BACKGROUND Coronary heart disease(CHD)and heart failure(HF)are the major causes of morbidity and mortality worldwide.Early and accurate diagnoses of CHD and HF are essential for optimal management and prognosis.Howeve...BACKGROUND Coronary heart disease(CHD)and heart failure(HF)are the major causes of morbidity and mortality worldwide.Early and accurate diagnoses of CHD and HF are essential for optimal management and prognosis.However,conventional diagnostic methods such as electrocardiography,echocardiography,and cardiac biomarkers have certain limitations,such as low sensitivity,specificity,availability,and cost-effectiveness.Therefore,there is a need for simple,noninvasive,and reliable biomarkers to diagnose CHD and HF.AIM To investigate serum cystatin C(Cys-C),monocyte/high-density lipoprotein cholesterol ratio(MHR),and uric acid(UA)diagnostic values for CHD and HF.METHODS We enrolled 80 patients with suspected CHD or HF who were admitted to our hospital between July 2022 and July 2023.The patients were divided into CHD(n=20),HF(n=20),CHD+HF(n=20),and control groups(n=20).The serum levels of Cys-C,MHR,and UA were measured using immunonephelometry and an enzymatic method,respectively,and the diagnostic values for CHD and HF were evaluated using receiver operating characteristic(ROC)curve analysis.RESULTS Serum levels of Cys-C,MHR,and UA were significantly higher in the CHD,HF,and CHD+HF groups than those in the control group.The serum levels of Cys-C,MHR,and UA were significantly higher in the CHD+HF group than those in the CHD or HF group.The ROC curve analysis showed that serum Cys-C,MHR,and UA had good diagnostic performance for CHD and HF,with areas under the curve ranging from 0.78 to 0.93.The optimal cutoff values of serum Cys-C,MHR,and UA for diagnosing CHD,HF,and CHD+HF were 1.2 mg/L,0.9×10^(9),and 389μmol/L;1.4 mg/L,1.0×10^(9),and 449μmol/L;and 1.6 mg/L,1.1×10^(9),and 508μmol/L,respectively.CONCLUSION Serum Cys-C,MHR,and UA are useful biomarkers for diagnosing CHD and HF,and CHD+HF.These can provide information for decision-making and risk stratification in patients with CHD and HF.展开更多
Objective Obesity-induced kidney injury contributes to the development of diabetic nephropathy(DN).Here,we identified the functions of ubiquitin-specific peptidase 19(USP19)in HK-2 cells exposed to a combination of hi...Objective Obesity-induced kidney injury contributes to the development of diabetic nephropathy(DN).Here,we identified the functions of ubiquitin-specific peptidase 19(USP19)in HK-2 cells exposed to a combination of high glucose(HG)and free fatty acid(FFA)and determined its association with TGF-beta-activated kinase 1(TAK1).Methods HK-2 cells were exposed to a combination of HG and FFA.USP19 mRNA expression was detected by quantitative RT-PCR(qRT-PCR),and protein analysis was performed by immunoblotting(IB).Cell growth was assessed by Cell Counting Kit-8(CCK-8)viability and 5-ethynyl-2′-deoxyuridine(EdU)proliferation assays.Cell cycle distribution and apoptosis were detected by flow cytometry.The USP19/TAK1 interaction and ubiquitinated TAK1 levels were assayed by coimmunoprecipitation(Co-IP)assays and IB.Results In HG+FFA-challenged HK-2 cells,USP19 was highly expressed.USP19 knockdown attenuated HG+FFA-triggered growth inhibition and apoptosis promotion in HK-2 cells.Moreover,USP19 knockdown alleviated HG+FFA-mediated PTEN-induced putative kinase 1(PINK1)/Parkin pathway inactivation and increased mitochondrial reactive oxygen species(ROS)generation in HK-2 cells.Mechanistically,USP19 stabilized the TAK1 protein through deubiquitination.Importantly,increased TAK1 expression reversed the USP19 knockdown-mediated phenotypic changes and PINK1/Parkin pathway activation in HG+FFA-challenged HK-2 cells.Conclusion The findings revealed that USP19 plays a crucial role in promoting HK-2 cell dysfunction induced by combined stimulation with HG and FFAs by stabilizing TAK1,providing a potential therapeutic strategy for combating DN.展开更多
BACKGROUND Refractory secondary hyperparathyroidism(SHPT)is a common complication observed in patients with end-stage renal disease and can result in ectopic calcification.Metastatic calcification involving the heart ...BACKGROUND Refractory secondary hyperparathyroidism(SHPT)is a common complication observed in patients with end-stage renal disease and can result in ectopic calcification.Metastatic calcification involving the heart valves and the conduction system can easily lead to arrhythmias,including atrioventricular block.This case report describes a maintenance hemodialysis patient with refractory SHPT resulting in a complete atrioventricular block(CAVB),which was eventually reversed to a first-degree atrioventricular block.CASE SUMMARY We present the case of a 31-year-old Asian female who was receiving maintenance hemodialysis because of lupus nephropathy.She developed SHPT,and an electrocardiogram revealed a first-degree atrioventricular block.Then,she underwent parathyroidectomy(PTX)with autotransplantation.Unfortunately,a few years later,she developed SHPT again,and an electrocardiogram revealed a CAVB.A few years after the second PTX surgery,the calcification of the left atrium and left ventricle improved,and her CAVB was reversed.CONCLUSION This case revealed that metastatic cardiac calcification can result in complete atrioventricular blockage.Following parathyroid surgery,calcification of the cardiac conduction system improved,leading to reversal of the atrioventricular block.It is important for dialysis patients to optimize intact parathyroid hormone therapy and pay attention to calcification metastasis.展开更多
Objectives:Sciadopitysin(SP)is aflavonoid in Ginkgo biloba that exhibits various pharmacological activities.This study aimed to investigate its antitumor effects and the underlying molecular mechanism of SP in hepatoce...Objectives:Sciadopitysin(SP)is aflavonoid in Ginkgo biloba that exhibits various pharmacological activities.This study aimed to investigate its antitumor effects and the underlying molecular mechanism of SP in hepatocellular carcinoma(HCC)cells.Methods:Network pharmacology was used for target prediction analysis.Cell Counting Kit-8(CCK-8)assay was used to test the cell viability.Flow cytometry was used to test the cell cycle distribution,apoptosis status,and reactive oxygen species(ROS)levels.Transwell and wound-healing assay was used to test the migration effect of SP on HepG2 cells.Western Blot assay was used to test the expression levels of proteins.Results:Network pharmacology analysis results showed that the mitogen-activated protein kinase(MAPK)and other signaling pathways are involved in the SP anti-HCC biological process.CCK-8 assay results demonstrated that SP showed an obvious killing effect on three types of HCC cells and low cytotoxic effect on normal cells.Western Blot andflow cytometry results showed that SP regulated MAPK/signal transducer and activator of transcription 3(STAT3)/nuclear factor kappa-B(NF-κB)signaling pathway to induce mitochondrion-dependent apoptosis in HepG2 cells.Additionally,SP can arrest the G0/G1 phase cell cycle via the protein kinase B(AKT)/p21/p27/cyclin-dependent kinase(CDK)/Cyclin signaling pathway.Wound healing and transwell assays showed that SP inhibited cell motility and invasion through the AKT/glycogen synthase kinase3β(GSK-3β)/vimentin/β-catenin signaling pathway.Conclusion:Thesefindings demonstrated that SP induced mitochondrion-dependent apoptosis,arrested cell cycle in the G0/G1 phase,and inhibited cell migration by regulating the ROS-mediated signaling pathway in HepG2 cells.Thus,SP could serve as a therapeutic agent for the treatment of human HCC.展开更多
AIM: To evaluate the efficacy and safety of pegylated- interferon alpha-2a in hemodialysis patients with chronic hepatitis C. METHODS: Thirty-six hemodialysis patients with chronic hepatitis C were enrolled in a con...AIM: To evaluate the efficacy and safety of pegylated- interferon alpha-2a in hemodialysis patients with chronic hepatitis C. METHODS: Thirty-six hemodialysis patients with chronic hepatitis C were enrolled in a controlled and prospective study. All patients were treatment naive, positive tested for anti-HCV antibodies, and positive tested for serum HCV-RNA. Twenty-two patients received 135 μg peglyated-interferon α-2a weekly for 48 wk (group A). The remaining patients were left untreated, eleven refused therapy, and three were not candidates for kidney transplantation and were allocated to the control group (group B). At the end of the treatment biochemical and virological response was evaluated, and 24 wk after completetion of therapy sustained virological response (SVR) was assessed. Side effects were monitored. RESULTS: Of 22 hemodialysis patients, 12 were male and 10 female, with a mean age of 35.2 ± 12.1 years. Virological end-of-treatment response was observed in 14 patients (82.4%) in group A and in one patient (7.1%) in group B (P = 0.001). Sustained virological response was observed in 11 patients (64.7%) in group A and in one patient in group B (7.1%). Biochemical response parameters normalized in 10/14 patients (71.4%) at the end of the treatment. ALT levels in group B were initially high in six patients and normalized in one of them (25%) at the end of the 48 wk. In five patients (22.7%) therapy had to be stopped at mo 4 due to complications of weakness, anemia, and bleeding. CONCLUSION: SVR could be achieved in 64.7% of patients on hemodialysis with chronic hepatitis C by a treatment with peglyated-interferon α-2a. Group A had a significantly better efficacy compared to the control group B, but the side effects need to be concerned.展开更多
Introduction: Heart and kidney diseases are common among patients admitted to hospital and they coexist in a significant number of cases. The interactions between the cardiovascular system and the kidney have been...Introduction: Heart and kidney diseases are common among patients admitted to hospital and they coexist in a significant number of cases. The interactions between the cardiovascular system and the kidney have been known and described for many years and have led to the description of cardio-renal syndrome. The objective of this study was to determine the frequency;to describe the clinical, etiological and prognostic aspects of acute renal failure in patients hospitalized for chronic congestive heart failure. Method: This was a descriptive retrospective study from January 2, 2018 to December 31, 2022. Included in this study were all the complete records of patients hospitalized for chronic congestive heart failure with serum creatinine ≥120 μmol/I. We’re not included in this study, incomplete files, records of patients hospitalized for other pathologies, records of patients hospitalized for chronic congestive heart failure with normal renal function. Our study variables were qualitative and quantitative divided into clinical, paraclinical and prognostic data. Our data were analyzed using the EPI-info 7.2.2.6 software. Data entry and presentation were carried out using Word, Excel and PowerPoint from the 2016 Office Pack. Results: We collected 830 files of which 114 met our selection criteria, a frequency of 13.73%. The mean age of the patients was 47 ± 19 years. The F/M sex ratio was 1.23. The dominant etiologies were hypertension followed by diabetes with respectively 60.5% and 23.7%. Toxic factors including tobacco accounted for 7.9% of cases. Dyspnea accounted for 86.8%. Most of our patients were grade 3 or 36% based on systolic blood pressure on admission with an average of 164.16 ± 33.95 mmHg and an average diastolic blood pressure of 93.24 ± 20.40 mmHg. Biologically, the serum creatinine revealed a high frequency of 201 - 400 μmol/l (33% of cases) with an average value of 586.49 ± 631.44 μmol/l with the extremes 2.960 and 2448.68 μmol/I. Anemia was moderate in 34.2% of cases. Cardiac ultrasound was performed on 81 patients, the results of which showed dilated cardiomyopathy in 48.2% of cases. Renal ultrasound was performed only by 18 patients, renal suffering was found with 8.8%. Almost all (92.11%) of the patients had an acute renal failure of functional origin. More than half (65.80%) of our patients were at risk. Diuretics were the most prescribed antihypertensives with 87.71% followed by ACE inhibitors 78.94%. The average length of hospitalization was 13.81 ± 7.66 days with extremes of 24 hours and 41 days. Conclusion:The association of acute renal failure and chronic congestive heart failure is a frequent situation. The diagnostic approach must be guided by the context and the data of a meticulous examination supplemented by an appropriate paraclinical assessment. Kidney renal failure is mostly functional.展开更多
Introduction: Ambulatory Blood Pressure Measurement (ABPM) is a non- invasive examination recommended for subjects at high cardiovascular risk, and those requiring a nocturnal drop in BP such as elderly and obese...Introduction: Ambulatory Blood Pressure Measurement (ABPM) is a non- invasive examination recommended for subjects at high cardiovascular risk, and those requiring a nocturnal drop in BP such as elderly and obese subjects, those with secondary hypertension or resistant, diabetics, subjects with metabolic syndrome or sleep apnea syndrome. The objective of this study was to evaluate the contribution of ABPM in the diagnosis and evaluation of the level of control of hypertension under treatment at the Bel Air international clinic. Materials and Methods: This is a retrospective, cross-sectional and descriptive study, carried out at the Bel Air International Clinic in Conakry (Guinea) between January 2019 and November 30, 2022. It included a consecutive series of 180 consenting patients recruited through an ambulatory measurement of 24-hour blood pressure from a FUGADA brand device. Results: We collected 180 patients, with a male predominance (sex-ratio M/F = 2.46). The mean age of the patients was 48.48 ± 14.23 years. The most represented age group was that of 32 to 42 years with 50 cases (27.8%) followed by that of 43 to 52 years with 42 cases or 23.3%. The indication was for diagnostic purposes in 106 cases 58.9%, the therapeutic evaluation in 58 patients (32.2%). The examination was prescribed by a cardiologist in 98 cases (54.4%), a general practitioner in 71 cases (39.4%), a neurologist in 11 cases (6.1%). In the therapeutic evaluation, high blood pressure was controlled in 24 patients (13.3%) and uncontrolled in 34 cases (18.9%). In the diagnostic indication, high blood pressure was confirmed in 79 cases (43.9%) with a statistically significant link (Chi2</sup> = 4.57 and p-value = 0.032). The nycthemeral mean was 187.27 ± 26.22 mmHg for systolic blood pressure (SBP) and 110.37 ± 19.06 mmHg for diastolic blood pressure (DBP), during the day, 151.64 ± 21.45 mmHg for SBP and 71.59 ± 8.67 mmHg for diastolic blood pressure. During the study 65 patients (36.1%) were identified as dippers and 115 patients (63.9%) were no-dipping. The antihypertensive protocol used was monotherapy in 68 cases (37.8%), dual therapy in 46 cases (25.6%), triple therapy in 17 cases (9.4%). However 39 patients or 21.7% were not taking any antihypertensive. Conclusion: This preliminary study, despite the modest sample size, showed the importance of ABPM as a tool for diagnosis, monitoring of hypertensive patients and therapeutic adaptation. A large-scale national study would be necessary for the rational use of ambulatory blood pressure measurement in our context in order to improve the management of hypertensive patients.展开更多
AIM: To investigate whether continuous veno-venous hemofiltration (CVVH) in different filtration rate to eliminate cytokines would result in different efficiency in acute pancreatitis, whether the saturation time o...AIM: To investigate whether continuous veno-venous hemofiltration (CVVH) in different filtration rate to eliminate cytokines would result in different efficiency in acute pancreatitis, whether the saturation time of filter membrane was related to different filtration rate, and whether the onset time of CWH could influence the survival of acute pancreatitis. METHODS: Thirty-seven patients were classified into four groups randomly. Group 1 underwent low-volume CVVH within 48 h of the onset of abdominal pain (early CVVH, n = 9). Group 2 received low-volume CVVH after 96 h of the onset of abdominal pain (late CVVH, n= 10). Group 3 underwent high-volume CVVH within 48 h of the onset of abdominal pain (early CVVH, n = 9). Group 4 received high-volume CVVH after 96 h of theonset of abdominal pain (late CVVH, n = 9). CVVH was sustained for at least 72 h. Blood was taken before hemofiltration, and ultrafiltrate was collected at the start of CVVH and every 12 h during CVVH period for the purpose of measuring the concentrations of TNF-α, IL-1β and IL-6. The concentrations of TNF-α, IL-1β and IL-6 were measured by swine-specific ELISA. The Solartron 1 255 B frequency response analyzer (British) was used to observe the resistance of filter membrane. RESULTS: The survival rate had a significant difference (94.44% vs68.42%, P〈0.01) high-volume and low-volume CVVH patients. The survival rate had also a significant difference (88.89% vs 73.68%, P〈0.05) between early and late CVVH patients. The hemodynamic deterioration (MAP, HR, CVP) was less severe in groups 4 and 1 bhan that in group 2, and in group 3 than in group 4. The adsorptive saturation time of filters membranes was 120-180 min if the filtration rate was 1 000-4 000 mL/h. After the first, second and third new hemofilters were changed, serum TNF-α concentrations had a negative correlationwith resistance (r: -0.91, -0.89, and -0.86, respectively in group 1; -0.89, -0.85, and -0.76, respectively in group 2; -0.88, -0.92, and -0.82, respectively in group 3; -0.84, -0.87, and -0.79, respectively in group 4). The decreasing extent of TNF-α, IL-1β and IL-6 was significantly different between group 3 and group I (TNF-α P〈0.05, IL-1β P〈0.05, IL-6 P〈0.01), between group 4 and group 2 (TNF-α P〈0.05, IL-1β P〈0.05, IL-6 P〈0.01), between group 1 and group 2 (TNF-α P〈0.05, IL-1β P〈0.05, IL-6 P〈0.05), and between group 3 and group 4 (TNF-α P〈0.01, IL-1β P〈0.01, IL-6 P〈0.05), respectively during CVVH period. The decreasing extent of TNF-α and IL-1β was also significantly different between survival patients and dead patients (TNF-α P〈0.05, IL-1β P〈0.05). In survival patients, serum concentration of TNF-α and IL-1β decreased more significantly than that in dead patients. CONCLUSION: High-volume and early CWH improve hemodynamic deterioration and survival in acute pancreatitis patients. High-volume CVVH can eliminate cytokines more effidently than low-volume CVVH. The survival rate is related to the decrease extent of TNF-α and IL-1β. The adsorptive saturation time of filter membranes are different under different filtration rate condition. The filter should be changed timely once filter membrane adsorption is saturated.展开更多
Non-alcoholic fatty liver disease(NAFLD) is a common liver disease and it represents the hepatic manifestation of metabolic syndrome, which includes type 2 diabetes mellitus(T2DM), dyslipidemia, central obesity an...Non-alcoholic fatty liver disease(NAFLD) is a common liver disease and it represents the hepatic manifestation of metabolic syndrome, which includes type 2 diabetes mellitus(T2DM), dyslipidemia, central obesity and hypertension. Glucagon-like peptide-1(GLP-1) analogues and dipeptidyl peptidase-4(DPP-4) inhibitors were widely used to treat T2 DM. These agents improve glycemic control, promote weight loss and improve lipid metabolism. Recent studies have demonstrated that the GLP-1 receptor(GLP-1R) is present and functional in human and rat hepatocytes. In this review, we present data from animal researches and human clinical studies that showed GLP-1 analogues and DPP-4 inhibitors can decrease hepatic triglyceride(TG) content and improve hepatic steatosis, although some effects could be a result of improvements in metabolic parameters. Multiple hepatocyte signal transduction pathways and m RNA from key enzymes in fatty acid metabolism appear to be activated by GLP-1 and its analogues. Thus, the data support the need for more rigorous prospective clinical trials to further investigate the potential of incretin therapies to treat patients with NAFLD.展开更多
Objective In this study, an in vitro hemofiltration model was set up to investigate adsorptive saturati on time of different membrane under different blood flow rate (Q B)and filt rate rate(Q F). Methods Ant...Objective In this study, an in vitro hemofiltration model was set up to investigate adsorptive saturati on time of different membrane under different blood flow rate (Q B)and filt rate rate(Q F). Methods Anticoagulated cattle blood (2000 mL per bag) was stimulated with 1μg·mL -1 endotoxin to induce i nflammatory mediators before hemofiltration (HF) using AN69, PS and PMMA filters in vitro. Adsorptive saturation time of membrane was observed using data br idge in different Q B and different Q F. TNF was measured by radioimmu noassays. Results Before the resistance level reached the peak value in the same group, resistance level increased significantly (P<0.01). After the peak value, there was no difference (P>05). It was suggested tha t the resistance level reached plateau at 150,120,90,120, and150 minutes in Q F of 100 mL·minute -1, 200 mL·minute -1, 300 mL·minute -1 , respectively and in Q F of 1L·hour -1, 2L·hour -1, 4L·hour -1, respectively. And with the Q B and Q F increasing, resistanc e level increased significantly (P<0.01) among different groups at the same time point in A, B, C, D and E group. Conclusion Membrane resis tance level online measured by Data Bridge can instantly reflect the degree of m embrane adsorption. Adsorptive saturation time of filter membrane in different f iltration flow rate and blood flow rate are different.展开更多
Aim: This observational clinical study tested the effect of injection frequency of the biosimilar epoetin zeta on the weekly dose needed to maintain stable hemoglobin levels in chronic kidney diseases (CKD) patients o...Aim: This observational clinical study tested the effect of injection frequency of the biosimilar epoetin zeta on the weekly dose needed to maintain stable hemoglobin levels in chronic kidney diseases (CKD) patients on intermittent high-flux hemodialysis (HD). Patients and Methods: CKD patients (n = 33) on regular HD therapy 3 times a week were treated for 18 months with epoetin zeta i.v. The hemoglobin levels, the weekly dose as well as the injection frequency of epoetin zeta were monitored at least every two weeks. Patients were followed in three time periods: 1) extended follow-up (months 1 - 18);2) intervention phase (months 19 - 21);and 3) post intervention observation phase (months 28 - 30). During extended follow-up the majority of patients (n = 21) received only one injection of epoetin zeta per week. During the intervention phase, injection frequency was increased to 3 injections per week in all patients accompanied by a reduction in weekly doses of approximately 20% - 30%. Following a 9 month period of dose adjustment all parameters were monitored again in the post-intervention phase. Results: During the first 18 months of epoetin zeta therapy the mean hemoglobin level was stable between 11 and 12 g/dl. The mean weekly dose of epoetin zeta was 7939 IU/week in month 6 and 7909 IU/week in month 18 (p = not significant). The mean frequency (injections/week) was 1.27 in month 6 and 1.29 in month 18 (not significant). Compared to month 18, at the end of the observation at month 30, hemoglobin levels were stable, mean injection frequency increased to 2.25 (p < 0.001) and the mean weekly dose decreased to 5469 IU/week (-31.7%, p < 0.001). Conclusions: Increasing the injection frequency of the short acting biosimilar epoetin zeta to two to three injections per week reduces the weekly dose and thereby the costs of ESA therapy of renal anemia significantly.展开更多
Dialysis patients have risk in Zoster virus because of low immune. Valacyclovir, used for Zoster virus, is digested in kidney and it has side effect of nerve virus on patients with malfimction kidneys. This article re...Dialysis patients have risk in Zoster virus because of low immune. Valacyclovir, used for Zoster virus, is digested in kidney and it has side effect of nerve virus on patients with malfimction kidneys. This article reviews 8 dialysis cases and discusses the proper Valacyclovir portion for peritoneal dialysis patients.展开更多
Acute kidney injury(AKI),associated with significant mor-bidity and mortality,is widely known to involve epithelial apoptosis,excessive inflammation,and fibrosis in re-sponse to ischemia or reperfusion injury,which re...Acute kidney injury(AKI),associated with significant mor-bidity and mortality,is widely known to involve epithelial apoptosis,excessive inflammation,and fibrosis in re-sponse to ischemia or reperfusion injury,which results in either chronic pathological changes or death.Therefore,it is imperative that investigations are conducted in order to fi nd effective,early diagnoses,and therapeutic targets needed to help prevent and treat AKI.However,the mech-anisms modulating the pathogenesis of AKI still remain largely undetermined.MicroRNAs(miRNAs),small non-coding RNA molecules,play an important role in several fundamental biological and pathological processes by a post transcriptional regulatory function of gene expres-sion.MicroRNA-21(miR-21)is a recently identifi ed,typi-cal miRNA that is functional as a regulator known to be involved in apoptosis as well as inflammatory and fi brotic signaling pathways in AKI.As a result,miR-21 is now considered a novel biomarker when diagnosing and treat-ing AKI.This article reviews the correlative literature and research progress regarding the roles of miR-21 in AKI.展开更多
The association between dyslipidemia and elevated fasting glucose in type 2 diabetes is well known. In non-diabetes, whether this association still exists, and whether dyslipidemia is an independent risk factor for hi...The association between dyslipidemia and elevated fasting glucose in type 2 diabetes is well known. In non-diabetes, whether this association still exists, and whether dyslipidemia is an independent risk factor for high fasting plasma glucose (FPG) levels are not clear. This cross-sectional study recruited 3460 non-diabetic Chinese subjects (1027 men, and 2433 women, aged 35-75 years old) who participated in a health survey. Men and women were classified into tertiles by levels of plasma lipids respectively. In women, the prevalence of impaired fasting glucose (IFG) was decreased with increased HDL-C. A stepwise increase in HDL-C was associated with decreasing FPG levels (lowest tertiles, FPG: 5.376 ± 0.018; middle tertiles, 5.324± 0.018; highest tertiles, 5.276±0.018mmol/L; P = 0.001). Reversely, FPG levels increased from lowest tertiles to highest tertiles of LDL-C, TC, and TG. we found that women in the first tertile with lower HDL-C level had a 1.75-fold increase in risk of IFG compared with non-diabetic women in the third tertile with higher HDL-C level (OR: 1.75; 95% CI: 1.20-2.56). In men, no significant association was found. We took age, BMI, waist/hip ratio, education, smoking, alcohol drinking, and physical exercise as adjusted variables. In Chinese non-diabetic women, dyslipidemia is independently associated with high levels of FPG; TG, HDL-C, and LDL-C are predictors of IFG independent of BMI and waist/hip ratio.展开更多
文摘BACKGROUND Coronary heart disease(CHD)and heart failure(HF)are the major causes of morbidity and mortality worldwide.Early and accurate diagnoses of CHD and HF are essential for optimal management and prognosis.However,conventional diagnostic methods such as electrocardiography,echocardiography,and cardiac biomarkers have certain limitations,such as low sensitivity,specificity,availability,and cost-effectiveness.Therefore,there is a need for simple,noninvasive,and reliable biomarkers to diagnose CHD and HF.AIM To investigate serum cystatin C(Cys-C),monocyte/high-density lipoprotein cholesterol ratio(MHR),and uric acid(UA)diagnostic values for CHD and HF.METHODS We enrolled 80 patients with suspected CHD or HF who were admitted to our hospital between July 2022 and July 2023.The patients were divided into CHD(n=20),HF(n=20),CHD+HF(n=20),and control groups(n=20).The serum levels of Cys-C,MHR,and UA were measured using immunonephelometry and an enzymatic method,respectively,and the diagnostic values for CHD and HF were evaluated using receiver operating characteristic(ROC)curve analysis.RESULTS Serum levels of Cys-C,MHR,and UA were significantly higher in the CHD,HF,and CHD+HF groups than those in the control group.The serum levels of Cys-C,MHR,and UA were significantly higher in the CHD+HF group than those in the CHD or HF group.The ROC curve analysis showed that serum Cys-C,MHR,and UA had good diagnostic performance for CHD and HF,with areas under the curve ranging from 0.78 to 0.93.The optimal cutoff values of serum Cys-C,MHR,and UA for diagnosing CHD,HF,and CHD+HF were 1.2 mg/L,0.9×10^(9),and 389μmol/L;1.4 mg/L,1.0×10^(9),and 449μmol/L;and 1.6 mg/L,1.1×10^(9),and 508μmol/L,respectively.CONCLUSION Serum Cys-C,MHR,and UA are useful biomarkers for diagnosing CHD and HF,and CHD+HF.These can provide information for decision-making and risk stratification in patients with CHD and HF.
基金supported by Natural Science Foundation of Shaanxi Province(No.2023-JC-YB-743 and No.2021JQ-905).
文摘Objective Obesity-induced kidney injury contributes to the development of diabetic nephropathy(DN).Here,we identified the functions of ubiquitin-specific peptidase 19(USP19)in HK-2 cells exposed to a combination of high glucose(HG)and free fatty acid(FFA)and determined its association with TGF-beta-activated kinase 1(TAK1).Methods HK-2 cells were exposed to a combination of HG and FFA.USP19 mRNA expression was detected by quantitative RT-PCR(qRT-PCR),and protein analysis was performed by immunoblotting(IB).Cell growth was assessed by Cell Counting Kit-8(CCK-8)viability and 5-ethynyl-2′-deoxyuridine(EdU)proliferation assays.Cell cycle distribution and apoptosis were detected by flow cytometry.The USP19/TAK1 interaction and ubiquitinated TAK1 levels were assayed by coimmunoprecipitation(Co-IP)assays and IB.Results In HG+FFA-challenged HK-2 cells,USP19 was highly expressed.USP19 knockdown attenuated HG+FFA-triggered growth inhibition and apoptosis promotion in HK-2 cells.Moreover,USP19 knockdown alleviated HG+FFA-mediated PTEN-induced putative kinase 1(PINK1)/Parkin pathway inactivation and increased mitochondrial reactive oxygen species(ROS)generation in HK-2 cells.Mechanistically,USP19 stabilized the TAK1 protein through deubiquitination.Importantly,increased TAK1 expression reversed the USP19 knockdown-mediated phenotypic changes and PINK1/Parkin pathway activation in HG+FFA-challenged HK-2 cells.Conclusion The findings revealed that USP19 plays a crucial role in promoting HK-2 cell dysfunction induced by combined stimulation with HG and FFAs by stabilizing TAK1,providing a potential therapeutic strategy for combating DN.
基金Supported by Weifang Health and Family Planning Commission Research Project,No.WFWSJK-2021-212.
文摘BACKGROUND Refractory secondary hyperparathyroidism(SHPT)is a common complication observed in patients with end-stage renal disease and can result in ectopic calcification.Metastatic calcification involving the heart valves and the conduction system can easily lead to arrhythmias,including atrioventricular block.This case report describes a maintenance hemodialysis patient with refractory SHPT resulting in a complete atrioventricular block(CAVB),which was eventually reversed to a first-degree atrioventricular block.CASE SUMMARY We present the case of a 31-year-old Asian female who was receiving maintenance hemodialysis because of lupus nephropathy.She developed SHPT,and an electrocardiogram revealed a first-degree atrioventricular block.Then,she underwent parathyroidectomy(PTX)with autotransplantation.Unfortunately,a few years later,she developed SHPT again,and an electrocardiogram revealed a CAVB.A few years after the second PTX surgery,the calcification of the left atrium and left ventricle improved,and her CAVB was reversed.CONCLUSION This case revealed that metastatic cardiac calcification can result in complete atrioventricular blockage.Following parathyroid surgery,calcification of the cardiac conduction system improved,leading to reversal of the atrioventricular block.It is important for dialysis patients to optimize intact parathyroid hormone therapy and pay attention to calcification metastasis.
基金supported by Sichuan Applied Psychology Research Center of Chengdu Medical College(Number:CSXL-23408)the Humanities and Social Science Research Planning Fund of the Ministry of Education of the People's Republic of China(22YJA630087).
基金This research was funded by the Heilongjiang Province Key Research and Development Plan Guidance Project(Grant No.GZ20220039)the National Natural Science Foundation of China(Grant No.82060118)+2 种基金the Program for Young Talents of Science and Technology in Universities of Inner Mongolia Autonomous Region(Grant No.NJYT24032)the Central Government Supports Local College Reform and Development Fund Talent Training Project(Grant No.2020GSP16)Heilongjiang Touyan Innovation Team Program(Grant No.2019HTY078).
文摘Objectives:Sciadopitysin(SP)is aflavonoid in Ginkgo biloba that exhibits various pharmacological activities.This study aimed to investigate its antitumor effects and the underlying molecular mechanism of SP in hepatocellular carcinoma(HCC)cells.Methods:Network pharmacology was used for target prediction analysis.Cell Counting Kit-8(CCK-8)assay was used to test the cell viability.Flow cytometry was used to test the cell cycle distribution,apoptosis status,and reactive oxygen species(ROS)levels.Transwell and wound-healing assay was used to test the migration effect of SP on HepG2 cells.Western Blot assay was used to test the expression levels of proteins.Results:Network pharmacology analysis results showed that the mitogen-activated protein kinase(MAPK)and other signaling pathways are involved in the SP anti-HCC biological process.CCK-8 assay results demonstrated that SP showed an obvious killing effect on three types of HCC cells and low cytotoxic effect on normal cells.Western Blot andflow cytometry results showed that SP regulated MAPK/signal transducer and activator of transcription 3(STAT3)/nuclear factor kappa-B(NF-κB)signaling pathway to induce mitochondrion-dependent apoptosis in HepG2 cells.Additionally,SP can arrest the G0/G1 phase cell cycle via the protein kinase B(AKT)/p21/p27/cyclin-dependent kinase(CDK)/Cyclin signaling pathway.Wound healing and transwell assays showed that SP inhibited cell motility and invasion through the AKT/glycogen synthase kinase3β(GSK-3β)/vimentin/β-catenin signaling pathway.Conclusion:Thesefindings demonstrated that SP induced mitochondrion-dependent apoptosis,arrested cell cycle in the G0/G1 phase,and inhibited cell migration by regulating the ROS-mediated signaling pathway in HepG2 cells.Thus,SP could serve as a therapeutic agent for the treatment of human HCC.
文摘AIM: To evaluate the efficacy and safety of pegylated- interferon alpha-2a in hemodialysis patients with chronic hepatitis C. METHODS: Thirty-six hemodialysis patients with chronic hepatitis C were enrolled in a controlled and prospective study. All patients were treatment naive, positive tested for anti-HCV antibodies, and positive tested for serum HCV-RNA. Twenty-two patients received 135 μg peglyated-interferon α-2a weekly for 48 wk (group A). The remaining patients were left untreated, eleven refused therapy, and three were not candidates for kidney transplantation and were allocated to the control group (group B). At the end of the treatment biochemical and virological response was evaluated, and 24 wk after completetion of therapy sustained virological response (SVR) was assessed. Side effects were monitored. RESULTS: Of 22 hemodialysis patients, 12 were male and 10 female, with a mean age of 35.2 ± 12.1 years. Virological end-of-treatment response was observed in 14 patients (82.4%) in group A and in one patient (7.1%) in group B (P = 0.001). Sustained virological response was observed in 11 patients (64.7%) in group A and in one patient in group B (7.1%). Biochemical response parameters normalized in 10/14 patients (71.4%) at the end of the treatment. ALT levels in group B were initially high in six patients and normalized in one of them (25%) at the end of the 48 wk. In five patients (22.7%) therapy had to be stopped at mo 4 due to complications of weakness, anemia, and bleeding. CONCLUSION: SVR could be achieved in 64.7% of patients on hemodialysis with chronic hepatitis C by a treatment with peglyated-interferon α-2a. Group A had a significantly better efficacy compared to the control group B, but the side effects need to be concerned.
文摘Introduction: Heart and kidney diseases are common among patients admitted to hospital and they coexist in a significant number of cases. The interactions between the cardiovascular system and the kidney have been known and described for many years and have led to the description of cardio-renal syndrome. The objective of this study was to determine the frequency;to describe the clinical, etiological and prognostic aspects of acute renal failure in patients hospitalized for chronic congestive heart failure. Method: This was a descriptive retrospective study from January 2, 2018 to December 31, 2022. Included in this study were all the complete records of patients hospitalized for chronic congestive heart failure with serum creatinine ≥120 μmol/I. We’re not included in this study, incomplete files, records of patients hospitalized for other pathologies, records of patients hospitalized for chronic congestive heart failure with normal renal function. Our study variables were qualitative and quantitative divided into clinical, paraclinical and prognostic data. Our data were analyzed using the EPI-info 7.2.2.6 software. Data entry and presentation were carried out using Word, Excel and PowerPoint from the 2016 Office Pack. Results: We collected 830 files of which 114 met our selection criteria, a frequency of 13.73%. The mean age of the patients was 47 ± 19 years. The F/M sex ratio was 1.23. The dominant etiologies were hypertension followed by diabetes with respectively 60.5% and 23.7%. Toxic factors including tobacco accounted for 7.9% of cases. Dyspnea accounted for 86.8%. Most of our patients were grade 3 or 36% based on systolic blood pressure on admission with an average of 164.16 ± 33.95 mmHg and an average diastolic blood pressure of 93.24 ± 20.40 mmHg. Biologically, the serum creatinine revealed a high frequency of 201 - 400 μmol/l (33% of cases) with an average value of 586.49 ± 631.44 μmol/l with the extremes 2.960 and 2448.68 μmol/I. Anemia was moderate in 34.2% of cases. Cardiac ultrasound was performed on 81 patients, the results of which showed dilated cardiomyopathy in 48.2% of cases. Renal ultrasound was performed only by 18 patients, renal suffering was found with 8.8%. Almost all (92.11%) of the patients had an acute renal failure of functional origin. More than half (65.80%) of our patients were at risk. Diuretics were the most prescribed antihypertensives with 87.71% followed by ACE inhibitors 78.94%. The average length of hospitalization was 13.81 ± 7.66 days with extremes of 24 hours and 41 days. Conclusion:The association of acute renal failure and chronic congestive heart failure is a frequent situation. The diagnostic approach must be guided by the context and the data of a meticulous examination supplemented by an appropriate paraclinical assessment. Kidney renal failure is mostly functional.
文摘Introduction: Ambulatory Blood Pressure Measurement (ABPM) is a non- invasive examination recommended for subjects at high cardiovascular risk, and those requiring a nocturnal drop in BP such as elderly and obese subjects, those with secondary hypertension or resistant, diabetics, subjects with metabolic syndrome or sleep apnea syndrome. The objective of this study was to evaluate the contribution of ABPM in the diagnosis and evaluation of the level of control of hypertension under treatment at the Bel Air international clinic. Materials and Methods: This is a retrospective, cross-sectional and descriptive study, carried out at the Bel Air International Clinic in Conakry (Guinea) between January 2019 and November 30, 2022. It included a consecutive series of 180 consenting patients recruited through an ambulatory measurement of 24-hour blood pressure from a FUGADA brand device. Results: We collected 180 patients, with a male predominance (sex-ratio M/F = 2.46). The mean age of the patients was 48.48 ± 14.23 years. The most represented age group was that of 32 to 42 years with 50 cases (27.8%) followed by that of 43 to 52 years with 42 cases or 23.3%. The indication was for diagnostic purposes in 106 cases 58.9%, the therapeutic evaluation in 58 patients (32.2%). The examination was prescribed by a cardiologist in 98 cases (54.4%), a general practitioner in 71 cases (39.4%), a neurologist in 11 cases (6.1%). In the therapeutic evaluation, high blood pressure was controlled in 24 patients (13.3%) and uncontrolled in 34 cases (18.9%). In the diagnostic indication, high blood pressure was confirmed in 79 cases (43.9%) with a statistically significant link (Chi2</sup> = 4.57 and p-value = 0.032). The nycthemeral mean was 187.27 ± 26.22 mmHg for systolic blood pressure (SBP) and 110.37 ± 19.06 mmHg for diastolic blood pressure (DBP), during the day, 151.64 ± 21.45 mmHg for SBP and 71.59 ± 8.67 mmHg for diastolic blood pressure. During the study 65 patients (36.1%) were identified as dippers and 115 patients (63.9%) were no-dipping. The antihypertensive protocol used was monotherapy in 68 cases (37.8%), dual therapy in 46 cases (25.6%), triple therapy in 17 cases (9.4%). However 39 patients or 21.7% were not taking any antihypertensive. Conclusion: This preliminary study, despite the modest sample size, showed the importance of ABPM as a tool for diagnosis, monitoring of hypertensive patients and therapeutic adaptation. A large-scale national study would be necessary for the rational use of ambulatory blood pressure measurement in our context in order to improve the management of hypertensive patients.
基金Supported by the Natural Science Foundation of Shaanxi Province,No. 2002C257
文摘AIM: To investigate whether continuous veno-venous hemofiltration (CVVH) in different filtration rate to eliminate cytokines would result in different efficiency in acute pancreatitis, whether the saturation time of filter membrane was related to different filtration rate, and whether the onset time of CWH could influence the survival of acute pancreatitis. METHODS: Thirty-seven patients were classified into four groups randomly. Group 1 underwent low-volume CVVH within 48 h of the onset of abdominal pain (early CVVH, n = 9). Group 2 received low-volume CVVH after 96 h of the onset of abdominal pain (late CVVH, n= 10). Group 3 underwent high-volume CVVH within 48 h of the onset of abdominal pain (early CVVH, n = 9). Group 4 received high-volume CVVH after 96 h of theonset of abdominal pain (late CVVH, n = 9). CVVH was sustained for at least 72 h. Blood was taken before hemofiltration, and ultrafiltrate was collected at the start of CVVH and every 12 h during CVVH period for the purpose of measuring the concentrations of TNF-α, IL-1β and IL-6. The concentrations of TNF-α, IL-1β and IL-6 were measured by swine-specific ELISA. The Solartron 1 255 B frequency response analyzer (British) was used to observe the resistance of filter membrane. RESULTS: The survival rate had a significant difference (94.44% vs68.42%, P〈0.01) high-volume and low-volume CVVH patients. The survival rate had also a significant difference (88.89% vs 73.68%, P〈0.05) between early and late CVVH patients. The hemodynamic deterioration (MAP, HR, CVP) was less severe in groups 4 and 1 bhan that in group 2, and in group 3 than in group 4. The adsorptive saturation time of filters membranes was 120-180 min if the filtration rate was 1 000-4 000 mL/h. After the first, second and third new hemofilters were changed, serum TNF-α concentrations had a negative correlationwith resistance (r: -0.91, -0.89, and -0.86, respectively in group 1; -0.89, -0.85, and -0.76, respectively in group 2; -0.88, -0.92, and -0.82, respectively in group 3; -0.84, -0.87, and -0.79, respectively in group 4). The decreasing extent of TNF-α, IL-1β and IL-6 was significantly different between group 3 and group I (TNF-α P〈0.05, IL-1β P〈0.05, IL-6 P〈0.01), between group 4 and group 2 (TNF-α P〈0.05, IL-1β P〈0.05, IL-6 P〈0.01), between group 1 and group 2 (TNF-α P〈0.05, IL-1β P〈0.05, IL-6 P〈0.05), and between group 3 and group 4 (TNF-α P〈0.01, IL-1β P〈0.01, IL-6 P〈0.05), respectively during CVVH period. The decreasing extent of TNF-α and IL-1β was also significantly different between survival patients and dead patients (TNF-α P〈0.05, IL-1β P〈0.05). In survival patients, serum concentration of TNF-α and IL-1β decreased more significantly than that in dead patients. CONCLUSION: High-volume and early CWH improve hemodynamic deterioration and survival in acute pancreatitis patients. High-volume CVVH can eliminate cytokines more effidently than low-volume CVVH. The survival rate is related to the decrease extent of TNF-α and IL-1β. The adsorptive saturation time of filter membranes are different under different filtration rate condition. The filter should be changed timely once filter membrane adsorption is saturated.
基金supported in part by grants from the National Basic Research Program of China(No.2012CB524900)Department of Science&Technology of Shandong Province,China(Nos.2012GSF11824 and 2011780)
文摘Non-alcoholic fatty liver disease(NAFLD) is a common liver disease and it represents the hepatic manifestation of metabolic syndrome, which includes type 2 diabetes mellitus(T2DM), dyslipidemia, central obesity and hypertension. Glucagon-like peptide-1(GLP-1) analogues and dipeptidyl peptidase-4(DPP-4) inhibitors were widely used to treat T2 DM. These agents improve glycemic control, promote weight loss and improve lipid metabolism. Recent studies have demonstrated that the GLP-1 receptor(GLP-1R) is present and functional in human and rat hepatocytes. In this review, we present data from animal researches and human clinical studies that showed GLP-1 analogues and DPP-4 inhibitors can decrease hepatic triglyceride(TG) content and improve hepatic steatosis, although some effects could be a result of improvements in metabolic parameters. Multiple hepatocyte signal transduction pathways and m RNA from key enzymes in fatty acid metabolism appear to be activated by GLP-1 and its analogues. Thus, the data support the need for more rigorous prospective clinical trials to further investigate the potential of incretin therapies to treat patients with NAFLD.
文摘Objective In this study, an in vitro hemofiltration model was set up to investigate adsorptive saturati on time of different membrane under different blood flow rate (Q B)and filt rate rate(Q F). Methods Anticoagulated cattle blood (2000 mL per bag) was stimulated with 1μg·mL -1 endotoxin to induce i nflammatory mediators before hemofiltration (HF) using AN69, PS and PMMA filters in vitro. Adsorptive saturation time of membrane was observed using data br idge in different Q B and different Q F. TNF was measured by radioimmu noassays. Results Before the resistance level reached the peak value in the same group, resistance level increased significantly (P<0.01). After the peak value, there was no difference (P>05). It was suggested tha t the resistance level reached plateau at 150,120,90,120, and150 minutes in Q F of 100 mL·minute -1, 200 mL·minute -1, 300 mL·minute -1 , respectively and in Q F of 1L·hour -1, 2L·hour -1, 4L·hour -1, respectively. And with the Q B and Q F increasing, resistanc e level increased significantly (P<0.01) among different groups at the same time point in A, B, C, D and E group. Conclusion Membrane resis tance level online measured by Data Bridge can instantly reflect the degree of m embrane adsorption. Adsorptive saturation time of filter membrane in different f iltration flow rate and blood flow rate are different.
文摘Aim: This observational clinical study tested the effect of injection frequency of the biosimilar epoetin zeta on the weekly dose needed to maintain stable hemoglobin levels in chronic kidney diseases (CKD) patients on intermittent high-flux hemodialysis (HD). Patients and Methods: CKD patients (n = 33) on regular HD therapy 3 times a week were treated for 18 months with epoetin zeta i.v. The hemoglobin levels, the weekly dose as well as the injection frequency of epoetin zeta were monitored at least every two weeks. Patients were followed in three time periods: 1) extended follow-up (months 1 - 18);2) intervention phase (months 19 - 21);and 3) post intervention observation phase (months 28 - 30). During extended follow-up the majority of patients (n = 21) received only one injection of epoetin zeta per week. During the intervention phase, injection frequency was increased to 3 injections per week in all patients accompanied by a reduction in weekly doses of approximately 20% - 30%. Following a 9 month period of dose adjustment all parameters were monitored again in the post-intervention phase. Results: During the first 18 months of epoetin zeta therapy the mean hemoglobin level was stable between 11 and 12 g/dl. The mean weekly dose of epoetin zeta was 7939 IU/week in month 6 and 7909 IU/week in month 18 (p = not significant). The mean frequency (injections/week) was 1.27 in month 6 and 1.29 in month 18 (not significant). Compared to month 18, at the end of the observation at month 30, hemoglobin levels were stable, mean injection frequency increased to 2.25 (p < 0.001) and the mean weekly dose decreased to 5469 IU/week (-31.7%, p < 0.001). Conclusions: Increasing the injection frequency of the short acting biosimilar epoetin zeta to two to three injections per week reduces the weekly dose and thereby the costs of ESA therapy of renal anemia significantly.
文摘Dialysis patients have risk in Zoster virus because of low immune. Valacyclovir, used for Zoster virus, is digested in kidney and it has side effect of nerve virus on patients with malfimction kidneys. This article reviews 8 dialysis cases and discusses the proper Valacyclovir portion for peritoneal dialysis patients.
文摘Acute kidney injury(AKI),associated with significant mor-bidity and mortality,is widely known to involve epithelial apoptosis,excessive inflammation,and fibrosis in re-sponse to ischemia or reperfusion injury,which results in either chronic pathological changes or death.Therefore,it is imperative that investigations are conducted in order to fi nd effective,early diagnoses,and therapeutic targets needed to help prevent and treat AKI.However,the mech-anisms modulating the pathogenesis of AKI still remain largely undetermined.MicroRNAs(miRNAs),small non-coding RNA molecules,play an important role in several fundamental biological and pathological processes by a post transcriptional regulatory function of gene expres-sion.MicroRNA-21(miR-21)is a recently identifi ed,typi-cal miRNA that is functional as a regulator known to be involved in apoptosis as well as inflammatory and fi brotic signaling pathways in AKI.As a result,miR-21 is now considered a novel biomarker when diagnosing and treat-ing AKI.This article reviews the correlative literature and research progress regarding the roles of miR-21 in AKI.
文摘The association between dyslipidemia and elevated fasting glucose in type 2 diabetes is well known. In non-diabetes, whether this association still exists, and whether dyslipidemia is an independent risk factor for high fasting plasma glucose (FPG) levels are not clear. This cross-sectional study recruited 3460 non-diabetic Chinese subjects (1027 men, and 2433 women, aged 35-75 years old) who participated in a health survey. Men and women were classified into tertiles by levels of plasma lipids respectively. In women, the prevalence of impaired fasting glucose (IFG) was decreased with increased HDL-C. A stepwise increase in HDL-C was associated with decreasing FPG levels (lowest tertiles, FPG: 5.376 ± 0.018; middle tertiles, 5.324± 0.018; highest tertiles, 5.276±0.018mmol/L; P = 0.001). Reversely, FPG levels increased from lowest tertiles to highest tertiles of LDL-C, TC, and TG. we found that women in the first tertile with lower HDL-C level had a 1.75-fold increase in risk of IFG compared with non-diabetic women in the third tertile with higher HDL-C level (OR: 1.75; 95% CI: 1.20-2.56). In men, no significant association was found. We took age, BMI, waist/hip ratio, education, smoking, alcohol drinking, and physical exercise as adjusted variables. In Chinese non-diabetic women, dyslipidemia is independently associated with high levels of FPG; TG, HDL-C, and LDL-C are predictors of IFG independent of BMI and waist/hip ratio.