结直肠癌患者血清GDF-15、G-CSF水平与临床病理特征及预后的关系

摘要 目的：探究结直肠癌血清生长分化因子-15（GDF-15）、粒细胞集落刺激因子（G-CSF）水平与患者临床病理参数、预后的关系,并分析其对结直肠癌的诊断价值。方法：采集结直肠癌患者、结直肠腺瘤患者及健康体检志愿者的血清样本,酶联免疫吸附测定（ELISA）实验检测血清GDF-15、G-CSF;分析结直肠癌患者血清GDF-15、G-CSF水平与患者临床病理参数的关系;Kaplan Meier生存曲线分析血清GDF-15、G-CSF水平与患者预后的关系;受试者工作特征曲线（ROC）分析血清GDF-15、G-CSF水平对结直肠癌的诊断价值。结果：结直肠癌患者血清GDF-15、G-CSF水平高于结直肠腺瘤患者及健康体检志愿者（均P<0.05）;血清GDF-15水平与肿瘤直径、分化程度、远处转移及TNM分期相关（均P<0.05）;血清G-CSF水平与肿瘤分化程度、远处转移及TNM分期相关（均P<0.05）;Kaplan Meier生存曲线结果显示,血清GDF-15低表达、G-CSF低表达患者的术后5年总生存率及中位生存时间均分别高于血清GDF-15高表达、G-CSF高表达患者（均P<0.05）;ROC分析结果表明,血清GDF-15、G-CSF有较好的诊断结直肠癌的价值,血清GDF-15、G-CSF联合应用的敏感度、特异度分别为0.876、0.863。结论：结直肠癌患者血清GDF-15、G-CSF水平升高,且均与患者病情恶性进展、不良预后相关;血清GDF-15、G-CSF是诊断结直肠癌的潜在指标。     

Expression of Fibroblast Growth Factor-21 in Muscle Is Associated with Lipodystrophy,Insulin Resistance and Lipid Disturbances in Patients with HIV

BackgroundFibroblast growth factor (FGF)-21 is a novel regulator of glucose and lipid metabolism. Recently, increased FGF-21 mRNA expression in muscle was found in patients with type 2 diabetes, but the role for FGF-21 in muscle is not well understood. Patients with HIV-infection and lipodystrophy are characterised by various degree of lipid-driven insulin resistance. We hypothesized that muscle FGF-21 mRNA would be altered in HIV patients with lipodystrophy.DesignTwenty-five HIV-infected men with lipodystrophy (LD) and 15 age-matched healthy controls, received an oral glucose tolerance test and a euglycemic-hyperinsulinemic clamp (50 mU/m2/min) combined with 6,6-H₂ glucose infusion. Muscle biopsies were obtained and FGF-21 mRNA and glycogen synthase (GS) activity were measured.ResultsSubjects with HIV were insulin resistant compared with non-HIV subjects. Compared to controls, HIV subjects demonstrated a twofold increase of plasma FGF-21 from 70.4±56.8 pg/ml vs 109.1±71.8 pg/ml, respectively (p = 0.04) and an eight-fold increase in muscular FGF-21 mRNA expression (p = 0.001). Muscle FGF-21 mRNA correlated inversely with the rate of disappearance of glucose during insulin clamp (r = −0.54, p = 0.0009), and the GS fractional velocity in muscle (r = −0.39, p = 0.03), and directly with fasting insulin (r = 0.50, p = 0.0022), HOMA-IR (r = 0.47, p = 0.004), triglycerides (r = 0.60. P = 0.0001), waist-to-hip ratio (r = 0.51, p = 0.0001) and limb fat mass (−0.46, p = 0.004), but not to plasma FGF-21.ConclusionFGF-21 mRNA is increased in skeletal muscle in HIV patients and correlates to whole-body (primarily reflecting muscle) insulin resistance, but not to plasma FGF-21. Those findings add to the evidence that FGF-21 is a myokine and may suggest that muscle FGF-21 is working in a local manner.     

Growth differentiation factor 15 in cardiovascular diseases: from bench to bedside

Context: Growth differentiation factor 15 (GDF-15) is a novel cytokine showing close association with cardiovascular diseases. The biological mechanism and clinical use of GDF-15 in cardiovascular diseases have been well demonstrated. We review recent investigations from both basic research and clinical trials into the biological role of GDF-15.

Methods: The data were obtained mainly from MedLine via PubMed and from our own investigations.

Results: Laboratory investigations revealed that GDF-15 has biphasic effects on cellular survival by several signaling pathways. GDF-15 participates in several cardiovascular pathological processes such as cardiac remodeling, ischemia/reperfusion injury and atherosclerotic plaque formation. As well, GDF-15 was found a prognostic biomarker of heart failure and acute coronary syndrome. The evidence for diagnostic or therapeutic utility is poor.

Conclusion: GDF-15 has great potential as a biomarker in cardiovascular diseases, especially for prognosis, and is seen as a myocardial protective cytokine, but the exact mechanism of GDF-15 in cardiovascular diseases remains unknown.     

Assessment of serum tenascin-C and growth differentiation factor-15 among type 2 diabetes mellitus patients with and without acute coronary syndrome

BackgroundHigh prevalence of type 2 diabetes mellitus (T2DM) is associated with a higher prevalence of acute coronary syndrome (ACS). Inflammation is one of the important contributors to the pathogenesis and complications of coronary atherosclerotic plaque. Growth Differentiation Factor-15 (GDF-15) and Tenascin-C (TNC) play an important role in the initiation of atherosclerotic plaque as well as its rupture. The aim of the study was to evaluate the association between serum GDF-15, TNC, and the risk of ACS among T2DM patients.MethodsAnthropometric parameters, routine biochemical investigations like liver and renal function tests, lipid profile, and Creatine Kinase-Total (CK-T), Creatine Kinase-MB (CK-MB) were measured in 42 T2DM patients with ACS and 42 T2DM patients. Serum GDF-15 and TNC were measured by Human Sandwich-ELISA kits.ResultsSerum GDF-15 and TNC levels were significantly higher in T2DM patients with ACS as compared to T2DM patients. Serum GDF-15 was significantly correlated with waist circumference, diastolic blood pressure, pulse, serum CK-T, and CK-MB. Serum TNC was significantly correlated with the pulse, serum CK-T, CK-MB, high-density lipoprotein-cholesterol, and blood urea nitro GEN. Multivariate linear regression analysis showed that waist circumference was independently positively associated with serum GDF-15.ConclusionsT2DM patients with higher serum GDF-15 and TNC levels were at higher risk of acute coronary syndrome independent of other cardiovascular risk factors.     

慢性肾脏病患者血清GDF-15的水平及临床意义

目的:探讨慢性肾脏病(Chronic Kidney Disease,CKD)患者血清生长分化因子-15(Growth Differentiation Factor-15,GDF-15)的表达及与其他肾功能相关临床指标的相关性。方法:选取西南医科大学附属医院2017年3月至2017年7月健康体检中心30例健康体检者对照组及肾病内科、内分泌科、心内科住院病房各期CKD患者150例,采用ELISA法测试验检其血清GDF-15水平。结果:除去CKD1期外,各期CKD患者eGFR及血清SCr、BUN、GDF-15水平均明显高于健康对照组,差异具有统计学意义(P0.05);随着CKD分期的增加,患者血清SCr、BUN、GDF-15浓度逐渐增加,且各组之间差异具有统计学意义(P0.05)。CKD3组患者血清UA浓度明显高于健康对照组、CKD1组(P0.05),CKD4组、CKD5组血清UA浓度明显高于健康对照组、CKD1组及CKD2组(P0.05)。GDF-15水平与eGFR水平呈负相关(r=-0.768,P0.01),与SCr水平呈正相关(r=0.751,P0.01),与BUN水平呈正相关(r=0.764,P0.01),与UA水平呈正相关(r=0.470,P0.01)。结论:GDF-15与慢性肾脏病的发生与发展密切相关。     

血清NLR、GDF-15及TRPC1与老年心力衰竭患者相关性分析

摘要 目的：探讨血清中性粒细胞与淋巴细胞比值（NLR）、生长分化因子-15（GDF-15）及瞬时受体电位通道1（TRPC1）与老年心力衰竭患者相关性。方法：选取我院2020年1月到2022年10月收治的100例老年慢性心力衰竭患者作为研究对象,将其分为心力衰竭组,另选取同期来我院体检的101名健康老年人作为对照组,98例心律失常老年患者作为心律失常组,对比三组受检者血清NLR、GDF-15及TRPC1水平,并应用受试者工作（ROC）曲线分析血清NLR、GDF-15及TRPC1对老年慢性心力衰竭的诊断价值。并依照NYHA心功能分级标准对100例心力衰竭患者进行评价,其中Ⅱ级23例,Ⅲ级38例,Ⅳ级39例,对比不同心功能分级患者血清NLR、GDF-15及TRPC1表达水平,应用Spearman相关分析分析血清NLR、GDF-15及TRPC1与老年心力衰竭患者心功能的相关性。结果：三组受检者血清NLR、GDF-15及TRPC1水平对比差异显著,心力衰竭组明显高于心律失常组和对照组（P＜0.05）;通过绘制ROC曲线,分析表1中组间具有明显差异的指标,确定其对老年心力衰竭的诊断效能,结果显示,曲线下面积（AUC）从依次为NLR（0.688）、GDF-15（0.667）、TRPC1（0.656）、三者联合（0.671）。NLR诊断灵敏度为67.61 %,特异度为66.85 %,GDF-15诊断灵敏度为60.03 %,特异度为67.53 %,TRPC1诊断灵敏度为61.24 %,特异度为66.53 %,三者联合诊断灵敏度为74.58 %,特异度为86.32 %;不同级别心功能的心力衰竭患者血清NLR、GDF-15及TRPC1水平对比差异显著,Ⅳ级心功能明显高于Ⅲ级、Ⅱ级（P＜0.05）;Spearman相关分析结果显示：NLR、GDF-15及TRPC1水平与老年心力衰竭患者心功能呈正相关（P＜0.05）。结论：血清NLR、GDF-15及TRPC1三者联合对于老年心力衰竭诊断灵敏度和特异度较高,且与患者心功能具有明显相关性,临床可考虑应用NLR、GDF-15及TRPC1作为超声心动图补充诊断手段,为临床诊断提供参考意见。     

Increased circulating and epicardial adipose tissue mRNA expression of fibroblast growth factor-21 after cardiac surgery: possible role in postoperative inflammatory response and insulin resistance

We studied the changes in serum fibroblast growth factor-21 (FGF-21) concentrations, its mRNA, and protein expression in skeletal muscle and adipose tissue of 15 patients undergoing cardiac surgery. Blood samples were obtained: prior to initiation of anesthesia, prior to the start of extracorporeal circulation, upon completion of the surgery, and 6, 24, 48, and 96 hours after the end of the surgery. Tissue sampling was performed at the start and end of surgery. The mean baseline serum FGF-21 concentration was 63.1 (43.03-113.95) pg/ml and it increased during surgery with peak 6 hours after its end [385.5 (274.55-761.65) pg/ml, p < 0.001], and returned to baseline value [41.4 (29.15-142.83) pg/ml] 96 hours after the end of the surgery. Serum glucose, insulin, CRP, IL-6, IL-8, MCP-1, and TNF-alpha concentrations significantly increased during the surgery. Baseline FGF-21 mRNA expression in skeletal muscle was higher than in both adipose tissue depots and it was not affected by the surgery. Epicardial fat FGF-21 mRNA increased after surgery. Muscle FGF-21 mRNA positively correlated with blood glucose levels at the end of the surgery. Our data suggest a possible role of FGF-21 in the regulation of glucose metabolism and insulin sensitivity in surgery-related stress.     

Comparison of urinary aflatoxin M1 and aflatoxin albumin adducts as biomarkers for assessing aflatoxin exposure in Tanzanian children

Purpose: To determine levels of urinary aflatoxin M1 (AFM1) in children and correlate the concentrations with previously reported aflatoxin albumin adduct (AF-alb) levels in these children.

Materials and methods: Matched urine and blood samples were collected from 84 Tanzanian children aged 6–14 months old. From 31 children in one village (Kigwa), samples were collected at three time points six months apart. Samples were collected from 31 and 22 children from two different regions at the second time point only. Urinary AFM1 was measured using a commercial enzyme-linked immunosorbent assay (ELISA) kit with a modified protocol to improve sensitivity. AF-alb was measured using an established ELISA method.

Results: The relative ranking of the three villages for exposure to aflatoxin based on either AFM₁ or AF-alb biomarker measurements was the same. In Kigwa village, both AFM1 and AF-alb levels were higher at six months post-harvest compared to baseline. However, at the next visit, the AFM1 levels dropped from a GM (interquartile range) of 71.0 (44.7, 112.6) at visit two to 49.3 (31.5, 77.3) pg/ml urine, whereas AF-alb levels increased from 47.3 (29.7, 75.2) to 52.7 (35.4, 78.3) pg/mg albumin between these two visits, reflecting the fact that AFM1 measures short-term exposure, whereas AF-alb measures longer term exposure. There was a correlation between AFB1 intake and AFM1 excretion (r=?0.442, p?≤?0.001).

Conclusions: Urinary AFM1 is a good biomarker for AFB1 exposure in Tanzanian children, reflecting geographical and temporal variations in exposure to this foodborne toxin.     

Growth Differentiation Factor (GDF)-15 Blocks Norepinephrine-induced Myocardial Hypertrophy via a Novel Pathway Involving Inhibition of Epidermal Growth Factor Receptor Transactivation

Accumulating evidence suggests that growth differentiation factor 15 (GDF-15) is associated with the severity and prognosis of various cardiovascular diseases. However, the effect of GDF-15 on the regulation of cardiac remodeling is still poorly understood. In this present study, we demonstrate that GDF-15 blocks norepinephrine (NE)-induced myocardial hypertrophy through a novel pathway involving inhibition of EGFR transactivation. Both in vivo and in vitro assay indicate that NE was able to stimulate the synthesis of GDF-15. The up-regulation of GDF-15 feedback inhibits NE-induced myocardial hypertrophy, including quantitation of [³H]leucine incorporation, protein/DNA ratio, cell surface area, and ANP mRNA level. Further research shows that GDF-15 could inhibit the phosphorylation of EGF receptor and downstream kinases (AKT and ERK1/2) induced by NE. Clinical research also shows that serum GDF-15 levels in hypertensive patients were significant higher than in healthy volunteers and were positively correlated with the thickness of the posterior wall of the left ventricle, interventricular septum, and left ventricular mass, as well as the serum level of norepinephrine. In conclusion, NE induces myocardial hypertrophy and up-regulates GDF-15, and this up-regulation of GDF-15 negatively regulates NE-induced myocardial hypertrophy by inhibiting EGF receptor transactivation following NE stimulation.     

Fibroblast Growth Factor 21 (FGF-21) in Peritoneal Dialysis Patients: Natural History and Metabolic Implications

Background

Human fibroblast growth factor 21 (FGF-21) is an endocrine liver hormone that stimulates adipocyte glucose uptake independently of insulin, suppresses hepatic glucose production and is involved in the regulation of body fat. Peritoneal dialysis (PD) patients suffer potential interference with FGF-21 status with as yet unknown repercussions.

Objectives

The aim of this study was to define the natural history of FGF-21 in PD patients, to analyze its relationship with glucose homeostasis parameters and to study the influence of residual renal function and peritoneal functional parameters on FGF-21 levels and their variation over time.

Methods

We studied 48 patients with uremia undergoing PD. Plasma samples were routinely obtained from each patient at baseline and at 1, 2 and 3 years after starting PD therapy.

Results

Plasma FGF-21 levels substantially increased over the first year and were maintained at high levels during the remainder of the study period (253 pg/ml (59; 685) at baseline; 582 pg/ml (60.5–949) at first year and 647 pg/ml (120.5–1116.6) at third year) (p<0.01). We found a positive correlation between time on dialysis and FGF-21 levels (p<0.001), and also, those patients with residual renal function (RRF) had significantly lower levels of FGF-21 than those without RRF (ρ -0.484, p<0.05). Lastly, there was also a significant association between FGF-21 levels and peritoneal protein losses (PPL), independent of the time on dialysis (ρ 0.410, p<0.05).

Conclusion

Our study shows that FGF-21 plasma levels in incident PD patients significantly increase during the first 3 years. This increment is dependent on or is associated with RRF and PPL (higher levels in patients with lower RRF and higher PPL). FGF-21 might be an important endocrine agent in PD patients and could act as hormonal signaling to maintain glucose homeostasis and prevent potential insulin resistance. These preliminary results suggest that FGF-21 might play a protective role as against the development of insulin resistance over time in patients undergoing a continuous glucose load.     

达格列净对2型糖尿病合并非酒精性脂肪性肝病患者血清FGF-21水平的影响

摘要 目的：分析血清成纤维细胞生长因子-21（FGF-21）与2型糖尿病（T2DM）合并非酒精性脂肪性肝病（NAFLD）患者常见指标及NAFLD纤维化评分（NFS）的相关性,进一步探讨达格列净对T2DM合并NAFLD患者血清FGF-21水平的影响。方法：选取2022年1月至2022年6月徐州医科大学附属徐州市立医院收治的80例T2DM合并NAFLD患者为研究对象（T2DM合并NAFLD组）,选择同期80例T2DM不合并NAFLD患者为T2DM组。收集腰围（WC）、身高、体重数据,计算体重指数（BMI）。测定空腹血糖（FPG）、糖化血红蛋白（HbA1c）、空腹胰岛素（FINS）、甘油三酯（TG）、总胆固醇（TC）、高密度脂蛋白胆固醇（HDL-c）,低密度脂蛋白胆固醇（LDL-c）、肌酐（Cr）、丙氨酸氨基转移酶（ALT）、天冬氨酸氨基转移酶（AST ）、白蛋白（Alb）、血小板计数（PLT）等指标,计算胰岛素抵抗指数（HOMA-IR）、NFS。采用酶联免疫吸附（ELISA）法测定FGF-21水平。比较T2DM组和T2DM合并NAFLD组各项指标的差异,探讨血清FGF-21水平与T2DM合并NAFLD患者其他指标的相关性,Logistic回归分析T2DM合并NAFLD的影响因素,受试者工作特征曲线（ROC）分析各影响因素对T2DM合并NAFLD的诊断价值。将80例T2DM合并NAFLD患者按随机数字表法随机分为二甲双胍组和达格列净组各40例,治疗前后观测各项指标变化,并密切监测不良反应。结果：T2DM合并NAFLD组患者WC、BMI、FINS、HbA1c、TG、AST、ALT、HOMA-IR、NFS及FGF-21均高于 T2DM组（P＜0.05）。相关性分析显示,FGF-21水平与T2DM合并NAFLD组患者WC、BMI、HbA1c、TG、HOMA-IR、NFS均存在正相关（P<0.05）。Logistic回归分析显示,BMI、HbA1c、FGF-21、HOMA-IR为影响T2DM患者合并NAFLD的危险因素。ROC曲线分析显示,BMI、HbA1c、FGF-21、HOMA-IR对T2DM合并NAFLD均具有一定预测价值,其中以FGF-21的预测效能最佳。治疗后,达格列净组TG、AST、ALT、NFS、FGF-21水平较二甲双胍组降低更为明显（P＜0.05）。结论：血清FGF-21水平为T2DM合并NAFLD的危险因素,参与了T2DM合并NAFLD发病及进展,且对T2DM合并NAFLD有较好的预测效能。相较于二甲双胍,达格列净可明显降低T2DM合并NAFLD患者血清FGF-21水平并改善NFS,具有一定程度的肝脏保护作用。     

尿毒症血液透析患者血清Lp-PLA2、FGF-23与自体动静脉内瘘成熟不良的关系研究

摘要 目的：探讨尿毒症血液透析患者血清脂蛋白相关磷脂酶A2（Lp-PLA2）、成纤维细胞生长因子-23（FGF-23）与自体动静脉内瘘（AVF）成熟不良的关系。方法：选取2021年2月～2022年12月联勤保障部队第908医院肾内科收治的170例接受血液透析的尿毒症患者,根据AVF成熟情况分为成熟不良组57例和成熟组113例。采用酶联免疫吸附法检测血清Lp-PLA2、FGF-23水平。通过多因素Logistic回归分析尿毒症血液透析患者AVF成熟不良的影响因素,受试者工作特征（ROC）曲线分析血清Lp-PLA2、FGF-23水平对尿毒症血液透析患者AVF成熟不良的预测效能。结果：成熟不良组血清Lp-PLA2、FGF-23水平高于成熟组（P＜0.05）。多因素Logistic回归分析显示,血磷、低密度脂蛋白胆固醇（LDL-C）、Lp-PLA2、FGF-23升高为尿毒症血液透析患者AVF成熟不良的独立危险因素（P＜0.05）。ROC曲线分析显示,血清Lp-PLA2、FGF-23水平单独和联合预测尿毒症血液透析患者AVF成熟不良的曲线下面积（AUC）分别为0.725、0.763、0.822,血清Lp-PLA2、FGF-23水平联合预测的AUC最大。结论：尿毒症血液透析患者血清Lp-PLA2、FGF-23水平升高与AVF成熟不良独立相关,血清Lp-PLA2、FGF-23水平联合对AVF成熟不良的预测效能良好。     

Serum levels of FGF-21 are increased in coronary heart disease patients and are independently associated with adverse lipid profile

Background

Fibroblast growth factor 21 (FGF-21) is a metabolic regulator with multiple beneficial effects on glucose homeostasis and lipid metabolism in animal models. The relationship between plasma levels of FGF-21 and coronary heart disease (CHD) in unknown.

Methodology/Principal Findings

This study aimed to investigate the correlation of serum FGF-21 levels and lipid metabolism in the patients with coronary heart disease. We performed a logistic regression analysis of the relation between serum levels of FGF-21 and CHD patients with and without diabetes and hypertension. This study was conducted in the Departments of Endocrinology and Cardiovascular Diseases at two University Hospitals. Participants consisted of one hundred and thirty-five patients who have been diagnosed to have CHD and sixty-one control subjects. Serum FGF-21 level and levels of fasting blood glucose; triglyceride; apolipoprotein B100; HOMA-IR; insulin; total cholesterol; HDL-cholesterol; LDL-cholesterol; and C-reactive protein were measured. We found that median serum FGF-21 levels were significantly higher in CHD than that of control subjects (P<0.0001). Serum FGF-21 levels in CHD patients with diabetes, hypertension, or both were higher than that of patients without these comorbidities. Serum FGF-21 levels correlated positively with triglycerides, fasting blood glucose, apolipoprotein B100, insulin and HOMA-IR but negatively with HDL-C and apolipoprotein A1 after adjusting for BMI, diabetes and hypertension. Logistic regression analysis demonstrated that FGF-21 showed an independent association with triglyceride and apolipoprotein A1.

Conclusions/Significance

High levels of FGF-21 are associated with adverse lipid profiles in CHD patients. The paradoxical increase of serum FGF-21 in CHD patients may indicate a compensatory response or resistance to FGF-21.     

急性ST段抬高型心肌梗死介入手术时间窗与血清FGF-21水平的相关性

摘要 目的：探究急性ST段抬高型心肌梗死介入手术时间窗与血清FGF-21水平的相关性。方法：选取2019年3月-2021年5月在我院接受PPCI手术并住院治疗且符合STEMI诊断标准的73例患者,根据FGF-21水平高低,将73例患者分为FGF-21低水平组（>140.41 ng/L,n=54例）和FGF-21高水平组（<140.41 ng/L,n=19例）。对比分析两组患者的一般临床资料、急救时间窗和SO-to-FMC时间差异,再通过Spearson法判断急救时间窗与FGF-21水平的相关性。结果：FGF-21低水平组患者的急救时间窗SO-to-FMC、FMC-to-B、D2B和STB均较FGF-21高水平组患者时间长,且SO-to-FMC时间>120 min是导致FGF-21水平变低的危险因素,介入手术时间窗指标与FGF-21水平均呈正相关（r=0.235、0.462、0.298、0.337）。高血压史、糖尿病史、首次医疗接触方式（急诊）和SO-to-FMC均是FGF-21水平变化的独立危险因素,且差异有统计学意义（P<0.05）。结论：SO-to-FMC时间和STB时间延长可能促进STEMI患者FGF-21水平异常,故应严格把握好院外的急救时间。     

The broadening spectrum of mitochondrial disease: Shifts in the diagnostic paradigm

Background

The diagnosis of mitochondrial disease requires a complex synthesis of clinical, biochemical, histological, and genetic investigations. An expanding number of mitochondrial diseases are being recognized, despite their phenotypic diversity, largely due to improvements in methods to detect mutations in affected individuals and the discovery of genes contributing to mitochondrial function. Improved understanding of the investigational pitfalls and the development of new laboratory methodologies that lead to a molecular diagnosis have necessitated the field to rapidly adopt changes to its diagnostic approach.

Scope of review

We review the clinical, investigational and genetic challenges that have resulted in shifts to the way we define and diagnose mitochondrial disease. Incorporation of changes, including the use of fibroblast growth factor 21 (FGF-21) and next generation sequencing techniques, may allow affected patients access to earlier molecular diagnosis and management.

Major conclusions

There have been important shifts in the diagnostic paradigm for mitochondrial disease. Diagnosis of mitochondrial disease is no longer reliant on muscle biopsy alone, but should include clinical assessment accompanied by the use of serological biomarkers and genetic analysis. Because affected patients will be defined on a molecular basis, oligosymptomatic mutation carriers should be included in the spectrum of mitochondrial disease. Use of new techniques such as the measurement of serum FGF-21 levels and next-generation-sequencing protocols should simplify the diagnosis of mitochondrial disease.

General significance

Improvements in the diagnostic pathway for mitochondrial disease will result in earlier, cheaper and more accurate methods to identify patients with mitochondrial disease. This article is part of a Special Issue entitled Frontiers of Mitochondrial Research.     

Relación del factor de crecimiento de fibroblastos 21 con indicadores de masa y función muscular en personas mayores con sobrepeso u obesidad. Estudio exploratorio

BackgroundAge-related decreases in muscle mass and function are associated with the development of metabolic impairments, particularly in the context of obesity. Fibroblast growth factor 21 (FGF-21) has been suggested as a common mediator of both processes. No known studies have examined the association between FGF-21 and muscle mass and function in overweight or obese older adults. With this in mind, this study aimed to investigate the association between plasma levels of FGF-21 and muscle mass and function outcomes in overweight or obese older adults.Materials and methodsExploratory study, which included 39 adults of 60-70 years old with body mass indexes > 25 kg/m². As study outcomes, measurements were made of appendicular muscle mass (AMM), grip strength, 5 times sit-to-stand test (5xSTT), as well as plasma levels of FGF-21, fasting glucose, and insulin. The homeostatic model assessment index (HOMA-IR) was also calculated to determine the presence of insulin resistance.ResultsSignificant relationships were found between plasma levels of FGF-21 vs 5xSTT (rho = 0.49; P < .05). Moreover, FGF-21 levels were significantly higher in those with insulin resistance (P < .05), as well as with having lower levels of AMM (P < .05).ConclusionThere is a relationship between the plasma levels of FGF-21 and muscle function outcomes in overweight or obese older adults. Future studies should investigate the potential causalities between these relationships.     

Multi-biomarker analysis in patients after transcatheter aortic valve implantation (TAVI)

Abstract

Background: In this study we sought to examine whether transcatheter aortic valve implantation (TAVI) is followed by a change in the plasma levels of novel cardiovascular biomarkers.

Methods: We collected blood samples of 79 patients with severe aortic valve stenosis undergoing TAVI before and at 7 days, 1 month, 3 months and 6 months post TAVI and analyzed the plasma concentrations of GDF-15, H-FABP, fetuin-A, galectin 3, sST2 and suPAR by means of ELISA.

Results: There was a significant increase in the concentration of fetuin-A (median: 52.44 mg/ml to 113.2 mg/ml, p?<?0.001) and a significant decrease of H–FABP after TAVI (median: 4.835 ng/ml to 2.534 ng/ml, p?<?0.001). The concentrations of suPAR and sST2 showed an initial increase (suPAR median: 2755 pg/ml 3489 pg/ml, p?<?0.001; sST2 median: 5832 pg/ml to 7137 pq/ml, p?<?0.001) and subsequently decreased significantly.

Conclusion: We hypothesize that the decrease of H-FABP and the increase of fetuin-A could be due to a hemodynamic improvement after valve replacement. The initial increase of suPAR could indicate an inflammatory stimulus and the significant increase in sST2 could be due to the mechanical strain caused by implantation of the valve.     

GDF15 as a central mediator for integrated stress response and a promising therapeutic molecule for metabolic disorders and NASH

BackgroundMitochondria is a key organelle for energy production and cellular adaptive response to intracellular and extracellular stresses. Mitochondrial stress can be evoked by various stimuli such as metabolic stressors or pathogen infection, which may lead to expression of ‘mitokines’ such as growth differentiation factor 15 (GDF15).Scope of reviewThis review summarizes the mechanism of GDF15 expression in response to organelle stress such as mitochondrial stress, and covers pathophysiological conditions or diseases that are associated with elevated GDF15 level. This review also illustrates the in vivo role of GDF15 expression in those stress conditions or diseases, and a potential of GDF15 as a therapeutic agent against metabolic disorders such as NASH.Major conclusionsMitochondrial unfolded protein response (UPRmt) is a critical process to recover from mitochondrial stress. UPRmt can induce expression of secretory proteins that can exert systemic effects (mitokines) as well as mitochondrial chaperons. GDF15 can have either protective or detrimental systemic effects in response to mitochondrial stresses, suggesting its role as a mitokine. Mounting evidence shows that GDF15 is also induced by stresses of organelles other than mitochondria such as endoplasmic reticulum (ER). GDF15 level is increased in serum or tissue of mice and human subjects with metabolic diseases such as obesity or NASH. GDF15 can modulate metabolic features of those diseases.General significanceGDF15 play a role as an integrated stress response (ISR) beyond mitochondrial stress response. GDF15 is involved in the pathogenesis of metabolic diseases such as NASH, and also could be a candidate for therapeutic agent against those diseases.