment of ADHD,hyperactivity / impulsivity effect is better than the attention deficit.In the treatment of TS,vocal tics onset is better than the motor tics.In comparison of ADHD with TS,TS symptoms improve faster than ADHD in the onset,but the final effect is quite.