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Supervisor: Ministry of Education of the People's Republic of China

Sponsor: Sichuan University

Host unit: Editorial Board of Journal of Sichuan University (Medical Science Edition)

Editor-in-Chief: Yuquan Wei

CN 51-1644/R

ISSN 1672-173X

Postal code: 62-72

Establishment Time: 1959

Address: 17,Section 3,Renmin Nanlu,Chengdu,Sichuan,610041,People's Republic of China

Tel: 028-85501320

Email: scuxbyxb@scu.edu.cn


History and clinical findings: A 76 year-old woman with 8-year history of diabetes mellitus and hypertension was admitted with gangrene of left great toe, 3rd, 4th and 5th toes. Twenty months ago, She started to receive hemodialysis due to end-stage renal disease . She did not have any history of reactive airway disease nor bradycardia that would contraindicate the use of topical beta-blocker. The X-ray of left lower limb and foot showed calcification of left superficial femoral artery, popliteal artery, anterior tibial artery, posterior tibial artery, dorsal foot artery and digital artery, as well as osteolytic destruction at distal end of metatarsal bone, and lateral dislocation of the 4th and 5th toes. Color Doppler ultrasound of bilateral lower extremity arteries showed obvious calcification of bilateral superficial femoral arteries, thrombosis of left popliteal artery, severe stenosis of left anterior tibial artery, occlusion of left posterior tibial artery, right anterior tibial artery and posterior tibial artery. Computed tomographic angiography (CTA) of bilateral lower limb arteries revealed moderate stenosis of left superficial femoral artery, occlusion of left popliteal artery, left posterior tibial artery and dorsal pedal artery, occulusion of right posterior tibial artery, but right dorsal pedal artery was visible. Diagnosis, treatment and follow-up : Diagnosis of diabetic foot (left, grade 4 ) and diabetic lower extremity arterial occlusion (left, stage 4) was made. Based on multidisciplinary team ( MDT) discussion, the patient was unable to undergo vascular bypass surgery, and left lower extermity amputation also was not suitable because of right atrial thrombosis.Therefore, conservative treatment was recommended. The specific scheme used clopidogrel for antiplatelet agglutination, Low Molecular Weight Heparin (Clexane) and warfarin for anticoagulation, lipo-alprostadil for vasodilation, as well as local debridement and ultrasonic debridement.The treatments were given for up to 9 weeks, but with no significant clinical response. So the patient was treated with vacuum-assisted closure and autologous platelet-rich gel therapy for the next 7 weeks, then applied with 1 drop of timolol maleate 0.5% ophthalmic solution per cm2 wound area every other day for another 6 weeks, the wound rapidly healed and re-epithelialized basically. The follow-up for 5 weeks showed that the wound healed completely without any discomfort. No side effect was found.
Primary aldosteronism (PA) is the most common cause of secondary hypertension. The diagnosis procedure of PA includes screening, confirmatory diagnosis and subtype classification. International and national guidelines recommended plasma aldosterone concentration (PAC) to plasma renin activity (PRA) ratio (ARR) to detect possible cases of PA, and one or more tests (fludrocortisone suppression test, saline infusion test, oral sodium loading test, or captopril challenge test) to confirm ARR positive patients. Adrenal venous sampling (AVS) is also recommended as the best method to distinguish unilateral and bilateral adrenal disease when surgical treatment is feasible and desired by the patient. However, many studies find that each of the above diagnostic method has shortcomings. Recently, more and more studies are attempting to explore new methods with higher diagnostic efficiency and more conveniences, including new screening tests, new confirmatory diagnostic tests, new imaging and pathological histology methods. In our studies, the regression model, which included upright PAC, upright PRA, and lowest potassium, is superior to ARR for PA screening; the blood potassium and the ratio of blood potassium to blood sodium after the saline infusion test are not suitable for PA subtyping. This article will review the advances and progress in PA diagnosis.
Objective To investigate the the feasibility and diagnostic efficiencyvalue of different screening indexesmethods for screening primary aldosteronism (PA). Methods The clinical data of 499 patients with PA and 479 patients with essential hypertension diagnosed from Jan. 2009 to Dec. 2018 were retrospectively analyzed. The diagnostic performance of different screening indexs was compared by plotting receiver operating characteristic curves (ROC). Results The area under the ROC curve (AUC) of the plasma aldosterone concentration (PAC) to plasma renin activity (PRA) ratio (ARR) was greater than that of the ratio of the upright PAC to the angiotensin Ⅱ (AT-Ⅱ) (AA2R), upright PRA, upright PAC, supine ARR, and lowest blood potassium (P<0.05). The AUC of logistic regression model was greater than that of upright ARR (96.3% vs. 94.6%, P<0.05). There was no significant difference in AUC between decision tree model and upright ARR (94.1% vs. 94.6%, P>0.05). In the test set, the AUC difference between the logistic regression model and the decision tree model was not statistically significant (96.3% vs. 94.1%, P > 0.05). The calibration curve of the logistic regression model is closer to the 45 ° line, and the consistency between the prediction probability and the actual probability of the logistic regression model is better than that of the decision tree model. Conclusion For the screening of PA, upright ARR seems to be the best single screening index, while AA2R (radioimmunoassay) is not recommended. The diagnostic efficacy of logistic regression model including upright PAC, PRA and lowest blood potassium is better than that of single upright ARR.
Objective To explore the electrolyte characteristics between different types of primary aldosteronism (PA), especially the value of serum potassium and the ratio of sodium to potassium after saline infusion test (SIT) in differential diagnosis of PA. Methods The clinical data was collected from 135 patients who received screening for the causes of hypertension from Jan. 2009 to Dec. 2018 in West China Hospital. The patients were divided into two groups: essential hypertension group (EH group, 34 patients) and primary aldosteronism group (PA group, 101 patients). PA patients were divided into aldosterone-producing adenoma group (APA group, 60 patients) and idiopathic hyperaldosteronism group (IHA group, 41 patients). To analyze the value of serum potassium and the ratio of sodium to potassium after SIT in the differential diagnosis of PA with receiver operating characteristic (ROC) curve. Results Compared with EH group, the serum potassium level of APA group was lower either before or after SIT (P<0.01). The ratio of sodium to potassium before and after SIT in APA group were higher than that in EH group (P<0.05). There were no differences between APA group and IHA group in the level of serum potassium and the ratio of sodium to potassium before SIT. The level of serum potassium after SIT in APA group was lower than that in IHA group (P<0.01), and the ratio of sodium to potassium was higher (P<0.05). The area under ROC curve (AUC) of serum potassium level and the ratio of sodium to potassium after SIT were 0.641 and 0.646, respectively, while the AUC of aldosterone level was 0.788. The optimal cut-off value of serum sodium level was 3.56 mmol/L, with a sensitivity and specificity of 46.7% and 85.4%. The optimal cut-off value of ratio of sodium to potassium was 39.09, with 53.3% and 80.5% in sensitivity and specificity. Conclusion The serum potassium and the ratio of sodium to potassium after SIT has limited diagnostic value for its low sensitivity in differential diagnosis of PA.
Objective To summary the clinical diagnosis and treatment of primary aldosteronism (PA) in West China Hospital (WCH) of Sichuan University during 2009-2018. Methods This study enrolled the patients diagnosed as PA and admitted in WCH of Sichuan University from January 2009 to December 2018. The information of the patients including epidemiological and clinical data, diagnosis and treatment as well as therapeutic outcomes were collected and analyzed. Results A total of 853 patients with 1 248 diagnostic cases were included in the analysis, and the diagnosis cases of PA increased year by year from 2009 to 2018. Most patients (74.33%) were confirmed the diagnosis in the Department of Endocrinology and Metabolism and then admitted to the hospital. PA was more frequent in female than in male, with a ratio of female to male about 1.34∶1. Hypertension was the most common chief complaint, in contrast, the proportion of fatigue and/or numbness as the symptoms of hypokalemia was declining. More and more patients were diagnosed because of imaging examination founding adrenal incidentoma. After 2016, more and more patients were diagnosed by recumbent saline suppression test and captopril challenge test, and the number of adrenal venous sampling to classify PA subtypes was increasing to help choosing different treatment options. The proportion of surgical treatment decreased year by year, and more and more patients adopted medical treatment or transferred to surgery with combined treatment instead of simple operation. Conclusion During the past 10 years, remarkable progress was made in the diagnosis and treatment of PA. Hypertension was the most important clinical manifestation of PA, so the screening of PA in hypertensive patients should be strengthened. Adrenal incidentaloma has become prevalent manifestation of PA with an increasing trend, which needs more attention in clinical practice.
Objective To investigate the clinical characteristics of aldosterone producing adenoma (APA) and idiopathic hyperaldosteronism (IHA) complicated with obstructive sleep apnea hypopnea syndrome (OSAHS) and the effect of OSAHS on renin-angiotensin-aldosterone system (RAAS) in APA and IHA patients. Methods The clinical data of 127 patients with primary aldosteronism (PA) diagnosed from May 2010 to Aug. 2019 were retrospectively analyzed. There were 70 cases of APA, 53 cases of IHA. Another 4 cases were primary adrenal hyperplasia (PAH), so not included into further analysis. According to the results of polysomnography, the 123 patients of APA or IHA were divided into OSAHS group (96 cases) and non-OSAHS group (27 cases ). The patients with OSAHS were divided into mild, moderate and severe subgroups based on apnea hypopnea index (AHI).The clinical characteristics, biochemical parameters, plasma renin activity, aldosterone levels, and the ratio of aldosterone to renin activity (ARR) in the patients of APA and IHA complicated with OSAHS were compared with those of the patients without OSAHS. Results There were 49 OSAHS cases (49/70, 70.0%) in APA patients. and 47 OSAHS cases (47/53, 88.7%) in IHA patients. The age, male ratio, body mass index (BMI), waist circumference, triglyceride, blood uric acid, and blood creatinine in APA patients with OSAHS were higher than those in APA patients without OSAHS (P<0.05), while high-density lipoprotein and estimated glomerular filtration rate (eGFR) were lower (P<0.05). Compared to the patients without OSAHS, IHA-OSAHS patients had higher BMI and waist circumference (P<0.05). Moderate/severe OSAHS-APA patients exhibited higher plasma renin activity levels and lower ARR values than the APA patients with no/mild OSAHS (P<0.05). There were no significant differences in plasma renin activity, aldosterone levels, and ARR values between moderate/severe OSAHS-IHA group and no/mild OSAHS-IHA group. Conclusion The prevalence of OSAHS is significantly higher in the patients with PA than normal population, and OSAHS may aggravate glycose, lipid and uric acid metabolism in PA patients. Moderate/severe OSAHS can increase renin levels and decrease ARR values in APA patients, but has no significant effect on RAAS in IHA patients.
Objective TRAIL-Mu3 was obtained by mutating the N-terminus of human tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) gene to an eight continuous arginine sequence. The present study was designed to explore the antitumor effect of this soluble mutant protein and the underlying mechanisms. Methods The inhibitory effect of TRAIL-Mu3 on the proliferation of lung cancer cell lines NCI-H460, A549, NCI-H1299 and calu-1 was tested by CCK8 assay. The apoptotic rates of A549 and NCI-H460 treated by TRAIL-Mu3 were detected by flow cytometer (FCM). The expressions of apoptosis related proteins death receptor (DR) 4, DR5, Caspase-3, Caspase-8 and X-linked inhibitor of apoptosis protein (XIAP) were detected by Western blot. Moreover, a subcutaneous xenograft tumor mouse model of NCI-H460 was established and treated with TRAIL-Mu3 daily or every other day or three times a week. The expressions of DR4, DR5, Caspase-3, Caspase-8 and XIAP were detected by immunohistochemical staining. Results The in vitro study demonstrated that as compared to the TRAIL, the TRAIL-Mu3 was more toxic and pro-apoptotic by up-regulation of the expression and activity of DR4, Caspase-3 and Caspase-8. Also, the animal study showed a similar antitumor effect between treatment with TRAIL-Mu3 every other day and three time a week, which was better than daily use. All treatments significantly suppressed the growth of xenograft tumor, increased the expression or activity of DR4 and Caspase-3, and down-regulated the expression of XIAP (P<0.05). Conclusion TRAIL-Mu3 could improve antitumor activity in vivo and in vitro through elevating DR4 expression, activating Caspase-3/-8, and inhibiting XIAP activation.
Objective To investigate the effects of short hairpin RNA (shRNA) on the proliferation, invasion, apoptosis and tumor formation of non-small cell lung cancer cisplatin-resistant cell line (A549/DDP) via silencing of colon cancer associated transcript 2 (CCAT2). Methods TA549/DDP cells were transfected with shRNA-CCAT2 (sh-CCAT2) or shRNA-negative control (shRNA-NC), and untransfected A549/DDP cells were used as the control group. CCAT2 mRNA expression in three groups of A549/DDP cells was detected by quantitative real-time PCR (qRT-PCR). The proliferation of three groups of A549/DDP cells treated with different mass concentrations of DDP (0-8 mg/L) was detected by MTT. According to the proliferation experiment results, 2 mg/L was selected as DDP concentration for subsequent experiments. The effects of 2 mg/L DDP treatment on the proliferation, apoptosis, and invasion ability of each group of cells (with untreated A549/DDP cells as the control group) were tested by clone formation experiments, flow cytometry analysis and Transwell experiments. The expression levels of cell proliferation marker proteins (Ki67, PCNA), apoptosis marker proteins (Caspase-3, Caspase-9) and invasion marker proteins (VEGF, MMP-14) were detected by Western blot. Nude mice were injected subcutaneously with A549/DDP cells, A549/DDP cells transfected with shRNA-NC or A549/DDP cells transfected with sh-CCAT2. DDP was intraperitoneally injected at the concentration of 2 mg per kilogram of mice body weight totally for 7 times with an interval of 3 d. A control group was injected subcutaneously with A549/DDP cells, and an equal volume of normal saline instead of DDP was injected intraperitoneally. The tumor volume was detected every 5 d for a total of 30 d. Mice were sacrificed and tumor tissues were taken out 30 d later. CCAT2 mRNA expression level in tumor tissues was detected by RT-PCR, and tumor cell apoptosis was detected by TUNEL staining. Results Compared with the control group and the shRNA-NC transfection group, the expression level of CCAT2 mRNA was decreased in sh-CCAT2 transfected A549/DDP cells (P<0.01). The decrease degree of cell proliferation was more pronounced after treating with 2 to 8 mg/L of DDP (P<0.01). Compared with the control group, in the three groups that treated with DDP, the formation of clones and the expression of proliferation marker proteins Ki67 and PCNA were reduce (P<0.01), while the rate of apoptosis and the expression of apoptosis marker proteins Caspase-3 and Caspase-9 were increased (P<0.01). Also, the number of invasion cell and the expression of invasion marker proteins VEGF and MMP-14 were reduced in the three groups that treated with DDP (P<0.01). Among the three groups of DDP-treated cells, the changes in sh-CCAT2 transfected cells was the most obvious (P<0.01). Compared with the control group, the tumor volume of the three DDP treatment groups was smaller and the differences were statistically significant at 30 d (P<0.01). The expression of CCAT2 mRNA was decreased in tumor tissues (P<0.01), while apoptosis increased (P<0.01). Among the three DDP treatment groups, the A549/DDP cell group transfected with sh-CCAT2 showed the most notable changes (P<0.01). Conclusion sh-CCAT2 can inhibit the proliferation of A549/DDP cells, induce apoptosis and reduce the cell invasion ability, thereby inhibiting the growth of A549/DDP cells.
Objective To study the relationship between down-regulated expression of X linked inhibitor of apoptosis protein (XIAP) gene and the reversal effect of taxol-resistance by using siRNA interference technology in the taxol-resistant ovarian cancer. Methods Randomly assigned the nude mice into six groups (6 in each group) . Group A: normal saline; Group B: taxol; Group C: siRNA-NC+normal saline; Group D: siRNA-NC+taxol; Group E: siRNA XIAP+normal saline; Group F: siRNA XIAP+taxol. Each group was dealt with the corresponding processing depending on the agreed protocol and the transplanted tumors had a multi-point injection with reagents related siRNA, one time every 3 days, 9 times (27 d) in total. Taxol (2 mg/kg) was used in the intraperitoneal injection, 0.2 mL every time, once a week, for four weeks. After 27 d of siRNA treatment, xenograft volumes and qualities were measured and the inhibitory rate was calculated; RNA expression levels and protein levels of XIAP gene in xenografts were detected respectively by real-time fluorescent quantitative PCR and Western blot. Apoptosis of the transplanted tumor cells was examined by TUNEL method. Results Among the six groups, the proliferation of transplanted tumor in Group F was the slowest, and the tumor inhibition rate was the highest compared with control Group A, followed by Group E, and the tumor inhibition rate was the lowest in Group C. Group F and E expressed the lowest XIAP mRNA and protein expressions (P<0.05, vs. the other 4 groups) .The apoptosis rate was highest in Group F, followed by Group E, and lowest in Group A and C (P<0.05). Conclusion XIAP siRNA has synergy with taxol in taxol-resistant ovarian cancer cells.
Objective To investigate the effects of ubiquitin-like PDH and ring finger domain 1 (UHRF1) on the expression ratio of estrogen receptor (ER) α/ERβ, and to explore the experimental mechanism of UHRF1 affecting the proliferation, invasion and migration of BCPAP cells in papillary thyroid carcinoma. Methods The protein and mRNA expressions of UHRF1, ERα and ERβ in normal thyroid Nthy-ori3-1 cells and thyroid papillary carcinoma BCPAP cells were detected by Western blot and qRT-PCR. BCPAP cells were treated with Scrambled siRNA and UHRF1 siRNA, respectively. The expressions of ERα and ERβ mRNAs were detected by qRT-PCR. MTT and Transwell were used to determine the proliferation, invasion and migration in each group of BCPAP cells. Results Compared with Nthy-ori3-1 cells, the expressions of UHRF1 and ERα proteins and mRNAs in BCPAP cells were significantly up-regulated (P<0.05), while the expressions of ERβ protein and mRNA were significantly down-regulated (P<0.05). Compared with the control group and Scrambled siRNA group, the expression of ERα mRNA in BCPAP cells transfected with UHRF1 siRNA was significantly decreased (P<0.05), while the expression of ERβ mRNA was significantly increased (P<0.05). The proliferation, invasion and migration of BCPAP cells transfected with UHRF1 siRNA were significantly decreased (P<0.05). Conclusion UHRF1 upregulates ERα/ERβ expression ratio and promotes proliferation, invasion and migration of BCPAP cells in papillary thyroid carcinoma.

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