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Objective: To investigate the effects and the mechanism of Calcyclin-binding protein (CacyBP) on the proliferation and invasion of non-small cell lung cancer (NSCLC) cells. Methods: Six lung cancer tissues and paired normal lung tissues were collected from NSCLC patients who underwent surgical treatment in Jinan Central Hospital during 2016. The expression of CacyBP in these tissues was examined by western blot. The protein and mRNA expression of CacyBP in human bronchial epithelial cells (16HBE), NSCLC cell lines including A549, H1299, H460 and H1975 were examined by western blot and reverse transcription-polymerase chain reaction (RT-PCR), respectively. RNAi and shRNA against negative control (NC) or CacyBP were transfected into A549 cell which were denoted as siNC group, siCacyBP-1 group, sicacyBP-2 group, shNC group and shCacyBP group, respectively. Control and Flag-CacyBP plasmids were transfected into A549 cells which were denoted as NC group and Flag-CacyBP group, respectively. Cell counting kit-8 (CCK-8), plate clone formation assay and flow cytometry assay were used to assess cell proliferation ability and cycle of A549. Wound healing assay and transwell assay were used to assess abilities of A549 cells migration and invasion. The protein expressions of epithelial-mesenchymal transition (EMT) markers including E-cadherin, N-cadherin, Snail1, Vimentin, and phosphorylation of protein kinase B (p-Akt) were examined in CacyBP depleted or overexpressed A549 cells. Results: The CacyBP protein level in NSCLC tissues was 0.41±0.23, significantly higher than 0.11±0.04 in normal lung tissues (P<0.05). The CacyBP protein expression levels in different NSCLC cell lines including A549, H1299, H460 and H1975 were 0.35±0.01, 0.38±0.01, 0.32±0.01 and 0.41±0.01, respectively, which were significantly higher than 0.03±0.01 in 16HBE cells (P<0.05). The result of RT-PCR was consistent with that of western blot. Compared with siNC group (absorbance was 1.54±0.03), siCacyBP-1 group and siCacyBP-2 group showed decreased cell proliferation (absorbances were 1.38±0.04 and 1.34±0.03, P<0.05). The number of cell colony in shNC group was 41.33±3.21, significantly higher than 22.00±3.61 in shCacyBP group (P<0.05). The proportion of G(1) phase in shCacyBP group was (61.35±5.45)%, higher than (49.61±1.54) % in shNC group (P<0.05). The proportion of S phase was (25.41±3.21)%, which was lower than (38.68±0.46)% of shNC group (P<0.05). The cell migration rate of shCacyBP group was (12.67±0.71)%, which was significantly lower than (35.50±2.07)% of shNC group (P<0.05). The numbers of cell migration and invasion in shNC group were 406.33±7.37 and 92.33±8.50, respectively, which were significantly higher than 224.67±10.01 and 66.00±7.94 in shCacyBP group (P<0.05). Compared with siNC group, the expression of epithelial marker E-cadherin was up-regulated, while the expressions of mesenchymal markers including N-cadherin, Vimentin, Snail1 and p-Akt were down-regulated in CacyBP depleted A549 cells. Compared with NC group, overexpression of CacyBP inhibited E-cadherin expression while promoted the expressions of N-cadherin, Snail1, Vimentin and p-Akt, which could be restored by LY294002. Conclusion: CacyBP may promote the proliferation and invasion of NSCLC cells by regulating Akt signal pathway.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Proteínas de Unión al Calcio , Carcinoma de Pulmón de Células no Pequeñas/genética , Proliferación Celular , Regulación Neoplásica de la Expresión Génica , Humanos , Neoplasias Pulmonares/genética , Vimentina/genéticaRESUMEN
Objective: To analyze the compliance and related factors of low-dose computed tomography (LDCT) screening among the high-risk population of lung cancer in three provinces participating in the cancer early diagnosis and early treatment program in urban areas of China. Methods: From October 2017 to October 2018, 17 983 people aged between 40 and 74 years old at high risk of lung cancer were recruited from Zhejiang, Anhui and Liaoning provinces. The basic demographic characteristics, living habits, history of the disease and family history of cancer were collected by using a cancer risk assessment questionnaire, and the data of participants examined by LDCT were obtained from the hospitals participating in the program. The screening compliance was quantified by the screening participation rate, and it was calculated as the proportion of participants completing LDCT scan among high-risk population. The related factors of LDCT screening compliance were analyzed by using a multivariate logistic regression model. Results: The age of 17 983 participants was (56.52±8.22) years old. Males accounted for 51.9% (N=9 332), and 69.5% (N=12 495) had ever smoked, including former smokers and current smokers. A total of 6 269 participants were screened by LDCT, and the screening participation rate was 34.86%. The results of multivariate logistic regression analysis showed that the age group of 50 to 69 years old, female, passive smokers, alcohol consumption, family history of lung cancer and history of chronic respiratory diseases were more likely to be screened by LDCT, while the compliance of LDCT screening in current smokers was low. Conclusions: The LDCT screening compliance of the high-risk population of lung cancer in urban areas of China still needs to be improved. Age, sex, smoking, drinking, family history of lung cancer and history of chronic respiratory disease are associated with screening compliance.
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Detección Precoz del Cáncer , Neoplasias Pulmonares , Adulto , Anciano , China/epidemiología , Femenino , Humanos , Neoplasias Pulmonares/diagnóstico por imagen , Neoplasias Pulmonares/epidemiología , Masculino , Tamizaje Masivo , Persona de Mediana Edad , Tomografía Computarizada por Rayos XRESUMEN
OBJECTIVE: Atopic eczema (AE) is a chronic relapsing inflammatory skin disease. This study aims to identify key genes related to the development of AE. MATERIALS AND METHODS: The GSE6012 dataset was obtained from the Gene Expression Omnibus (GEO) database. The limma package was used to analyze differentially expressed genes (DEGs). Then, the weighted gene co-expression network analysis (WGCNA) package was utilized to generate weighted correlation networks of up-and downregulated genes. Additionally, the WGCNA package was used for enrichment analyses to explore the underlying functions of DEGs in modules (weighted correlation sub-networks) significantly associated with AE. RESULTS: A total of 515 DEGs were identified between lesional and non-lesional skin samples. For the upregulated genes, the blue module was found to have a significant positive correlation with AE. Importantly, small proline-rich protein 2C (SPRR2C) and defensin, beta 4A (DEFB4A) exhibited higher |log fold change (FC) values and were the key nodes of the network. Moreover, KEGG pathway analysis revealed that the upregulated genes in the blue module were primarily involved in cytokine-cytokine receptor interaction. Additionally, for the downregulated genes, the brown module was found to have a significant positive correlation with AE. Further, WNT inhibitory factor 1 (WIF1), cryptochrome 2 (CRY2), and keratin 19 (KRT19) had higher |log FC| values and were key nodes of the network. CONCLUSIONS: SPRR2C, DEFB4A, WIF1, CRY2, KRT19 and cytokine-cytokine receptor interaction might be correlated with the development of AE.
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Proteínas Adaptadoras Transductoras de Señales/genética , Proteínas Ricas en Prolina del Estrato Córneo/genética , Criptocromos/genética , Dermatitis Atópica/genética , Queratina-19/genética , beta-Defensinas/genética , Citocinas/genética , Humanos , Receptores de Citocinas/genéticaRESUMEN
Objective: To analyze the clinico pathological features, differential diagnosis and prognosis of metastatic renal cell carcinomas. Methods: The clinical data, histology, immunophenotype and follow-up data of 196 patients with metastatic renal cell carcinoma diagnosed from 1994 to 2017 at the Department of Pathology, Changhai Hospital, Naval Military Medical University, Shanghai, China were analyzed retrospectively. Results: There were 142 males and 54 females, with a median age of 61 years. The top three metastatic sites for the 196 cases of metastatic renal cell carcinoma were lung (31.1%, 61/196), bone (29.1%, 57/196) and digestive system (19.4%, 38/196). Among the pathological subtypes of metastasis, the proportion of clear cell renal cell carcinoma was 94.4% (185/196) and that of type II papillary renal cell carcinoma was 3.6% (7/196). The TFE3 translocated renal cell carcinoma and congestive tubular carcinoma were rare, with 3 cases and 1 case, respectively. CK, vimentin, CAâ ¨ and CD10 were expressed in all metastatic clear cell renal cell carcinomas. CK7, CD10 and P504s were expressed in papillary renal cell carcinomas. TFE3 was expressed in TFE3 translocated renal cell carcinoma. The collecting duct carcinoma was positive for HCK. Conclusions: Lung metastasis and bone metastasis are still the most frequent metastatic sites of renal cell carcinoma. Five years after primary lesion resection may be the high risk time for metastasis. Most of the metastases are solitary when they are first identified. To better diagnose and identify the renal origin of a metastatic renal cell carcinoma, one should consider morphological characteristics, clinical history information of the metastasis and the combined immunohistochemistry of CK, vimentin, CD10, CK7, TFE3, PAX2 and PAX8.
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Carcinoma de Células Renales , Neoplasias Renales , Biomarcadores de Tumor/genética , Carcinoma de Células Renales/cirugía , China , Femenino , Humanos , Neoplasias Renales/genética , Neoplasias Renales/cirugía , Masculino , Persona de Mediana Edad , Estudios RetrospectivosRESUMEN
Objective: To analyze the clinical characteristics of patients with uremic tumoral calcinosis (UTC). Methods: A total of 10 patients with UTC were enrolled in this study, who were admitted in the Department of Nephrology, China-Japan Friendship Hospital and Beijing Chuiyangliu Hospital from March 2013 to February 2019. Results: The average age of 4 male and 6 female patients on regular hemodialysis was (39.90±8.57) years. The average dialysis duration was(5.90±2.57) years. Three patients presented as single lesion of one joint, the other 7 patients as involvement of multiple large joints. Serum calcium was elevated in 2 patients,both over 2.75 mmol/L. Serum hyperphosphatemia was seen in all patients with average level 2.22 (1.94,2.44) mmol/L. Serum intact parathyroid hormone (iPTH) was remarkably increased in 9 patients with average level 1 348.0(854.8,1 800.0) ng/L, while only 1 patient reported slight elevation (92.4 ng/L).High-sensitivity C-reactive protein increased in all 10 patients with average 35.81 (17.60,74.20) mg/L. The imaging findings before treatment suggested that a large number of irregular masses of calcification shadows deposited in the soft tissue adjacent to the joints. The outlines of calcification were clear without significant bone absorption. Nine patients with severe secondary hyperparathyroidism (SHPT) were treated with parathyroidectomy, resulting in lesions diminishing or even disappearing. A total of 32 parathyroid glands were resected, and pathological results showed that 7 parathyroids were diffuse hyperplasia, 11 as diffuse/nodular hyperplasia, the rest 14 as nodular hyperplasia. At least one hyperplastic parathyroid gland was seen in each patient. Only 1 patient received medical therapy yet no obvious improvement was observed. Conclusion: UTC is a rare complication in patients on regular hemodialysis, which is usually associated with severe SHPT. Parathyroid surgery may improve the clinical outcome.
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Calcinosis/complicaciones , Hiperparatiroidismo Secundario , Diálisis Renal/efectos adversos , Uremia , Adulto , China , Femenino , Humanos , Hiperparatiroidismo Secundario/cirugía , Masculino , Persona de Mediana Edad , Hormona Paratiroidea/sangre , Paratiroidectomía , Uremia/complicacionesRESUMEN
OBJECTIVE: It was the aim of this study to explore the role and mechanism of long non-coding RNA (lncRNA) AFAP1-AS1 in the progression of bladder cancer (BCa) by in vitro experiments. PATIENTS AND METHODS: AFAP1-AS1 levels in 40 pairs of clinical BCa tissue samples and normal ones collected from BCa patients were determined, and paired sample t-test was applied to compare the differences between groups. The prognosis data of patients with BCa were collected, and survival analysis and t-test were performed to specify the interplay between AFAP1-AS1 and the prognosis of BCa patients. Subsequently, AFAP1-AS1 expression level in BCa and normal cells were further confirmed by quantitative Real Time-Polymerase Chain Reaction (qRT-PCR), and Cell Counting Kit-8 (CCK-8), 5-Ethynyl-2'-deoxyuridine (EdU), and transwell assays were performed to figure out the influence of this lncRNA on the proliferation ability and invasiveness of BCa cells. Meanwhile, the interaction between AFAP1-AS1 and its sense mRNA was analyzed. We used co-transfection technology to simultaneously transfect si-AFAP1-AS1 and pcDNA3.1-AFAP1 or their corresponding negative controls into BCa cells, and cell proliferation and invasion ability in different subgroups were determined to explore the underlying mechanism through which AFAP1-AS1 plays a role in BCa progression. RESULTS: No matter in BCa tissues or in cell samples, compared to the corresponding normal controls, AFAP1-AS1 was found highly expressed; at the same time, in invasive bladder cancer tissues, the expression level of AFAP1-AS1 was also higher than that in non-invasive tissues. Meanwhile, survival analysis revealed that patients with BCa with high expression of AFAP1-AS1 owned a shorter overall survival rate than those with low expression, indicating a negative interplay between AFAP1-AS1 expression and patients' prognosis. In addition, in BCa cell lines, according to the results of CCK-8, EDU, and transwell assays, the proliferative capacity, as well as the invasive ability of BCa cells, were found weakened after downregulation of AFAP1-AS1. Meanwhile, a negative interplay was discovered between AFAP1-AS1 and its sense mRNA. Finally, the results of cell reversal experiment using co-transfection technique revealed that overexpression of AFAP1 can reverse the inhibitory impact of lncRNAAFAP1-AS1 on the malignant ability of BCa cells. CONCLUSIONS: AFAP1-AS1 may enhance the proliferation ability as well as the invasiveness of BCa cells so as to aggravate the degree of BCa malignancy.
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ARN Largo no Codificante/genética , Neoplasias de la Vejiga Urinaria/genética , Línea Celular , Movimiento Celular/genética , Proliferación Celular/genética , Humanos , Proteínas de Microfilamentos/genética , ARN Mensajero , Neoplasias de la Vejiga Urinaria/patologíaRESUMEN
OBJECTIVE: To explore the risk factors of lung cancer in non-smoking Chinese women and to provide evidence for lung cancer prevention and control. METHODS: Information was collected on case-control studies published in the journals, both nationally and internationally from January, 1995 to November, 2014 that reported correlations between lung cancer and risk factors. Pooled odds ratio (OR) and 95% confidence interval (CI) of risk factors on lung cancer in non-smoking Chinese women were calculated, using the Meta-analysis method, with sensitivity and publication bias tested. RESULTS: Information on 24 case-control studies was selected including 11 946 cumulative cases and 12 596 controls. Pooled ORs (95% CI) were shown as: history of lung diseases 1.89 (1.57, 2.27), history of tuberculosis 1.86 (1.53, 2.27), history of chronic bronchitis 1.51 (1.04, 2.19), family history of cancers 2.02 (1.67, 2.44), family history of lung cancers 2.45 (1.80, 3.34), passive smoking (at workplace in adult period 1.47 (1.28, 1.69), at home in adulthood 1.22 (1.09, 1.36), in all life's time 1.52 (1.29, 1.79), kitchen smog while cooking 2.21 (1.27, 2.96), position of kitchen 1.76 (1.48, 2.09), and frequency of deep frying per week 2.24 (1.61, 3.12) etc. respectively. CONCLUSION: Major risk factors related to lung cancer in non-smoking Chinese women would include lung diseases, family history of cancers, and passive smoking (tobacco smog and cooking smog). Particularly, the combination of family history and the degree of cooking presented stronger correlation effects, indicating that genetic and environmental factors jointly played an important role in the development of lung cancer.
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Neoplasias Pulmonares/epidemiología , Adulto , Estudios de Casos y Controles , China/epidemiología , Culinaria , Salud de la Familia/estadística & datos numéricos , Femenino , Humanos , Oportunidad Relativa , Factores de Riesgo , Fumar/epidemiología , Contaminación por Humo de Tabaco/efectos adversosRESUMEN
OBJECTIVE: To evaluate the effect of ß-blockers in patients with septic shock. METHODS: PubMed, EMBASE, Cochrane central registration of controlled trials, CNKI and Wanfang Data were searched to identify relevant studies from inception to October 2015.Statistical analysis was performed using STATA 12.0.The random effects model was used due to wide clinical variability across the trials. RESULTS: After application of the inclusion criteria, 7 trials with 392 patients were included, involving 3 randomized controlled trials (RCT) and 4 quasi-experiments.The results of the meta-analysis for the quasi-experiments showed that compared with baseline, heart rates (standardized mean difference (SMD)=-2.51, 95%CI: -4.32--0.70, P=0.007) and lactate levels (SMD=-0.34, 95%CI: -0.67--0.02, P=0.039) significantly decreased, while no significant differences were seen for mean arterial pressure (SMD=0.01, 95%CI: -0.42-0.44, P=0.969), cardiac index (SMD=-0.35, 95%CI: -1.15-0.44, P=0.385) or norepinephrine requirements (SMD=-0.06, 95%CI: -0.38-0.27, P=0.726) after 24-hour therapy. Among randomized controlled trials, ß-blockers, compared with standard care, was associated with reductions in heart rates (P<0.001) , 28-day mortality (RR=0.60, 95%CI: 0.48-0.75, P<0.001) and troponin I levels (P<0.001). While no differences were found between the two groups in other hemodynamic and cardiac function variables, such as mean arterial pressure, cardiac index or stroke volume index (P>0.05). CONCLUSIONS: The currently available evidence indicates that the use of ß-blockers is associated with a significant decrease in heart rate, troponin I levels and 28-day mortality in patients with septic shock, while mean arterial pressure, cardiac index and stroke volume index might remain unchanged.Large scale, muti-center RCTs need to be carried out to confirm the effects of ß-blockers in patients with septic shock.
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Choque Séptico , Antagonistas Adrenérgicos beta , Frecuencia Cardíaca , Hemodinámica , Humanos , Norepinefrina , Ensayos Clínicos Controlados Aleatorios como Asunto , Volumen SistólicoRESUMEN
OBJECTIVES: To evaluate the prevalence of affective disorders and identify their associated factors among Chinese mothers of preschool children diagnosed with autism spectrum disorders. METHODS: This cross-sectional study was conducted at the Autism Spectrum Disorders Multidisciplinary Clinic of the United Christian Hospital from August 2012 to June 2013. All mothers of a consecutive series of preschool children diagnosed with autism spectrum disorders at their first visit to the clinic were recruited. Information regarding the child-related, maternal, and environmental factors was collected. Psychiatric diagnoses were made according to the Chinese-Bilingual Structured Clinical Interview for DSM-IV Axis I Disorders. Independent factors associated with maternal affective disorders were determined by univariate and multivariate analyses. RESULTS: Of the 121 subjects, the point prevalence of affective disorders as a group was 29.8%. The point prevalence of major depressive disorders, adjustment disorders, anxiety disorders, and bipolar affective disorders was 14.9%, 10.7%, 3.3% and 0.8%, respectively. A higher level of disruptive and self-absorbed behaviours in the children (as assessed by the Developmental Behaviour Checklist), a higher level of affiliate stigma (as assessed by 22-item Affiliate Stigma Scale), and a history of psychiatric disorders were independently associated with current affective disorders. CONCLUSION: Psychiatric disorders, predominantly affective disorders, are common among Chinese mothers of preschool children with autism spectrum disorders. Identification of independent factors associated with maternal affective disorders can aid in the early detection of cases and planning of early intervention programmes to address both child and maternal psychological needs.
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Trastorno del Espectro Autista/epidemiología , Trastornos del Humor/epidemiología , Madres/psicología , Madres/estadística & datos numéricos , Adulto , Trastorno del Espectro Autista/psicología , Preescolar , China/epidemiología , Estudios Transversales , Femenino , Humanos , Masculino , Trastornos del Humor/psicología , Relaciones Madre-Hijo , PrevalenciaRESUMEN
This study aimed to investigate the effects of administration of low-dose cyclosporine A (CsA) alone and the combination of low-dose CsA and a low-dose hormone for the treatment of elderly patients with membranous nephropathy. We divided 27 patients into two groups as follows: low-dose CsA group (group A) and the group receiving a combination of a low-dose hormone and low-dose CsA (group B). The treatment and follow-up times were ≥ 6 months. We observed no difference in gender, age, serum creatinine levels, estimated glomerular filtration rate (eGFR), and 24-h urinary protein levels between the two groups before treatment; in addition, the rates of complete and partial remission were not different 6 months after treatment. The rate of complications in group B was higher than that in group A (84.6 vs 35.7%, respectively; t = 0.018). While the pretreatment eGFR of patients who achieved remission was significantly higher than that of patients who did not achieve remission, the 24-h urinary protein levels and incidence of hypertension were significantly lower than those of patients who did not achieve remission (t = 0.042, 0.035 and 0.043, respectively). The efficacy of administration of low-dose CsA alone and in combination with a low-dose hormone was similar; the efficacy was related to eGFR, urinary protein levels, and the incidence of hypertension before the treatment. The side effects of administration of CsA alone were significantly lower than those of the combination treatment.
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Ciclosporina/uso terapéutico , Glomerulonefritis Membranosa/tratamiento farmacológico , Anciano , Anciano de 80 o más Años , Creatinina/sangre , Ciclosporina/administración & dosificación , Ciclosporina/efectos adversos , Relación Dosis-Respuesta a Droga , Quimioterapia Combinada , Femenino , Estudios de Seguimiento , Tasa de Filtración Glomerular , Glucocorticoides/administración & dosificación , Glucocorticoides/efectos adversos , Glucocorticoides/uso terapéutico , Humanos , Inmunosupresores/administración & dosificación , Inmunosupresores/efectos adversos , Inmunosupresores/uso terapéutico , Masculino , Metilprednisolona/administración & dosificación , Metilprednisolona/efectos adversos , Metilprednisolona/uso terapéutico , Estudios Prospectivos , Proteinuria/orina , Resultado del Tratamiento , Infecciones Urinarias/inducido químicamenteRESUMEN
This semiquantitative immunohistochemical study investigated the clinical significance of S100A4 and vascular endothelial growth factor C (VEGF-C) protein expression in gastric carcinoma. Correlations between S100A4 and VEGF-C immunoreactivity and clinicopathological characteristics were evaluated using 108 gastric carcinoma specimens and 20 specimens of tissue adjacent to gastric carcinoma. S100A4 and VEGF-C expression in carcinoma was higher than that in adjacent tissues. S100A4 expression was significantly related to tumour size and lymph node metastasis, whereas VEGF-C expression was associated with invasion depth, lymph node metastasis and tumour, node, metastasis (TNM) stage. A significant correlation was found between S100A4 and VEGF-C expression. Patients expressing S100A4 or VEGF-C showed no significant reduction in 5-year survival rate compared with those not expressing these proteins. Sex, age, tumour size, invasion depth, lymph node involvement, TNM stage, S100A4 expression and VEGF-C expression had a common effect on carcinoma prognosis but none was an independent prognostic factor.
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Proteínas S100/metabolismo , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patología , Factor C de Crecimiento Endotelial Vascular/metabolismo , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Femenino , Estudios de Seguimiento , Humanos , Técnicas para Inmunoenzimas , Metástasis Linfática , Masculino , Persona de Mediana Edad , Invasividad Neoplásica , Pronóstico , Estudios Retrospectivos , Proteína de Unión al Calcio S100A4 , Factores SexualesRESUMEN
The relationship between plasma adiponectin and severity of coronary artery disease (CAD) in 683 cases of suspected CAD from north-east China was determined. Cases were divided into four groups, as follows: group 1, no stenosis; group 2, > 50% stenosis of one vessel; group 3, > 50% stenosis of two vessels; group 4, > 50% stenosis of three or more vessels. Group 1 was classified as a non-CAD group (control) and groups 2, 3 and 4 were classified as CAD groups. Plasma adiponectin levels were significantly correlated with coronary artery stenosis and were lower in the CAD groups than in the non-CAD group. Adiponectin concentration decreased from group 2 to group 4, but this difference was not significant. Adiponectin levels among females were also lower than for males in the CAD groups. There was a significant difference between plasma adiponectin levels in patients with coronary stenoses versus those without, but there were no significant differences between the three CAD groups in terms of plasma adiponectin levels.
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Adiponectina/sangre , Enfermedad de la Arteria Coronaria/sangre , Enfermedad de la Arteria Coronaria/epidemiología , China/epidemiología , Angiografía Coronaria , Enfermedad de la Arteria Coronaria/patología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Grupos de Población , Factores de RiesgoRESUMEN
Evidence suggests that glycogen synthase kinase-3beta (GSK3B) activity is increased significantly in the brain of patients with major depressive disorders (MDD). Inhibition of GSK3B is thought to be a key feature in the therapeutic mechanism of antidepressants. To investigate whether common genetic variants in the GSK3B gene are associated with MDD and the therapeutic response to antidepressants, four polymorphisms (rs334558 (-50 T>C), rs13321783 (IVS7+9227 A>G), rs2319398 (IVS7+11660 G>T) and rs6808874 (IVS11+4251 T>A)) of the GSK3B gene were genotyped in 230 Chinese MDD patients and 415 controls. Among the MDD patients, 168 accepted selective serotonin reuptake inhibitor (SSRI) (fluoxetine or citalopram) antidepressant treatment and therapeutic evaluation for 4 weeks and 117 for 8 weeks. Significant association with MDD was not shown in the alleles and genotypes of single loci or four-locus haplotypes. However, three of the four polymorphisms investigated were significantly associated with 4-week antidepressant therapeutic effect (P=0.002-0.011). Of the four-locus haplotype analysis, the GSK3B TAGT carriers showed a poorer response to antidepressants in 4-week (P<0.0001) and 8-week (P=0.015) evaluation compared with other haplotype groups and would quite likely be the non-remitter to 8-week antidepressant treatment (P=0.006). Our findings show, for the first time, that GSK3B genetic variants play a role in the SSRI antidepressant therapeutic response and support the hypothesis that drugs regulating GSK3B activity may represent a novel treatment strategy for MDD.
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Antidepresivos de Segunda Generación/uso terapéutico , Trastorno Depresivo Mayor/tratamiento farmacológico , Glucógeno Sintasa Quinasa 3/genética , Inhibidores Selectivos de la Recaptación de Serotonina/uso terapéutico , Adulto , Alelos , China , Trastorno Depresivo Mayor/enzimología , Trastorno Depresivo Mayor/genética , Genotipo , Glucógeno Sintasa Quinasa 3 beta , Haplotipos , Humanos , Persona de Mediana Edad , FarmacogenéticaRESUMEN
Serotonin systems appear to play a key role in the pathogenesis of major depression and the therapeutic mechanisms of antidepressants. The firing rate of dorsal raphe serotonergic neurons is controlled by somatodendritic 5-hydroxytryptamine 1A (HTR1A) autoreceptors, and desensitization of these receptors is implicated in the antidepressant mechanism of selective serotonin reuptake inhibitors. We tested whether a functional polymorphism (C-1019G) in the promoter region of the HTR1A gene and serotonin-related genetic variants are related to fluoxetine antidepressant effect. We genotyped the HTR1A C-1019G polymorphism as well as polymorphisms in the serotonin transporter gene-linked polymorphic region (SERTPR), variable-number tandem-repeat polymorphisms in intron 2 (STin2) of the serotonin transporter gene, serotonin 2A receptor (T102C), tryptophan hydroxylase (A218C), and G-protein beta3 subunit (C825T) in 224 Chinese patients from southern Taiwan with major depression, who accepted 4-week fluoxetine treatment and therapeutic evaluation. Our results demonstrated that the HTR1A -1019C/C carriers (P=0.009) and SERTPR l/l carriers (P<0.001) showed a better response to fluoxetine, while other polymorphisms were not associated with fluoxetine therapeutic response. The major limitation of this study is the lack of a placebo control. Future prospective study with placebo control may help to predict and individualize antidepressant treatment.
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Antidepresivos de Segunda Generación/uso terapéutico , Pueblo Asiatico/genética , Trastorno Depresivo Mayor/tratamiento farmacológico , Fluoxetina/uso terapéutico , Polimorfismo Genético , Receptor de Serotonina 5-HT1A/genética , Adulto , Trastorno Depresivo Mayor/genética , Femenino , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Regiones Promotoras Genéticas , Proteínas de Transporte de Serotonina en la Membrana Plasmática/genética , Taiwán , Resultado del TratamientoRESUMEN
The serotonin transporter (5-HTT) is the site of primary action for the selective serotonin reuptake inhibitors (SSRIs). Previous Western reports have demonstrated that the lallele of the 5-HTT gene-linked polymorphic-region (5-HTTLPR) polymorphism is associated with better SSRI antidepressive effects than the s allele, however, another study of a Korean population has produced a contrasting finding. The present study tested the hypothesis that the 5-HTTLPR genetic polymorphism is associated with SSRI antidepressant response by evaluating total and cluster depressive symptoms for 121 Chinese patients diagnosed with major depression. Analysis of the results reveals that patients with the l/l genotype had a significantly better response to SSRI (fluoxetine) when compared with s allele carriers, as evaluated on the basis of total (P = 0.013), core (P = 0.011), and psychic-anxiety (P = 0.005) and somatic-anxiety (P = 0.002) Hamilton Depression Rating Scale-score percentage change. Our findings confirm reports that the l allele is associated with better SSRI response.
Asunto(s)
Antidepresivos/uso terapéutico , Proteínas Portadoras/genética , Trastorno Depresivo/tratamiento farmacológico , Trastorno Depresivo/genética , Glicoproteínas de Membrana/genética , Proteínas de Transporte de Membrana , Proteínas del Tejido Nervioso , Polimorfismo Genético , Regiones Promotoras Genéticas , Adulto , Antidepresivos de Segunda Generación/uso terapéutico , Pueblo Asiatico/genética , China , Femenino , Fluoxetina/uso terapéutico , Humanos , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Proteínas de Transporte de Serotonina en la Membrana PlasmáticaRESUMEN
The serotonergic system has been implicated in the production of the N1 and P2 components of auditory evoked potentials (AEPs). Moreover, studies have indicated the influence of heritability in the genesis of these AEP components. The serotonin transporter is the major site of serotonin reuptake into the presynaptic neuron, and it has been determined that variants in the serotonin transporter gene-linked polymorphic region (5-HTTLPR) may affect gene transcription activity. The present study tested the hypothesis that the 5-HTTLPR genetic polymorphism is associated with the N1 and P2 components of AEPs in a sample of 127 Chinese patients (mean age: 41.6 years; male/female ratio: 58/69) diagnosed with major depression. Analysis of the results revealed a significantly shorter P2 latency for patients bearing the s/s genotype in comparison with l allele carriers, especially for the female patients (p = 0.004). The 5-HTTLPR polymorphism accounted for 3.4% of the variance in P2 latency. Our findings suggest a relationship between the 5-HTTLPR polymorphism and AEP P2 latency, and further studies of other genetic polymorphisms in the serotonergic system may help to predict this latency.
Asunto(s)
Proteínas Portadoras/genética , Trastorno Depresivo/genética , Trastorno Depresivo/fisiopatología , Potenciales Evocados Auditivos/genética , Glicoproteínas de Membrana/genética , Proteínas de Transporte de Membrana , Proteínas del Tejido Nervioso , Regiones Promotoras Genéticas/genética , Adulto , ADN/genética , Femenino , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Polimorfismo Genético , Proteínas de Transporte de Serotonina en la Membrana PlasmáticaRESUMEN
P300 has been demonstrated abnormal for a variety of neuropsychiatric disorders, and heritability has been proposed. We analyzed the event-related potentials for three DRD2 genotype groups in 134 normal young females. The results demonstrate that there is no association for DRD2 genotype and P300 components. Our negative findings in normal subjects suggest association demonstrated for P300 latency and the DRD2 allele may be disease dependent.