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    Increased C-Peptide Immunoreactivity in Insulin Autoimmune Syndrome (Hirata Disease) Due to High Molecular Weight Proinsulin. Kay Richard G,Barker Peter,Burling Keith,Cohen Mark,Halsall David,Reimann Frank,Gribble Fiona M,Semple Robert K,Church David Clinical chemistry BACKGROUND:Determination of C-peptide is important in the investigation of unexplained hyperinsulinemic hypoglycemia because a high C-peptide concentration usually indicates endogenous insulin hypersecretion. Insulin autoimmune syndrome (IAS) denotes hyperinsulinemic hypoglycemia due to insulin-binding antibodies that prolong insulin half-life. C-peptide clearance is considered to be unaffected, and although a marked C-peptide immunoreactivity in hypoglycemic samples has been reported, it has been suspected to be artifactual. High-resolution mass spectrometry enables examination of the basis of C-peptide-immunoreactivity in IAS. METHODS:Precipitation of plasma with polyethylene glycol was followed by C-peptide immunoassay. Plasma peptides extracted by solvent precipitation were characterized by nano-LC-MS/MS and analyzed using an untargeted data-dependent method. Peptides related to proinsulin, in amino acid sequence, were identified using proprietary bioinformatics software and confirmed by repeat LC-MS/MS analysis. Gel filtration chromatography coupled to LC-MS/MS was used to identify proinsulin-related peptides present in IAS immunocomplexes. Results were compared with those from C-peptide immunoassay. RESULTS:Polyethylene glycol precipitation of IAS plasma, but not control plasma, depleted C-peptide immunoreactivity consistent with immunoglobulin-bound C-peptide immunoreactivity. LC-MS/MS detected proinsulin and des 31,32 proinsulin at higher abundance in IAS plasma compared with control plasma. Analysis by gel filtration chromatography coupled to LC-MS/MS demonstrated proinsulin and des 31,32 proinsulin, but no C-peptide, in plasma immunocomplexes. CONCLUSIONS:Antibody binding can enrich proinsulin and des 31,32 proinsulin in IAS immunocomplexes. Proinsulin cross-reactivity in some C-peptide immunoassays can lead to artifactually increased C-peptide results. 10.1093/clinchem/hvab043
    Variable hematologic presentation of autoimmune gastritis: age-related progression from iron deficiency to cobalamin depletion. Hershko Chaim,Ronson Aaron,Souroujon Moshe,Maschler Itzhak,Heyd Judith,Patz Julian Blood Iron deficiency is a known complication of achlorhydria and may precede the development of pernicious anemia. Among 160 patients with autoimmune gastritis identified by hypergastrinemia and strongly positive antiparietal antibodies, we explored the overlap between 83 subjects presenting with iron deficiency anemia (IDA), 48 with normocytic indices, and 29 with macrocytic anemia. Compared with macrocytic patients, patients with IDA were 21 years younger (41 +/- 15 years versus 62 +/- 15 years) and mostly women. All groups had a high prevalence of thyroid disease (20%) and diabetes (8%) suggestive of the autoimmune polyendocrine syndrome. Stratification by age cohorts from younger than 20 years to older than 60 years showed a regular and progressive increase in mean corpuscular volume (MCV) from 68 +/- 9 to 95 +/- 16 fl, serum ferritin levels from 4 +/- 2 to 37 +/- 41 microg/L, gastrin level from 166 +/- 118 to 382 +/- 299 pM/L (349 +/- 247 to 800 +/- 627 pg/mL), and a decrease in cobalamin level from 392 +/- 179 to 108 +/- 65 pg/mL. The prevalence of Helicobacter pylori infection was 87.5% at age younger than 20 years, 47% at age 20 to 40 years, 37.5% at 41 to 60 years, and 12.5% at age older than 60 years. These findings challenge the common notion that pernicious anemia is a disease of the elderly and imply a disease starting many years before the establishment of clinical cobalamin deficiency, by an autoimmune process likely triggered by H pylori. 10.1182/blood-2005-09-3534
    Divalent metal transporter 1 regulates iron-mediated ROS and pancreatic β cell fate in response to cytokines. Hansen Jakob Bondo,Tonnesen Morten Fog,Madsen Andreas Nygaard,Hagedorn Peter H,Friberg Josefine,Grunnet Lars Groth,Heller R Scott,Nielsen Anja Østergren,Størling Joachim,Baeyens Luc,Anker-Kitai Leeat,Qvortrup Klaus,Bouwens Luc,Efrat Shimon,Aalund Mogens,Andrews Nancy C,Billestrup Nils,Karlsen Allan E,Holst Birgitte,Pociot Flemming,Mandrup-Poulsen Thomas Cell metabolism Reactive oxygen species (ROS) contribute to target-cell damage in inflammatory and iron-overload diseases. Little is known about iron transport regulation during inflammatory attack. Through a combination of in vitro and in vivo studies, we show that the proinflammatory cytokine IL-1β induces divalent metal transporter 1 (DMT1) expression correlating with increased β cell iron content and ROS production. Iron chelation and siRNA and genetic knockdown of DMT1 expression reduce cytokine-induced ROS formation and cell death. Glucose-stimulated insulin secretion in the absence of cytokines in Dmt1 knockout islets is defective, highlighting a physiological role of iron and ROS in the regulation of insulin secretion. Dmt1 knockout mice are protected against multiple low-dose streptozotocin and high-fat diet-induced glucose intolerance, models of type 1 and type 2 diabetes, respectively. Thus, β cells become prone to ROS-mediated inflammatory damage via aberrant cellular iron metabolism, a finding with potential general cellular implications. 10.1016/j.cmet.2012.09.001
    Vitamin D Decreases Hepcidin and Inflammatory Markers in Newly Diagnosed Inflammatory Bowel Disease Paediatric Patients: A Prospective Study. Journal of Crohn's & colitis BACKGROUND AND AIMS:The role of hepcidin in inflammatory bowel disease [IBD] in children with anaemia is poorly understood. However, it has been shown that vitamin D suppresses hepcidin expression. We aimed to assess serum hepcidin levels and the effect of vitamin D treatment on those levels in newly diagnosed IBD paediatric patients. METHODS:Eighty-five children were prospectively recruited in the Dana-Dwek Children's Hospital [40 newly diagnosed IBD, 45 healthy controls, 47% female, mean age 13.5 ± 3.4 years]. Blood samples for measurement of interleukin 6 [IL-6], C-reactive protein [CRP], hepcidin, iron parameters and 25-hydroxyvitamin D [25-(OH)-D] levels were obtained at baseline. Patients with mild-to-moderate signs and symptoms of IBD were treated with 4000 units of vitamin D daily for 2 weeks, after which the blood tests were repeated. RESULTS:Basal hepcidin, IL-6, CRP and platelet counts were significantly higher, and haemoglobin, serum iron and transferrin levels were significantly lower in the IBD children compared to controls [p < 0.001]. Eighteen patients completed 2 weeks of treatment with vitamin D. Following treatment, serum 25-(OH)-D concentrations increased by 40% [from 22.5 to 32.5 ng/mL], and serum hepcidin, CRP and ferritin levels decreased by 81%, 81% and 40% [from 33.9 to 6.7 ng/mL, from 23.9 to 4.7 mg/L, and from 27 to 16 ng/mL, respectively] [p ≤ 0.001]. CONCLUSION:Serum hepcidin levels were significantly higher in IBD paediatric patients compared to controls. Following vitamin D treatment, serum hepcidin concentration decreased significantly. These findings suggest a potential role for vitamin D in treating anaemia in IBD children. CLINICALTRIALS.GOV NUMBER:NCT03145896. 10.1093/ecco-jcc/jjz056
    The effect of serum albumin level on iron-induced oxidative stress in chronic renal failure patients. Sezer M Tugrul,Akin Huseyin,Demir Murat,Erturk Jale,Aydin Zeynep D,Savik Emin,Tunc Nese Journal of nephrology BACKGROUND:Intravenous iron (IVIR) administration is widely used to treat anemia in chronic renal failure (CRF) patients and causes oxidative stress. Despite the fact that proteins are extremely susceptible to oxidative stress, there have been no studies investigating the relationship between the severity of iron-induced acute oxidative stress and serum albumin. Therefore, we wanted to investigate the relation between the severity of iron-induced acute oxidative stress and serum albumin level in CRF patients. METHODS:A total of 68 patients (22 on hemodialysis, 24 on continuous ambulatory peritoneal dialysis and 22 predialytic CRF) with absolute iron deficiency were included to the study. Patients with acute inflammatory status, serum ferritin level > or = 100 ng/mL, transferrin saturation > or = 20%, hemoglobin level > or = 12 g/dL or serum C-reactive protein (CRP) level > or = 10 mg/dL were excluded. Serum direct 8-isoprostoglandin F2 alpha (IsoPG-F2 alpha) level was used as an oxidative stress marker. After baseline sampling, 100 mg ferric sucrose was infused within 30 minutes. Blood samples were drawn to assess changes in oxidative stress marker at the end of the IVIR infusion and at 240 minutes. Patients with serum albumin level <4 g/dL were defined as hypoalbuminemic and > or = 4 g/dL as normoalbuminemic. RESULTS:There were 34 hypoalbuminemic and 34 normoalbuminemic patients. Serum IsoPG-F2 alpha level increased in all patients after the administration of IVIR. The severity of iron-induced acute oxidative stress was more prominent in patients with a low serum albumin level. Serum albumin level, presence of diabetes mellitus (DM) and hemoglobin level were found as significant predictors of time-dependent changes in serum IsoPG-F2 alpha level. When the analyses were repeated in nondiabetic patients, serum albumin level was similarly found to be a significant predictor of time-dependent changes in serum IsoPG-F2 alpha level. CONCLUSION:This study demonstrated a negative interaction between iron-induced acute oxidative stress and serum albumin level in CRF patients. Because CRF patients with low serum albumin level are at greater risk for iron-induced acute oxidative stress, new strategies are necessary in this population.
    Iron deficiency in patients with nonalcoholic Fatty liver disease is associated with obesity, female gender, and low serum hepcidin. Siddique Asma,Nelson James E,Aouizerat Bradley,Yeh Matthew M,Kowdley Kris V, Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association BACKGROUND & AIMS:Iron deficiency is often observed in obese individuals. The iron regulatory hormone hepcidin is regulated by iron and cytokines interleukin (IL) 6 and IL1β. We examine the relationship between obesity, circulating levels of hepcidin, and IL6 and IL1β, and other risk factors in patients with nonalcoholic fatty liver disease (NAFLD) with iron deficiency. METHODS:We collected data on 675 adult subjects (>18 years old) enrolled in the Nonalcoholic Steatohepatitis Clinical Research Network. Subjects with transferrin saturation <20% were categorized as iron deficient, whereas those with transferrin saturation ≥20% were classified as iron normal. We assessed clinical, demographic, anthropometric, laboratory, dietary, and histologic data from patients, and serum levels of hepcidin and cytokines IL6 and IL1β. Univariate and multivariate analysis were used to identify risk factors for iron deficiency. RESULTS:One-third of patients (231 of 675; 34%) were iron deficient. Obesity, diabetes, and metabolic syndrome were more common in subjects with iron deficiency (P < .01), compared with those that were iron normal. Serum levels of hepcidin were significantly lower in subjects with iron deficiency (61 ± 45 vs 81 ± 51 ng/mL; P < .0001). Iron deficiency was significantly associated with female gender, obesity, increased body mass index and waist circumference, presence of diabetes, lower alcohol consumption, black or American Indian/Alaska Native race (P ≤ .018), and increased levels of IL6 and IL1β (6.6 vs 4.8 for iron normal, P ≤ .0001; and 0.45 vs 0.32 for iron normal, P ≤ .005). CONCLUSIONS:Iron deficiency is prevalent in patients with NAFLD and associated with female gender, increased body mass index, and nonwhite race. Serum levels of hepcidin were lower in iron-deficient subjects, reflecting an appropriate physiologic response to decreased circulating levels of iron, rather than a primary cause of iron deficiency in the setting of obesity and NAFLD. 10.1016/j.cgh.2013.11.017
    Effects of in vitro glycation on Fe3+ binding and Fe3+ isoforms of transferrin. Van Campenhout Ann,Van Campenhout Christel,Lagrou Albert René,Manuel-Y-Keenoy Begoña Clinical chemistry BACKGROUND:In diabetes, protein function is altered by glycation, but the impact on the Fe3+ binding and antioxidant functions of transferrin (Tf) is largely unknown. The aim of the present study was to investigate the effects of glycation on the distribution of Fe3+ on the two Fe3+ -binding sites of Tf. METHODS:In vitro glycation of Tf was accomplished by preincubation with glucose for 14 days. Tf was loaded with Fe3+ compounds to achieve theoretical Tf Fe3+ saturations of 32%, 64%, and 96% (monitored by spectrophotometry). Fe3+ -Tf isoforms were separated by isoelectric focusing. RESULTS:Fe3+ binding was highest when Tf was incubated with Fe:nitrilotriacetic acid and reached a steady state overnight. Increasing the Fe3+ load led to a shift of isoform profile toward the diferric form (Fe2-Tf): in freshly prepared Tf, Fe2-Tf represented 6%, 30%, and 66% of all isoforms at 32%, 64%, and 96% theoretical Fe3+ saturation, respectively. Fe3+ was equally distributed to the monoferric Tf forms with Fe3+ bound to the amino (Fe1N-Tf) and carboxy termini (Fe1C-Tf). Glycation decreased binding of Fe3+ to Tf (monitored at 450 nm). At low theoretical Fe3+ saturation (32%), glycation increased the mean (SD) proportion of Fe2-Tf: 18 (3)% in the presence of 33.3 mmol/L glucose vs 12 (4)% with 0 mmol/L glucose (P = 0.01). In contrast, at 96% theoretical Fe3+ saturation, Fe2-Tf decreased linearly with increasing glycation (r = 0.97; P = 0.008). Preincubation, independent of glycation, favored the Fe1N-Tf isoform at 64% theoretical Fe3+ saturation [27 (0.7)% vs 23 (1.1)% of the Fe1C-Tf isoform; P = 0.009]. CONCLUSIONS:Glycation impairs Fe3+ binding and affects Fe3+ -Tf isoform distribution depending on concentration. The diagnostic implications of these results need further elucidation in clinical studies. 10.1373/clinchem.2004.033811
    HDL (High-Density Lipoprotein) and ApoA-1 (Apolipoprotein A-1) Potentially Modulate Pancreatic α-Cell Glucagon Secretion. Mancuso Elettra,Mannino Gaia Chiara,Fuoco Anastasia,Leo Antonio,Citraro Rita,Averta Carolina,Spiga Rosangela,Russo Emilio,De Sarro Giovambattista,Andreozzi Francesco,Sesti Giorgio Arteriosclerosis, thrombosis, and vascular biology OBJECTIVE:Subjects with low levels of HDL (high-density lipoprotein) and ApoA-1 (apolipoprotein A-1) have increased risk to develop type 2 diabetes. HDL levels are an independent predictor of β-cell function and positively modulate it. Type 2 diabetes is characterized by defects in both β and α-cell function, but the effect of HDL and ApoA1 on α-cell function is unknown. Approach and Results: We observed a significant negative correlation (=-0.422, <0.0001) between HDL levels and fasting glucagon in a cohort of 132 Italian subjects. In a multivariable regression analysis including potential confounders such as age, sex, BMI, triglycerides, total cholesterol, fasting and 2-hour postload glucose, and fasting insulin, the association between HDL and fasting glucagon remained statistically significant (β=-0.318, =0.006). CD1 mice treated with HDL or ApoA-1 for 3 consecutive days showed a 32% (<0.001) and 23% (<0.05) reduction, respectively, in glucagon levels following insulin-induced hypoglycemia, compared with controls. Treatment of pancreatic αTC1 clone 6 cells with HDL or ApoA-1 for 24 hours resulted in a significant reduction of glucagon expression (<0.04) and secretion (<0.01) after an hypoglycemic stimulus and increased Akt (RAC-alpha serine/threonine-protein kinase) and FoxO1 (forkhead/winged helix box gene, group O-1) phosphorylation. Pretreatment with Akt inhibitor VIII, PI3K (phosphatidylinositol 3-kinase) inhibitor LY294002, and HDL receptor SCARB-1 (scavenger receptor class B type 1) inhibitor BLT-1 (block lipid transport-1) restored αTC1 cell response to low glucose levels. CONCLUSIONS:These results support the notion that HDL and ApoA-1 modulate glucagon expression and secretion by binding their cognate receptor SCARB-1, and activating the PI3K/Akt/FoxO1 signaling cascade in an in vitro α-cell model. Overall, these results raise the hypothesis that HDL and ApoA-1 may have a role in modulating glucagon secretion. 10.1161/ATVBAHA.120.314640
    Gut Microbiota-Associated Activation of TLR5 Induces Apolipoprotein A1 Production in the Liver. Yiu Jensen H C,Chan Kam-Suen,Cheung Jamie,Li Jin,Liu Yan,Wang Yao,Fung William W L,Cai Jieling,Cheung Samson W M,Dorweiler Bernhard,Wan Eric Y F,Tso Patrick,Xu Aimin,Woo Connie W Circulation research RATIONALE:Dysbiosis of gut microbiota plays an important role in cardiovascular diseases but the molecular mechanisms are complex. An association between gut microbiome and the variance in HDL-C (high-density lipoprotein-cholesterol) level was suggested in a human study. Besides, dietary fat was shown to increase both HDL-C and LDL-C (low-density lipoprotein-cholesterol) levels. We speculate that certain types of gut bacteria responding to dietary fat may help to regulate HDL-C level and potentially affect atherosclerotic development. OBJECTIVE:We aimed to investigate whether and how high-fat diet (HFD)-associated gut microbiota regulated HDL-C level. METHODS AND RESULTS:We found that HFD increased gut flagellated bacteria population in mice. The increase in HDL-C level was adopted by mice receiving fecal microbiome transplantation from HFD-fed mouse donors. HFD led to increased hepatic but not circulating flagellin, and deletion of TLR5 (Toll-like receptor 5), a receptor sensing flagellin, suppressed HFD-stimulated HDL-C and ApoA1 (apolipoprotein A1) levels. Overexpression of TLR5 in the liver of TLR5-knockout mice was able to partially restore the production of ApoA1 and HDL-C levels. Mechanistically, TLR5 activation by flagellin in primary hepatocytes stimulated ApoA1 production through the transcriptional activation responding to the binding of NF-κB (nuclear factor-κB) on promoter region. Furthermore, oral supplementation of flagellin was able to stimulate hepatic ApoA1 production and HDL-C level and decrease atherosclerotic lesion size in apolipoprotein E-deficient () mice without triggering hepatic and systemic inflammation. The stimulation of ApoA1 production was also seen in human ApoA1-transgenic mice treated with oral flagellin. CONCLUSIONS:Our finding suggests that commensal flagellated bacteria in gut can facilitate ApoA1 and HDL-C productions in liver through activation of TLR5 in hepatocytes. Hepatic TLR5 may be a potential drug target to increase ApoA1. 10.1161/CIRCRESAHA.120.317362
    Association of LDL:HDL ratio with prediabetes risk: a longitudinal observational study based on Chinese adults. Lipids in health and disease BACKGROUND:Low-density lipoprotein:high-density lipoprotein cholesterol ratio (LDL:HDL ratio) has a good performance in identifying diabetes mellitus (DM) and insulin resistance. However, it is not yet clear whether the LDL:HDL ratio is associated with a high-risk state of prediabetes. METHODS:This cohort study retrospectively analyzed the data of 100,309 Chinese adults with normoglycemia at baseline. The outcome event of interest was new-onset prediabetes. Using multivariate Cox regression and smoothing splines to assess the association of LDL:HDL ratio with prediabetes. RESULTS:During an average observation period of 37.4 months, 12,352 (12.31%) subjects were newly diagnosed with prediabetes. After adequate adjustment for important risk factors, the LDL:HDL ratio was positively correlated with the prediabetes risk, and the sensitivity analysis further suggested the robustness of the results. Additionally, in stratified analysis, we discovered significant interactions between LDL:HDL ratio and family history of DM, sex, body mass index and age (all P-interaction < 0.05); among them, the LDL:HDL ratio-related prediabetes risk decreased with the growth of body mass index and age, and increased significantly in women and people with a family history of DM. CONCLUSIONS:The increased LDL:HDL ratio in the Chinese population indicates an increased risk of developing prediabetes, especially in women, those with a family history of DM, younger adults, and non-obese individuals. 10.1186/s12944-022-01655-5
    Associations between the HDL-C/ApoA-I ratio and fasting glucose levels differ by glucose deciles, HDL-C/ApoA-I ratio ranges and sex. Diabetes research and clinical practice AIMS:To learn how high-density lipoprotein cholesterol (HDL-C) and apolipoprotein A-I (ApoA-I) are associated with fasting blood glucose (FBG). METHODS:A cross-sectional study was performed in 97,801 males and 70,773 females without known disease. RESULTS:The ratio of HDL-C/ApoA-I is more stable for predicting fasting glucose levels than HDL-C or ApoA-I alone. In subjects with HDL-C/ApoA-I ≤ 0.9, HDL-C/ApoA-I ratios were negatively associated with FBG levels, with similar patterns between sexes, and the associations gradually strengthened along with the deciles of FBG increase. In subjects with HDL-C/ApoA-I > 0.9, FBG remained at relatively lower levels in both sexes, while the associations between the FBG level and the HDL-C/ApoA-I ratio turned from negative in the lowest five deciles to positive in the highest two deciles of FBG levels in males. Adjustment for known confounders only slightly attenuated the above association patterns. Subpopulations with HDL-C/ApoA-I ≤ 0.9 were distributed in the higher ranges of triglyceride (TG), non-HDL-C, total cholesterol (TC) and ApoA-I levels and lower ranges of HDL-C levels. CONCLUSIONS:The HDL-C/ApoA-I ratio sorted TG, non-HDL-C, TC, ApoA-I and HDL-C levels and hence might combine more coordinating metabolic characteristics of these lipids in association with blood glucose homeostasis. 10.1016/j.diabres.2022.110021
    Association between iron deficiency and A1C Levels among adults without diabetes in the National Health and Nutrition Examination Survey, 1999-2006. Diabetes care OBJECTIVE:Iron deficiency has been reported to elevate A1C levels apart from glycemia. We examined the influence of iron deficiency on A1C distribution among adults without diabetes. RESEARCH DESIGN AND METHODS:Participants included adults without self-reported diabetes or chronic kidney disease in the National Health and Nutrition Examination Survey 1999-2006 who were aged > or =18 years of age and had complete blood counts, iron studies, and A1C levels. Iron deficiency was defined as at least two abnormalities including free erythrocyte protoporphyrin >70 microg/dl erythrocytes, transferrin saturation <16%, or serum ferritin < or =15 microg/l. Anemia was defined as hemoglobin <13.5 g/dl in men and <12.0 g/dl in women. RESULTS:Among women (n = 6,666), 13.7% had iron deficiency and 4.0% had iron deficiency anemia. Whereas 316 women with iron deficiency had A1C > or =5.5%, only 32 women with iron deficiency had A1C > or =6.5%. Among men (n = 3,869), only 13 had iron deficiency and A1C > or =5.5%, and only 1 had iron deficiency and A1C > or =6.5%. Among women, iron deficiency was associated with a greater odds of A1C > or =5.5% (odds ratio 1.39 [95% CI 1.11-1.73]) after adjustment for age, race/ethnicity, and waist circumference but not with a greater odds of A1C > or =6.5% (0.79 [0.33-1.85]). CONCLUSIONS:Iron deficiency is common among women and is associated with shifts in A1C distribution from <5.5 to > or =5.5%. Further research is needed to examine whether iron deficiency is associated with shifts at higher A1C levels. 10.2337/dc09-0836
    Ferritin and transferrin are associated with metabolic syndrome abnormalities and their change over time in a general population: Data from an Epidemiological Study on the Insulin Resistance Syndrome (DESIR). Vari Istvan S,Balkau Beverley,Kettaneh Adrian,André Philippe,Tichet Jean,Fumeron Frédéric,Caces Emile,Marre Michel,Grandchamp Bernard,Ducimetière Pierre, Diabetes care OBJECTIVE:The aim of this work was to study cross-sectional and longitudinal relations between iron stocks (ferritin) and the iron transport protein (transferrin) with the metabolic syndrome and its abnormalities. RESEARCH DESIGN AND METHODS:A total of 469 men and 278 premenopausal and 197 postmenopausal women from the French Data from an Epidemiological Study on the Insulin Resistance Syndrome (DESIR) cohort, aged 30-65 years, were followed over 6 years. RESULTS:Higher concentrations of both ferritin and transferrin were associated with the International Diabetes Federation (IDF) and the National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults Adult Treatment Panel III original and revised definitions of the metabolic syndrome at baseline: for the IDF definition of the metabolic syndrome, the standardized, age-adjusted odds ratios (95% CI) for log(ferritin) were 1.49 (1.14-1.94) for men, 2.10 (1.27-3.48) for premenopausal women, and 1.80 (1.21-2.68) for postmenopausal women; for transferrin they were, respectively, 1.94 (1.53-2.47), 2.22 (1.32-3.75), and 2.14 (1.47-3.10). After 6 years of follow-up, the change in the presence of the metabolic syndrome was associated with higher baseline values in all three groups: log(ferritin), 1.46 (1.13-1.89), 1.28 (0.85-1.94), and 1.62 (1.10-2.38); and transferrin, 1.41 (1.10-1.81), 1.63 (1.05-2.52), and 1.51 (1.02-2.22). Among syndrome components, hypertriglyceridemia at 6 years was the component most strongly associated with baseline ferritin and transferrin. The odds of an incident IDF-defined metabolic syndrome after 6 years was more than fourfold higher when ferritin and transferrin values were both above the group-specific top tertile, in comparison with participants with both parameters below these thresholds. CONCLUSIONS:This is the first prospective study associating ferritin and transferrin with the metabolic syndrome and its components. When both markers of the iron metabolism are elevated, the incidence of the metabolic syndrome is increased in men and both pre- and postmenopausal women. 10.2337/dc06-2312
    Relative Risk of Cardiovascular Disease Is Higher in Women With Type 2 Diabetes, but Not in Those With Prediabetes, as Compared With Men. Succurro Elena,Fiorentino Teresa Vanessa,Miceli Sofia,Perticone Maria,Sciacqua Angela,Andreozzi Francesco,Sesti Giorgio Diabetes care OBJECTIVE:Most but not all studies suggest that women with type 2 diabetes have higher relative risk (RR) for cardiovascular disease (CVD) than men. More uncertainty exists on whether the RR for CVD is higher in women with prediabetes compared with men with prediabetes. RESEARCH DESIGN AND METHODS:In a cross-sectional study, in 3,540 adults with normal glucose tolerance (NGT), prediabetes, and diabetes, we compared the RR for prevalent nonfatal CVD between men and women. In a longitudinal study including 1,658 adults with NGT, prediabetes, and diabetes, we compared the RR for incidences of major adverse outcomes, including all-cause death, coronary heart disease, and cerebrovascular disease events, after 5.6 years of follow-up. RESULTS:Women with prediabetes and diabetes exhibited greater relative differences in BMI, waist circumference, blood pressure, total cholesterol, LDL cholesterol, HDL cholesterol, triglycerides, fasting glucose, hs-CRP, and white blood cell count than men with prediabetes and diabetes when compared with their NGT counterparts. We found a higher RR for prevalent CVD in women with diabetes (RR 9.29; 95% CI 4.73-18.25; < 0.0001) than in men (RR 4.56; 95% CI 3.07-6.77; < 0.0001), but no difference in RR for CVD was observed comparing women and men with prediabetes. In the longitudinal study, we found that women with diabetes, but not those with prediabetes, have higher RR (RR 5.25; 95% CI 3.22-8.56; < 0.0001) of incident major adverse outcomes than their male counterparts (RR 2.72; 95% CI 1.81-4.08; < 0.0001). CONCLUSIONS:This study suggests that women with diabetes, but not those with prediabetes, have higher RR for prevalent and incident major adverse outcomes than men. 10.2337/dc20-1401
    Prediabetes defined by HbA and by fasting glucose: differences in risk factors and prevalence. Rodriguez-Segade Santiago,Rodriguez Javier,Camiña Félix,Sanmartín-Portas Luís,Gerpe-Jamardo Josefa,Pazos-Couselo Marcos,García-López Jose M,Alonso-Sampedro Manuela,González-Quintela Arturo,Gude Francisco Acta diabetologica AIMS:To investigate, in a sample of nondiabetic adults from a Spanish community, the differences between prediabetes as defined by HbA ("H-prediabetes") and by fasting plasma glucose (FPG) ("F-prediabetes") in regard to prevalence and the influence of potential risk factors, adjusting the latter for confounders. METHODS:A total of 1328 nondiabetic participants aged ≥ 18 years were classified as normoglycemic, H-prediabetic [HbA 5.7-6.4% (39-47 mmol/mol)] or F-prediabetic (FPG 5.6-6.9 mmol/L). Multivariable analyses were used to compare the impacts of risk factors on the prevalence of H-prediabetes, F-prediabetes and their conjunctive and disjunctive combinations ("HaF-prediabetes" and "HoF-prediabetes," respectively). RESULTS:Some 29.9% of participants were HoF-prediabetic, 21.7% H-prediabetic, 16.3% F-prediabetic and only 8.1% HaF-prediabetic. Whatever the definition of prediabetes, increasing age, fasting insulin and LDL cholesterol were each a risk factor after adjustment for all other variables. Increasing BMI and decreasing mean corpuscular hemoglobin (MCH) were additional risk factors for H-prediabetes; male sex and increasing uric acid for F-prediabetes and increasing BMI for HaF-prediabetes. The participants satisfying the compound condition "hypertension or hyperlipidemia or obesity or hyperuricemia" (59.9% of the whole study group) included 83.1% of all subjects with HoF-prediabetes. CONCLUSIONS:In this population, the most sensitive risk factor for detection of prediabetes was age, followed by fasting insulin, LDL cholesterol, BMI, MCH, male sex and uric acid, with differences depending on the definition of prediabetes. MCH, an indirect measure of erythrocyte survival, significantly influences the prevalence of HbA-defined prediabetes. This study suggests that screening of individuals with selected risk factors may identify a high proportion of prediabetic persons. 10.1007/s00592-019-01342-5
    The transferrin/log(ferritin) ratio: a new tool for the diagnosis of iron deficiency anemia. Castel Rob,Tax Martine G H M,Droogendijk Jolanda,Leers Math P G,Beukers Ruud,Levin Mark-David,Sonneveld Pieter,Berendes Paul B Clinical chemistry and laboratory medicine BACKGROUND:Serum ferritin is the best single laboratory test to diagnose iron deficiency anemia (IDA). Ferritin levels <20 μg/L are highly specific for IDA, and ferritin levels >100 μg/L usually exclude IDA. However, ferritin concentrations between 20 and 100 μg/L are often inconclusive. The objective of this study was to improve the diagnosis of IDA when ferritin levels are inconclusive. METHODS:We evaluated the predictive performance of classic (ferritin, mean corpuscular volume, transferrin and serum iron) and modern [reticulocyte hemoglobin content, serum transferrin receptor and soluble transferrin receptor (sTfR)/log(ferr)] iron status parameters to diagnose IDA in 2084 anemic, non-hospitalized patients. The results were validated in an independent cohort of 274 anemic patients. RESULTS:In our study population, 29% (595 patients) of the patients had a ferritin level between 20 and 100 μg/L, hampering diagnosis of IDA. None of the classic or modern parameters was capable of completely separating the IDA population from the non-IDA population. However, using a new parameter, the transferrin/log(ferritin) ratio, the IDA and non-IDA populations can be completely separated. At a cut-off value of 1.70, the transferrin/log(ferritin) ratio indicates IDA in 29% of the patients with inconclusive ferritin levels. CONCLUSIONS:The transferrin/log(ferritin) ratio is a practical new tool that improves diagnosis of iron deficiency when ferritin levels are inconclusive. 10.1515/cclm-2011-0594
    Evaluation of Ferritin and Transferrin Ratio as a Prognostic Marker for Hepatocellular Carcinoma. Vohra Ishaan,Attar Bashar,Katiyar Vatsala,Palacios Pedro,Randhawa Tejinder,Baig Muhammad Arslan,Flores Estefania,Wang Yuchen,Mutneja Hemant,Sharma Sachit,Lingamneni Prashanth,Farooq Muhammad Zain,Bhaskaran Naveen,Gandhi Seema,Vettiankal Gijo,Demetria Melchor Journal of gastrointestinal cancer PURPOSE OF THE STUDY:Hepatocellular carcinoma (HCC) has tripled in incidence over the past 20 years and now ranks as the third leading cause of mortality attributed to cancer. Underlying pathophysiology is sustained hepatic inflammation which results in hepatocellular dysplasia and thus an environment prone to HCC. Considering the essential role of inflammation in the pathogenesis of HCC, we evaluated the prognostic utility of ferritin-transferrin ratio (FTR) in HCC. METHODS:We retrospectively reviewed the electronic medical records of patients with HCC (diagnosed on radiographic criteria and/or biopsy) from 2000 through 2015. We collected data regarding the patient demographics, laboratory investigations at the time of HCC diagnosis and prior to the initiation of treatment. Overall survival was calculated from the time of diagnosis, cases were censored at the date of last follow-up, if date of death was not known. Kaplan-Meier curves were estimated to evaluate the prognostic significance of FTR. Receiver operating characteristics (ROC) curve was plotted for FTR to predict mortality and identify cut-off value by optimized Youden's index. RESULTS:Among the 176 patients identified by initial screening, 116 patients were eventually included for analysis. Overall median survival was 11.9 months. FTR, of note, was significantly lower in alive (6.9, p < 0.001). In univariate analysis, alfa-fetoprotein (AFP), aspartate aminotransferase (AST), serum ferritin (SF), transferrin (TFS), and FTR were significantly associated with mortality. On multivariate analysis for mortality, FTR, AFP, and epidemiologic factors predictive of mortality including male gender and advanced HCC were significant. CONCLUSION:The ferritin-transferrin ratio (FTR), calculated at the time of HCC diagnosis could predict mortality in our cohort of patients. With an optimal cut-off of 7.7 for FTR were stratified into high- and low-risk groups. The hazard ratio between the two groups was 2.36 (p < 0.003). Future studies with longitudinal follow-up of FTR at intervals and important time points (e.g., perioperative) might provide more insights to its prognostic value. 10.1007/s12029-020-00373-4
    Hepatic iron stores are increased as assessed by magnetic resonance imaging in a Chinese population with altered glucose homeostasis. Zheng Xuan,Jiang Tao,Wu Hong,Zhu Dezeng,Wang Ling,Qi Rui,Li Min,Ling Changquan The American journal of clinical nutrition BACKGROUND:Emerging scientific evidence has disclosed a correlation between iron metabolism and type 2 diabetes (T2D). OBJECTIVE:The objective of this study was to test the hypothesis that body iron stores are higher in a Chinese population with altered glucose homeostasis. DESIGN:Serum iron, ferritin, and soluble transferrin receptor concentrations were measured in 298 subjects, including 70 subjects with normal glucose tolerance (NGT group), 60 subjects with prediabetes (prediabetes group), and 168 subjects with T2D (T2D group). Hepatic iron stores in 88 subjects were assessed by using a magnetic resonance imaging (MRI) T2* gradient-recalled-echo technique. A general linear model ANOVA was performed for comparisons between groups after adjustment for age and BMI. Stepwise multiple linear regression analysis was used to identify factors associated with the MRI-estimated hepatic iron concentration (M-HIC). RESULTS:Mean (±SD) M-HIC and R2* values in the prediabetes and T2D groups were significantly higher than in the NGT group (M-HIC: 40.6 ± 8.6 and 39.3 ± 10.7 μmol/g compared with 27.8 ± 9.1 μmol/g; R2* values: 47.9 ± 11.9 and 47.3 ± 11.5 s(-1) compared with 34.9 ± 7.0 s(-1); all P < 0.01). No significant difference was shown in M-HIC and R2* values between prediabetes and T2D groups. The M-HIC independently contributed to 43.3% of the glycated hemoglobin variance after adjustment for main clinical indexes (P < 0.001). The proportions of subjects with mild hepatic iron overload in the NGT, prediabetes, and T2D groups were 12.5%, 70.6%, and 63.6%, respectively. CONCLUSIONS:To our knowledge, our findings provide novel evidence to support the hypothesis of a mild iron overload in patients with prediabetes and T2D. A cohort study concerned with the effect of the attenuation of excess iron on glucose metabolism in a prediabetic population is warranted. 10.3945/ajcn.111.015743
    Increased serotransferrin and ceruloplasmin turnover in diet-controlled patients with type 2 diabetes. Golizeh Makan,Lee Kwangwon,Ilchenko Serguei,Ösme Abdullah,Bena James,Sadygov Rovshan G,Kashyap Sangeeta R,Kasumov Takhar Free radical biology & medicine Type 2 diabetes mellitus (T2DM) is associated with oxidative stress and perturbed iron metabolism. Serotransferrin (Trf) and ceruloplasmin (Cp) are two key proteins involved in iron metabolism and anti-oxidant defense. Non-enzymatic glycation and oxidative modification of plasma proteins are known to occur under hyperglycemia and oxidative stress. In this study, shotgun proteomics and HO-based metabolic labeling were used to characterize post-translational modifications and assess the kinetics of Trf and Cp in T2DM patients and matched controls in vivo. Six early lysine (Amadori) and one advanced arginine glycation were detected in Trf. No glycation, but five asparagine deamidations, were found in Cp. T2DM patients had increased fractional catabolic rates of both Trf and Cp that correlated with HbA (p < 0.05). The glycated Trf population was subject to an even faster degradation compared to the total Trf pool, suggesting that hyperglycemia contributed to an increased Trf degradation in T2DM patients. Enhanced production of Trf and Cp kept their levels stable. The changes in Trf and Cp turnover were associated with increased systemic oxidative stress without any alteration in iron status in T2DM. These findings can help better understand the potential role of altered Trf and Cp metabolism in the pathogenesis of T2DM and other diseases. 10.1016/j.freeradbiomed.2017.10.373
    Albumin and fibrinogen kinetics in sepsis: a prospective observational study. Omiya Keisuke,Sato Hiroaki,Sato Tamaki,Wykes Linda,Hong Mengyin,Hatzakorzian Roupen,Kristof Arnold S,Schricker Thomas Critical care (London, England) BACKGROUND:The measurement of circulating substrate concentrations does not provide information about substrate kinetics. It, therefore, remains unclear if a decrease in plasma concentration of albumin, as seen during critical illness, is a consequence of suppressed production in the liver or increased peripheral clearance. In this study, using stable isotope tracer infusions, we measured albumin and fibrinogen kinetics in septic patients and in a control group of non-septic subjects. METHODS:With the approval from the institutional Research Ethics Board and after obtaining written informed consent from patients or their substitute decision maker, mechanically ventilated patients with sepsis and patients scheduled for elective coronary artery bypass grafting were enrolled. Patients in the non-sepsis group were studied on the day before surgery. The stable isotope L-[ring-H]phenylalanine was used to measure absolute synthesis rates (ASR) of albumin and fibrinogen. A priming dose of L-[ring-H]phenylalanine (4 µmol/kg) was given followed by a six-hour infusion at a rate of 0.15 µmol/kg/min. At baseline and hourly thereafter, blood was drawn to measure isotope enrichments by gas chromatography/mass spectrometry. Very low density lipoprotein apolipoprotein-B 100 isotopic enrichment was used to represent the isotopic enrichment of the phenylalanine precursor pool from which the liver synthesizes proteins. Plasma albumin and fibrinogen concentrations were also measured. RESULTS:Mean plasma albumin in septic patients was decreased when compared to non-septic patients, while synthesis rates were comparable. Mean plasma fibrinogen and ASR in septic patients was increased when compared to non-septic patients. In non-septic patients, no statistically significant correlation between plasma albumin and ASR was observed but plasma fibrinogen significantly correlated with ASR. In septic patients, plasma albumin and fibrinogen significantly correlated with ASR. CONCLUSIONS:While septic patients showed lower plasma albumin levels than non-septic patients, albumin synthesis was similar in the two groups suggesting that hypoalbuminemia during sepsis was not caused by suppressed hepatic production but a result of enhanced clearance from the circulation. Hyperfibrinogenemia in septic patients was a consequence of increased fibrinogen production. TRIAL REGISTRATION:ClinicalTrials.gov: NCT02865408 (registered on August 12, 2016) and ClinicalTrials.gov: NCT02549443 (registered on September 15, 2015). 10.1186/s13054-021-03860-7
    In vitro formation of homocysteine in whole blood in the presence of anticoagulants. Tamura Tsunenobu,Baggott Joseph E Clinical chemistry 10.1373/clinchem.2007.101642
    Influence of iron metabolism indices on glycated haemoglobin but not glycated albumin levels in premenopausal women. Koga Masafumi,Saito Hiroshi,Mukai Mikio,Matsumoto Soeko,Kasayama Soji Acta diabetologica We have recently shown that in premenopausal women without anaemia, glycated haemoglobin (HbA(1C)) is inversely associated with mean corpuscular haemoglobin (MCH). Based on the hypothesis that iron deficient state (IDS) due to menstruation may influence erythrocyte metabolism and thereby HbA(1C) levels, we examined the relation of iron metabolism indices with HbA(1C) in premenopausal women. HbA(1C), serum glycated albumin (GA) and iron metabolism indices were determined in 104 premenopausal women with normal glucose tolerance. Among them, 17 were diagnosed with iron deficiency anaemia (IDA) and 30 with IDS. The other 57 subjects were diagnosed with normal iron state (NIS). HbA(1C) levels showed significant inverse association with serum iron, serum transferrin saturation and serum ferritin in 104 study participants. Multivariate regression analysis identified serum ferritin as negatively associated with HbA(1C). These were also observed in 87 premenopausal women without IDA. HbA(1C) levels in IDA subjects and in IDS subjects were higher than it in NIS subjects, while GA levels were not different among the three groups of subjects. In conclusions, iron metabolism indices influence HbA(1C) levels, but not serum GA levels, in premenopausal women. 10.1007/s00592-009-0123-6
    Large-scale retrospective analyses of the effect of iron deficiency anemia on hemoglobin A1c concentrations. Rao Lokinendi V,Pratt George W,Bi Caixia,Kroll Martin H Clinica chimica acta; international journal of clinical chemistry INTRODUCTION:HbA1c is a reliable biomarker for diagnosing and prognosis of diabetes, but many clinical scenarios and interfering factors can affect the test results. Any conditions that affect red cell turnover, such as iron-deficiency anemia (IDA), can lead to spurious HbA1c results. Reports on how IDA affects HbA1c concentrations are contradictory, and to understand better the association between HbA1c concentrations and IDA, we conducted a large-scale retrospective study. METHODS:Test results for HbA1c concentrations were retrieved from the years 2015-2019. We evaluated over 12,000 patients with IDA and 21,000 patients without IDA. Patients were classified as having IDA if samples with below the age-based ranges for serum iron, ferritin, or transferrin iron saturation and above age-based ranges for transferrin iron-binding capacity or transferrin concentrations. Kruskal-Wallis statistical analyses method was used to test whether the two samples follow the same distribution and significance. RESULTS:The median HbA1c concentration was 5.7% among IDA classified patients and 5.4% among normal samples (P < 0.001) for females. For males, the median HbA1c concentration was 6.0% among IDA classified patients and 5.6% among normal samples (P < 0.001). CONCLUSION:Patients classified as IDA can have increased HbA1c concentrations than patients without IDA. Clinicians should consider IDA status before making therapeutic decisions based on HbA1c concentrations. 10.1016/j.cca.2022.02.005
    Iron sucrose augments homocysteine-induced endothelial dysfunction in normal subjects. Zheng H,Huang X,Zhang Q,Katz S D Kidney international Intravenous iron is commonly used in conjunction with erythropoietic agents to treat anemia in patients with chronic kidney disease. Iron has been proposed to promote oxidative stress and endothelial dysfunction in vascular tissues. We studied the acute effects of intravenous iron sucrose on homocysteine-induced endothelial dysfunction in the brachial artery of normal human subjects. In all, 40 healthy subjects received intravenous iron sucrose 100 mg or placebo over 30 min immediately before ingestion of 100 mg/kg of oral methionine in a double-blind, randomized study. Flow- and nitroglycerin-mediated dilation in the brachial artery, serum markers of iron stores, and homocysteine and nitrotyrosine levels were measured before and after study drug administration. Intravenous iron significantly increased transferrin saturation and non-transferrin-bound iron (NTBI) when compared with placebo. Flow-mediated dilation significantly decreased from baseline 1 h after administration of iron sucrose when compared with placebo (from 6.66+/-0.47 to 1.93+/-0.35% after iron sucrose vs from 6.00+/-0.40 to 5.61+/-0.46% after placebo, P<0.001), but did not differ between groups at 4 h (1.10+/-0.39 vs 1.33+/-0.51%). Nitroglycerin-mediated vasodilation, and homocysteine and 3-nitrotyrosine levels did not differ after administration of iron sucrose and placebo. Intravenous administration of iron sucrose in the setting of transient hyperhomocysteinemia induced by methionine ingestion significantly increased transferrin saturation and plasma levels of NTBI and significantly attenuated flow-mediated dilation in the brachial artery when compared with placebo. This potential mechanistic link between intravenous iron and endothelial dysfunction warrants further study of cardiovascular effects of intravenous iron in anemic chronic kidney disease populations. 10.1038/sj.ki.5000046
    Plasma homocysteine affects fibrin clot permeability and resistance to lysis in human subjects. Undas Anetta,Brozek Jan,Jankowski Milosz,Siudak Zbigniew,Szczeklik Andrew,Jakubowski Hieronim Arteriosclerosis, thrombosis, and vascular biology OBJECTIVE:Homocysteine (Hcy) is a risk factor for thrombosis. We investigated a hypothesis that the clot permeability and its resistance to fibrinolysis is associated with plasma total Hcy (tHcy) in human subjects. METHODS AND RESULTS:We studied healthy men not taking any medication (n=76), male patients with advanced coronary artery disease (CAD) taking low-dose aspirin (n=33), men with diabetes mellitus diagnosed recently (median hemoglobin A(1c) 7.65%; n=16), and patients with isolated hypercholesterolemia (>7.0 mmol/L; n=15). We assessed clot permeability and turbidimetric lysis time as the determinants of fibrin clot structure. In a regression model, including age and fibrinogen, plasma tHcy was an independent predictor of clot permeation and fibrinolysis time in healthy subjects (R2=0.88, P<0.0001 and R2=0.54, P<0.0001, respectively). In CAD patients, tHcy and fibrinogen were stronger predictors of the permeation coefficient (R2=0.84; P<0.0001) than was fibrinogen alone (R2=0.66; P<0.0001), whereas tHcy was the only predictor of lysis time (R2=0.69; P<0.0001). Elevated tHcy levels observed after methionine load were not associated with any of the fibrin clot properties. In patients with diabetes or hypercholesterolemia, the influence of Hcy on permeation and, to a lesser extent, on the lysis time was obscured by dominant effects of glucose and cholesterol. In 20 asymptomatic men with hyperhomocysteinemia treated with folic acid, reduction in tHcy levels resulted in increased clot permeability (P=0.0002) and shorter lysis time (P<0.0001). CONCLUSIONS:Our results indicate that plasma tHcy predicts clot permeation and susceptibility to fibrinolysis in healthy men and CAD patients. Our data are consistent with a mechanism of thrombosis in hyperhomocysteinemia, which involves modification of fibrinogen by Hcy-thiolactone. 10.1161/01.ATV.0000219688.43572.75
    SOD3 and IL-18 Predict the First Kidney Disease-Related Hospitalization or Death during the One-Year Follow-Up Period in Patients with End-Stage Renal Disease. Antioxidants (Basel, Switzerland) End-stage renal disease (ESRD) patients experience oxidative stress due to excess exogenous or endogenous oxidants and insufficient antioxidants. Hence, oxidative stress and inflammation cause endothelial damage, contributing to vascular dysfunction and atherosclerosis. Therefore, ESRD patients suffer more cardiovascular and hospitalization events than healthy people. This study aims to test the correlations between ROS, SOD3, IL-2, IL-6, and IL-18 and the first kidney disease-related hospitalization or death events in ESRD patients undergoing regular hemodialysis. A total of 212 participants was enrolled, including 45 normal healthy adults and 167 ESRD patients on regular dialysis. Blood samples from all participants were collected for ROS, SOD3, IL-2, IL-6, and IL-18 measurement at the beginning of the study, and every kidney disease-related admission or death was recorded for the next year. Multivariate analysis was conducted by fitting a linear regression model, logistic regression model, and Cox proportional hazards model to estimate the adjusted effects of risk factors, prognostic factors, or predictors on continuous, binary, and survival outcome data. The results showed that plasma SOD3 and serum IL-18 were two strong predictors of the first kidney disease-related hospitalization or death. In the Cox proportional hazards models (run in R), higher IL-18 concentration (&gt;69.054 pg/mL) was associated with a hazard ratio of 3.376 for the first kidney disease-related hospitalization or death (95% CI: 1.2644 to 9.012), while log(SOD3) &lt; 4.723 and dialysis clearance (Kt/V; 1.11 &lt; value &lt; 1.869) had a hazard ratio = 0.2730 (95% CI: 0.1133 to 0.6576) for reducing future kidney disease-related hospitalization or death. Other markers, including body mass index (BMI), transferrin saturation, total iron binding capacity, and sodium and alkaline phosphate, were also found to be significant in our study. These results reveal the new predictors SOD3 and IL-18 for the medical care of end-stage renal disease patients. 10.3390/antiox11061198
    Ferritin and Percent Transferrin Saturation Levels Predict Type 2 Diabetes Risk and Cardiovascular Disease Outcomes. Zacharski Leo R,Shamayeva Galina,Chow Bruce K,DePalma Ralph G Current diabetes reviews INTRODUCTION:Type 2 diabetes (T2D) and cardiovascular disease (CVD) risk associate with ferritin and percent transferrin saturation (%TS) levels. However, increased risk has been observed at levels considered within the "normal range" for these markers. OBJECTIVE:To define normative ferritin and %TS levels associated with T2D and CVD risk. METHODS:Six-monthly ferritin, %TS and hemoglobin levels from 1,277 iron reduction clinical trial participants with CVD (peripheral arterial disease, 37% diabetic) permitted pair-wise analysis using Loess Locally Weighted Smoothing plots. Curves showed continuous quantitative ferritin, hemoglobin (reflecting physiologic iron requirements), and %TS (reflecting iron transport and sequestration) levels over a wide range of values. Inflection points in the curves were compared to ferritin and %TS levels indicating increased T2D and CVD risk in epidemiologic and intervention studies. RESULTS:Increasing ferritin up to about 80 ng/mL and %TS up to about 25% TS corresponded to increasing hemoglobin levels, and minimal T2D and CVD risk. Displaced Loess trajectories reflected lower hemoglobin levels in diabetics compared to non-diabetics. Ferritin levels up to about 100 ng/mL paralleled proportionately increasing %TS levels up to about 55%TS corresponding to further limitation of T2D and CVD risk. Ferritin levels over 100 ng/mL did not associate with hemoglobin levels and coincided with increased T2D and CVD risk. CONCLUSIONS:Recognition of modified normal ranges for ferritin from about 15 ng/mL up to about 80- 100 ng/mL and %TS from about 15% up to about 25-55% may improve the value of iron biomarkers to assess and possibly lower T2D and CVD risk. 10.2174/1573399813666170504163138
    Low serum iron is associated with high serum intact FGF23 in elderly men: The Swedish MrOS study. Lewerin Catharina,Ljunggren Östen,Nilsson-Ehle Herman,Karlsson Magnus K,Herlitz Hans,Lorentzon Mattias,Ohlsson Claes,Mellström Dan Bone BACKGROUND:Fibroblast growth factor (FGF23) is a protein that is produced by osteoblasts and osteocytes. Increased serum levels of FGF23 have been associated with increased risks of osteoporotic fractures and cardiovascular disease, particularly in participants with poor renal function. Serum iron (Fe) has been suggested as a regulator of FGF23 homeostasis. OBJECTIVE:To determine whether Fe and iron status are determinants of the levels of intact FGF23 (iFGF23) in elderly men. METHODS:The MrOS study is a population-based study of elderly men (N=1010; mean age, 75.3years; range, 69-81years). The levels of Fe, transferrin saturation (TS), and ferritin were evaluated in relation to the serum concentrations of iFGF23 before and after adjustments for confounders. RESULTS:TS <15% was found in 3.5% (34/977) of the participants, who had a higher median level iFGF23 compared with the remaining subjects (47.4μmol/L vs. 41.9μmol/L, p=0.008). The levels of iFGF23 correlated negatively (un-adjusted) with the levels of Fe (r=-0.17, p<0.001), TS (r=-0.16, p<0.001) and serum ferritin (r=-0.07, p=0.022). In addition, in participants with estimated glomerular filtration rate eGFRCystatin C>60mL/min, the levels of iFGF23 correlated (age-adjusted) negatively with the levels of Fe (r=-0.15, p<0.001) and TS (r=-0.17, p<0.001). The level of iFGF23 correlated positively (un-adjusted) with lumbar spine bone mineral density (BMD) (r=0.14, p<0.001), total body BMD (r=0.11, p=0.001), and total hip BMD (r=0.09, p=0.004). The corresponding correlations, when adjusted for age, weight, and height were: r=0.08, p=0.018; r=0.05, p=0.120; and r=0.02, p=0.624, respectively. No associations were found between BMD and the levels of Fe or TS. Multiple step-wise linear regression analyses [adjusting for age, body mass index (BMI), comorbidity index, cystatin C, C-reactive protein (hs-CRP), serum vitamin D 25-OH (25OHD), phosphate, calcium, parathyroid hormone (PTH), erythropoietin, hemoglobin, lumbar spine BMD, apolipoprotein B/A1 ratio] were performed in three separate models with Fe, TS or ferritin as potential explanatory variables. Fe and TS, but not ferritin, were independent predictors of iFGF23 level (standardized β-values: -0.10, p<0.001; -0.10, p<0.001; and -0.05, p=0.062, respectively). CONCLUSION:Low levels of Fe in elderly men are associated with high levels of iFGF23, independently of markers of inflammation and renal function, suggesting an iron-related pathway for FGF23 regulation. 10.1016/j.bone.2017.02.005
    Serum cystatin C level is associated with carotid arterial wall elasticity in subjects with type 2 diabetes mellitus: A potential marker of early-stage atherosclerosis. Kaneko Rei,Sawada Shojiro,Tokita Ai,Honkura Rieko,Tamura Noriko,Kodama Shinjiro,Izumi Tomohito,Takahashi Kei,Uno Kenji,Imai Junta,Yamada Tetsuya,Miyachi Yukiya,Hasegawa Hideyuki,Kanai Hiroshi,Ishigaki Yasushi,Katagiri Hideki Diabetes research and clinical practice AIMS:Detection of early-stage atherosclerosis in type 2 diabetes mellitus (T2DM) patients is important for preventing cardiovascular disease. A phased tracking method for evaluating arterial wall elasticity sensitively detects early-stage atherosclerosis. However, biochemical markers for early-stage atherosclerosis have yet to be established. METHODS:This cross-sectional study enrolled 180 T2DM patients, who were classified as not having atherosclerosis according to the carotid intima-media thickness (IMT) criteria. We measured serum cystatin C, the estimated glomerular filtration rate (eGFR) and urinary albumin-to-creatinine ratio (ACR), and analyzed the associations between these markers and arterial wall elasticity (Eθ), IMT and the cardio-ankle velocity index. RESULTS:Multiple linear regression analyses revealed that cystatin C was significantly associated with Eθ, while neither eGFR nor ACR showed an association. Furthermore, among the examined atherosclerotic markers, Eθ was most reliably associated with cystatin C. Additionally, the association between cystatin C and Eθ disappeared in the low elasticity subgroup, which included subjects in whom no atherosclerotic changes had yet been initiated. CONCLUSIONS:In T2DM patients without apparent arterial wall thickening, cystatin C is strongly and independently associated with arterial wall elasticity, which reflects the degree of subclinical atherosclerosis. Thus, cystatin C is a potentially useful marker of early-stage atherosclerosis. 10.1016/j.diabres.2018.02.003
    The Relationship between Erythrocytes and Diabetes Mellitus. Wang Yaqi,Yang Peiyuan,Yan Zhaoli,Liu Zhi,Ma Qiang,Zhang Zehong,Wang Yunxia,Su Yan Journal of diabetes research High blood glucose level (hyperglycemia) is a leading indicator of diabetes mellitus (DM). Erythrocytes are the most abundant cells in the circulation and the first to perceive changes in plasma composition. Long-lasting hyperglycemia affects the structure and function of erythrocytes. The detection of erythrocyte-related indicators can provide a valuable reference for the prevention, diagnosis, and treatment of DM and its complications. This paper reviews the normal structure and function of erythrocytes, the changes in erythrocytes in patients with diabetes, and the role of erythrocytes in the development of diabetic complications to provide more indicators for the early prevention of DM complications and to monitor the therapeutic effect of DM. 10.1155/2021/6656062
    Application Value of Predictive Model Based on Maternal Coagulation Function and Glycolipid Metabolism Indicators in Early Diagnosis of Gestational Diabetes Mellitus. Frontiers in public health Objective:To investigate whether first-trimester fasting plasma glucose (FPG), blood coagulation function and lipid metabolism could predict gestational diabetes mellitus (GDM) risk. Methods:From October 2020 to May 2021, a total of 584 pregnant women who took prenatal care in Shanghai Jiaotong University Affiliated Sixth People's Hospital were chosen as the observation subjects. The clinical information and serum samples of all pregnant women were collected at 10-13 weeks of gestation and the blood coagulation function, fasting blood glucose and lipid profiles of the pregnant women were detected. A 75 g oral glucose tolerance test was performed up to 24-28 weeks of gestation. One hundred forty-two pregnant women with GDM and 442 pregnant women without GDM were detected. Data were expressed by x ± s or median (interquartile range) and were analyzed using student's -test, Wilcoxon rank sum test and Logistic regression analysis. The area under the curve (AUC) was calculated by receiver operating characteristic curve (ROC) to analyze the predictive values. Results:Compared with non-GDM group, age, pre-pregnancy BMI, FPG, FIB, D-Dimer, FDP, FPG, TC, TG, LDL-C, sdLDL-C, APOB and APOE in GDM group were significantly higher than those in non-GDM group, while PT, INR, APTT and TT were significantly lower than those in non-GDM group. Univariate logistic regression analysis was used to explore the risk factors of GDM. Gestational age, pre-pregnancy BMI, FPG, PT, INR, APTT, FIB, TT, D-Dimer, TC, TG, LDL-C, sdLDL-C, APOB and APOE were all independent predictors of GDM. Multivariatelogistic regression showed that pre-pregnancy BMI, FPG, APTT, TT, TG, LDL-C, sdLDL-C and APOB were risk factors for GDM. The AUC of the established GDM risk prediction model was 0.892 (0.858-0.927), and the sensitivity and specificity were 80.71 and 86.85%, respectively; which were greater than that of pre-pregnancy BMI, FPG, APTT, TT,TG, LDL-C, sdLDL-C, APOB alone, and the difffference was statistically signifificant ( < 0.05). Conclusions:FPG, APTT, TT, TG, LDL-C, sdLDL-C, APOB and pre-pregnancy BMI in early pregnancy has important clinical value for the prediction of GDM, We combined these laboratory indicators and established a GDM risk prediction model, which is conducive to the early identification, intervention and treatment of GDM, so as to reduce the morbidity of maternal and infant complications. 10.3389/fpubh.2022.850191
    A genome-wide association study identifies three loci associated with mean platelet volume. Meisinger Christa,Prokisch Holger,Gieger Christian,Soranzo Nicole,Mehta Divya,Rosskopf Dieter,Lichtner Peter,Klopp Norman,Stephens Jonathan,Watkins Nicholas A,Deloukas Panos,Greinacher Andreas,Koenig Wolfgang,Nauck Matthias,Rimmbach Christian,Völzke Henry,Peters Annette,Illig Thomas,Ouwehand Willem H,Meitinger Thomas,Wichmann H-Erich,Döring Angela American journal of human genetics Mean platelet volume (MPV) is increased in myocardial and cerebral infarction and is an independent and strong predictor for postevent morbidity and mortality. We conducted a genome-wide association study (GWAS), the KORA (Kooperative Gesundheitsforschung in der Region Augsburg) F3 500K study, and found MPV to be strongly associated with three common single-nucleotide polymorphisms (SNPs): rs7961894 located within intron 3 of WDR66 on chromosome 12q24.31, rs12485738 upstream of the ARHGEF3 on chromosome 3p13-p21, and rs2138852 located upstream of TAOK1 on chromosome 17q11.2. We replicated all three SNPs in another GWAS from the UK and in two population-based samples from Germany. In a combined analysis including 10,048 subjects, the SNPs had p values of 7.24 x 10(-48) for rs7961894, 3.81 x 10(-27) for rs12485738, and 7.19 x 10(-28) for rs2138852. These three quantitative trait loci together accounted for 4%-5% of the variance in MPV. In-depth sequence analysis of WDR66 in 382 samples from the extremes revealed 20 new variants and a haplotype with three coding SNPs and one SNP at the transcription start site associated with MPV (p = 6.8 x 10(-5)). In addition, expression analysis indicated a direct correlation of WDR66 transcripts and MPV. These findings may not only enhance our understanding of platelet activation and function, but may also provide a focus for several novel research avenues. 10.1016/j.ajhg.2008.11.015
    [Functional state of kidneys and cardiovascular risk in patients with urolithiasis in an outpatient setting]. Murkamilov I T,Aitbaev K A,Fomin V V,Murkamilova Zh A,Yusupov F A,Schastlivenko A I Urologiia (Moscow, Russia : 1999) AIM:To analyze the functional state of the kidneys and vascular stiffness in patients with urinary stone disease in an outpatient setting. MATERIAL AND METHODS:A total of 110 patients with urinary stone disease aged 17-72 years were included in the study. The stone size was 2,67 (1,90-3,49) mm. A clinical examination included evaluation of vascular stiffness, serum level of creatinine, cystatin C, calcium, phosphorus, sodium, magnesium, uric acid and total cholesterol. The glomerular filtration rate (eGFR) was calculated based on the formulas CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) and MDRD (Modification of Diet in Renal Disease) and Hoek's equations using creatinine and cystatin C, respectively. RESULTS:Most often, urinary stone disease was associated with arterial hypertension (75%), a sedentary lifestyle (66.3%), hypercholesterolemia (53.6%), obesity (47.2%), hyperuricemia (44.5%) and smoking (40.9%). The median and interquartile range of eGFR according to CKD-EPI, MDRD and Hoek's equations was 100.00 (78.00;113.00) ml/min, 96.00 (71.00;106.00) ml/min and 77.65 (61.50; 93.60) ml/min, respectively. The normal GFR was significantly more often detected by the formula CKD-EPI (66.3%) in comparison with the Hoek's equations (52.7%), p<0.05. A decrease in mild GFR was found in 21 (19.0%) patients according to CKD-EPI and 33 (30.0%) according to Hoek's equations (p<0.05). In the subgroup of patients with a mild to moderate decrease in GFR according to the Hoek's equations, stiffness index and resistive index were significantly higher than in the similar subgroup of patients with decrease of GFR measured using the CKD-EPI formula (p<0.05). A negative correlation between GFR calculated using three formulas and Augmentation Index was established. CONCLUSIONS:In patients with urinary stone disease, potential cardiovascular risk factors are very common. The study of serum cystatin C level with calculation of GFR according to Hoek's equations in individuals with urolithiasis allows to evaluate total renal nitrogen excretion, as well as the level of the cardiovascular risk in the early stages of the disease.
    Role of impaired iron transport on exercise performance in heart failure patients. European journal of preventive cardiology AIMS:Impaired iron transport (IIT) occurs frequently in heart failure (HF) patients, even in the absence of anaemia and it is associated with a poor quality of life and prognosis. The impact of IIT on exercise capacity, as assessed by the cardiopulmonary exercise test (CPET), in HF is at present unknown. The aim of this article is to evaluate in HF patients the impact on exercise performance of IIT, defined as transferrin saturation (TSAT) <20%. METHODS AND RESULTS:We collected data of 676 patients hospitalized for HF. All underwent laboratory analysis, cardiac ultrasound, and CPET. Patients were grouped by the presence/absence of IIT and anaemia (haemoglobin <13 and <12 g/dL in male and female, respectively): Group 1 (G1) no anaemia, no IIT; Group 2 (G2) anaemia, no IIT; Group 3 (G3) no anaemia, IIT; Group 4 (G4) anaemia and IIT. Peak oxygen uptake (peakVO2) reduced from G1 to G3 and from G2 to G4 (G1: 1266 ± 497 mL/min, G2: 1011 ± 385 mL/min, G3: 1041 ± 395 mL/min, G4: 833 ± 241 mL/min), whereas the ventilation to carbon dioxide relationship slope (VE/VCO2 slope) increased (G1: 31.8 ± 7.5, G2: 34.5 ± 7.4, G3: 36.1 ± 10.2, G4: 37.5 ± 8.4). At multivariate regression analysis, peakVO2 independent predictors were anaemia, brain natriuretic peptide (BNP), and left ventricular ejection fraction, whereas VE/VCO2 slope independent predictors were IIT and BNP. CONCLUSION:In HF IIT is associated with exercise performance impairment independently from anaemia, and it is a predictor of elevated VE/VCO2 slope, a pivotal index of HF prognosis. 10.1093/eurjpc/zwab216
    Criteria for Iron Deficiency in Patients With Heart Failure. Masini Gabriele,Graham Fraser J,Pellicori Pierpaolo,Cleland John G F,Cuthbert Joseph J,Kazmi Syed,Inciardi Riccardo M,Clark Andrew L Journal of the American College of Cardiology BACKGROUND:Guidelines on heart failure (HF) define iron deficiency (ID) as a serum ferritin <100 ng/mL or, when 100-299 ng/mL, a transferrin saturation (TSAT) <20%. Inflammation (common in HF) may hinder interpretation of serum ferritin. OBJECTIVES:This study sought to investigate how different definitions of ID affect its prevalence and relationship to prognosis in ambulatory patients with chronic HF. METHODS:Prevalence, relationship with patients' characteristics, and outcomes of various ID definitions were evaluated among patients with HF referred to a regional clinic (Hull LifeLab) from 2001 to 2019. RESULTS:Of 4,422 patients with HF (median age 75 years [range: 68-82 years], 60% men, 32% with reduced left ventricular ejection fraction), 46% had TSAT <20%, 48% had serum iron ≤13 μmol/L, 57% had serum ferritin <100 ng/mL, and 68% fulfilled current guideline criteria for ID, of whom 35% had a TSAT >20%. Irrespective of definition, ID was more common in women and those with more severe symptoms, anemia, or preserved ejection fraction. TSAT <20% and serum iron ≤13 μmol/L, but not guideline criteria, were associated with higher 5-year mortality (HR: 1.27; 95% CI: 1.14-1.43; P < 0.001; and HR: 1.37; 95% CI: 1.22-1.54; P < 0.001, respectively). Serum ferritin <100 ng/mL tended to be associated with lower mortality (HR: 0.91; 95% CI: 0.81-1.01; P = 0.09). CONCLUSIONS:Different definitions of ID provide discordant results for prevalence and prognosis. Definitions lacking specificity may attenuate the benefits of intravenous iron observed in trials while definitions lacking sensitivity may exclude patients who should receive intravenous iron. Prespecified subgroup analyses of ongoing randomized trials should address this issue. 10.1016/j.jacc.2021.11.039
    Differences in Clinical Profile and Outcomes of Low Iron Storage vs Defective Iron Utilization in Patients With Heart Failure: Results From the DEFINE-HF and BIOSTAT-CHF Studies. Grote Beverborg Niels,van der Wal Haye H,Klip IJsbrand T,Anker Stefan D,Cleland John,Dickstein Kenneth,van Veldhuisen Dirk J,Voors Adriaan A,van der Meer Peter JAMA cardiology Importance:Iron deficiency is present in half of patients with heart failure (HF) and is associated with increased morbidity and an impaired prognosis. Iron deficiency due to low iron storage (LIS) and defective iron utilization (DIU) are not entirely the same clinical problem, although they generally receive the same treatment. Objective:To define and describe similarities and differences between LIS and DIU in patients with HF. Design, Setting, and Participants:This analysis included data from 2 prospective observational studies: the Definition of Iron Deficiency in Chronic Heart Failure (DEFINE-HF) study, a single-center study conducted from 2013 to 2015 including 42 patients with a reduced left ventricular ejection fraction of 45% or less scheduled for coronary artery bypass graft surgery, and the A Systems Biology Study to Tailored Treatment in Chronic Heart Failure (BIOSTAT-CHF) study, a multinational study conducted from 2010 to 2014 including 2357 patients with worsening HF from 69 centers in 11 countries. The median (interquartile range) follow-up time was 1.8 (1.3-2.3) years. Data were analyzed from January 2018 to January 2019. Main Outcomes and Measures:The DEFINE-HF cohort was set up to derive a definition for different etiologies of iron deficiency using bone marrow iron staining as the criterion standard. This definition was applied to the BIOSTAT-CHF cohort to assess its association with clinical profile, biomarkers, and the primary composite end point of all-cause mortality or HF hospitalizations. Results:Among the 42 patients in the DEFINE-HF study, 10 (24%) were women, and the mean (SD) age was 68.0 (9.5) years. Low iron storage was defined as a bone marrow-validated combination of transferrin saturation less than 20% and a serum ferritin concentration of 128 ng/mL or less; DIU was defined as transferrin saturation less than 20% and a serum ferritin concentration greater than 128 ng/mL. These criteria were applied to 2356 patients with worsening HF in the BIOSTAT-CHF study; 1074 (45.6%) were women, and the mean (SD) age was 68.9 (12.0) years. A total of 1453 patients with worsening HF (61.6%) had iron deficiency, of whom 960 (66.1%) had LIS and 493 (33.9%) had DIU. Low iron storage was characterized by a higher proportion of anemia and a poorer quality of life, while DIU was characterized by higher levels of various inflammatory markers. Both LIS and DIU were associated with an impaired 6-minute walking test. Low iron storage was independently associated with the composite end point of all-cause mortality or HF hospitalizations (hazard ratio, 1.47; 95% CI, 1.26-1.71; P < .001), while DIU was not (hazard ratio, 1.05; 95% CI, 0.87-1.26; P = .64). Conclusions and Relevance:In this study, both LIS and DIU were prevalent in patients with HF and had a distinct clinical profile. Only LIS was independently associated with increased rates of morality and HF hospitalizations, while DIU was not. 10.1001/jamacardio.2019.1739
    Iron deficiency is related to low functional outcome in patients at early rehabilitation after acute stroke. Journal of cachexia, sarcopenia and muscle BACKGROUND:Iron deficiency (ID) is a common co-morbidity in patients with cardiovascular disease and contributes to impaired functional capacity. The relevance of ID in patients in recovery after acute stroke is not known. We assessed the prevalence of ID and anaemia in relation to functional capacity and to recovery during early rehabilitation after stroke. METHODS:This observational study enrolled consecutively 746 patients with ischaemic or haemorrhagic stroke at in-patient early rehabilitation (age 68 ± 13 years, female 47%, ischaemic stroke 87%). Functional capacity was assessed before and after rehabilitation using Barthel index (reha-BI), motricity index (MI), trunk control test (TCT), and functional ambulatory category (FAC). ID was defined as ferritin <100 μg/L or as transferrin saturation (TSAT) < 20% if ferritin was 100- < 300 μg/L or if CrP > 5 mg/L. Anaemia was defined as Hb < 12 g/dL (women) and <13 g/dL (men). RESULTS:The prevalence of ID and anaemia before rehabilitation were 45% and 46%, respectively, and remained high at discharge (after 27 ± 17 days) at 40% and 48%, respectively. Patients with ID had lower functional capacity compared with patients without ID (reha-BI 20 [±86] vs. 40 [±80], MI 64 [±66] vs. 77 [±41], TCT 61 [±76] vs. 100 [±39], FAC 1 [±4] vs. 4 [±4]; median [IQR], all P < 0.001). ID was related to inflammation (OR 2.68 [95% CI 1.98-3.63], P < 0.001), female sex (OR 2.13 [95% CI 1.59-2.85], P < 0.001), haemorrhagic stroke (OR 1.70 [95% CI 1.11-2.61], P = 0.015), initial treatment on stroke unit (OR 3.59 [95% CI 1.08-11.89], P < 0.001), and anaemia (OR 2.94 [95% CI 2.18-3.96], P < 0.001), while age, BMI, and renal function were not related to ID. In adjusted analysis, ID was associated with low functional capacity in all functional scores: reha-BI (OR 1.66 [95% CI 1.08-2.54], P = 0.02), motricity index (OR 1.94 [95% CI 1.36-2.76], P < 0.001), trunk control test (OR 2.34 [95% CI] 1.64-3.32, P < 0.001) and functional ambulatory category (OR 1.77 [95% CI 1.2-2.63], P < 0.02). Functional capacity improved during rehabilitation regardless of presence of ID, but functional outcome remained significantly lower in patients with ID at the end of rehabilitation (rehab BI and MI, both P < 0.001). CONCLUSIONS:Iron deficiency and anaemia are common and persistent findings in patients after acute stroke. ID and anaemia are independently related to lower functional capacity after acute stroke and to poor functional outcome after rehabilitation. Regular assessment of iron status may identify patients at risk of low functional recovery. 10.1002/jcsm.12927
    Serum ferritin is a risk factor for stroke in postmenopausal women. van der A Daphne L,Grobbee Diederick E,Roest Mark,Marx Joannes J M,Voorbij Hieronymus A,van der Schouw Yvonne T Stroke BACKGROUND AND PURPOSE:Iron is an essential element for the human body. It has, however, been suggested that excessive iron stores may increase the risk of vascular disease. So far, epidemiologic studies on stroke are sparse. METHODS:We studied the association between iron status and stroke risk in a population-based cohort of 11 471 Dutch postmenopausal women between 49 and 70 years of age. Women were included between 1993 and 1997 and followed up until January 1, 2000, for cerebrovascular events. We conducted a case-cohort study by using all stroke cases (n=63) and a random sample of the baseline cohort (n=1134). Serum ferritin, serum iron, and transferrin saturation were measured as markers of iron status. A weighted Cox proportional-hazards model was used to estimate crude and multivariate-adjusted hazard ratios for tertiles of different iron parameters in relation to stroke. RESULTS:In a multivariate model, the highest tertile of serum ferritin concentration was associated with an increased risk of stroke (hazard ratio [HR], 1.45; 95% confidence interval [CI], 0.87 to 2.42) compared with the lowest tertile. For ischemic stroke, the increase was more pronounced (HR, 2.23; 95% CI, 1.05 to 4.73) and reached statistical significance. CONCLUSIONS:Neither serum iron nor transferrin saturation was associated with an increased stroke risk. However, higher serum ferritin concentrations in postmenopausal women are associated with an increased risk of ischemic stroke. 10.1161/01.STR.0000173172.82880.72
    Correlation between microalbuminuria and atherosclerotic intracranial and extracranial arterial stenosis in patients with cerebral infarction. Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia BACKGROUND AND AIMS:Microalbuminuria (MAU) reflects the generalized vascular endothelial dysfunction. Whether MAU has correlation with atherosclerotic intracranial and extracranial arterial stenosis in cerebral infarction patients is not known and is explored in the present investigation. METHODS:We enrolled 255 cerebral infarction patients hospitalized at the department of neurology. All patients underwent digital subtraction angiography (DSA) to evaluate the severity and distribution of intracranial and extracranial arterial stenosis. MAU was expressed as the urine albumin-to-creatinine ratio (UACR). We collected basic information, medical history reviews and laboratory results of each participant. The multivariate logistic regression analysis was utilized to analyze the risk factors for severity and distribution of cerebral arterial stenosis. RESULTS:The prevalence of MAU in patients with cerebral infarction was 39.2%, patients with MAU had older age, lower blood uric acid, higher systolic blood pressure (SBP), higher prevalence of hypertension and diabetes (p < 0.05) and higher incidence of atherosclerotic intracranial and extracranial arterial stenosis (χ2 = 5.900, p = 0.015). In multiple logistic regression analysis for intracranial and extracranial arterial stenosis more than 50% or occlusion groups, UACR (OR 1.088 95%CI 1.012-1.170p = 0.022), male (OR 2.196 95%CI 1.085-4.442p = 0.029) as well as SBP (OR 5.870 95%CI 1.026-1.048p = 0.015) showed statistical significance. But UACR had no correlation with the distribution of intracranial and extracranial artery stenosis after adjusting for all potential confounders. CONCLUSIONS:Microalbuminuria was an independent risk factor for intracranial and extracranial arterial stenosis more than 50% or occlusion. 10.1016/j.jocn.2022.05.011
    Early prediction of response to recombinant human erythropoietin in patients with the anemia of renal failure by serum transferrin receptor and fibrinogen. Beguin Y,Loo M,R'Zik S,Sautois B,Lejeune F,Rorive G,Fillet G Blood Recombinant human erythropoietin (rHuEpo) has been shown to be effective in correcting the anemia of chronic renal failure, but the dose needed may be variable. The reason for this variation is not known, but several factors could be involved, such as iron deficiency, inflammation, aluminum intoxication, hyperparathyroidism, blood losses, or marrow dysfunction. Treatment with rHuEpo was given intravenously thrice weekly after hemodialysis to 64 consecutive unselected patients with the anemia of chronic renal failure. The starting dose was 50 U/kg/dose, which was increased to 75 and 100 U/kg/dose if no response was observed after 1 and 2 months of treatment. After a minimum follow-up of 6 months, response was evaluated as early (hematocrit [Hct] > or = 30% before 3 months) or late (Hct > or = 30% after 3 months) response, or failure (target Hct not attained). We examined the value of various laboratory parameters (baseline values and early changes) as predictors of response to rHuEpo. The best prediction by pretreatment parameters only was obtained with baseline serum transferrin receptor (TfR) (< or > or = 3,500 ng/mL) and fibrinogen (< or > or = 4 g/L): 100% response rate when both parameters were low, versus only 29% when they were both high, and versus 67% when one was low and the other high. When the 2-week TfR increment was greater than 20%, the response rate was 96%. When TfR increment was less than 20%, the response rate was 100% when baseline TfR and fibrinogen were low, 12% when fibrinogen was elevated, and 62% when fibrinogen was low but baseline TfR high. The predictive value of baseline TfR and fibrinogen and of the 2-week increment of TfR was confirmed by life table analysis and stepwise discriminant analysis. Major reasons for failure or late response were identified and included subclinical inflammation, iron deficiency, functional iron deficiency, marrow disorders, hemolysis, bleeding, and low Epo dose. We conclude that response to rHuEpo can be predicted early by pretreatment fibrinogen and TfR, together with early changes of TfR levels. These prognostic factors illustrate the importance of the early erythropoietic response, subclinical inflammation, and functional iron deficiency. Early recognition of a low probability of response in a given patient could help identify and correct specific causes of treatment failure to hasten clinical improvement and avoid prolonged ineffective use of an expensive medication.
    Serum bilirubin levels are inversely associated with PAI-1 and fibrinogen in Korean subjects. Cho Hyun Sun,Lee Sung Won,Kim Eun Sook,Shin Juyoung,Moon Sung Dae,Han Je Ho,Cha Bong Yun Atherosclerosis OBJECTIVES:Oxidative stress may contribute to atherosclerosis and increased activation of the coagulation pathway. Bilirubin may reduce activation of the hemostatic system to inhibit oxidative stress, which would explain its cardioprotective properties shown in many epidemiological studies. This study investigated the association of serum bilirubin with fibrinogen and plasminogen activator inhibitor-1 (PAI-1), respectively. METHODS:A cross-sectional analysis was performed on 968 subjects (mean age, 56.0 ± 11.2 years; 61.1% men) undergoing a general health checkup. Serum biochemistry was analyzed including bilirubin subtypes, insulin resistance (using homeostasis model of assessment [HOMA]), C-reactive protein (CRP), fibrinogen, and PAI-1. RESULTS:Compared with subjects with a total bilirubin (TB) concentration of <10.0 μmol/L, those with a TB concentration of >17.1 μmol/L had a smaller waist circumference, a lower triglyceride level, a lower prevalence of metabolic syndrome, and decreased HOMA-IR and CRP levels. Correlation analysis revealed linear relationships of fibrinogen with TB and direct bilirubin (DB), whereas PAI-1 was correlated with DB. After adjustment for confounding factors, bilirubin levels were inversely associated with fibrinogen and PAI-1 levels, respectively. Multivariate regression models showed a negative linear relationship between all types of bilirubin and fibrinogen, whereas there was a significant linear relationship between PAI-1 and DB. CONCLUSIONS:High bilirubin concentrations were independently associated with low levels of fibrinogen and PAI-1, respectively. The association between TB and PAI-1 was confined to the highest TB concentration category whereas DB showed a linear association with PAI-1. Bilirubin may protect against the development of atherothrombosis by reducing the hemostatic response. 10.1016/j.atherosclerosis.2015.11.008
    Serum Transferrin Predicts New-Onset Type 2 Diabetes in Koreans: A 4-Year Retrospective Longitudinal Study. Kim Jong Dai,Lim Dong-Mee,Park Keun-Young,Park Se Eun,Rhee Eun Jung,Park Cheol-Young,Lee Won-Young,Oh Ki Won Endocrinology and metabolism (Seoul, Korea) BACKGROUND:It is well known that high serum ferritin, a marker of iron storage, predicts incident type 2 diabetes. Limited information is available on the association between transferrin, another marker of iron metabolism, and type 2 diabetes. Thus, we investigated the association between transferrin and incident type 2 diabetes. METHODS:Total 31,717 participants (mean age, 40.4±7.2 years) in a health screening program in 2005 were assessed via cross-sectional analysis. We included 30,699 subjects who underwent medical check-up in 2005 and 2009 and did not have type 2 diabetes at baseline in this retrospective longitudinal analysis. RESULTS:The serum transferrin level was higher in the type 2 diabetes group than in the non-type 2 diabetes group (58.32±7.74 μmol/L vs. 56.17±7.96 μmol/L, P&lt;0.001). Transferrin correlated with fasting serum glucose and glycosylated hemoglobin in the correlational analysis (r=0.062, P&lt;0.001 and r=0.077, P&lt;0.001, respectively) after full adjustment for covariates. Transferrin was more closely related to homeostasis model assessment of insulin resistance than to homeostasis model assessment of β cell function (r=0.042, P&lt;0.001 and r=-0.019, P=0.004, respectively) after full adjustment. Transferrin predicted incident type 2 diabetes in non-type 2 diabetic subjects in a multivariate linear regression analysis; the odds ratio (95% confidence interval [CI]) of the 3rd tertile compared to that in the 1st tertile of transferrin for incident diabetes was 1.319 (95% CI, 1.082 to 1.607) after full adjustment (P=0.006). CONCLUSION:Transferrin is positively associated with incident type 2 diabetes in Koreans. 10.3803/EnM.2020.721
    Vitamin D, parathyroid hormone, and cardiovascular events among older adults. Kestenbaum Bryan,Katz Ronit,de Boer Ian,Hoofnagle Andy,Sarnak Mark J,Shlipak Michael G,Jenny Nancy S,Siscovick David S Journal of the American College of Cardiology OBJECTIVES:The aim of this study was to evaluate associations of 25-hydroxyvitamin D (25-OHD) and parathyroid hormone (PTH) concentrations separately and in combination with incident cardiovascular events and mortality during 14 years of follow-up in the CHS (Cardiovascular Health Study). BACKGROUND:Vitamin D deficiency and PTH excess are common in older adults and may adversely affect cardiovascular health. METHODS:A total of 2,312 participants who were free of cardiovascular disease at baseline were studied. Vitamin D and intact PTH were measured from previously frozen serum using mass spectrometry and a 2-site immunoassay. Outcomes were adjudicated cases of myocardial infarction, heart failure, cardiovascular death, and all-cause mortality. RESULTS:There were 384 participants (17%) with serum 25-OHD concentrations <15 ng/ml and 570 (25%) with serum PTH concentrations ≥ 65 pg/ml. After adjustment, each 10 ng/ml lower 25-OHD concentration was associated with a 9% greater (95% confidence interval [CI]: 2% to 17% greater) relative hazard of mortality and a 25% greater (95% CI: 8% to 44% greater) relative hazard of myocardial infarction. Serum 25-OHD concentrations <15 ng/ml were associated with a 29% greater (95% CI: 5% to 55% greater) risk for mortality. Serum PTH concentrations ≥ 65 pg/ml were associated with a 30% greater risk for heart failure (95% CI: 6% to 61% greater) but not other outcomes. There was no evidence of an interaction between serum 25-OHD and PTH concentrations and cardiovascular events. CONCLUSIONS:Among older adults, 25-OHD deficiency is associated with myocardial infarction and mortality; PTH excess is associated with heart failure. Vitamin D and PTH might influence cardiovascular risk through divergent pathways. 10.1016/j.jacc.2011.03.069
    Elevated parathyroid hormone, but not vitamin D deficiency, is associated with increased risk of heart failure in older men with and without cardiovascular disease. Wannamethee S Goya,Welsh Paul,Papacosta Olia,Lennon Lucy,Whincup Peter H,Sattar Naveed Circulation. Heart failure BACKGROUND:Hyperparathyroidism and low vitamin D status have been implicated in the pathogenesis of heart failure (HF). We examined the prospective associations between parathyroid hormone (PTH), circulating 25-hydroxyvitamin D, and markers of mineral metabolism and risk of incident HF in older men with and without established cardiovascular disease. METHODS AND RESULTS:Prospective study of 3731 men aged 60 to 79 years with no prevalent HF followed up for a mean period of 13 years, in whom there were 287 incident HF cases. Elevated PTH (≥55.6 pg/mL; top quarter) was associated with significantly higher risk of incident HF after adjustment for lifestyle characteristics, diabetes mellitus, blood lipids, blood pressure, lung function, heart rate, renal dysfunction, atrial fibrillation, forced expiratory volume in 1 second, and C-reactive protein (hazards ratio, 1.66; 95% confidence interval, 1.30-2.13). The increased risk was seen in both men with and without previous myocardial infarction or stroke (hazards ratio, 1.72; 95% confidence interval, 1.07-2.76; hazards ratio, 1.70; 95% confidence interval, 1.25-2.30, respectively). Elevated PTH was significantly associated with N-terminal probrain natriuretic peptide, a marker of left ventricular wall stress. By contrast, 25-hydroxyvitamin D and other markers of mineral metabolism including serum calcium and phosphate showed no significant association with incident HF after adjustment for age. CONCLUSIONS:Elevated PTH, but not 25-hydroxyvitamin D or other markers of mineral metabolism, is associated with increased risk of HF in both older men with and without myocardial infarction/stroke. This increased risk was not explained by its association with known risk factors for HF. Further studies are now needed to elucidate the mechanisms underlying this association. 10.1161/CIRCHEARTFAILURE.114.001272
    Thyroid-stimulating hormone levels within the reference range are associated with serum lipid profiles independent of thyroid hormones. Wang Furong,Tan Yinyin,Wang Chenggang,Zhang Xu,Zhao Yuanfei,Song Xinhong,Zhang Bingchang,Guan Qingbo,Xu Jin,Zhang Ji,Zhang Dongzhi,Lin Haiyan,Yu Chunxiao,Zhao Jiajun The Journal of clinical endocrinology and metabolism CONTEXT AND OBJECTIVE:Dyslipidemia in thyroid dysfunction has always been attributed to changes in thyroid hormone (TH) levels. We hypothesized that TSH plays an important role in lipid metabolism independent of TH. DESIGN AND SETTING:We conducted a cross-sectional study to investigate the relationship between serum TSH levels and lipid profiles after controlling for free T(3), free T(4), total T(3), total T(4) and nonthyroid factors relevant to lipid metabolism in euthyroid Chinese subjects. MAIN OUTCOME MEASURES:General linear analysis was performed to determine whether the impact of TSH on serum lipid levels is independent of the TH levels. Moreover, path analysis, an evolutionary multivariable regression technique, was conducted to test whether there is a direct and/or indirect effect between serum TSH and total cholesterol (TC) levels. Additionally, the odds ratios (95% confidence interval) for hypercholesterolemia in relation to TSH categories were calculated. RESULTS:A total of 3664 euthyroid subjects were finally analyzed. There was a significant linear trend toward higher log TC (P = 0.021) and log triglyceride (P = 0.001) levels with increasing serum TSH levels within the reference range, which remained significant after adjusting for factors such as TH levels, age, and smoking. Most importantly, the total effect of TSH on TC levels (total effect(TC, TSH) = 0.05253) includes a direct effect (direct effect(TC, TSH) = 0.05979) and an indirect effect via TH. Compared with subjects in the lower part of the reference range (TSH level, 0.27-0.61 mIU/liter), the adjusted odds ratio for hypercholesterolemia was 3.239 (95% confidence interval, 1.392-7.538; P = 0.007) for those in the upper category (TSH level, 4.61-5.5 mIU/liter). CONCLUSIONS:The variation in normal TSH levels is partially related to the lipid components and hypercholesterolemia in euthyroid subjects and includes both TH-dependent and TH-independent effects. Our study suggests the importance of controlling TSH in hypothyroid subjects. 10.1210/jc.2012-1133
    A Prospective Study of Early-pregnancy Thyroid Markers, Lipid Species, and Risk of Gestational Diabetes Mellitus. Wang Yi,Sun Fengjiang,Wu Ping,Huang Yichao,Ye Yi,Yang Xue,Yuan Jiaying,Liu Yan,Zeng Huayan,Wen Ying,Qi Xiaorong,Yang Chun-Xia,Wang Yixin,Liu Gang,Chen Da,Li Liangzhong,Pan Xiong-Fei,Pan An The Journal of clinical endocrinology and metabolism CONTEXT:While the associations between thyroid markers and gestational diabetes mellitus (GDM) have been extensively studied, the results are inconclusive and the mechanisms remain unclear. OBJECTIVE:We aimed to investigate the prospective associations of thyroid markers in early gestation with GDM risk, and examine the mediating effects through lipid species. METHODS:This study included 6068 pregnant women from the Tongji-Shuangliu Birth Cohort. Maternal serum thyroid markers (free triiodothyronine (fT3), free thyroxine (fT4), thyroid-stimulating hormone, thyroid peroxidase antibody, and thyroglobulin antibody) were measured before 15 weeks. Deiodinase activity was assessed by fT3/fT4 ratio. Plasma lipidome were quantified in a subset of 883 participants. RESULTS:Mean age of the participants was 26.6 ± 3.7 years, and mean gestational age was 10.3 ± 2.0 weeks. Higher levels of fT4 were associated with a decreased risk of GDM (OR = 0.73 comparing the extreme quartiles; 95% CI 0.54, 0.98, Ptrend = .043), while higher fT3/fT4 ratio was associated with an increased risk of GDM (OR = 1.43 comparing the extreme quartiles; 95% CI 1.06, 1.93, Ptrend = .010) after adjusting for potential confounders. Multiple linear regression suggested that fT3/fT4 ratio was positively associated with alkylphosphatidylcholine 36:1, phosphatidylethanolamine plasmalogen 38:6, diacylglyceride 18:0/18:1, sphingomyelin 34:1, and phosphatidylcholine 40:7 (false discovery rate [FDR] adjusted P < .05). Mediation analysis indicated 67.9% of the association between fT3/fT4 ratio and GDM might be mediated through the composite effect of these lipids. CONCLUSION:Lower concentration of serum fT4 or higher fT3/fT4 ratio in early pregnancy was associated with an increased risk of GDM. The association of fT3/fT4 ratio with GDM was largely mediated by specific lipid species. 10.1210/clinem/dgab637
    Sensitivity to Thyroid Hormone Indices Are Closely Associated With NAFLD. Lai Shuiqing,Li Jiarong,Wang Zixiao,Wang Wei,Guan Haixia Frontiers in endocrinology Background:Previous studies on the association between thyroid function and non-alcoholic fatty liver disease (NAFLD) have contradicted. Acquired resistance to thyroid hormone theory might provide a reasonable explanation for these contradictions. We aimed to analyze the association between sensitivity to thyroid hormone indices with NAFLD. Methods:A total of 4,610 individuals from the health medical center of the First Hospital of China Medical University were included in this study. The previously used thyroid feedback quantile-based index (TFQI) was calculated. Also, we substituted free triiodothyronine (FT) into the TFQI formulas to get the TFQI index. NAFLD was defined using abdominal ultrasound. Results:Study results showed that FT/FT and TFQI were positively correlated with the triglyceride (TG), total cholesterol (TC), and low-density lipoprotein cholesterol (LDL-C) levels (<0.05) and negatively correlated with high-density lipoprotein cholesterol (HDL-C) level (<0.05). In contrast, TFQI was positively correlated with HDL-C level ( < 0.05). After adjustment for multiple confounders, FT, FT/FT, and TFQI were positively associated with the risks of dyslipidemia and NAFLD ( < 0.05). TFQI and FT/FT performed better than TFQI on ROC analyses for NAFLD prediction, although the diagnostic sensitivity and specificity at the optimal cut-points were low. However, no association was observed between TFQI with the risks of dyslipidemia and NAFLD. Conclusion:TFQI and FT/FT can be used as new indicators for predicting dyslipidemia and NAFLD, although with low sensitivity and specificity at the optimal cut-points, while TFQI has insufficient evidence in predicting dyslipidemia and NAFLD. 10.3389/fendo.2021.766419
    Association between Uric Acid and Bone Mineral Density in Postmenopausal Women with Type 2 Diabetes Mellitus in China: A Cross-Sectional Inpatient Study. Journal of diabetes research OBJECTIVE:To analyze the association between uric acid levels and bone mineral density in postmenopausal women with type 2 diabetes mellitus. METHODS:We retrospectively analyzed 262 postmenopausal women with type 2 diabetes mellitus, to assess uric acid levels and bone mineral density using the score of dual-energy X-ray absorptiometry. RESULTS:(1) Women in the osteoporosis group demonstrated higher uric acid levels and lower estimated glomerular filtration rate ( < 0.05, respectively). (2) Uric acid levels were positively correlated with the hip and lumbar spine bone mineral density and score ( = 0.17, < 0.05; = 0.25, < 0.05; = 0.17, < 0.05; and = 0.28, < 0.05, respectively). Meanwhile, there was a positive relation between estimated glomerular filtration rate and hip bone mineral density ( = 0.22, < 0.05). (3) Logistic regression analysis showed that age, body mass index, and diabetic duration are independent risk factors for osteoporosis in postmenopausal women with type 2 diabetes mellitus. The level of estimated glomerular filtration rate and uric acid levels were not independent effect factors for osteoporosis in menopausal women. CONCLUSION:Uric acid levels are neither a protective factor nor a risk factor for osteoporosis in women with type 2 diabetes mellitus. 10.1155/2020/3982831
    Where are we now? Emerging opportunities and challenges in the management of secondary hyperparathyroidism in patients with non-dialysis chronic kidney disease. Ketteler Markus,Ambühl Patrice Journal of nephrology Rising levels of parathyroid hormone (PTH) are common in patients with chronic kidney disease (CKD) not on dialysis and are associated with an elevated risk of morbidity (including progression to dialysis) and mortality. However, there are several challenges for the clinical management of secondary hyperparathyroidism (SHPT) in this population. While no recognised target level for PTH currently exists, it is accepted that patients with non-dialysis CKD should receive early and regular monitoring of PTH from CKD stage G3a. However, studies indicate that adherence to monitoring recommendations in non-dialysis CKD may be suboptimal. SHPT is linked to vitamin D [25(OH)D] insufficiency in non-dialysis CKD, and correction of low 25(OH)D levels is a recognised management approach. A second challenge is that target 25(OH)D levels are unclear in this population, with recent evidence suggesting that the level of 25(OH)D above which suppression of PTH progressively diminishes may be considerably higher than that recommended for the general population. Few therapeutic agents are licensed for use in non-dialysis CKD patients with SHPT and optimal management remains controversial. Novel approaches include the development of calcifediol in an extended-release formulation, which has been shown to increase 25(OH)D gradually and provide a physiologically-regulated increase in 1,25(OH)D that can reliably lower PTH in CKD stage G3-G4 without clinically meaningful increases in serum calcium and phosphate levels. Additional studies would be beneficial to assess the comparative effects of available treatments, and to more clearly elucidate the overall benefits of lowering PTH in non-dialysis CKD, particularly in terms of hard clinical outcomes. 10.1007/s40620-021-01082-2
    Hyperuricemia is associated with secondary hyperparathyroidism in patients with chronic kidney disease. International urology and nephrology PURPOSE:Hyperuricemia is common among patients with chronic kidney disease (CKD). In the general population, hyperuricemia is associated with secondary hyperparathyroidism (SHPT), in a mechanism that involves vitamin D metabolism. Data for patients with CKD, however, are scarce. We aimed to evaluate the relationship between hyperuricemia and mineral and bone metabolism, particularly hyperparathyroidism. METHODS:This is a retrospective study that included 922 adult patients with stages 3, 4, or 5 CKD, not on dialysis. Clinical, demographic, and biochemical data were collected from charts and included uric acid, parathyroid hormone (PTH), 25(OH)-vitamin D, calcium, phosphate, renal function (estimated glomerular filtration rate-eGFR), and medications such as allopurinol, furosemide, and cholecalciferol. SHPT was defined as PTH > 65 pg/ml. RESULTS:Our patients were mostly Caucasian women, with a mean age of 64 ± 16 years. SHPT and hyperuricemia were observed in 70% and 62.4% of patients, respectively. Patients with SHPT presented higher levels of uric acid (7.2 ± 1.8 vs. 6.6 ± 1.7 mg/dL, p = 0.0001) and a higher frequency of hyperuricemia (66% vs. 33%, p = 0.0001). Patients with hyperuricemia were mostly female, with lower eGFR, higher phosphate, and higher PTH. The risk of hypovitaminosis D was higher among patients with SHPT (69.7% vs. 53.1%, p = 0.0001). Hyperuricemia remained independently associated with hyperparathyroidism, (p = 0.033) even after adjustments for eGFR, calcium, phosphate, hypovitaminosis D, and use of allopurinol, calcitriol, furosemide, and cholecalciferol. CONCLUSION:Hyperuricemia seems to be a contributing factor for SHPT in patients with CKD. The mechanisms behind this finding have yet to be elucidated. 10.1007/s11255-022-03116-5
    Serum Parathyroid Hormone Predicts Mortality in Coronary Angiography Patients with Type 2 Diabetes. Brandtner Eva Maria,Muendlein Axel,Leiherer Andreas,Armbruster Franz Paul,Dschietzig Thomas Bernd,Geiger Kathrin,Fraunberger Peter,Saely Christoph H,Drexel Heinz The Journal of clinical endocrinology and metabolism BACKGROUND:Elevated serum levels of parathyroid hormone (PTH), one of the main regulators of calcium homeostasis and vitamin D metabolism, have been proposed as predictors of mortality. The impact of type 2 diabetes mellitus (T2DM) on the putative association between PTH and mortality has not been investigated thus far. AIM:The aim of our study was to investigate the impact of T2DM on the power of PTH to predict mortality risk. METHODS:Serum PTH levels were determined in 904 consecutive Caucasian patients referred to coronary angiography for the evaluation of established or suspected stable coronary artery disease (CAD), including 235 patients with T2DM. Prospectively, deaths were recorded over a mean follow-up period of 6.3 years. RESULTS:PTH at baseline did not differ significantly between patients with and without T2DM (P = .307). Cox regression analysis revealed that the serum PTH level strongly predicted all-cause mortality in patients with T2DM (hazard ratio [HR] = 2.35 [1.37-4.03]; P = .002), whereas PTH did not predict all-cause mortality in patients without T2DM (HR = 1.04 [0.81-1.32]; P = .766). The interaction term PTH × T2DM was significant (P = .006), indicating a significantly stronger impact of PTH on mortality risk in patients with T2DM than in individuals without diabetes. The impact of PTH on mortality risk in patients with T2DM remained significant after adjustment for glycated hemoglobin A1c, diabetes duration, classical cardiovascular risk factors, serum levels of vitamin D, and kidney function (HR = 2.10 [1.10-4.10]; P = .030). CONCLUSION:We conclude that PTH is a significantly stronger predictor of all-cause mortality in patients with T2DM than in those without T2DM. 10.1210/clinem/dgaa512
    Attenuated PTH responsiveness to vitamin D deficiency among patients with type 2 diabetes and chronic hyperglycemia. Al-Jebawi Ahmed F,YoussefAgha Ahmed H,Al Suwaidi Hanan Sulaiman,Albadwawi Moza Saif,Al Marzooqi Asma Shabib,Banihammad Ashjan Hassan,Almarzooqi Samia Hussain,Alkaabi Mouza Khalifa Diabetes research and clinical practice BACKGROUND:The short and long-term relationship between hyperglycemia and PTH level among patients suffering from both diabetes type 2 and vitamin D deficiency were evaluated. METHODS:This was a cross sectional study performed at Dubai Diabetes Center, UAE. To demonstrate the relationship between hyperglycemia and PTH level, subjects with type 2 diabetes and vitamin D deficiency (124 adults) were divided into 4 groups based on their FPG and HbA1c levels. RESULTS:Mean vitamin D and PTH levels among subjects with HbA1c≤7% (53mmol/mol) were 14.05ng/ml and 19.51pg/ml respectively. On the other hand, mean vitamin D and PTH levels among subjects with HbA1c≥10% (86mmol/mol) were significantly lower at 11.77ng/ml and 17.75pg/ml respectively. The product of vitamin D and PTH among subjects with an HbA1c≤7% (53mmol/mol) was 250.380, compared with only 197.710 among subjects with HbA1c≥10 (86mmol/mol). Regression analysis for subjects older than 50years shows a significant negative effect of HbA1c on the PTH level. Mean calcium level among subjects with HbA1c≤7% (53mmol/mol) was 8.80mg/dl compared with 8.94mg/dl when HbA1c is ≥10% (86mmol/mol) with no statistical difference. Although high FPG was associated with a lower PTH level, such association was not statistically significant. CONCLUSIONS:Chronic hyperglycemia, as assessed by A1C level, is associated with a significantly attenuated PTH responsiveness to vitamin D deficiency without a significant change in calcium level. On the other hand, there was no significant association between FPG and PTH level. 10.1016/j.diabres.2017.04.006
    Magnesium modifies the association between serum phosphate and the risk of progression to end-stage kidney disease in patients with non-diabetic chronic kidney disease. Sakaguchi Yusuke,Iwatani Hirotsugu,Hamano Takayuki,Tomida Kodo,Kawabata Hiroaki,Kusunoki Yasuo,Shimomura Akihiro,Matsui Isao,Hayashi Terumasa,Tsubakihara Yoshiharu,Isaka Yoshitaka,Rakugi Hiromi Kidney international It is known that magnesium antagonizes phosphate-induced apoptosis of vascular smooth muscle cells and prevents vascular calcification. Here we tested whether magnesium can also counteract other pathological conditions where phosphate toxicity is involved, such as progression of chronic kidney disease (CKD). We explored how the link between the risk of CKD progression and hyperphosphatemia is modified by magnesium status. A post hoc analysis was run in 311 non-diabetic CKD patients who were divided into four groups according to the median values of serum magnesium and phosphate. During a median follow-up of 44 months, 135 patients developed end-stage kidney disease (ESKD). After adjustment for relevant clinical factors, patients in the lower magnesium-higher phosphate group were at a 2.07-fold (95% CI: 1.23-3.48) risk for incident ESKD and had a significantly faster decline in estimated glomerular filtration rate compared with those in the higher magnesium-higher phosphate group. There were no significant differences in the risk of these renal outcomes among the higher magnesium-higher phosphate group and both lower phosphate groups. Incubation of tubular epithelial cells in high phosphate and low magnesium medium in vitro increased apoptosis and the expression levels of profibrotic and proinflammatory cytokine; these changes were significantly suppressed by increasing magnesium concentration. Thus, magnesium may act protectively against phosphate-induced kidney injury. 10.1038/ki.2015.165
    Gamma-glutamyltransferase and cancer incidence: the Ohsaki cohort study. Tsuboya Toru,Kuriyama Shinichi,Nagai Masato,Hozawa Atsushi,Sugawara Yumi,Tomata Yasutake,Kakizaki Masako,Nishino Yoshikazu,Tsuji Ichiro Journal of epidemiology BACKGROUND:Although experimental studies have shown that gamma-glutamyltransferase (GGT) has a role in tumor progression, epidemiologic evidence for a relationship between GGT and cancer incidence is limited. The present study investigated the association between GGT and cancer incidence and assessed the role of alcohol consumption in this association. METHODS:We examined a cohort of 15 031 Japanese adults aged 40 to 79 years who attended a health checkup in 1995 and were free of cancer at that time. GGT was measured using the Szasz method. The participants were then followed from 1 January 1996 until 31 December 2005, and cancer incidence was recorded by using the Miyagi Regional Cancer Registry. Hazard ratios (HRs) and 95% confidence intervals (CIs) were computed for each quartile of GGT and compared. The lowest quartile (GGT <13.0 IU/ml) was used as the reference category. RESULTS:We documented 1505 cancers. Among participants in the highest quartile (GGT ≥31.0 IU/ml), the multivariate HR for any cancer was 1.28 (95% CI, 1.08-1.53; P for trend, <0.001), the HR for colorectal cancer was significantly greater than unity, and the HRs for esophageal, pancreatic, and breast cancers were greater than unity but not significantly so. This positive trend was observed only in current drinkers. CONCLUSIONS:Our findings suggest that there is a positive relationship between GGT and cancer incidence only for alcohol-related cancers in current drinkers and that the positive association of GGT with cancer incidence largely reflects alcohol consumption. 10.2188/jea.je20110071
    Association between alcohol consumption and pancreatic cancer risk differs by glycaemic status: A nationwide cohort study. Park Joo-Hyun,Han Kyungdo,Hong Jung Yong,Park Young Suk,Park Joon Oh European journal of cancer (Oxford, England : 1990) BACKGROUND:The dose-response association between alcohol consumption and the subsequent pancreatic cancer risk by individuals' glycaemic status is unclear. RESEARCH DESIGN AND METHOD:This large-scale nationwide cohort study included 9,514,171 adults without cancer who underwent health examinations under the Korean National Health Insurance Service in 2009 and were followed-up until December 2017 for pancreatic cancer development. Multivariable Cox proportional hazards regression analysis was performed. RESULTS:During a median follow-up period of 7.3 years, 12,818 patients were newly-diagnosed with pancreatic cancer. Among individuals with normoglycemia, a J-shaped association was observed between the frequency of alcohol consumption (1-2 and ≥5 days/week: hazards ratio [HR]; 95% CI, 0.91; 0.85-0.97 and 1.13; 1.002-1.27, respectively) and pancreatic cancer risk, after adjusting for potential confounders. However, in patients with impaired fasting glucose (IFG), pancreatic cancer risk increased with increased frequency and average daily amount of alcohol consumption (all P for trend <0.01). IFG combined with heavy alcohol consumption (30 g/day) was associated with 38% increased pancreatic cancer risk (HR, 1.38; 95% CI, 1.23-1.54). Diabetes was associated with an increased pancreatic cancer risk regardless of alcohol consumption and 70% increased risk even in non-drinkers (HR, 1.70; 95% CI, 1.61-1.80). CONCLUSIONS:The J-shaped dose-response association between alcohol consumption and pancreatic cancer risk was observed only in individuals with normoglycemia, not in patients with IFG and diabetes. Complete alcohol abstinence may help reduce pancreatic cancer risk in patients with IFG and diabetes. 10.1016/j.ejca.2021.12.027
    Comparative study on hemoglobin A1c, glycated albumin and glycosylated serum protein in aplastic anemia patients with Type 2 diabetes mellitus. Suo Minghuan,Wen Dongmei,Wang Weijia,Zhang Tingting Bioscience reports OBJECTIVE:To differentiate the value of hemoglobin A1c (HbA1c), glycated albumin (GA) and glycosylated serum protein (GSP) in monitoring blood glucose of patients with aplastic anemia. METHODS:42 patients with aplastic anemia (AA) and 30 patients with AA and Type 2 diabetes mellitus (T2DM) were enrolled in the study, in comparison with 114 healthy subjects and 88 subjects with T2DM. HbA1c, GA, GSP, fasting plasma glucose (FPG), hemoglobin (Hb) and albumin (ALB) were measured, and group comparison and correlation analysis were carried out. RESULTS:Compared with the non-diabetes patients while ALB were <30 g/l or 30-40 g/l, the HbA1c and GSP values in AA, T2DM and AA+T2DM patients were significantly higher while the GA values were lower. Moreover, no differences in FPG levels. The AA+T2DM patients with ALB >40 g/l had higher HbA1c level, with no difference in GA, GSP and FPG levels. There was a positive correlation between HbA1c and GA in healthy group (ALB ≥ 40 g/l), AA patients (ALB 30-40 g/l and ≥40 g/l), T2DM patients (ALB 30-40 g/l and ≥40 g/l) and AA+T2DM patients (ALB 30-40 g/l and ≥40 g/l) but not in those with ALB < 30 g/l. CONCLUSION:The HbA1c results were affected by moderate-to-severe anemia, but not mild anemia. HbA1c is not recommended to detect blood glucose levels in AA patients (Hb < 90 g/l) or AA patients (ALB < 30 g/l). FPG and GSP are not suitable for AA patients. 10.1042/BSR20192300
    Higher serum uric acid to HDL-cholesterol ratio is associated with onset of non-alcoholic fatty liver disease in a non-obese Chinese population with normal blood lipid levels. BMC gastroenterology BACKGROUND:Recent studies have demonstrated the presence of associations between metabolic syndrome and the onset of nonalcoholic fatty liver disease (NAFLD). Metabolic syndrome, in turn, has been found to be linked to high serum uric acid to HDL-cholesterol ratios (UHR). However, the relationship between UHR values and the occurrence of NAFLD in non-obese individuals remains unknown. The present study aimed to examine the possible correlation between UHR values and NAFLD onset among a non-obese Chinese population without dyslipidemia, as well as comparing the predictive value of UHR versus other NAFLD onset predictors. METHODS:A total of 9837 non-obese patients, with normal blood lipid levels, were included in a 5-year retrospective cohort study, and the onset of NAFLD in these patients was diagnosed by liver ultrasound. RESULTS:Out of the 9837 patients, 855 were diagnosed with NAFLD during the 5-year follow-up period, for an overall total prevalence of 8.7% at the end of the study period. Across quintiles 1, 2, 3, 4 and 5 of UHR (respectively, ratios of ≤ 120.88, 120.89-154.01, 154.02-189.91, 189.92-240.46, and ≥ 240.47), the prevalence of NAFLD among the patients increased from 2.4%, 5%, 7.9%, 10.3%, and 17.8%, respectively. After adjustments for age, gender, liver and kidney functional markers, as well as metabolic indicators, multivariate Cox proportional hazard regression analysis demonstrated that the hazard ratio (HR) was the highest in quintile 5, at 1.76 (1.12-2.75), and the lowest in quintile 1. The area under the curve (AUC) for UHR (0.690) was higher than that for serum uric acid (UA, 0.666) and HDL-C (0.636), suggesting the predictive ability of UHR for NAFLD onset was better than either alone. This finding was further supported by the presence of an independent association between UHR and NAFLD, even within the normal range of UA and HDL-C; the HR (95% confidence interval, CI) for NAFLD was 1.002 (1.000-1.004). Compared with other significant predictors, AUC for UHR (0.67) was similar to that of low-density lipoprotein cholesterol (LDL-C)/high-density lipoprotein cholesterol (HDL-C, 0.68), non-high-density lipoprotein cholesterol (NHDL-C)/HDL-C (0.68) and alanine aminotransferase (ALT)/aspartate aminotransferase (AST) ratios (0.7), and was higher than that of LDL-C (0.63), remnant cholesterol (RC,0.59), and albumin (ALB)/alkaline phosphatase (ALP) ratio (0.61). The sensitivity of UHR (71%) was the highest among all indicators. In the subgroup with ALT < 40U/L, the AUC for UHR was 0.70, which was the highest among all predictors; among ALT > 40U/L, UHR was able to predict the occurrence of NAFLD (AUC = 0.61, p = 0.007), which was not the case for RC (P = 0.441), ALB/ALP (P = 0.419), and ALT/AST (P = 0.159). CONCLUSIONS:UHR serve as an inexpensive and reliable predictor of NAFLD onset in non-obese Chinese people with normal blood lipid levels, allowing for identification of individuals at high risk for NAFLD. 10.1186/s12876-022-02263-4
    A New Predictor of Mortality in ST-Elevation Myocardial Infarction: The Uric Acid Albumin Ratio. Angiology Several studies have shown that high uric acid (UA) and low serum albumin (SA) values increase the risk of cardiovascular disease and mortality in ST-elevation myocardial infarction (STEMI). We determined whether the uric acid/albumin ratio (UAR) is a predictor of mortality in STEMI patients. All patients who presented at our center with a diagnosis of STEMI and underwent percutaneous intervention from 2015 to 2020 were screened consecutively; 4599 patients were included. A Cox proportional hazards model was used to evaluate UAR, and adjusted predictors obtained from laboratory findings and clinical characteristics contributed to mortality. Also, a regression model was presented with a directed acyclic graph (DAG). The median age of the patients was 58 years (IQR [interquartile range]: 50-67); 3581 patients (77.9%) were male. The incidence of mortality in the entire patient group was 11.9%. Median follow-up duration of all groups was 42 months. Multivariate Cox proportional regression (model-1) analysis showed age (increase 50 to 67 years; HR [hazard ratio]: 1.34, 95% CI 1.18-1.52) and UAR (increase 1.15-1.73; HR: 1.33, 95% CI 1.16-1.52) were associated with mortality. UAR may be a prognostic factor for mortality in STEMI patients and an easily accessible parameter to identify high-risk patients. 10.1177/00033197211066362
    Vascular toxicity of urea, a new "old player" in the pathogenesis of chronic renal failure induced cardiovascular diseases. Giardino Ida,D'Apolito Maria,Brownlee Michael,Maffione Angela Bruna,Colia Anna Laura,Sacco Michele,Ferrara Pietro,Pettoello-Mantovani Massimo Turk pediatri arsivi Chronic kidney disease in children is an irreversible process that may lead to end-stage renal disease. The mortality rate in children with end-stage renal disease who receive dialysis increased dramatically in the last decade, and it is significantly higher compared with the general pediatric population. Furthermore, dialysis and transplant patients, who have developed end-stage renal disease during childhood, live respectively far less as compared with age/race-matched populations. Different reports show that cardiovascular disease is the leading cause of death in children with end-stage renal disease and in adults with childhood-onset chronic kidney disease, and that children with chronic kidney disease are in the highest risk group for the development of cardiovascular disease. Urea, which is generated in the liver during catabolism of amino acids and other nitrogenous metabolites, is normally excreted into the urine by the kidneys as rapidly as it is produced. When renal function is impaired, increasing concentrations of blood urea will steadily accumulate. For a long time, urea has been considered to have negligible toxicity. However, the finding that plasma urea is the only significant predictor of aortic plaque area fraction in an animal model of chronic renal failure -accelerated atherosclerosis, suggests that the high levels of urea found in chronic dialysis patients might play an important role in accelerated atherosclerosis in this group of patients. The aim of this review was to provide novel insights into the role played by urea in the pathogenesis of accelerated cardiovascular disease in renal failure. 10.5152/TurkPediatriArs.2017.6314
    Multi-variable biomarker approach in identifying incident heart failure in chronic kidney disease: results from the Chronic Renal Insufficiency Cohort study. European journal of heart failure AIMS:Heart failure (HF) is one of the leading causes of cardiovascular morbidity and mortality in the ever-growing population of patients with chronic kidney disease (CKD). There is a need to enhance early prediction to initiate treatment in CKD. We sought to study the feasibility of a multi-variable biomarker approach to predict incident HF risk in CKD. METHODS AND RESULTS:We examined 3182 adults enrolled in the Chronic Renal Insufficiency Cohort (CRIC) without prevalent HF who underwent serum/plasma assays for 11 blood biomarkers at baseline visit (B-type natriuretic peptide [BNP], CXC motif chemokine ligand 12, fibrinogen, fractalkine, high-sensitivity C-reactive protein, myeloperoxidase, high-sensitivity troponin T (hsTnT), fibroblast growth factor 23 [FGF23], neutrophil gelatinase-associated lipocalin, fetuin A, aldosterone). The population was randomly divided into derivation (n = 1629) and validation (n = 1553) cohorts. Biomarkers that were associated with HF after adjustment for established HF risk factors were combined into an overall biomarker score (number of biomarkers above the Youden's index cut-off value). Cox regression was used to explore the predictive role of a biomarker panel to predict incident HF. A total of 411 patients developed incident HF at a median follow-up of 7 years. In the derivation cohort, four biomarkers were associated with HF (BNP, FGF23, fibrinogen, hsTnT). In a model combining all four biomarkers, BNP (hazard ratio [HR] 2.96 [95% confidence interval 2.14-4.09]), FGF23 (HR 1.74 [1.30-2.32]), fibrinogen (HR 2.40 [1.74-3.30]), and hsTnT (HR 2.89 [2.06-4.04]) were associated with incident HF. The incidence of HF increased with the biomarker score, to a similar degree in both derivation and validation cohorts: from 2.0% in score of 0% to 46.6% in score of 4 in the derivation cohort to 2.4% in score of 0% to 43.5% in score of 4 in the validation cohort. A model incorporating biomarkers in addition to clinical factors reclassified risk in 601 (19%) participants (352 [11%] participants to higher risk and 249 [8%] to lower risk) compared with clinical risk model alone (net reclassification improvement of 0.16). CONCLUSION:A basic panel of four blood biomarkers (BNP, FGF23, fibrinogen, and hsTnT) can be used as a standalone score to predict incident HF in patients with CKD allowing early identification of patients at high-risk for HF. Addition of biomarker score to clinical risk model modestly reclassifies HF risk and slightly improves discrimination. 10.1002/ejhf.2543
    Role of comorbidities in heart failure prognosis Part 2: Chronic kidney disease, elevated serum uric acid. Tedeschi Andrea,Agostoni Piergiuseppe,Pezzuto Beatrice,Corra' Ugo,Scrutinio Domenico,La Gioia Rocco,Raimondo Rosa,Passantino Andrea,Piepoli Massimo F European journal of preventive cardiology Despite improvements in pharmacotherapy, morbidity and mortality rates in community-based populations with chronic heart failure still remain high. The increase in medical complexity among patients with heart failure may be reflected by an increase in concomitant non-cardiovascular comorbidities, which are recognized as independent prognostic factors in this population. Heart failure and chronic kidney disease share many risk factors, and often coexist. The presence of kidney failure is associated with incremented risk of cardiovascular and non-cardiovascular mortality in heart failure patients. Chronic kidney disease is also linked with underutilization of evidence-based heart failure therapy that may reduce morbidity and mortality. More targeted therapies would be important to improve the prognosis of patients with these diseases. In recent years, serum uric acid as a determinant of cardiovascular risk has gained interest. Epidemiological, experimental and clinical data show that patients with hyperuricaemia are at increased risk of cardiac, renal and vascular damage and cardiovascular events. Moreover, elevated serum uric acid predicts worse outcome in both acute and chronic heart failure. While studies have raised the possibility of preventing heart failure through the use of uric acid lowering agents, the literature is still inconclusive on whether the reduction in uric acid will result in a measurable clinical benefit. Available evidences suggest that chronic kidney disease and elevated uric acid could worsen heart failure patients' prognosis. The aim of this review is to analyse a possible utilization of these comorbidities in risk stratification and as a therapeutic target to get a prognostic improvement in heart failure patients. 10.1177/2047487320957793
    The relationship between IL-10 levels and cardiovascular events in patients with CKD. Yilmaz Mahmut Ilker,Solak Yalcin,Saglam Mutlu,Cayci Tuncer,Acikel Cengizhan,Unal Hilmi Umut,Eyileten Tayfun,Oguz Yusuf,Sari Sebahattin,Carrero Juan Jesus,Stenvinkel Peter,Covic Adrian,Kanbay Mehmet Clinical journal of the American Society of Nephrology : CJASN BACKGROUND AND OBJECTIVES:Cardiovascular disease is the leading cause of death in patients with CKD. IL-10 is considered an antiatherosclerotic cytokine. However, previous studies have failed to observe an association between IL-10 and cardiovascular disease in CKD. This study aimed to evaluate whether serum IL-10 levels were associated with the risk of cardiovascular events in CKD patients. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS:Four hundred three patients with stages 1-5 CKD were followed for a mean of 38 (range=2-42) months for fatal and nonfatal cardiovascular events. IL-10 and IL-6 were measured at baseline together with surrogates of endothelial function (flow-mediated dilatation) and proinflammatory markers (high-sensitivity C-reactive protein and pentraxin-3). The association between IL-10 and flow-mediated dilatation through linear regression analyses was evaluated. The association between IL-10 and the risk of cardiovascular events was assessed with Cox regression analysis. RESULTS:IL-10, IL-6, high-sensitivity C-reactive protein, and pentraxin-3 levels were higher among participants with lower eGFR. Both fatal (25 of 200 versus 6 of 203 patients) and combined fatal and nonfatal (106 of 200 versus 23 of 203 patients) cardiovascular events were more common in patients with IL-10 concentration above the median. Flow-mediated dilatation was significantly lower in patients with higher serum IL-10 levels, but IL-10 was not associated with flow-mediated dilatation in multivariate analysis. Kaplan-Meier survival curves showed that patients with IL-10 below the median value (<21.5 pg/ml) had higher cumulative survival compared with patients who had IL-10 levels above the median value (log-rank test, P<0.001). CONCLUSIONS:IL-10 levels increase along with the reduction of kidney function. Higher serum IL-10 levels were associated with the risk of cardiovascular events during follow-up. We speculate that higher IL-10 levels in this context signify an overall proinflammatory milieu. 10.2215/CJN.08660813
    Osteoprotegerin is a marker of cardiovascular mortality in patients with chronic kidney disease stages 3-5. Marques Gustavo Lenci,Hayashi Shirley,Bjällmark Anna,Larsson Matilda,Riella Miguel,Olandoski Marcia,Lindholm Bengt,Nascimento Marcelo Mazza Scientific reports Cardiovascular disease (CVD) is the leading cause of death in patients with chronic kidney disease (CKD). Osteoprotegerin (OPG), known to regulate bone mass by inhibiting osteoclast differentiation and activation, might also play a role in vascular calcification. Increased circulating OPG levels in patients with CKD are associated with aortic calcification and increased mortality. We assessed the predictive role of OPG for all-cause and cardiovascular mortality in patients with CKD stages 3-5 over a 5-year follow-up period. We evaluated the relationship between OPG and all-cause and cardiovascular mortality in 145 CKD patients (stages 3-5) in a prospective observational follow-up study. Inflammation markers, including high-sensitivity C-reactive protein, standard echocardiography, and estimation of intima-media thickness in the common carotid artery, were assessed at baseline, and correlations with OPG levels were determined. The cutoff values for OPG were defined using ROC curves for cardiovascular mortality. Survival was assessed during follow up lasting for up to 5.5 years using Fine and Gray model. A total of 145 (89 men; age 58.9 ± 15.0 years) were followed up. The cutoff value for OPG determined using ROC was 10 pmol/L for general causes mortality and 10.08 pmol/L for CV causes mortality. Patients with higher serum OPG levels presented with higher mortality rates compared to patients with lower levels. Aalen-Johansen cumulative incidence curve analysis demonstrated significantly worse survival rates in individuals with higher baseline OPG levels for all-cause and cardiovascular mortality (p < 0.001). In multivariate analysis, OPG was a marker of general and cardiovascular mortality independent of sex, age, CVD, diabetes, and CRP levels. When CKD stages were included in the multivariate analysis, OPG was an independent marker of all-cause mortality but not cardiovascular mortality. Elevated serum OPG levels were associated with higher all-cause and cardiovascular mortality risk, independent of age, CVD, diabetes, and inflammatory markers, in patients with CKD. 10.1038/s41598-021-82072-z
    Cardiac troponin T predicts mortality in patients with end-stage renal disease. Dierkes J,Domröse U,Westphal S,Ambrosch A,Bosselmann H P,Neumann K H,Luley C Circulation BACKGROUND:Patients with end-stage renal disease have a high risk of premature death, mainly as the result of cardiovascular disease (CVD), which is not sufficiently explained by the conventional risk factors. We therefore prospectively investigated total mortality and cardiovascular events in 102 patients on hemodialysis and assessed the prognostic value of baseline disease status and laboratory variables including total homocysteine and cardiac troponin T. METHODS AND RESULTS:Patients were followed for 2 years or until their first event of CVD (for outcome variable cardiovascular events, n=33) or death (for outcome variable total mortality, n=28). Survival was computed by the Kaplan-Meier method. Cox proportional hazards model was used to determine independent predictors of CVD events or total mortality. Cardiac troponin T emerged as the most powerful predictor of mortality, resulting in an almost 7-fold risk increase at concentrations >0.10 ng/mL (hazard ratio 6.85, 95% CI 3. 04 to 15.45). Total homocysteine level greater than median was also associated with mortality (hazard ratio 2.44, 95% CI 1.10 to 5.40). These hazard ratios did not change substantially after adjustment for other risk factors. Significant predictors for CVD events were baseline diabetes, cerebrovascular disease, serum glucose, and triglycerides. After adjustment, only glucose and triglycerides remained significantly related to CVD events (hazard ratio with 95% CI 1.33 [1.12 to 1.57] and 1.14 [1.04 to 1.26], respectively, for a 1-mmol/L increase in concentration). CONCLUSIONS:We conclude that total homocysteine and particularly cardiac troponin T are important predictors of mortality in patients with end-stage renal disease, whereas other laboratory variables and baseline disease status have less prognostic value. 10.1161/01.cir.102.16.1964
    High ferritin and low transferrin saturation are associated with pre-diabetes among a national representative sample of U.S. adults. Cheung Ching-Lung,Cheung Tommy T,Lam Karen S L,Cheung Bernard M Y Clinical nutrition (Edinburgh, Scotland) BACKGROUND & AIMS:Iron overload is known to cause diabetes. However, the underlying mechanism is poorly understood. We therefore studied the association of different markers of iron metabolism, namely ferritin, erythrocyte protoporphyrin and transferrin saturation (TSAT, as defined by a percentage of transferrin that is saturated with iron) with pre-diabetes (preDM) in US adults without chronic kidney disease, anemia, and iron deficiency. METHODS:Data on 2575 participants of the National Health and Nutrition Examination Survey (NHANES) 1999-2002 who were free of diabetes, chronic kidney disease, iron deficiency, and anemia were analyzed. Data on 3876 participants of the NHANES III (1988-1994) were used as replication. Homeostasis model assessment of insulin resistance (HOMA-IR), blood glycosylated hemoglobin level (HbA1C), fasting glucose, insulin, and preDM (defined as a fasting plasma glucose 100-125 mg/dl or an HBA1C value 5.7-6.4%) were measured as the outcomes. RESULTS:Logistic regression analyses indicated independent associations of high ferritin (Ptrend = 0.028) and low TSAT (P(trend) = 0.029) with preDM after adjusting for sociodemographics, physical activity (active/sedementary), metabolic and inflammatory markers (triglycerides, total cholesterol, HDL cholesterol, mean arterial pressure, CRP, white cell count, and albumin), and liver enzymes (GGT, Alk phos, AST, and ALT). The NHANES III data showed similar associations. Combining the results showed a more significant association for high ferritin (P(meta) = 0.016) and low TSAT (P(meta) = 0.002). Moreover, TSAT was associated with HbA1C, fasting glucose, insulin, and HOMA-IR (P(meta) ≤ 0.001). CONCLUSIONS:Higher ferritin and lower TSAT are associated with higher risk of preDM in a general population without confounding diseases. Further research is needed to examine the underlying mechanism of these two indices, especially TSAT, in the pathophysiology of preDM. 10.1016/j.clnu.2012.11.024
    Vitamin D Deficiency in Patients with Diabetes in French Guiana: Epidemiology and Relation with Microvascular and Macrovascular Complications. Girard Elise,Nacher Mathieu,Bukasa-Kakamba John,Fahrasmane Aniza,Adenis Antoine,Massicard Mickael,Drak Alsibai Kinan,De Toffol Bertrand,Bekima Raissa,Thelusme Liliane,Okambabelle Diana,Demar Magalie,Aurelus Jean M,Sabbah Nadia Nutrients Vitamin D (VD) insufficiency is common among patients with diabetes in French Guiana. The study aimed to evaluate the prevalence of VD deficiency in the different type of diabetes encountered and to analyze the relationship between VD deficiency and diabetes complications. METHODS:An observational study was conducted between May 2019 and May 2020 in French Guiana, based on data from the CODIAM study (Diabetes Cohort in French Amazonia), describing the characteristics of patients with diabetes mellitus. Among 600 patients enrolled with diabetes, 361 had an available VD assay. RESULTS:The mean 25(OH)VD (hydroxycalciferol) level was 27.9 ng/mL. The level of VD was inversely proportional to the HbA1c (glycated hemoglobin) level. Patients with angina pectoris had a greater proportion of deficiencies VD < 20 ng/mL than those without angina. By contrast, patients with retinopathy had higher vitamin D concentrations than those without retinopathy. There was no association between vitamin D and arteriopathy, stroke, nephropathy and polyneuropathy. VD deficiency was more frequent in women, and in patients with a high school education. CONCLUSION:The prevalence of VD deficiency was high in patients with diabetes in French Guiana, emphasizing the importance of VD supplementation. 10.3390/nu13124302
    Vitamin D affects the neutrophil-to-lymphocyte ratio in patients with type 2 diabetes mellitus. Wang Si-Yang,Shen Ting-Ting,Xi Bei-Li,Shen Zhan,Zhang Xian Journal of diabetes investigation AIMS/INTRODUCTION:Chronic inflammation is an underlying feature of type 2 diabetes mellitus. Hypovitaminosis D is associated with type 2 diabetes mellitus, but whether it contributes to chronic inflammation is unclear. We examined the effects of vitamin D on various immune markers to evaluate its contribution to systemic inflammation in type 2 diabetes mellitus. MATERIALS AND METHODS:We retrospectively analyzed data from type 2 diabetes mellitus patients, people with prediabetes and control patients without diabetes (n = 9,746). Demographic and clinical variables were evaluated using descriptive statistics and generalized linear regression. A stratified analysis based on total serum vitamin D was also carried out. RESULTS:Neutrophil count was a significant predictor of 1,5-anhydroglucitol and glycated hemoglobin (HbA1c) in patients with prediabetes (1,5-anhydroglucitol: β = -0.719, P < 0.001 and HbA1c: β = -0.006, P = 0.002) and patients with diabetes (1,5-anhydroglucitol: β = 0.207, P = 0.004 and HbA1c: β = -0.067, P = 0.010). Lymphocyte count was a significant predictor of HbA1c in patients without diabetes (β = 0.056, P < 0.001) and patients with prediabetes (β = 0.038, P < 0.001). The neutrophil-to-lymphocyte ratio (NLR) was a significant predictor of HbA1c in patients without diabetes (β = -0.001, P = 0.032). No immune markers differed significantly based on vitamin D level among patients without diabetes (P> 0.05 for all). Among patients with prediabetes, those who were vitamin D-deficient had the highest NLR (P = 0.040). Among patients with diabetes, those who were vitamin D-deficient had the highest neutrophil count (P = 0.001), lowest lymphocyte count (P = 0.016) and highest NLR (P < 0.001). CONCLUSIONS:The NLR is strongly influenced by serum vitamin D level. Given the high prevalence of hypovitaminosis D and elevated NLR among chronic disease patients and the elderly, our results suggest that clinical interpretation of NLR as a predictive marker of type 2 diabetes mellitus-related inflammation should consider vitamin D level, age and pre-existing morbidity. 10.1111/jdi.13338
    Association Between 25(OH)Vitamin D, HbA1c and Albuminuria in Diabetes Mellitus: Data From a Population-Based Study (VIDAMAZON). Felício João Soares,de Rider Britto Hana Andrade,Cortez Pedro Celeira,de Souza Resende Fabrício,de Lemos Manuela Nascimento,de Moraes Lorena Vilhena,de Aquino Vitória Teixeira,de Souza Parente Fernanda,de Queiroz Natércia Neves Marques,Abrahão Neto João Felício,de Alcântara Angélica Leite,da Silva Wanderson Maia,de Souza Neto Norberto Jorge Kzan,Freire Piani Pedro Paulo,de Souza Ícaro José Araújo,Silva Lilian de Souza D'Albuquerque,de Oliveira Maria Clara Neres Iunes,Said Nivin Mazen,Nascimento de Lemos Gabriela,de Melo Franciane Trindade Cunha,Gomes Daniela Lopes,Contente Braga de Souza Ana Carolina,de Sá Oliveira Dos Reis Melissa,Leal Valéria Suênya Galvão,Lobato Isabel Jane Campos,Felício Karem Miléo Frontiers in endocrinology Background:The effect of glycemic control on diabetic kidney disease (DKD) is well known. Recent evidence has suggested that Vitamin D (VD) may have a nephroprotective effect in diabetes, but the relationship between VD, glycemic control, and albuminuria has yet to be clarified. Objective:Evaluate the relationship between 25-hydroxy-vitamin D [25(OH)D], HbA1c, and albuminuria in Diabetes Mellitus (DM). Patients and Methods:Cross-sectional study with 1576 individuals with DM who had 25(OH)D, HbA1c, and albuminuria levels measured. Patients with abnormal creatinine levels were excluded, in order to avoid interference on VD levels by impaired kidney function. Results:Patients with HbA1c ≥7% had lower 25(OH)D when compared to patients with HbA1c <7% (29.7 ± 10.2 28.1 ± 9.9 ng/ml, p = 0.003) and 25(OH)D levels seems to predict 1.5% of HbA1c behavior. The 25(OH)D concentrations in patients with normoalbuminuria were higher than the levels observed in those with micro or macroalbuminuria (29.8 ± 9.0 26.8 ± 8.6 and 25.1 ± 7.6, respectively, p = 0.001), patients who had 25(OH)D <20 ng/ml and 25(OH)D <30 ng/ml were at a higher risk of presenting albuminuria [OR = 2.8 (95% CI = 1.6 - 4.9), p<0.001, and OR = 2.1 (95% CI = 1.3 - 4.6), p<0.001, respectively]. In our regression model, albuminuria was influenced by HbA1c (r² = 0.076, p<0.00001) and 25(OH)D (r² = 0.018, p = 0.002) independently. Conclusion:Our study found an association between vitamin D levels, HbA1c and DKD. Additionally, our data suggest that the association between urinary albumin excretion and vitamin D levels is independent of glycemic control in patients with diabetes. Even though our patients presented normal creatinine levels, it is necessary further prospective studies to confirm if this association precedes or not the loss of renal function. 10.3389/fendo.2021.723502
    General glycosylated hemoglobin goals potentially increase myocardial infarction severity in diabetes patients with comorbidities: Insights from a nationwide multicenter study. Che Qianzi,Zhang Yan,Wang Jianan,Wan Zheng,Fu Xianghua,Chen Jiyan,Yan Hongbing,Chen Yundai,Ge Junbo,Chen Dafang,Huo Yong Journal of diabetes investigation AIMS/INTRODUCTION:We aimed to investigate the relationship between glycemic status and coronary artery disease (CAD) extent and severity in ST-elevation myocardial infarction (STEMI) patients, and further examine whether diabetes patients could benefit from glycosylated hemoglobin (HbA1c) below the recommended level. MATERIALS AND METHODS:Consecutive STEMI patients admitted in 2015-2017 across 244 hospitals were included in the China STEMI Care Project-2. We carried out a cross-sectional study comprising 8,370 participants with a record of HbA1c testing after admission. CAD extent and severity were assessed by admission heart rate, Killip classification and the number of stenosed vessels based on the coronary angiogram. RESULTS:Diabetes patients showed a greater risk for higher Killip class, admission tachycardia (admission heart rate ≥100 b.p.m.) and multivessel CAD (presence of left main and/or triple vessel disease). Likewise, HbA1c level was significantly associated with CAD extent and severity. While dividing diabetes patients according to general HbA1c targets (HbA1c ≤6.5, 6.5-7.0 and ≥7.0%), diabetes patients with HbA1c ≤6.5% showed a 1.30-fold higher risk for multivessel CAD (adjusted odds ratio 1.30, 95% confidence interval 1.05-1.62). In stratified analysis, the association was even stronger in patients with hypertension (adjusted odds ratio 1.41, 95% confidence interval 1.08-1.86) or hyperlipidemia (adjusted odds ratio 1.57, 95% confidence interval 1.17-2.12). CONCLUSIONS:HbA1c level is independently correlated with CAD extent and severity in STEMI patients. HbA1c below generally recommended levels might still increase the risk of CAD progression, especially for diabetes patients with hypertension or hyperlipidemia. 10.1111/jdi.13287
    Gender- and age-related differences in homocysteine concentration: a cross-sectional study of the general population of China. Xu Ranran,Huang Fei,Wang Yiru,Liu Qingquan,Lv Yongman,Zhang Qian Scientific reports The primary goals of this study were to evaluate the gender- and age-related differences in homocysteine concentration in the general population of China and possible influencing factors. A total of 7872 subjects, divided into male and female groups, participated in this retrospective study. The average homocysteine level, prevalence of hyperhomocysteinemia, and independent factors affecting homocysteine concentration were analyzed. The homocysteine level was significantly higher in males than in females in each age range (aged 20-30, aged 30-40, aged 40-50, aged 50-60, aged 60-80, aged over 80) (P < 0.0001), and the trend did not abate with age. The homocysteine concentration first decreased and then increased, being lowest at 30-50 years of age and significantly increased after 50 years of age. Factors associated with homocysteine concentration in males were smoking status (current smokers versus ex-smokers: β: 0.112), estimated glomerular filtration rate (β =  - 0.192), blood urea nitrogen (β =  - 0.14), diastolic blood pressure (β =  - 0.113), free triiodothyronine (β =  - 0.091), serum potassium (β =  - 0.107) and cystatin C (β = 0.173). In females, independent factors associated with homocysteine concentration were cystatin C (β = 0.319), albumin (β = 0.227), free thyroxine (β = 0.179), age (β = 0.148), free triiodothyronine (β =  - 0.217) and serum potassium (β =  - 0.153). The homocysteine level was significantly higher in males than in females and increased markedly after 50 years of age in both groups. The independent factors associated with increased homocysteine concentration differed between males and females. 10.1038/s41598-020-74596-7
    The Relationship between Folic Acid and Vitamin B12 Serum Levels with High Sensitivity C-reactive Protein and Homocysteine in Chronic Hemodialysis Patients: A Cross-sectional Study. Lydia Aida,Priantono Dimas,Harimurti Kuntjoro,Alwi Idrus Acta medica Indonesiana BACKGROUND:Folic acid (FA) and vitamin B12 treatment have been routinely prescribed to lower serum homocysteine levels and to reduce inflammation. However, no study has been conducted to determine serum folic acid (SFA) and vitamin B12 (B12) levels in patients who have twice-weekly hemodialysis. The aim of our study was to assess serum folate and B12  levels in chronic hemodialysis patients and their relationship with hsCRP and homocysteine levels. METHODS:Our study was a cross-sectional study involcing patients who had twice-weekly hemodialysis in Dr Cipto Mangunkusumo National Hospital Jakarta, Indonesia. Predialysis blood samples were taken to measure SFA, B12, homocysteine and hsCRP levels. Patients with medical conditions affecting the assays were excluded. Spearman correlation was used to compare variables. RESULTS:Eighty subjects enrolled in this study. Among those of non-given folic acid and vitamin B-12 supplementation, only 3.85% of subjects had low folic acid levels, and none had low vitamin B12 levels. A moderate negative correlation between serum folic acid and homocysteine level (p≤0.001; r=-0.42) and a weak correlation between serum vitamin B12 and homocysteine level (p=0.009; r=-0.29) was found. Among the high-risk cardiovascular group (CRP>3, n=49), there is a moderate negative correlation between serum folic acid and homocysteine level (p≤0.001; r=-0.561) and a weak negative correlation between vitamin B12 and homocysteine level (p=0.018; r=-0.338). CONCLUSION:There is a significant negative correlation between serum vitamin B12 and folic acid with homocysteine levels, especially in high-risk cardiovascular group.
    TG: HDL-C Ratio as Insulin Resistance Marker for Metabolic Syndrome in Children With Obesity. Frontiers in endocrinology Insulin resistance (IR) is an important variable in the diagnosis of metabolic syndrome (MetS). Currently, IR is not part of the existing pediatric definition of MetS, instead elevated fasting blood glucose (FBG) is measured as an indicator of hyperglycemia. Arguably, many obese children with severe IR are still able to regulate their FBG well. Hence, this study aimed to assess the utility of triglyceride-to-high-density lipoprotein cholesterol (TG : HDL-C) ratio as an IR marker in the modeling of pediatric MetS among children with obesity using structural equation modeling (SEM). A total of 524 blood samples from children with obesity (age 10-16 years old) were analyzed for FBG, lipids, insulin, leptin, and adiponectin. Both exploratory (EFA) and confirmatory factor analysis (CFA) were used to examine TG : HDL-C ratio as an IR marker in pediatric MetS. EFA shows that TG: HDL-C ratio (standardized factor loading = 0.904) groups together with homeostasis model assessment-estimated insulin resistance (HOMA-IR) (standardized factor loading = 0.664), indicating a strong correlation to the IR factor. Replacing FBG with TG: HDL-C ratio improved the modeling of MetS structure in children with obesity. Our MetS model of TG: HDL-C ratio as IR component shows comparable model fitness indices (goodness of fit, Akaike's information criterion, and Bayesian information criterion) with leptin:adiponectin ratio (platinum standard for adiposity:IR marker) model. The least model fit was seen when using FBG as an IR surrogate. TG : HDL-C ratio performed better as IR surrogate in MetS structures (standardized factor loading = 0.39) compared to FBG (standardized factor loading = 0.27). TG: HDL-C ratio may be considered as an IR component in pediatric MetS. 10.3389/fendo.2022.852290
    Endogenous hepcidin and its agonist mediate resistance to selected infections by clearing non-transferrin-bound iron. Stefanova Deborah,Raychev Antoan,Arezes Joao,Ruchala Piotr,Gabayan Victoria,Skurnik Mikael,Dillon Barbara J,Horwitz Marcus A,Ganz Tomas,Bulut Yonca,Nemeth Elizabeta Blood The iron-regulatory hormone hepcidin is induced early in infection, causing iron sequestration in macrophages and decreased plasma iron; this is proposed to limit the replication of extracellular microbes, but could also promote infection with macrophage-tropic pathogens. The mechanisms by which hepcidin and hypoferremia modulate host defense, and the spectrum of microbes affected, are poorly understood. Using mouse models, we show that hepcidin was selectively protective against siderophilic extracellular pathogens ( O9) by controlling non-transferrin-bound iron (NTBI) rather than iron-transferrin concentration. NTBI promoted the rapid growth of siderophilic but not nonsiderophilic bacteria in mice with either genetic or iatrogenic iron overload and in human plasma. Hepcidin or iron loading did not affect other key components of innate immunity, did not indiscriminately promote intracellular infections (), and had no effect on extracellular nonsiderophilic O8 or Hepcidin analogs may be useful for treatment of siderophilic infections. 10.1182/blood-2017-03-772715
    Vitamin K status, all-cause mortality, and cardiovascular disease in adults with chronic kidney disease: the Chronic Renal Insufficiency Cohort. The American journal of clinical nutrition BACKGROUND:Vascular calcification contributes to cardiovascular disease (CVD) and mortality in individuals with chronic kidney disease (CKD). Vitamin K-dependent proteins function as calcification inhibitors in vascular tissue. OBJECTIVES:We sought to determine the association of vitamin K status with mortality and CVD events in adults with CKD. METHODS:Plasma dephospho-uncarboxylated matrix gla protein ((dp)ucMGP), which increases when vitamin K status is low, and plasma phylloquinone (vitamin K1), which decreases when vitamin K status is low, were measured in 3066 Chronic Renal Insufficiency Cohort participants (median age = 61 y, 45% female, 41% non-Hispanic black, median estimated glomerular filtration rate [eGFR] = 41 mL/min/1.73m2). The association of vitamin K status biomarkers with all-cause mortality and atherosclerotic-related CVD was determined using multivariable Cox proportional hazards regression. RESULTS:There were 1122 deaths and 599 atherosclerotic CVD events over the median 12.8 follow-up years. All-cause mortality risk was 21-29% lower among participants with plasma (dp)ucMGP <450 pmol/L (n = 2361) compared with those with plasma (dp)ucMGP ≥450 pmol/L (adjusted HRs [95% CIs]: <300 pmol/L = 0.71 [0.61, 0.83], 300-449 pmol/L = 0.77 [0.66, 0.90]) and 16-19% lower among participants with plasma phylloquinone ≥0.50 nmol/L (n = 2421) compared to those with plasma phylloquinone <0.50 nmol/L (adjusted HRs: 0.50, 0.99 nmol/L = 0.84 [0.72, 0.99], ≥1.00 nmol/L = 0.81 [0.70, 0.95]). The risk of atherosclerotic CVD events did not significantly differ across plasma (dp)ucMGP or phylloquinone categories. CONCLUSIONS:Two biomarkers of vitamin K status were associated with a lower all-cause mortality risk but not atherosclerotic CVD events. Additional studies are needed to clarify the mechanism underlying this association and evaluate the impact of improving vitamin K status in people with CKD. 10.1093/ajcn/nqab375
    Sex-Specific Absolute Delta Thresholds for High-Sensitivity Cardiac Troponin T. Clinical chemistry BACKGROUND:Sex differences in high-sensitivity cardiac troponin (hs-cTn) concentrations from healthy populations have led to the establishment of sex-specific upper reference limits for hs-cTn assays. This study assessed the performance of sex-specific delta (i.e., changes in concentrations) thresholds for the hs-cTnT assay for ruling in acute myocardial infarction (AMI) in different emergency department (ED) populations. METHODS:This retrospective study consisted of 2 cohorts (Cohort 1 derivation and Cohort 2 validation). Cohort 1 consisted of 18 056 ED patients who had serial hs-cTnT measured using a 0-h/3-h algorithm at a US medical center, with Cohort 2 consisting of 1137 ED patients with 0-h/3-h sampling at a Canadian medical center. The primary outcome was AMI diagnosis with sex-specific deltas derived based on the Youden index and specificity estimates (i.e., ≥90%) in Cohort 1 and validated in Cohort 2. RESULTS:In Cohort 1, 42% of all patients had 0-h hs-cTnT above the sex-specific 99th percentile. Males had higher 0-h hs-cTnT (median 17 ng/L) and absolute deltas (median 2 ng/L) than females (0-h median 11 ng/L, P < 0.0001; deltas median 1 ng/L, P < 0.0001) in non-AMI patients but not in patients with AMI. For ruling in AMI, the sex-specific delta thresholds based on 90% specificity (14 ng/L for males, 11 ng/L for females) performed best and resulted in 91% diagnostic accuracy in both males and females. The sex-specific delta thresholds yielding high specificity estimates were confirmed in the validation data set. CONCLUSIONS:Sex-specific absolute delta thresholds can be used to rule in AMI and are robust across different study populations. 10.1093/clinchem/hvab230
    High-sensitivity cardiac troponin T is a biomarker for atherosclerosis in systemic lupus erythematous patients: a cross-sectional controlled study. Divard Gillian,Abbas Rachid,Chenevier-Gobeaux Camille,Chanson Noémie,Escoubet Brigitte,Chauveheid Marie-Paule,Dossier Antoine,Papo Thomas,Dehoux Monique,Sacre Karim Arthritis research & therapy BACKGROUND:Cardiovascular disease (CVD) is the main cause of death in systemic lupus erythematous (SLE) patients. The Framingham score underestimates the risk for CVD in this population. Our study aimed to determine whether serum high-sensitivity cardiac troponin T (HS-cTnT) might help to identify SLE patients at risk for CVD. METHODS:The presence of carotid plaques was prospectively assessed by ultrasound in 63 consecutive SLE patients asymptomatic for CVD and 18 controls. Serum HS-cTnT concentration was measured using the electrochemiluminescence method. Factors associated with carotid plaques were identified and multivariate analysis was performed. RESULTS:Framingham score was low in both SLE patients (median 1 (range 1-18%)) and controls (1 (1-13%)). Nevertheless, 23 (36.5%) SLE patients, but only 2 (11.1%) controls (p = 0.039), had carotid plaque detected by vascular ultrasound. In the multivariate analysis, only age (p = 0.006) and SLE status (p = 0.017) were independently associated with carotid plaques. Serum HS-cTnT concentration was detectable (i.e. >3 ng/L) in 37 (58.7%) SLE patients and 6 (33.3%) controls (p = 0.057). Interestingly, 87% of SLE patients with carotid plaques, but only 42.5% of SLE patients without plaques (p < 0.001), had detectable HS-cTnT. Conversely, 54.5% of SLE patients with detectable HS-cTnT, but only 11.5% with undetectable HS-cTnT (p < 0.001), had a carotid plaque. In the multivariate analysis, only body mass index (p = 0.006) and HS-cTnT (p = 0.033) were statistically associated with carotid plaques in SLE patients. Overall, the risk of having a carotid plaque was increased by 9 (odds ratio 9.26, 95% confidence interval 1.55-90.07) in SLE patients in whom HS-cTnT was detectable in serum. CONCLUSION:Serum HS-cTnT level is high and associated with carotid plaques in SLE patients who are at an apparently low risk for CVD according to the Framingham score. HS-cTnT may be a useful biomarker for SLE-associated atherosclerosis. 10.1186/s13075-017-1352-7
    Early elevation in plasma high-sensitivity troponin T and morbidity after elective noncardiac surgery: prospective multicentre observational cohort study. Ackland Gareth L,Abbott Tom E F,Jones Timothy F,Leuwer Martin,Pearse Rupert M, , , , British journal of anaesthesia BACKGROUND:Elevated high-sensitivity troponin (hsTnT) after noncardiac surgery is associated with higher mortality, but the temporal relationship between early elevated troponin and the later development of noncardiac morbidity remains unclear. METHODS:Prospective observational study of patients aged ≥45 yr undergoing major noncardiac surgery at four UK hospitals (two masked to hsTnT). The exposure of interest was early elevated troponin, as defined by hsTnT >99th centile (≥15 ng L) within 24 h after surgery. The primary outcome was morbidity 72 h after surgery, defined by the Postoperative Morbidity Survey (POMS). Secondary outcomes were time to become morbidity-free and Clavien-Dindo ≥grade 3 complications. RESULTS:Early elevated troponin (median 21 ng L [16-32]) occurred in 992 of 4335 (22.9%) patients undergoing elective noncardiac surgery (mean [standard deviation, sd] age, 65 [11] yr; 2385 [54.9%] male). Noncardiac morbidity was more frequent in 494/992 (49.8%) patients with early elevated troponin compared with 1127/3343 (33.7%) patients with hsTnT <99th centile (odds ratio [OR]=1.95; 95% confidence interval [CI], 1.69-2.25). Patients with early elevated troponin had a higher risk of proven/suspected infectious morbidity (OR=1.54; 95% CI, 1.24-1.91) and critical care utilisation (OR=2.05; 95% CI, 1.73-2.43). Clavien-Dindo ≥grade 3 complications occurred in 167/992 (16.8%) patients with early elevated troponin, compared with 319/3343 (9.5%) patients with hsTnT <99th centile (OR=1.78; 95% CI, 1.48-2.14). Absence of early elevated troponin was associated with morbidity-free recovery (OR=0.44; 95% CI, 0.39-0.51). CONCLUSIONS:Early elevated troponin within 24 h of elective noncardiac surgery precedes the subsequent development of noncardiac organ dysfunction and may help stratify levels of postoperative care in real time. 10.1016/j.bja.2020.02.003
    Platelets as therapeutic targets to prevent atherosclerosis. Nording Henry,Baron Lasse,Langer Harald F Atherosclerosis Cardiovascular disease remains the main cause of death worldwide. For this reason, strategies for the primary prevention of atherosclerosis and atherosclerosis-related pathologies like stroke or myocardial infarction are needed. Platelets are key players of atherosclerosis-related vascular thrombotic pathologies and their role as targets in secondary prevention of atherosclerosis-related complications is uncontested. However, platelets also play an important role in the initiation and progression of atherosclerosis. Currently, though, there is no generally valid recommendation for the use of antiplatelet therapy in primary prevention of cardiovascular disease. Recent clinical studies have shown that the benefit from antiplatelet therapy in primary prevention is counteracted by the entailed bleeding risk. This review addresses the important role platelets play in initiating and sustaining vascular inflammation, which drives atherosclerosis. Specifically, platelet-lipid interactions as well as platelet-endothelium interactions in the context of atherosclerosis are illustrated. We also depict how platelets help recruit immune cells like monocytes, neutrophils or dendritic cells to the subendothelial space. Finally, we portray the role of complement and platelets in atherosclerosis. Platelets appear to act as mediators of tissue homeostasis and may also modulate the microenvironment of the atherosclerotic plaque. Overall, this review addresses the role of platelets in atherosclerosis with particular focus on potential targets for pharmacological interventions into platelet functions distinct from aggregation. By eliminating the bleeding risk of antiplatelet therapy, platelets are likely to regain a role in primary prevention of cardiovascular disease. 10.1016/j.atherosclerosis.2020.05.018
    Cardiovascular disease biomarkers are associated with declining renal function in type 2 diabetes. Jenks Sara J,Conway Bryan R,McLachlan Stela,Teoh Wei Leng,Williamson Rachel M,Webb David J,Welsh Paul,Sattar Naveed,Strachan Mark W J,Price Jackie F Diabetologia AIMS/HYPOTHESIS:We investigated whether biochemical cardiovascular risk factors and/or markers of subclinical cardiovascular disease were associated with the development of reduced renal function in people with type 2 diabetes. METHODS:A cohort of 1066 Scottish men and women aged 60-74 years with type 2 diabetes from the Edinburgh Type 2 Diabetes Study were followed up for a median of 6.7 years. New-onset reduced renal function was defined as two eGFRs <60 ml min (1.73 m) at least 3 months apart with a > 25% decline from baseline eGFR. Ankle brachial pressure index (ABI), N-terminal pro-B-type natriuretic peptide (NT-proBNP) and high-sensitivity troponin T (hsTnT) were measured at baseline. Pulse wave velocity (PWV) and carotid intima media thickness were measured 1 year into follow-up. Data were analysed using Cox proportional hazards models. RESULTS:A total of 119 participants developed reduced renal function during follow-up. ABI, PWV, NT-proBNP and hsTnT were all associated with onset of decline in renal function following adjustment for age and sex. These associations were attenuated after adjustment for additional diabetes renal disease risk factors (systolic BP, baseline eGFR, albumin:creatinine ratio and smoking pack-years), with the exception of hsTnT which remained independently associated (HR 1.51 [95% CI 1.22, 1.87]). Inclusion of hsTnT in a predictive model improved the continuous net reclassification index by 0.165 (0.008, 0.286). CONCLUSIONS/INTERPRETATION:Our findings demonstrate an association between hsTnT, a marker of subclinical cardiac ischaemia, and subsequent renal function decline. Further research is required to establish the predictive value of hsTnT and response to intervention. 10.1007/s00125-017-4297-0
    Association Between Renal Function and Troponin T Over Time in Stable Chronic Kidney Disease Patients. Chesnaye Nicholas C,Szummer Karolina,Bárány Peter,Heimbürger Olof,Magin Hasan,Almquist Tora,Uhlin Fredrik,Dekker Friedo W,Wanner Christoph,Jager Kitty J,Evans Marie, , Journal of the American Heart Association Background People with reduced glomerular filtration rate (GFR) often have elevated cardiac troponin T (cTnT) levels. It remains unclear how cTnT levels develop over time in those with chronic kidney disease (CKD). The aim of this study was to prospectively study the association between cTnT and GFR over time in older advanced-stage CKD patients not on dialysis. Methods and Results The EQUAL (European Quality Study) study is an observational prospective cohort study in stage 4 to 5 CKD patients aged ≥65 years not on dialysis (incident estimated GFR, <20 mL/min/1.73 m²). The EQUAL cohort used for the purpose of this study includes 171 patients followed in Sweden between April 2012 and December 2018. We used linear mixed models, adjusted for important groups of confounders, to investigate the effect of both measured GFR and estimated GFR on high-sensitivity cTnT (hs-cTnT) trajectory over 4 years. Almost all patients had at least 1 hs-cTnT measurement elevated above the 99th percentile of the general reference population (≤14 ng/L). On average, hs-cTnT increased by 16%/year (95% CI, 13-19; <0.0001). Each 15 mL/min/1.73 m lower mean estimated GFR was associated with a 23% (95% CI, 14-31; <0.0001) higher baseline hs-cTnT and 9% (95% CI, 5-13%; <0.0001) steeper increase in hs-cTnT. The effect of estimated GFR on hs-cTnT trajectory was somewhat lower than a previous myocardial infarction (15%), but higher than presence of diabetes mellitus (4%) and male sex (5%). Conclusions In CKD patients, hs-cTnT increases over time as renal function decreases. Lower CKD stage (each 15 mL/min/1.73 m lower) is independently associated with a steeper hs-cTnT increase over time in the same range as other established cardiovascular risk factors. 10.1161/JAHA.119.013091
    Platelet phagocytosis by leukocytes in a patient with cerebral hemorrhage and thrombocytopenia caused by gram-negative bacterial infection. Wu Xiuji,Li Youjun,Yang Xiaoyang The Journal of international medical research Bacteria-induced thrombocytopenia is a common clinical disease that is often ignored by clinical and scientific research. Thus, exploring the mechanism and principle of bacteria-induced thrombocytopenia could facilitate the development of new diagnostic, preventative, and treatment modalities for thrombocytopenia. This case report describes a case of platelet phagocytosis by neutrophils and monocytes in a patient with cerebral hemorrhage and thrombocytopenia caused by gram-negative bacterial infection. After the infection was eradicated, platelet phagocytosis was alleviated, and his platelet count normalized. Cellular immunity may be an important cause of bacteria-induced thrombocytopenia in patients with cerebral hemorrhage. 10.1177/03000605221079102
    The prognostic impact of uric acid in acute heart failure according to coexistence of diabetes mellitus. Cidade-Rodrigues Catarina,Cunha Filipe M,Elias Catarina,Oliveira Diana,Bettencourt Paulo,Lourenço Patrícia Nutrition, metabolism, and cardiovascular diseases : NMCD BACKGROUND AND AIMS:Increased uric acid levels predict higher mortality in heart failure (HF) patients. Patients with diabetes mellitus (DM) appear to have increased xanthine oxidase activity. We aimed to study if the association between uric acid and mortality in acute HF was different according to the coexistence of DM. METHODS AND RESULTS:We studied a cohort of patients hospitalized due to acute HF in 2009-2010. Patients with no uric acid measurement upon admission were excluded from the analysis. FOLLOW-UP:2 years; endpoint: all-cause mortality. Patients with elevated uric acid (>80.0 mg/L) were compared with those with lower values. We used a multivariate Cox-regression analysis to assess the prognostic impact of uric acid (both continuous and categorical variable: cut-off 80.0 mg/L). The analysis was stratified according to coexistence of DM. We studied 569 acute HF patients, 44.6%male, mean age 76 years, 290 were diabetic. Median admission uric acid: 81.2 mg/L and 52.2%had uric acid >80.0 mg/L. Elevated uric acid predicted all-cause mortality in acute HF only in patients with DM. The multivariate-adjusted HR of 2-year mortality was 1.68 (95 % CI: 1.15-2.46) for diabetic HF patients with uric acid>80.0 mg/L compared to those with lower levels (p = 0.008) and 1.10 (95 % CI: 1.03-1.18) per each 10 mg/L increase in uric acid (p = 0.007). In non-diabetic HF patients, uric acid was not associated with mortality. CONCLUSIONS:Increased uric acid predicts ominous outcome in acute HF patients with diabetes, however, it is not prognostic associated in non-diabetics. Uric acid may play a different role in acute HF depending on DM status. 10.1016/j.numecd.2021.07.032
    Association between uric acid level and incidence of albuminuria in patients with type 2 diabetes mellitus: A 4.5-year cohort study. Lai Yun-Ju,Chen Yu-Yen,Ku Po-Wen,Chen Li-Jung,Yen Yung-Feng Medicine ABSTRACT:Using animal models and molecular biology researches, hyperuricemia has been shown to instruct renal arteriolopathy, arterial hypertension, and microvascular injury involving the renin-angiotensin system and resulting in renal function impairment. Nevertheless, the association between uric acid levels and the development of albuminuria has been under-investigated in patients with type 2 diabetes mellitus. Patients with type 2 diabetes and regular outpatient visits were recruited from the Puli Branch of the Taichung Veterans General Hospital in Taiwan since January 2014. Demographics, lifestyle features, and medical history were gathered by well-trained interviewers. All participants underwent comprehensive physical examinations, including a biochemical assay of venous blood specimens and urine samples after an 8-hour overnight fast. Participants were followed until June 2018. The primary outcome was the albuminuria incidence. Univariable and multivariable Cox regression analysis were employed to explore the relation between uric acid and incident albuminuria. Uric acid cutoffs for incident albuminuria were determined with the receiver operator characteristic curve. We included 247 qualified subjects (mean age: 64.78 years old [standard deviation = 11.29 years]; 138 [55.87%] men). During a 4.5-year follow-up duration, 20 subjects with incident albuminuria were recognized. Serum uric acid was significantly associated with an increased risk of incident albuminuria (adjusted hazard ratio = 2.39; 95% confidence interval: 1.53-3.75; P < .001) with potential confounders adjustment. The uric acid cutoff point was 6.9 mg/dL (area under the curve 0.708, sensitivity 60.0%, specificity 84.58%) for incident albuminuria. Serum uric acid was associated with incident albuminuria among patients with type 2 diabetes. 10.1097/MD.0000000000027496
    Albumin, bilirubin, uric acid and cancer risk: results from a prospective population-based study. Kühn Tilman,Sookthai Disorn,Graf Mirja E,Schübel Ruth,Freisling Heinz,Johnson Theron,Katzke Verena,Kaaks Rudolf British journal of cancer BACKGROUND:It has long been proposed that albumin, bilirubin and uric acid may inhibit cancer development due to their anti-oxidative properties. However, there is a lack of population-based studies on blood levels of these molecules and cancer risk. METHODS:Associations between pre-diagnostic serum albumin, bilirubin and uric acid and the risks of common cancers as well as cancer death in the EPIC-Heidelberg cohort were evaluated by multivariable Cox regression analyses. A case-cohort sample including a random subcohort (n=2739) and all incident cases of breast (n=627), prostate (n=554), colorectal (n=256), and lung cancer (n=195) as well as cancer death (n=761) that occurred between baseline (1994-1998) and 2009 was used. RESULTS:Albumin levels were inversely associated with breast cancer risk (hazard ratio (95% CI): 0.71 (0.51, 0.99), P=0.004) and overall cancer mortality (HR (95% CI): 0.64 (0.48, 0.86), P<0.001) after multivariable adjustment. Uric acid levels were also inversely associated with breast cancer risk (HR (95% CI): 0.72 (0.53, 0.99), P=0.043) and cancer mortality (HR (95% CI): 0.75 (0.58, 0.98), P=0.09). There were no significant associations between albumin or uric acid and prostate, lung and colorectal cancer. Serum bilirubin was not associated with any cancer end point. CONCLUSIONS:The present findings indicate that higher levels of albumin and uric acid are related to lower risks of breast cancer and cancer mortality. Further studies are needed to assess whether the observed associations are causal. 10.1038/bjc.2017.313
    High level of individual lipid profile and lipid ratio as a predictive marker of poor glycemic control in type-2 diabetes mellitus. Artha I Made Junior Rina,Bhargah Agha,Dharmawan Nyoman Khrisna,Pande Utami Wijayaswari,Triyana Komang Agus,Mahariski Pande Agung,Yuwono Jessica,Bhargah Varennia,Prabawa I Putu Yuda,Manuaba Ida Bagus Amertha Putra,Rina I Ketut Vascular health and risk management Diabetes is often accompanied by undiagnosed dyslipidemia. The aim of the study is to investigate the clinical relevance of lipid profiles and lipid ratios as predictive biochemical models for glycemic control in patients with type 2 diabetes mellitus (T2DM). This is a retrospective study recruiting 140 patients with T2DM during a one-year period, 2018-2019, at the Diabetic Center Sanglah General Hospital and Internal Medicine Polyclinic Puri Raharja General Hospital. Demographic characteristics, glycosylated hemoglobin (HBA1c) , and lipid profile were recorded and analyzed using SPSS version 25.0 for Windows. The sample is then classified into good (HBA1c≤7) and poor (HBA1c>7) glycemic control. Risk analysis model, receiver operator characteristics (ROC) analysis, and correlation test were used to evaluate the association of HBA1c level with lipid profile and lipid ratio parameters. Lipid profile findings such as total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C) , triglycerides (TG), and lipid ratio parameter (LDL-C to high-density lipoprotein cholesterol (HDL-C) ratio) were higher in patients in the poor glycemic control group (<0.05) and HDL-C was significantly lower in patients with poor glycemic control (=0.001). There is a significant positive correlation between LDL, total cholesterol, LDL-C, TG, and TC to HDL-C ratio, triglycerides, and TC/HDL-C ratio with HBA1c level. Meanwhile, a negative correlation was observed on HDL-C with the HBA1c level. Only TC/HDL-C ratio and LDL-C/HDL-C ratio parameters may be used as predictive models (AUC>0.7), with cutoff point, sensitivity, and specificity of 4.68 (77%; 52%) and 3.06 (98%; 56%) respectively. A risk analysis model shows that the LDL-C/HDL-C ratio parameter is the most influential risk factor in the occurrence of poor glycemic control (adjusted OR =38.76; 95% CI: 27.32-56.64; <0.001). Lipid profiles (LDL-C) and lipid ratios (LDL-C/HDL-C and TC/HDL-C ratio) show potential markers that can be used in predicting glycemic control in patients with T2DM. 10.2147/VHRM.S209830
    Pulmonary surfactant protein B carried by HDL predicts incident CVD in patients with type 1 diabetes. Journal of lipid research Atherosclerotic CVD is the major cause of death in patients with type 1 diabetes mellitus (T1DM). Alterations in the HDL proteome have been shown to associate with prevalent CVD in T1DM. We therefore sought to determine which proteins carried by HDL might predict incident CVD in patients with T1DM. Using targeted MS/MS, we quantified 50 proteins in HDL from 181 T1DM subjects enrolled in the prospective Coronary Artery Calcification in Type 1 Diabetes study. We used Cox proportional regression analysis and a case-cohort design to test associations of HDL proteins with incident CVD (myocardial infarction, coronary artery bypass grafting, angioplasty, or death from coronary heart disease). We found that only one HDL protein-SFTPB (pulmonary surfactant protein B)-predicted incident CVD in all the models tested. In a fully adjusted model that controlled for lipids and other risk factors, the hazard ratio was 2.17 per SD increase of SFTPB (95% confidence interval, 1.12-4.21, P = 0.022). In addition, plasma fractionation demonstrated that SFTPB is nearly entirely bound to HDL. Although previous studies have shown that high plasma levels of SFTPB associate with prevalent atherosclerosis only in smokers, we found that SFTPB predicted incident CVD in T1DM independently of smoking status and a wide range of confounding factors, including HDL-C, LDL-C, and triglyceride levels. Because SFTPB is almost entirely bound to plasma HDL, our observations support the proposal that SFTPB carried by HDL is a marker-and perhaps mediator-of CVD risk in patients with T1DM. 10.1016/j.jlr.2022.100196
    Milk polar lipids reduce lipid cardiovascular risk factors in overweight postmenopausal women: towards a gut sphingomyelin-cholesterol interplay. Vors Cécile,Joumard-Cubizolles Laurie,Lecomte Manon,Combe Emmanuel,Ouchchane Lemlih,Drai Jocelyne,Raynal Ketsia,Joffre Florent,Meiller Laure,Le Barz Mélanie,Gaborit Patrice,Caille Aurélie,Sothier Monique,Domingues-Faria Carla,Blot Adeline,Wauquier Aurélie,Blond Emilie,Sauvinet Valérie,Gésan-Guiziou Geneviève,Bodin Jean-Pierre,Moulin Philippe,Cheillan David,Vidal Hubert,Morio Béatrice,Cotte Eddy,Morel-Laporte Françoise,Laville Martine,Bernalier-Donadille Annick,Lambert-Porcheron Stéphanie,Malpuech-Brugère Corinne,Michalski Marie-Caroline Gut OBJECTIVE:To investigate whether milk polar lipids (PL) impact human intestinal lipid absorption, metabolism, microbiota and associated markers of cardiometabolic health. DESIGN:A double-blind, randomised controlled 4-week study involving 58 postmenopausal women was used to assess the chronic effects of milk PL consumption (0, 3 or 5 g-PL/day) on lipid metabolism and gut microbiota. The acute effects of milk PL on intestinal absorption and metabolism of cholesterol were assessed in a randomised controlled crossover study using tracers in ileostomy patients. RESULTS:Over 4 weeks, milk PL significantly reduced fasting and postprandial plasma concentrations of cholesterol and surrogate lipid markers of cardiovascular disease risk, including total/high-density lipoprotein-cholesterol and apolipoprotein (Apo)B/ApoA1 ratios. The highest PL dose preferentially induced a decreased number of intestine-derived chylomicron particles. Also, milk PL increased faecal loss of coprostanol, a gut-derived metabolite of cholesterol, but major bacterial populations and faecal short-chain fatty acids were not affected by milk PL, regardless of the dose. Acute ingestion of milk PL by ileostomy patients shows that milk PL decreased cholesterol absorption and increased cholesterol-ileal efflux, which can be explained by the observed co-excretion with milk sphingomyelin in the gut. CONCLUSION:The present data demonstrate for the first time in humans that milk PL can improve the cardiometabolic health by decreasing several lipid cardiovascular markers, notably through a reduced intestinal cholesterol absorption involving specific interactions in the gut, without disturbing the major bacterial phyla of gut microbiota. TRIAL REGISTRATION NUMBER:NCT02099032 and NCT02146339; Results. 10.1136/gutjnl-2018-318155
    SOAT1 is a new prognostic factor of colorectal cancer. Irish journal of medical science Colorectal cancer (CRC) is one of the most common malignant gastrointestinal cancers. Metastasis is the major leading cause of death in patients with CRC, and many patients treated with radical surgery were diagnosed with metastasis during follow-up. However, the underlying molecular mechanisms regulating CRC metastasis are still elusive. Sterol o-acyltransferase 1 (SOAT1) is a critical participant in maintaining intracellular cholesterol balance. Here, by analyzing the clinical specimens and in vitro cell line experiments, we evaluated the clinical relevance and role of SOAT1 in regulating CRC metastasis. The results revealed that SOAT1 was overexpressed in colon cancer tissues compared to peritumor tissues at mRNA and protein levels. High intratumor SOAT1 expression correlates to lymph node metastasis and indicates poor patient disease-free survival and overall survival. The silencing of SOAT1 strongly inhibited the migration and invasion ability of CRC tumor cells. These results demonstrated that SOAT1 was upregulated in colon cancer. Upregulation of SOAT1 expression may promote CRC progression by enhancing the migration and invasion ability of CRC. Our results indicate that targeting SOAT1 activity may be applied as a promising therapeutic strategy for preventing the metastasis of CRC after radical surgical treatment. 10.1007/s11845-021-02746-5
    Platelet number is positively and independently associated with glycated hemoglobin in non-diabetic overweight and obese subjects. De Pergola G,Giagulli V A,Guastamacchia E,Bartolomeo N,Tatoli R,Lampignano L,Silvestris F,Triggiani V Nutrition, metabolism, and cardiovascular diseases : NMCD BACKGROUND AND AIMS:A significant increase in platelet count may be a risk factor for atherosclerotic cardiovascular disease. This study investigates the association between platelet number and glucose metabolism, evaluated by glycated hemoglobin (HbA1c) levels, in a apparently healthy population represented by overweight and obese subjects with normal glucose and HbA1c levels. METHODS AND RESULTS:As many as 240 subjects, 177 women and 63 men, aged 18-70 years, were enrolled. Body mass index (BMI), waist circumference (WC), systolic and diastolic blood pressure levels, platelet count and fasting blood glucose, insulin, insulin resistance, HbA1c, uric acid, triglyceride, total cholesterol, high and low density lipoprotein cholesterol concentrations were evaluated. Concerning the univariate correlation analyses between platelets number and all other variables, platelet count was significantly (and positively) correlated only with HbA1c (P < 0.05) and female sex (P < 0.01). HbA1c (P < 0.05), female sex (P < 0.001), and diastolic blood pressure (P < 0.01), positively, and age (P < 0.05) and systolic blood pressure (P < 0.05), negatively, were significantly and independently associated to platelet count in a final multiple regression analysis. CONCLUSION:This is the first study showing a strong positive and independent relationship between HbA1c and platelet number in non-diabetic overweight and obese subjects. 10.1016/j.numecd.2018.12.007
    High-density lipoprotein as a modulator of platelet and coagulation responses. van der Stoep Marco,Korporaal Suzanne J A,Van Eck Miranda Cardiovascular research Platelets and coagulation factors are involved in the process of haemostasis, which ensures undisturbed blood flow upon vessel wall damage. However, excessive platelet aggregation and/or coagulation may lead to arterial or venous thrombosis. Pro-atherogenic lipoproteins, including native and oxidized low-density lipoprotein (LDL), are associated with an increased susceptibility to thrombosis. In contrast, numerous epidemiological studies have established an inverse correlation between high-density lipoprotein (HDL) levels and the risk for thrombosis. In addition to its role in reverse cholesterol transport, HDL also interacts with platelets, the coagulation cascade, and the vascular endothelium. Native HDL prevents platelet hyperreactivity by limiting intraplatelet cholesterol overload, as well as by modulating platelet signalling pathways after binding platelet HDL receptors such as scavenger receptor class B type I (SR-BI) and apoER2'. The antithrombotic properties of native HDL are also related to the suppression of the coagulation cascade and stimulation of clot fibrinolysis. Furthermore, HDL stimulates the endothelial production of nitric oxide and prostacyclin, which are potent inhibitors of platelet activation. Thus, HDL's antithrombotic actions are multiple and therefore, raising HDL may be an important therapeutic strategy to reduce the risk of arterial and venous thrombosis. 10.1093/cvr/cvu137
    The relation of mean platelet volume with microalbuminuria and glomerular filtration rate in obese individuals without other metabolic risk factors: the role of platelets on renal functions. Esen Bennur,Atay Ahmet Engin,Gunoz Nalan,Gokmen Emel Saglam,Sari Hakan,Cakir Ilkay,Kayabasi Hasan,Sit Dede Clinical nephrology INTRODUCTION:Mean platelet volume (MPV) is an indirect indicator of platelet activity that plays a major role in the pathogenesis of endothelial injury. Obese individuals have higher microalbuminuria which is the initial step of renal endothelial injury. We aimed to analyze the relation of microalbuminuria and MPV in obese individuals without metabolic risk factors. METHODS:A total of 290 obese individuals (body mass index (BMI)>30 kg/m2) without an accompanying chronic disorder, and 204 nonobese healthy subjects were enrolled into the study. All participants underwent physical examination. Biochemical, hemogram, and hormonal parameters along with urine albumin analysis were performed. Glomerular filtration rate (GFR) was measured by Cockcroft-Gault (GFRC&G), modification of diet in renal disease (MDRD). The BMI was calculated as weight/height2 (kg/m2). Logistic regression analysis was used to analyze relation of variables. RESULTS:The patient group consisted of 171 (59%) female (mean age: 37.15±8.05 years) and 119 (41%) male (mean age 38.98±10.68 years) obese individuals. 130 (63.7%) age matched female (mean age 36.18±8.26 years) and 74 (36.3%) age matched male (mean age 36.49±10.25 years) controls were assigned to the control group. There was a significant difference between groups with regard to BMI, spot microalbuminuria, spot urine microalbuminuria/creatinine ratio but not with to MPV and spot urine creatinine (p: 0.01, 0.004, 0.002; respectively). GFR measured by MDRD and Cockcroft-Gault formula were significantly higher in the obese group (p<0.001 for both). Correlation analysis revealed a significant correlation between BMI and spot urine microalbuminuria, spot urine microalbuminuria/creatinine ratio, GFR (Cockcroft-Gault Formula), Homeostasis Model Assessment of Insulin resistance (HOMA-IR), insulin, C-peptide, diastolic blood pressure, glucose, uric acid, total cholesterol, low density lipoprotein (LDL)-cholesterol, c-reactive protein (CRP), thyroid stimulating hormone (TSH), leukocyte count, platelet count. MPV was inversely and significantly correlated with spot urine creatinine, systolic blood pressure, triglyceride, C-peptide, and platelet count. Mean urea, creatinine, uric acid, triglyceride, total cholesterol, LDL-cholesterol, insulin, C-peptide, HOMA-IR were significantly higher in obese male individuals while obese female individuals had higher levels of mean high density lipoprotein (HDL), CRP, TSH, platelet count, spot urine microalbumin/creatinine rate, and GFR measured by MDRD. CONCLUSIONS:Obese individuals have higher microalbuminuria and nonsignificantly elevated MPV, however, urine albumin loss is independent of MPV. 10.5414/CN108534
    Relationship between serum cholesterol and indices of erythrocytes and platelets in the US population. Fessler Michael B,Rose Kathryn,Zhang Yanmei,Jaramillo Renee,Zeldin Darryl C Journal of lipid research Whereas dyslipidemia has been associated with leukocytosis, the relationship between serum cholesterol and other hematopoietic lineages is poorly defined. Erythrocytes and platelets, anucleate cells relegated to nonspecific diffusional exchange of cholesterol with serum, have been proposed to have a distinct relationship to cholesterol from leukocytes. We examined the relationship between serum cholesterol and circulating erythrocyte/platelet indices in 4,469 adult participants of the National Health and Nutrition Examination Survey (NHANES) 2005-2006. In linear regression analyses, serum non-high density lipoprotein-cholesterol (non-HDL-C) was positively associated with mean erythrocyte number, hematocrit, hemoglobin concentration, platelet count, and platelet crit independently of age, gender, race/ethnicity, smoking, body mass index, serum folate, and C-reactive protein. The magnitude of the relationship was most marked for platelets, with lowest versus highest non-HDL-C quartile subjects having geometric mean platelet counts of 258,000/μl versus 281,000/μl, respectively (adjusted model, P < 0.001 for trend). These associations persisted in a sensitivity analysis excluding several conditions that affect erythrocyte/platelet and/or serum cholesterol levels, and were also noted in an independent analysis of 5,318 participants from NHANES 2007-2008. As non-HDL-C, erythrocytes, and platelets all impact cardiovascular disease risk, there is a need for advancing understanding of the underlying interactions that govern levels of these three blood components. 10.1194/jlr.P037614
    The platelet to high density lipoprotein -cholesterol ratio is a valid biomarker of nascent metabolic syndrome. Jialal Ishwarlal,Jialal Ganesh,Adams-Huet Beverley Diabetes/metabolism research and reviews AIMS:The metabolic syndrome (MetS) is a major global problem, and inflammation and insulin resistance appear to be key underpinnings in this cardio-metabolic cluster. MetS predisposes to an increased risk of diabetes and atherosclerotic cardiovascular disease (ASCVD). It has a procoagulant diathesis which included increased platelet activity and impaired fibrinolysis. High density lipoprotein (HDL) appears to be anti-thrombotic. Accordingly, we examined the ratios between platelets to HDL-cholesterol(C) and adiponectin (Adipo) in patients with nascent MetS without the confounding of diabetes, ASCVD and smoking to determine their validity as biomarkers of MetS. METHODS:Patients with nascent MetS (n = 58) and matched controls (n = 44) were recruited. Fasting blood samples were obtained for complete blood counts, basic metabolic panel, lipids, insulin, and Adipo. Ratios of platelets to HDL-C and Adipo were calculated. RESULTS:Following adjustment for adiposity, only the platelet: HDL ratio was significantly increased in MetS and increased with severity of MetS. Receiver operating characteristic curve analysis showed that the platelet: HDL-C area under the curve (AUC) significantly added to both platelets and platelet lymphocyte ratio AUCs. Also the platelet: HDL-C ratio correlated with all cardio-metabolic features of MetS, high sensitivity C-reactive protein, insulin resistance chemerin, and leptin. CONCLUSIONS:The ratio of platelets: HDL-C is significantly increased in patients with nascent MetS and appear to be a valid biomarker of MetS. It could also emerge as a biomarker for athero-thrombotic risk. However, these preliminary findings need confirmation in large prospective studies. 10.1002/dmrr.3403
    Prediction of gestational diabetes mellitus in the first 19 weeks of pregnancy using machine learning techniques. The journal of maternal-fetal & neonatal medicine : the official journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal Obstetricians AIM:Our objective was to develop a first 19 weeks risk prediction model with several potential gestational diabetes mellitus (GDM) predictors including hepatic and renal and coagulation function measures. METHODS:A total of 490 pregnant women, 215 with GDM and 275 controls, participated in this case-control study. Forty-three blood examination indexes including blood routine, hepatic and renal function, and coagulation function were obtained. Support vector machine (SVM) and light gradient boosting machine (lightGBM) were applied to estimate possible associations with GDM and build the predict model. Cutoff points were estimated using receiver operating characteristic curve analysis. RESULTS:It was observed that a cutoff of Prothrombin time (PAT-PT) and Activated partial thromboplastin time (PAT-APTT) could reliably predict GDM with sensitivity of 88.3% and specificity of 99.47% (AUC of 94.2%). If we only use hepatic and renal function examination, a cutoff of DBIL and FPG with sensitivity of 82.6% and specificity of 90.0% (AUC of 91.0%) was obvious and a negative correlation with PAT-PT (=-0.430549) and patient activated partial thromboplastin time (PAT-APTT) (=-0.725638). A negative correlation with direct bilirubin (DBIL) (=-0.379882) and positive correlation with fasting plasma glucose (FPG) ( = 0.458332) neglect coagulation function examination. CONCLUSION:The results of this study point out the possible roles of PAT-PT and PAT-APTT as potential novel biomarkers for the prediction and earlier diagnosis of GDM. A first 19 weeks risk prediction model, which incorporates novel biomarkers, accurately identifies women at high risk of GDM, and relevant measures can be applied early to achieve the prevention and control effects. 10.1080/14767058.2020.1786517
    A unified framework identifies new links between plasma lipids and diseases from electronic medical records across large-scale cohorts. Nature genetics Plasma lipids are known heritable risk factors for cardiovascular disease, but increasing evidence also supports shared genetics with diseases of other organ systems. We devised a comprehensive three-phase framework to identify new lipid-associated genes and study the relationships among lipids, genotypes, gene expression and hundreds of complex human diseases from the Electronic Medical Records and Genomics (347 traits) and the UK Biobank (549 traits). Aside from 67 new lipid-associated genes with strong replication, we found evidence for pleiotropic SNPs/genes between lipids and diseases across the phenome. These include discordant pleiotropy in the HLA region between lipids and multiple sclerosis and putative causal paths between triglycerides and gout, among several others. Our findings give insights into the genetic basis of the relationship between plasma lipids and diseases on a phenome-wide scale and can provide context for future prevention and treatment strategies. 10.1038/s41588-021-00879-y
    Novel Role of T Cells and IL-6 (Interleukin-6) in Angiotensin II-Induced Microvascular Dysfunction. Senchenkova Elena Y,Russell Janice,Yildirim Alper,Granger D Neil,Gavins Felicity N E Hypertension (Dallas, Tex. : 1979) Hypertension is an established risk factor for subsequent cardiovascular diseases, with Ang II (angiotensin II) playing a major role in mediating thrombotic and inflammatory abnormalities. Although T cells and IL-6 (interleukin-6) play an important role in adaptive immune responses, little is known about their role(s) in the thromboinflammatory responses associated with Ang II. Here we show using intravital microscopy coupled with the light/dye injury model that Rag-1 deficient (Rag-1) and IL-6 deficient (IL-6) mice are afforded protection against Ang II-induced thrombosis. Blocking IL-6 receptors (using CD126 and gp130 antibodies) significantly diminished Ang II-mediated thrombosis and inflammatory cell recruitment in mice. Furthermore, the adoptive transfer of IL-6-derived T cells into Rag-1 mice failed to accelerate Ang II-induced thrombosis compared with Rag-1 mice reconstituted with wild-type-derived T cells, suggesting T cell IL-6 mediates the thrombotic abnormalities associated Ang II hypertension. Interestingly, adoptive transfer of WT T cells into Rag-1/Ang II mice resulted in increased numbers of immature platelets, which constitutes a more active platelet population, that is, prothrombotic and proinflammatory. To translate our in vivo findings, we used clinical samples to demonstrate that IL-6 also predisposes platelets to an interaction with collagen receptors, thereby increasing the propensity for platelets to aggregate and cause thrombosis. In summary, we provide compelling evidence for the involvement of IL-6, IL-6R, and T-cell-dependent IL-6 signaling in Ang II-induced thromboinflammation, which may provide new therapeutic possibilities for drug discovery programs for the management of hypertension. 10.1161/HYPERTENSIONAHA.118.12286
    Diabetic ketoacidosis. Dhatariya Ketan K,Glaser Nicole S,Codner Ethel,Umpierrez Guillermo E Nature reviews. Disease primers Diabetic ketoacidosis (DKA) is the most common acute hyperglycaemic emergency in people with diabetes mellitus. A diagnosis of DKA is confirmed when all of the three criteria are present - 'D', either elevated blood glucose levels or a family history of diabetes mellitus; 'K', the presence of high urinary or blood ketoacids; and 'A', a high anion gap metabolic acidosis. Early diagnosis and management are paramount to improve patient outcomes. The mainstays of treatment include restoration of circulating volume, insulin therapy, electrolyte replacement and treatment of any underlying precipitating event. Without optimal treatment, DKA remains a condition with appreciable, although largely preventable, morbidity and mortality. In this Primer, we discuss the epidemiology, pathogenesis, risk factors and diagnosis of DKA and provide practical recommendations for the management of DKA in adults and children. 10.1038/s41572-020-0165-1
    Risk factors for retinopathy in hemodialysis patients with type 2 diabetes mellitus. Scientific reports There is limited knowledge on the prevalence and risk factors of diabetic retinopathy (DR) in dialysis patients. We have investigated the association between diabetes mellitus and lipid-related biomarkers and retinopathy in hemodialysis patients. We reviewed 1,255 hemodialysis patients with type 2 diabetes mellitus (T2DM) who participated in the German Diabetes and Dialysis Study (4D Study). Associations between categorical clinical, biochemical variables and diabetic retinopathy were examined by logistic regression. On average, patients were 66 ± 8 years of age, 54% were male and the HbA1c was 6.7% ± 1.3%. DR, found in 71% of the patients, was significantly and positively associated with fasting glucose, HbA1c, time on dialysis, age, systolic blood pressure, body mass index and the prevalence of other microvascular diseases (e.g. neuropathy). Unexpectedly, DR was associated with high HDL cholesterol and high apolipoproteins AI and AII. Patients with coronary artery disease were less likely to have DR. DR was not associated with gender, smoking, diastolic blood pressure, VLDL cholesterol, triglycerides, and LDL cholesterol. In summary, the prevalence of DR in patients with type 2 diabetes mellitus requiring hemodialysis is higher than in patients suffering from T2DM, who do not receive hemodialysis. DR was positively related to systolic blood pressure (BP), glucometabolic control, and, paradoxically, HDL cholesterol. This data suggests that glucose and blood pressure control may delay the development of DR in patients with diabetes mellitus on dialysis. 10.1038/s41598-020-70998-9
    Zinc, copper, and oxysterol levels in patients with type 1 and type 2 diabetes mellitus. Samadi Afshin,Isikhan Selen Yilmaz,Tinkov Alexey A,Lay Incilay,Doşa Monica Daniela,Skalny Anatoly V,Skalnaya Margarita G,Chirumbolo Salvatore,Bjørklund Geir Clinical nutrition (Edinburgh, Scotland) BACKGROUND:The present study has the objective to assess the zinc (Zn), copper (Cu), and oxysterols plasma levels in type 1 (DM1) (n = 26) and type 2 (DM2) (n = 80) diabetes patients, as compared to healthy controls (n = 71), in order to testify whether metal levels may have a significant impact on the association between oxysterols and diabetes. METHODS:Plasma trace elements and plasma oxysterols were assessed using atomic absorption spectrometry and LC-MS/MS, respectively. Lifestyle, smoking status, alcohol intake, and drug usage, as well as microvascular complications, were also monitored and reported. RESULTS:The obtained data demonstrated that both DM1 and DM2 patients were characterized by significantly elevated HbA1c, FBG, TC, LDL-C, VLDL-C, and TG levels as compared to controls. Plasma Zn levels and Zn/Cu ratio in DM1 and DM2 patients were about 3- and 2-fold lower than controls. No significant differences in plasma Cu levels were reported. The 7-ketocholesterol (7-kchol) levels in DM1 and DM2 patients exceeded these values in healthy individuals by 2.5 and 5-fold, respectively. Similarly, cholestan-3β, 5α, 6β-triol (chol-triol) levels were more than 3- and 6-fold higher when compared to the respective values in non-diabetic controls. In regression models decreased plasma Zn and elevated oxysterol levels were significantly associated with HbA1c and fasting plasma glucose levels, after adjustment for anthropometric and clinical variables, as well as routine biochemical markers. CONCLUSIONS:Plasma Zn concentration is inversely associated with both 7-kchol and chol-triol levels. Assessment of Zn and oxysterol levels may be used both for risk assessment and as targets for the treatment of diabetes mellitus. 10.1016/j.clnu.2019.07.026
    Association of gamma-glutamyl transferase and alanine aminotransferase with type 2 diabetes mellitus incidence in middle-aged Japanese men: 12-year follow up. Journal of diabetes investigation AIMS/INTRODUCTION:To prospectively investigate whether simultaneous elevation of gamma-glutamyl transferase (GGT) and alanine aminotransferase (ALT) is associated with the increase of type 2 diabetes mellitus incidence independent of alcohol drinking, body mass index and triglycerides. METHODS:A total of 2,775 Japanese male workers who had no history of type 2 diabetes mellitus were followed. High GGT and ALT were defined as the top tertiles (GGT cutpoint: 49 IU/L, ALT cutpoint: 28 IU/L). Three groups were created using these dichotomized GGT and ALT cutpoints: both low, either high or both high. Multivariable Cox proportional hazards models were carried out adjusted for potential confounding factors. RESULTS:A total of 276 type 2 diabetes mellitus cases were identified during 12 years (27,040 person-years) of follow up. Participants with simultaneously elevated GGT and ALT had a significantly higher incidence of type 2 diabetes mellitus, even after adjustment for fasting insulin and fasting blood glucose compared with the group without GGT or ALT elevation. Similar associations were observed in non- or light-to-moderate alcohol drinkers, as well as in participants with normal weight. However, the association was weaker in participants with triglycerides <150 mg/dL. We then evaluated whether the addition of GGT and ALT would improve the prediction of type 2 diabetes mellitus incidence, and found that their inclusion significantly increased the C-statistic, net reclassification improvement and integrated discrimination improvement. CONCLUSIONS:Simultaneous elevation of GGT and ALT was significantly associated with type 2 diabetes mellitus incidence, independent of potential confounding factors, including alcohol drinking and obesity, although the association might require concomitant elevation of triglycerides. Inclusion of GGT and ALT improved type 2 diabetes mellitus risk prediction. 10.1111/jdi.12930
    Higher level of GGT during mid-pregnancy is associated with increased risk of gestational diabetes mellitus. Kong Man,Liu Chaoqun,Guo Yanfang,Gao Qing,Zhong Chunrong,Zhou Xuezhen,Chen Renjuan,Xiong Guoping,Yang Xuefeng,Hao Liping,Yang Nianhong Clinical endocrinology OBJECTIVE:This study was to explore the link between gamma-glutamyl transferase (GGT), alanine transaminase (ALT) and aspartate transaminase (AST) levels during early-middle pregnancy and subsequent risk of gestational diabetes mellitus (GDM). METHODS:In a prospective cohort study, pregnant women enrolled prior to 16 weeks of gestation were followed up until delivery. GGT, AST and ALT levels were tested during weeks 14-18 of gestation and oral glucose tolerance test was conducted during 24-28 weeks to screen GDM. RESULTS:The GDM rate was 8.1% (122/1512). Mean GGT level was higher in GDM than non-GDM women (18.7 ± 13.0 vs 14.5 ± 7.0, P < .001). The higher GGT level was 26.9~74.0 U/L, which was significantly associated with increased risk of GDM. The adjusted RR (95% CI) comparing higher GGT level versus lower was 5.40 (3.36-8.68). No significant correlation was found between ALT or AST levels and the risk of GDM. CONCLUSIONS:The results suggest that pregnant women with higher serum GGT during early-middle pregnancy have higher risk of developing GDM. A GGT level >26.9 U/L may indicate an increased risk of developing GDM later and should be further concerned. 10.1111/cen.13558
    Could non-HDL-cholesterol be a better marker of atherogenic dyslipidemia in obstructive sleep apnea? Basoglu Ozen K,Tasbakan Mehmet S,Kayikcioglu Meral Sleep medicine BACKGROUND/OBJECTIVE:Obstructive sleep apnea (OSA) is independently associated with dyslipidemia, a surrogate marker of atherosclerosis. Low-density lipoprotein (LDL)-cholesterol is accepted as a major independent risk factor for cardiovascular disease. However, non-high-density lipoprotein (HDL)-cholesterol is a better marker of atherogenic dyslipidemia and recommended as a target of lipid lowering therapy. We aimed to assess the prevalence of atherogenic dyslipidemia, and relationship between OSA severity and serum LDL-cholesterol and non-HDL cholesterol levels in OSA patients. METHODS:We retrospectively evaluated treatment naïve 2361 subjects admitted to the sleep laboratory of a university hospital for polysomnography. All subjects' lipid profile including total cholesterol, LDL-cholesterol, HDL-cholesterol, triglycerides, and non-HDL-cholesterol were measured. RESULTS:Out of 2361 patients (mean age 49.6 ± 11.9 years; 68.9% male, apnea-hypopnea index 36.6 ± 28.4/h), 185 (7.8%) had no OSA and 2176 (92.2%) had OSA. Atherogenic dyslipidemia prevalence was high (57-66%) in OSA patients, and especially increased in severe OSA compared to other groups (p < 0.05). Though total and LDL-cholesterol did not differ between those with and without OSA, non-HDL-cholesterol (p = 0.020), and triglycerides (p = 0.001) were higher and HDL-cholesterol levels (p = 0.018) were lower in OSA patients than non-OSA. Non-HDL-cholesterol was significantly correlated with OSA severity (p < 0.001) and hypoxia parameters (p < 0.01), whereas LDL-cholesterol showed no correlation. CONCLUSIONS:Atherogenic dyslipidemia is highly prevalent and non-HDL-cholesterol levels are significantly increased, predominantly in severe OSA patients. Non-HDL-cholesterol but not LDL-cholesterol, is significantly correlated with OSA severity and hypoxia parameters. Therefore, it could be better to use non-HDL-cholesterol, which is a guideline recommended target of lipid therapy, as a marker of atherosclerotic cardiovascular risk in OSA patients. 10.1016/j.sleep.2021.09.021
    The role of the plasma glycosylated hemoglobin A1c/Apolipoprotein A-l ratio in predicting cardiovascular outcomes in acute coronary syndrome. Song Feier,Zhou Yu,Zhang Kunyi,Liang Yuan-Feng,He Xuyu,Li Liwen Nutrition, metabolism, and cardiovascular diseases : NMCD BACKGROUND AND AIMS:Glucose and lipid metabolism are major prognostic indicators of coronary heart disease. The ratio of plasma glycosylated hemoglobin A1c (HbA1c) to apolipoprotein A-l (ApoA-l) is an indirect measure of insulin resistance. The study aimed to evaluate whether the HbA1c/ApoA-1 ratio can predict the prognosis in patients with the acute coronary syndrome (ACS). METHODS AND RESULTS:A total of 476 ACS patients diagnosed by coronary angiography were enrolled in this longitudinal, observational, retrospective study. Plasma HbA1c, fasting blood glucose and lipid profile were measured. Patients were stratified according to the tertiles of HbA1c/ApoA-l levels. Cox proportional hazard model was used to examine the predictive value of HbA1c/ApoA-l for study endpoints. The association between the Log HbA1c/ApoA-l ratio and major adverse cardiovascular events (MACEs) was estimated using multiple logistic regression. Baseline characteristics showed a mean age of 66 ± 8 years, and 52.5% were hypertensive, 26.8% diabetic, and 54.5% current or prior smokers. During a mean follow-up period of 22.3 ± 1.7 months, 59 deaths occurred. After adjusting for age, gender, smoking, hypertension, diabetes, and coronary artery disease severity, patients in the highest HbA1c/ApoA-l ratio tertile had a 4.36-fold increased risk of mortality compared with those in the lowest tertile. The multivariate logistic regression showed that the Log HbA1c/ApoA-l ratio was associated with MACEs (Odds ratio 2.95, p = 0.013). CONCLUSION:After adjusting for traditional cardiovascular risk factors and ACS severity scores, the HbA1c/ApoA-1 ratio remained an independent predictor of all-cause mortality and MACEs in the ACS patients undergoing angiography. 10.1016/j.numecd.2020.10.008
    Associations between TG/HDL ratio and insulin resistance in the US population: a cross-sectional study. Endocrine connections BACKGROUND:Clinical data on the relationship between triglycerides (TG)/HDL ratio and insulin resistance (IR) suggest that TG/HDL ratio may be a risk factor for IR. However, there is evidence that different races have different risk of developing IR. The relationship on TG/HDL ratio and IR in various populations needs to be improved. Therefore, we investigated whether TG/HDL ratio was linked to IR in different groups in the United States after controlling for other covariates. METHODS:The current research was conducted in a cross-sectional manner. From 2009 to 2018, the National Health and Nutrition Examination Survey (NHANES) had a total of 49,696 participants, all of whom were Americans. The target-independent variable was TG/HDL ratio measured at baseline, and the dependent variable was IR. Additionally, the BMI, waist circumference, education, race, smoking, alcohol use, alanine transaminase, aspartate transaminase, and other covariates were also included in this analysis. RESULTS:The average age of the 10,132 participants was 48.6 ± 18.4 years, and approximately 4936 (48.7%) were males. After correcting for confounders, fully adjusted logistic regression revealed that TG/HDL ratio was correlated with IR (odds ratio = 1.51, 95% CI 1.42-1.59). A nonlinear interaction between TG/HDL ratio and IR was discovered, with a point of 1.06. The impact sizes and CIs on the left and right sides of the inflection point were 6.28 (4.66-8.45) and 1.69 (1.45-1.97), respectively. According to subgroup analysis, the correlation was strong in females, alcohol users, and diabetes patients. Meanwhile, the inverse pattern was observed in the aged, obese, high-income, and smoking populations. CONCLUSION:In the American population, the TG/HDL ratio is positively associated with IR in a nonlinear interaction pattern. 10.1530/EC-21-0414
    Is a High HDL-Cholesterol Level Always Beneficial? Franczyk Beata,Rysz Jacek,Ławiński Janusz,Rysz-Górzyńska Magdalena,Gluba-Brzózka Anna Biomedicines The specific interest concerning HDL cholesterol (HDL-C) is related to its ability to uptake and return surplus cholesterol from peripheral tissues back to the liver and, therefore, to its role in the prevention of cardiovascular diseases, such as atherosclerosis and myocardial infarction, but also transient ischemic attack and stroke. Previous epidemiological studies have indicated that HDL-C concentration is inversely associated with the risk of cardiovascular disease and that it can be used for risk prediction. Some genetic disorders are characterized by markedly elevated levels of HDL-C; however, they do not translate into diminished cardiovascular risk. The search of the potential causative relationship between HDL-C and adverse events has shifted the attention of researchers towards the composition and function of the HDL molecule/subfractions. HDL possesses various cardioprotective properties. However, currently, it appears that higher HDL-C is not necessarily protective against cardiovascular disease, but it can even be harmful in extremely high quantities. 10.3390/biomedicines9091083
    TG/HDL Ratio: A marker for insulin resistance and atherosclerosis in prediabetics or not? Journal of family medicine and primary care BACKGROUND:The spectrum of Diabetes Mellitus and various complications associated with it have been regarded as major global health challenges. Raised TG/HDL has been regarded as one of the valid markers for Insulin resistance. It leads to increased risk of CVD by causing Insulin resistance and also by its own effect on the vessel wall. Detection of raised TG/HDL ratio and early intervention before the patients develop clinical disease can help in mitigation of future consequences of CVD. AIMS:The aim of our study was to compare TG/HDL ratio between prediabetics and controls and further to look for any correlation between the TG/HDL ratio value with HOMA-IR and Carotid Intima Media Thickness (CIMT) in prediabetics. SETTINGS AND DESIGNS:A cross sectional study. METHODS AND MATERIAL:Study was done at ABVIMS and Dr RML Hospital, New Delhi. 60 prediabetics and 60 age, sex, BMI matched controls were employed. In both cases and controls fasting and postprandial blood glucose, glycated Hemoglobin (HbA1C) and fasting Insulin levels were measured. HOMA-IR values in both the groups were calculated using fasting glucose and Insulin levels. Serum lipid profile was obtained and TG/HDL ratio was analysed in two groups. Values obtained were compared between the two groups. CIMT was only measured in cases using B mode ultrasonography. STATISTICAL ANALYSIS AND RESULTS:Median (IQR) of fasting plasma Insulin (μIU/ml) in cases was 11.3 (10.175-13.505) versus that in controls being 5.73 (4.3-7.1). HOMA-IR (IQR) values in cases and controls were 3.12 (2.73 - 3.595) and 1.21 (0.918 - 1.505) respectively. Median (IQR) for TG/HDL ratio was 3.26 (2.712 - 4) for cases and 2.05 (1.755- 2.502) for controls. However no correlation was observed between either the mean CIMT (mm) or HOMA-IR with TG/HDL ratio. CONCLUSIONS:Diabetes Mellitus and its various complications are of a great burden to society. Diagnosing the risk factors early before the onset of these manifestations can help us in combating these major issues. One of the risk factors among them is raised TG/HDL ratio. Early detection of elevated TG/HDL in prediabetics may serve in early detection of atherosclerotic complications and help physicians in framing primary preventive strategies for tackling ASCVD in patients with prediabetes and full-blown Diabetes. 10.4103/jfmpc.jfmpc_165_21
    Disturbances of the transfer of cholesterol to high-density lipoprotein (HDL) in patients with peripheral artery disease with or without type 2 diabetes mellitus. Vascular medicine (London, England) INTRODUCTION:Low high-density lipoprotein (HDL)-cholesterol is frequent in patients with peripheral artery disease (PAD) and also in type 2 diabetes mellitus (T2DM), the major risk factor for PAD. The transfer of cholesterol from the other lipoproteins to HDL is an important aspect of HDL metabolism and function, and may contribute to atherogenic mechanisms that lead to PAD development. OBJECTIVE:The aim of this study was to investigate the status of cholesterol transfers in patients with PAD without or with T2DM. METHODS:Patients with PAD ( = 19), with PAD and T2DM (PAD + DM, = 19), and healthy controls ( = 20), all paired for age, sex, and BMI were studied. Transfer of both forms of cholesterol, unesterified (UC) and esterified (EC), was performed by incubating plasma with a donor nanoemulsion containing radioactive UC and EC, followed by chemical precipitation and HDL radioactive counting. RESULTS:Low-density lipoprotein (LDL)-cholesterol and triglycerides were similar in the three groups. Compared to controls, HDL-C was lower in PAD + DM ( < 0.05), but not in PAD. Transfer of UC was lower in PAD + DM than in PAD and controls (4.18 ± 1.17%, 5.13 ± 1.44%, 6.59 ± 1.25%, respectively, < 0.001). EC transfer tended to be lower in PAD + DM than in controls (2.96 ± 0.60 vs 4.12 ± 0.89%, = 0.05). Concentrations of cholesteryl ester transfer protein (CETP) and lecithin-cholesterol acyltransferase (LCAT), both involved in HDL metabolism, were not different among the three groups. CONCLUSION:Deficient cholesterol transfer to HDL may play a role in PAD pathogenesis. Since UC transfer to HDL was lower in PAD + DM compared to PAD alone, it is possible that defective HDL metabolism may contribute to the higher PAD incidence in patients with T2DM.Keywords. 10.1177/1358863X211021142
    The Reciprocal Relationship between LDL Metabolism and Type 2 Diabetes Mellitus. Bonilha Isabella,Hajduch Eric,Luchiari Beatriz,Nadruz Wilson,Le Goff Wilfried,Sposito Andrei C Metabolites Type 2 diabetes mellitus and insulin resistance feature substantial modifications of the lipoprotein profile, including a higher proportion of smaller and denser low-density lipoprotein (LDL) particles. In addition, qualitative changes occur in the composition and structure of LDL, including changes in electrophoretic mobility, enrichment of LDL with triglycerides and ceramides, prolonged retention of modified LDL in plasma, increased uptake by macrophages, and the formation of foam cells. These modifications affect LDL functions and favor an increased risk of cardiovascular disease in diabetic individuals. In this review, we discuss the main findings regarding the structural and functional changes in LDL particles in diabetes pathophysiology and therapeutic strategies targeting LDL in patients with diabetes. 10.3390/metabo11120807
    Peri-operative monocyte count is a marker of poor prognosis in gastric cancer: increased monocytes are a characteristic of myeloid-derived suppressor cells. Urakawa Shinya,Yamasaki Makoto,Goto Kumiko,Haruna Miya,Hirata Michinari,Morimoto-Okazawa Akiko,Kawashima Atsunari,Iwahori Kota,Makino Tomoki,Kurokawa Yukinori,Yamada Tomomi,Mori Masaki,Doki Yuichiro,Wada Hisashi Cancer immunology, immunotherapy : CII Gastric cancer (GC) is the most common malignant tumor in digestive organs, and the prognosis of GC patients who have undergone surgery remains poor because of frequent recurrence. Therefore, the identification of new markers to predict the outcome of these patients is needed. Monocyte count is a negative prognostic factor associated with inflammation. We investigated the relationship between peripheral monocytes in the peri-operative period and prognosis in GC patients. A high pre-operative monocyte count was identified as a prognostic factor in a retrospective analysis of 278 stage II and III GC patients who underwent curative gastrectomy. In contrast, an increased post-operative monocyte count compared to the pre-operative monocyte count was a marker of poor prognosis, particularly for early relapse. In a prospective analysis of 75 GC patients, a subset of the increased post-operative monocytes was similar to CD14 HLA-DR CD11b CD33 cells by flow cytometry, and these monocytes produced IDO and arginase and suppressed T cell functions; therefore, we classified these cells as monocytic myeloid-derived suppressive cells (M-MDSCs). Peri-operative neutrophils and C-reactive protein (CRP), which are also related to inflammation, did not affect the prognosis of GC patients, and a neutrophil immunosuppressive function was not observed. These results suggest that peripheral monocytes in the peri-operative period in GC patients are a useful marker for the prognosis of GC patients, and a subset of increased post-operative monocytes may be characterized as M-MDSCs. 10.1007/s00262-019-02366-0
    Decline of serum CA724 as a probable predictive factor for tumor response during chemotherapy of advanced gastric carcinoma. Zou Li,Qian Jun Chinese journal of cancer research = Chung-kuo yen cheng yen chiu OBJECTIVE:To evaluate the predictive value of decline in the serum level of carbohydrate antigen 724 (CA724) on tumor response during the chemotherapy in patients with advanced gastric carcinoma (GC). METHODS:The serum CA724 level was determined by electrochemiluminescence immunoassay, while the objective response rate (ORR) was assessed according to response evaluation criteria in solid tumors (RECIST). The association of the changes of serum concentration of CA724 with ORR was analyzed. RESULTS:The ORR in CA724 (pretreatment serum level) high and low groups was 32.3% (20/62) and 52.8% (19/36), respectively (P=0.045). The relationship between the reduction of CA724 and the ORR was statistically significant (P=0.044). Receiver operating characteristic (ROC) curve established the best cutoff value of the decrease ratio of CA724 as 20.5%. CONCLUSIONS:CA724 decline seems to indicate chemotherapy efficacy in patients with advanced GC, and an average drop of 20.5% in serum CA724 appears to predict the sensitivity to chemotherapy. 10.3978/j.issn.1000-9604.2014.07.02
    Bilirubin as a metabolic hormone: the physiological relevance of low levels. Creeden Justin F,Gordon Darren M,Stec David E,Hinds Terry D American journal of physiology. Endocrinology and metabolism Recent research on bilirubin, a historically well-known waste product of heme catabolism, suggests an entirely new function as a metabolic hormone that drives gene transcription by nuclear receptors. Studies are now revealing that low plasma bilirubin levels, defined as "hypobilirubinemia," are a possible new pathology analogous to the other end of the spectrum of extreme hyperbilirubinemia seen in patients with jaundice and liver dysfunction. Hypobilirubinemia is most commonly seen in patients with metabolic dysfunction, which may lead to cardiovascular complications and possibly stroke. We address the clinical significance of low bilirubin levels. A better understanding of bilirubin's hormonal function may explain why hypobilirubinemia might be deleterious. We present mechanisms by which bilirubin may be protective at mildly elevated levels and research directions that could generate treatment possibilities for patients with hypobilirubinemia, such as targeting of pathways that regulate its production or turnover or the newly designed bilirubin nanoparticles. Our review here calls for a shift in the perspective of an old molecule that could benefit millions of patients with hypobilirubinemia. 10.1152/ajpendo.00405.2020
    Anti-hepatic fibrosis effects of AD-2 affecting the Raf-MEK signaling pathway and inflammatory factors in thioacetamide-induced liver injury. Li Tao,Su GuangYue,Zhao YuQing Journal of food science 25-Hydroxylprotopanaxadiol-3β, 12β, 20-triol (25-OH-PPD or AD-2) belongs to dammarane ginsenoside, and is commonly obtained from the acidic hydrolysate of total ginsensides of Panax ginseng. This study investigated the potential mechanism of AD-2 toward improving thioacetamide (TAA)-induced hepatic fibrosis in mice. Mice were divided into seven groups: control group, TAA model group, TAA + AD-2 (5, 10, and 20 mg/kg) groups, TAA + silymarin (100 mg/kg) group, and TAA + Fu Fang Biejia (FFBj; 300 mg/kg) group. All mice were treated to intraperitoneal TAA injection to establish a hepatic fibrosis model, and drugs were administered orally. The mechanism and related pathways underlying the AD-2-mediated action against hepatic fibrosis were explored by Western blotting and immunohistochemical staining. After AD-2 treatment, the expression levels of Lipin-1, SREBP1, and F4/80 significantly decreased, meanwhile the protein expressions levels of IL1β, IL1R1, IL18, Bax, Bid, Bcl-2, and cFlips also decreased. Furthermore, AD-2 inhibited RAF and MEK pathways. The results demonstrate that AD-2 can alleviate hepatic fibrosis. The mechanism is likely related to the regulation of lipid accumulation, inflammatory response, apoptosis pathway, and Raf-MEK signaling pathways, which provide a basis for clinical research for the treatment of hepatic fibrosis. PRACTICAL APPLICATION: Ginsenoside is one of the main active ingredients of ginseng, and can alleviate the symptoms of various diseases, for example, hepatic fibrosis. This paper mainly used Western blotting to explore its possible mechanism of action. The goal was to provide a reference for the development of traditional Chinese medicines for hepatic fibrosis. 10.1111/1750-3841.15731
    Magnesium status and supplementation influence vitamin D status and metabolism: results from a randomized trial. Dai Qi,Zhu Xiangzhu,Manson JoAnn E,Song Yiqing,Li Xingnan,Franke Adrian A,Costello Rebecca B,Rosanoff Andrea,Nian Hui,Fan Lei,Murff Harvey,Ness Reid M,Seidner Douglas L,Yu Chang,Shrubsole Martha J The American journal of clinical nutrition Background:Previous in vitro and in vivo studies indicate that enzymes that synthesize and metabolize vitamin D are magnesium dependent. Recent observational studies found that magnesium intake significantly interacted with vitamin D in relation to vitamin D status and risk of mortality. According to NHANES, 79% of US adults do not meet their Recommended Dietary Allowance of magnesium. Objectives:The aim of this study was to test the hypothesis that magnesium supplementation differentially affects vitamin D metabolism dependent on baseline 25-hydroxyvitamin D [25(OH)D] concentration. Methods:The study included 180 participants aged 40-85 y and is a National Cancer Institute independently funded ancillary study, nested within the Personalized Prevention of Colorectal Cancer Trial (PPCCT), which enrolled 250 participants. The PPCCT is a double-blind 2 × 2 factorial randomized controlled trial conducted in the Vanderbilt University Medical Center. Doses for both magnesium and placebo were customized based on baseline dietary intakes. Subjects were randomly assigned to treatments using a permuted-block randomization algorithm. Changes in plasma 25-hydroxyvitamin D3 [25(OH)D3], 25-hydroxyvitamin D2 [25(OH)D2], 1,25-dihydroxyvitamin D3, 1,25-dihydroxyvitamin D2, and 24,25-dihydroxyvitamin D3 [24,25(OH)2D3] were measured by liquid chromatography-mass spectrometry. Results:The relations between magnesium treatment and plasma concentrations of 25(OH)D3, 25(OH)D2, and 24,25(OH)2D3 were significantly different dependent on the baseline concentrations of 25(OH)D, and significant interactions persisted after Bonferroni corrections. Magnesium supplementation increased the 25(OH)D3 concentration when baseline 25(OH)D concentrations were close to 30 ng/mL, but decreased it when baseline 25(OH)D was higher (from ∼30 to 50 ng/mL). Magnesium treatment significantly affected 24,25(OH)2D3 concentration when baseline 25(OH)D concentration was 50 ng/mL but not 30 ng/mL. On the other hand, magnesium treatment increased 25(OH)D2 as baseline 25(OH)D increased. Conclusion:Our findings suggest that optimal magnesium status may be important for optimizing 25(OH)D status. This trial was registered at clinicaltrials.gov as NCT03265483. 10.1093/ajcn/nqy274
    Antifibrotic effects of hypocalcemic vitamin D analogs in murine and human hepatic stellate cells and in the CCl mouse model. Laboratory investigation; a journal of technical methods and pathology Liver cirrhosis is a life-threatening consequence of liver fibrosis. The aim of this study was to investigate the antifibrotic potential of clinically available vitamin D analogs compared to that of calcitriol in vitro and in vivo. Murine hepatic stellate cells, Kupffer cells, and human LX-2 cells were treated with vitamin D analogs, and the profibrotic behavior of these cells was studied. In vivo liver fibrosis was induced using CCl until measurable fibrosis was established. Animals were then treated with calcitriol and paricalcitol. Vitamin D and its analogs showed antifibrotic effects in vitro. Treatment with active vitamin D (calcitriol, CAL) and its analogs reduced the protein expression of α-smooth muscle actin (α-SMA) in mHSC. In human LX-2 cells alfacalcidol reduced transforming growth factor-β (TGF-β) induced platelet-derived growth factor receptor-β protein expression and contractility while paricalcitol (PCT), in its equipotent dose to CAL, reduced TGF-β induced α-SMA protein expression, and ACTA2 and TGF-β mRNA expression. No effects of a treatment with vitamin D and its analogs were observed in Kupffer cells. In vivo, PCT-treated mice had significantly lower calcium levels than CAL-treated mice. CAL and PCT reduced the hepatic infiltration of CD11b-positive cells and alanine transaminase levels, while PCT but not CAL significantly inhibited fibrosis progression, with a favorable side effect profile in the CCl model. We conclude that hypocalcemic vitamin D analogs should be considered in future studies investigating vitamin D for the treatment of liver fibrosis. 10.1038/s41374-019-0310-1
    Vitamin D/VDR attenuate cisplatin-induced AKI by down-regulating NLRP3/Caspase-1/GSDMD pyroptosis pathway. Jiang Siqing,Zhang Hao,Li Xin,Yi Bin,Huang Lihua,Hu Zhaoxin,Li Aimei,Du Jie,Li Yanchun,Zhang Wei The Journal of steroid biochemistry and molecular biology Vitamin D/Vitamin D receptor (VDR) has been shown to inhibit the NF-κB-mediated inflammatory effects. Up-regulation of the NLRP3(Recombinant NLR Family, Pyrin Domain Containing Protein 3)/Caspase-1/GSDMD (Gasdermin D) pathway through NF-κb is one of the key mechanisms leading to pyroptosis. This study aims to explore the effects of vitamin D/VDR on the pyroptosis pathway in cisplatin induced acute kidney injury (AKI) models. Our results showed that in wide type mice, renal function loss, tissue injury and cell death induced by cisplatin were alleviated by pretreatment of high-dose paricalcitol(a VDR agonist) accompanied with up-regulated VDR and decreased expression of NLRP3, GSDMD-N, Cleaved-Caspase-1 and mature Interleukin- 1β (features of pyroptosis). While, in VDR knock out mice, cisplatin induced more severer renal injury and further increased pyroptosis related protein than the wild type mice and the effect of paricalcitol were also eliminated. In tubular cell specific VDR-over expressing mice, those renal injury index as well as pyroptosis phenotype were significantly reduced by low-dose paricalcitol pretreatment with upregulated VDR expression compared with WT mice. In vitro data using gain and lose function experiments in Human tubular epithelial cell (HK-2) were consistent with the observation as in vivo work. Our further experiments in both animal and cell culture work has found that the level of IκBα(Inhibitor of NF-κB) were decreased and the nuclear level of NF-κB p65 of renal tubular cells were increased after cisplatin injury while VDR activation by paricalcitol could reverse up-regulation of nuclear NF-κB p65 with reduced cell pyroptosis. These data suggested that vitamin D/VDR could alleviate cisplatin-induced acute renal injury partly by inhibiting NF-κB-mediated NLRP3/Caspase-1/GSDMD pyroptosis. 10.1016/j.jsbmb.2020.105789
    Free vitamin D levels in steroid-sensitive nephrotic syndrome and healthy controls. Banerjee Sushmita,Basu Surupa,Akhtar Shakil,Sinha Rajiv,Sen Ananda,Sengupta Jayati Pediatric nephrology (Berlin, Germany) INTRODUCTION:Body stores of vitamin D are measured as "total" serum 25-hydroxy vitamin D (25(OH)D). Its largest component is protein bound and lost in urine in nephrotic syndrome (NS). Our study investigates whether "free" 25(OH)D levels are a better guide to bone health and need for vitamin D supplementation in patients with steroid-sensitive NS (SSNS). METHODS:A cross-sectional study was performed in children with SSNS and healthy controls. Blood was tested for albumin, creatinine, calcium, phosphate, ALP, total and free (by direct ELISA) 25(OH)D, iPTH, and urine for protein-creatinine ratio. RESULTS:Seventy-nine NS patients (48 in relapse, 31 in remission) and 60 healthy controls were included. The levels of total 25(OH)D were significantly different (lowest in NS relapse and highest in controls) (p < 0.001). Corrected calcium and phosphate levels were normal, and there were no differences in free 25(OH)D, ALP, or iPTH levels between groups. Only total and not free 25(OH)D correlated significantly and negatively with urinary protein creatinine ratios (r = - 0.42 vs. 0.04). Free 25(OH)D values of 3.75 and 2.85 pg/ml corresponded to total 25(OH)D levels of 20 and 12 ng/ml, respectively, in healthy controls. CONCLUSION:These results confirm that total 25(OH)D levels are low in NS and related to degree of proteinuria. However levels of free 25(OH)D, ALP, and iPTH did not change in relapse or remission in comparison with healthy controls. Our results suggest that in proteinuric renal diseases, free 25(OH)D rather than total 25(OH)D levels should be used to diagnose vitamin D deficiency and guide therapy. 10.1007/s00467-019-04433-1
    A Biological Circuit Involving Mef2c, Mef2d, and Hdac9 Controls the Immunosuppressive Functions of CD4+Foxp3+ T-Regulatory Cells. Di Giorgio Eros,Wang Liqing,Xiong Yan,Christensen Lanette M,Akimova Tatiana,Han Rongxiang,Samanta Arabinda,Trevisanut Matteo,Brancolini Claudio,Beier Ulf H,Hancock Wayne W Frontiers in immunology The Mads/Mef2 (Mef2a/b/c/d) family of transcription factors (TFs) regulates differentiation of muscle cells, neurons and hematopoietic cells. By functioning in physiological feedback loops, Mef2 TFs promote the transcription of their repressor, Hdac9, thereby providing temporal control of Mef2-driven differentiation. Disruption of this feedback is associated with the development of various pathologic states, including cancer. Beside their direct involvement in oncogenesis, Mef2 TFs indirectly control tumor progression by regulating antitumor immunity. We recently reported that in CD4+CD25+Foxp3+ T-regulatory (Treg) cells, Mef2d is required for the acquisition of an effector Treg (eTreg) phenotype and for the activation of an epigenetic program that suppresses the anti-tumor immune responses of conventional T and B cells. We now report that as with Mef2d, the deletion of Mef2c in Tregs switches off the expression of and and leads to enhanced antitumor immunity in syngeneic models of lung cancer. Mechanistically, Mef2c does not directly bind the regulatory elements of and , but its loss-of-function in Tregs induces the expression of the transcriptional repressor, Hdac9. As a consequence, Mef2d, the more abundant member of the Mef2 family, is converted by Hdac9 into a transcriptional repressor on these loci. This leads to the impairment of Treg suppressive properties and to enhanced anti-cancer immunity. These data further highlight the central role played by the Mef2/Hdac9 axis in the regulation of CD4+Foxp3+ Treg function and adds a new level of complexity to the analysis and study of Treg biology. 10.3389/fimmu.2021.703632
    Overexpression and biological function of MEF2D in human pancreatic cancer. Song Zhiwang,Feng Chan,Lu Yonglin,Gao Yong,Lin Yun,Dong Chunyan American journal of translational research To explore the expression, clinical significance, biological function, and potential mechanism of MEF2D in pancreatic cancer, the expression of MEF2D in human pancreatic cancer tissues and corresponding adjacent normal tissues was analyzed through immunohistochemical staining. The association between MEF2D expression, clinicopathological parameters, overall survival, and disease-free survival was evaluated. Human pancreatic cancer cell lines BxPC-1 and SW1990 were selected to investigate the effect of MEF2D knockdown on cell proliferation, migration, and invasion. Western blot analysis was used to assess the effect of MEF2D expression on the Akt/GSK pathway, as well as the protein expression of cyclin B1, cyclin D1, matrix metalloprotein (MMP)-2, and MMP-9. Our results revealed that the expression of MEF2D was increased in pancreatic cancer tissues compared to adjacent normal tissues and the increased expression of MEF2D was associated with tumor size, histological differentiation, and TNM stage of pancreatic cancer patients. Moreover, the expression of MEF2D was an independent prognostic indicator for pancreatic cancer patients. In addition, knockdown of MEF2D in pancreatic cancer cells inhibited cell proliferation, migration, and invasion by down-regulating the protein expression of cyclin B1, cyclin D1, MMP-2, and MMP-9. Knockdown of MEF2D reduced the levels of phosphorylated Akt and GSK-3β. Our data indicated that MEF2D expression was increased in pancreatic cancer and was an independent molecular prognostic factor for pancreatic cancer patients. Furthermore, we showed that MEF2D controlled cell proliferation, migration, and invasion abilities in pancreatic cancer via the Akt/GSK-3β signaling pathway.
    MEF2D sustains activation of effector Foxp3+ Tregs during transplant survival and anticancer immunity. Di Giorgio Eros,Wang Liqing,Xiong Yan,Akimova Tatiana,Christensen Lanette M,Han Rongxiang,Samanta Arabinda,Trevisanut Matteo,Bhatti Tricia R,Beier Ulf H,Hancock Wayne W The Journal of clinical investigation The transcription factor MEF2D is important in the regulation of differentiation and adaptive responses in many cell types. We found that among T cells, MEF2D gained new functions in Foxp3+ T regulatory (Treg) cells due to its interactions with the transcription factor Foxp3 and its release from canonical partners, like histone/protein deacetylases. Though not necessary for the generation and maintenance of Tregs, MEF2D was required for the expression of IL-10, CTLA4, and Icos, and for the acquisition of an effector Treg phenotype. At these loci, MEF2D acted both synergistically and additively to Foxp3, and downstream of Blimp1. Mice with the conditional deletion in Tregs of the gene encoding MEF2D were unable to maintain long-term allograft survival despite costimulation blockade, had enhanced antitumor immunity in syngeneic models, but displayed only minor evidence of autoimmunity when maintained under normal conditions. The role played by MEF2D in sustaining effector Foxp3+ Treg functions without abrogating their basal actions suggests its suitability for drug discovery efforts in cancer therapy. 10.1172/JCI135486
    Abnormal acetylation of FOXP3 regulated by SIRT-1 induces Treg functional deficiency in patients with abdominal aortic aneurysms. Jiang Han,Xin Shijie,Yan Yumeng,Lun Yu,Yang Xiao,Zhang Jian Atherosclerosis BACKGROUND AND AIMS:Acetylation levels of FOXP3 could influence its expression level and SIRT1 is a deacetylase, which could regulate the acetylation level of FOXP3. We aimed to investigate the mechanism of Treg dysfunction, which might be caused by abnormal acetylation of FOXP3 regulated by SIRT1 in abdominal aortic aneurysm (AAA) patients. METHODS:Peripheral CD4 T cells from AAA patients, abdominal aortic atherosclerotic occlusive disease (AOD) patients, and healthy donors (HC) were analyzed by flow cytometry to determine the percentage of CD4CD25 Tregs and CD4CD25FOXP3 T cells in CD4 T cells. Expression of FOXP3 and SIRT1 was analyzed by Western Blot. Cultured CD4 T cells were treated with SIRT1 specific inhibitor EX-527 or left untreated. Acetylation expression of FOXP3 in CD4 T cells was analyzed by immunoprecipitation and Western Blot. The suppressive function of Treg was analyzed by CFSE-assay. RESULTS:AAA patients had significantly lower CD4CD25FOXP3 T cells. Western blot results showed that AAA CD4 T cells had significantly less FOXP3 expression but significantly higher SIRT1 expression. After EX-527 treatment, CD4CD25FOXP3 T cells and FOXP3 expression in the AAA group were significantly increased. FOXP3 acetylation level in the AAA group was lower than in control groups. After EX-527 treatment, it was significantly increased. AAA Tregs exhibited less suppressive activity, EX-527 treatment significantly increased the suppressive activity of AAA Tregs. CONCLUSIONS:Our data demonstrate that reduced FOXP3 expression and Treg function in AAA patients are regulated by SIRT1-induced FOXP3 deacetylation. EX-527 could up-regulate FOXP3 acetylation and increase number and suppressive function of Treg in AAA patients. 10.1016/j.atherosclerosis.2018.02.001
    Paeoniflorin ameliorates murine lupus nephritis by increasing CD4Foxp3 Treg cells via enhancing mTNFα-TNFR2 pathway. Liang Chun-Ling,Lu Weihui,Qiu Feifei,Li Dan,Liu Huazhen,Zheng Fang,Zhang Qunfang,Chen Yuchao,Lu Chuanjian,Li Bin,Dai Zhenhua Biochemical pharmacology Treg cells are essential for re-establishing self-tolerance in lupus. However, given that direct Treg therapies may be inadequate to control autoimmunity and inflammation, a strategy of inducing or expanding endogenous Treg cells in vivo may be a good option. Macrophages are main tissue-infiltrating cells and play a role in promoting Treg differentiation while paeoniflorin (PF), a monoterpene glycoside, exhibits anti-inflammatory and immunoregulatory effects. Here, we studied the effects of PF on CD4FoxP3 Treg frequency and the potential mechanisms involving M2 macrophages. We demonstrated that PF ameliorated lupus nephritis in lupus-prone B6/gld mice by reducing urinary protein, serum creatinine and anti-dsDNA levels, diminishing renal cellular infiltration, improving renal immunopathology and downregulating renal gene and protein expressions of key cytokines, including IFN-γ, IL-6, IL-12 and IL-23. PF also lowered the percentage of CD44CD62L effector T cells while augmenting CD4FoxP3 Treg frequency in B6/gld mice. Importantly, PF increased TNFR2 expression on CD4FoxP3 Tregs, but not CD4FoxP3 T cells, in vivo and in vitro. Furthermore, we found that CD206 subset of F4/80CD11b macrophages expressed a higher level of mTNF-α than their CD206 counterparts while PF increased mTNF-α expression on CD206 macrophages in vitro and in vivo. In vitro studies showed that mTNF-α M2 macrophages were more potent in inducing Treg differentiation and proliferation than their mTNF-α counterparts, whereas the effects of mTNF-α M2 macrophages were largely reversed by separation of M2 macrophages using a transwell or TNFR2-blocking Ab in the culture. Finally, PF also promoted in vitro Treg generation induced by M2 macrophages. Thus, we demonstrated that mTNFα-TNFR2 interaction is a new mechanism responsible for Treg differentiation mediated by M2 macrophages. We provided the first evidence that PF may be used to treat lupus nephritis. 10.1016/j.bcp.2021.114434
    Taraxacum mongolicum extract inhibited malignant phenotype of triple-negative breast cancer cells in tumor-associated macrophages microenvironment through suppressing IL-10 / STAT3 / PD-L1 signaling pathways. Deng Xin-Xin,Jiao Yan-Na,Hao Hui-Feng,Xue Dong,Bai Chang-Cai,Han Shu-Yan Journal of ethnopharmacology ETHNOPHARMACOLOGICAL RELEVANCE:Triple-negative breast cancer (TNBC) is the most aggressive and the worst prognosis breast cancer with limited treatment options. Taraxacum mongolicum (also called dandelion) is a traditional Chinese medicine has been used to treat mastitis, breast abscess, and hyperplasia of mammary glands since ancient times. In modern pharmacological research, dandelion has been proven with anti-breast cancer activities. We previously reported that dandelion extract could induce apoptosis in TNBC cells. However, its anti-tumor effects and mechanisms in the tumor microenvironment have not yet been elucidated. AIM OF THE STUDY:Tumor-associated macrophages (TAMs) play an important role in regulating the interaction between tumor cells and the immune system. The present study aimed to investigate the effects and mechanisms of dandelion extract on TNBC cells under the microenvironment of TAMs, as well as its influence on the polarization of M2 macrophages. MATERIALS AND METHODS:M2 macrophages were induced by phorbol-12-myristate 13-acetate (PMA) and interleukin 4 (IL-4), and verified by flow cytometry, quantitative RT-PCR (qRT-PCR), Western blotting, and ELISA. MDA-MB-231 and MDA-MB-468 TNBC cells were co-cultured with the supernatant of M2 macrophage which providing the TAMs microenvironment. The antitumor activity of dandelion extract in TNBC cells was evaluated by MTT assay. The invasive and migratory capacity of TNBC cells was measured by transwell assays. The expression of protein and gene was assessed by Western blotting and qRT-PCR, respectively. RESULTS:TAMs microenvironment promoted the proliferation, migration, and invasion of TNBC cells. However, dandelion extract inhibited the malignant property of MDA-MB-231 and MDA-MB-468 cells induced by TAMs. Both of TAMs and IL-10 caused STAT3 activation and PD-L1 higher expression, the immunosuppressive molecules in TNBC cells, and this effect can be attenuated by IL-10 neutralizing antibody. Dandelion extract exerted inhibition on STAT3 and PD-L1 in TNBC cells under TAMs microenvironment. Furthermore, in M2 macrophages, dandelion extract remarkably promoted the expression of M1-like marker TNF-α, IL-8, and iNOS, but reduced M2-like marker IL-10, CD206, Arginase-1, and TGF-β. CONCLUSION:Dandelion extract inhibited the proliferation, migration and invasion of TNBC cells in TAMs microenvironment through suppressing IL-10/STAT3/PD-L1 immunosuppressive signaling pathway. Furthermore, dandelion extract promoted the polarization of macrophages from M2 to M1 phenotype. Thus, our results indicated that dandelion may serve as a promising therapeutic strategy for TNBC by modulating tumor immune microenvironment. 10.1016/j.jep.2021.113978
    Unstable Foxp3+ regulatory T cells and altered dendritic cells are associated with lipopolysaccharide-induced fetal loss in pregnant interleukin 10-deficient mice. Prins Jelmer R,Zhang Bihong,Schjenken John E,Guerin Leigh R,Barry Simon C,Robertson Sarah A Biology of reproduction Maternal interleukin (IL) 10 deficiency elevates susceptibility to fetal loss induced by the model Toll-like receptor agonist lipopolysaccharide, but the mechanisms are not well elucidated. Here, we show that Il10 null mutant (Il10(-/-)) mice exhibit altered local T cell responses in pregnancy, exhibiting pronounced hyperplasia in para-aortic lymph nodes draining the uterus with >6-fold increased CD4(+) and CD8(+) T cells compared with wild-type controls. Among these CD4(+) cells, Foxp3(+) T regulatory (Treg) cells were substantially enriched, with 11-fold higher numbers at Day 9.5 postcoitum. Lymph node hypertrophy in Il10(-/-) mice was associated with more activated phenotypes in dendritic cells and macrophages, with elevated expression of MHCII, scavenger receptor, and CD80. Affymetrix microarray revealed an altered transcriptional profile in Treg cells from pregnant Il10(-/-) mice, with elevated expression of Ctse (cathepsin E), Il1r1, Il12rb2, and Ifng. In vitro, Il10(-/-) Treg cells showed reduced steady-state Foxp3 expression, and polyclonal stimulation caused greater loss of Foxp3 and reduced capacity to suppress IL17 in CD4(+)Foxp3(-) T cells. We conclude that despite a substantially expanded Treg cell pool, the diminished stability of Treg cells, increased numbers of effector T cells, and altered phenotypes in dendritic cells and macrophages in pregnancy all potentially confer vulnerability to inflammation-induced fetal loss in Il10(-/-) mice. These findings suggest that IL10 has a pivotal role in facilitating robust immune protection of the fetus from inflammatory challenge and that IL10 deficiency could contribute to human gestational disorders in which altered T cell responses are implicated. 10.1095/biolreprod.115.128694
    HDAC1-3 inhibitor MS-275 enhances IL10 expression in RAW264.7 macrophages and reduces cigarette smoke-induced airway inflammation in mice. Leus Niek G J,van den Bosch Thea,van der Wouden Petra E,Krist Kim,Ourailidou Maria E,Eleftheriadis Nikolaos,Kistemaker Loes E M,Bos Sophie,Gjaltema Rutger A F,Mekonnen Solomon A,Bischoff Rainer,Gosens Reinoud,Haisma Hidde J,Dekker Frank J Scientific reports Chronic obstructive pulmonary disease (COPD) constitutes a major health burden. Studying underlying molecular mechanisms could lead to new therapeutic targets. Macrophages are orchestrators of COPD, by releasing pro-inflammatory cytokines. This process relies on transcription factors such as NF-κB, among others. NF-κB is regulated by lysine acetylation; a post-translational modification installed by histone acetyltransferases and removed by histone deacetylases (HDACs). We hypothesized that small molecule HDAC inhibitors (HDACi) targeting class I HDACs members that can regulate NF-κB could attenuate inflammatory responses in COPD via modulation of the NF-κB signaling output. MS-275 is an isoform-selective inhibitor of HDAC1-3. In precision-cut lung slices and RAW264.7 macrophages, MS-275 upregulated the expression of both pro- and anti-inflammatory genes, implying mixed effects. Interestingly, anti-inflammatory IL10 expression was upregulated in these model systems. In the macrophages, this was associated with increased NF-κB activity, acetylation, nuclear translocation, and binding to the IL10 promoter. Importantly, in an in vivo model of cigarette smoke-exposed C57Bl/6 mice, MS-275 robustly attenuated inflammatory expression of KC and neutrophil influx in the lungs. This study highlights for the first time the potential of isoform-selective HDACi for the treatment of inflammatory lung diseases like COPD. 10.1038/srep45047
    Loss of MEF2D expression inhibits differentiation and contributes to oncogenesis in rhabdomyosarcoma cells. Zhang Meiling,Truscott Jamie,Davie Judith Molecular cancer BACKGROUND:Rhabdomyosarcoma (RMS) is a highly malignant pediatric cancer that is the most common form of soft tissue tumors in children. RMS cells have many features of skeletal muscle cells, yet do not differentiate. Thus, our studies have focused on the defects present in these cells that block myogenesis. METHODS:Protein and RNA analysis identified the loss of MEF2D in RMS cells. MEF2D was expressed in RD and RH30 cells by transient transfection and selection of stable cell lines, respectively, to demonstrate the rescue of muscle differentiation observed. A combination of techniques such as proliferation assays, scratch assays and soft agar assays were used with RH30 cells expressing MEF2D to demonstrate the loss of oncogenic growth in vitro and xenograft assays were used to confirm the loss of tumor growth in vivo. RESULTS:Here, we show that one member of the MEF2 family of proteins required for normal myogenesis, MEF2D, is largely absent in RMS cell lines representing both major subtypes of RMS as well as primary cells derived from an embryonal RMS model. We show that the down regulation of MEF2D is a major cause for the failure of RMS cells to differentiate. We find that MyoD and myogenin are bound with their dimerization partner, the E proteins, to the promoters of muscle specific genes in RMS cells. However, we cannot detect MEF2D binding at any promoter tested. We find that exogenous MEF2D expression can activate muscle specific luciferase constructs, up regulate p21 expression and increase muscle specific gene expression including the expression of myosin heavy chain, a marker for skeletal muscle differentiation. Restoring expression of MEF2D also inhibits proliferation, cell motility and anchorage independent growth in vitro. We have confirmed the inhibition of tumorigenicity by MEF2D in a tumor xenograft model, with a complete regression of tumor growth. CONCLUSIONS:Our data indicate that the oncogenic properties of RMS cells can be partially attributed to the loss of MEF2D expression and that restoration of MEF2D may represent a useful therapeutic strategy to decrease tumorigenicity. 10.1186/1476-4598-12-150
    MEF2D-NR4A1-FAM134B2-mediated reticulophagy contributes to amino acid homeostasis. Autophagy ABBREVIATIONS:AAD: amino acid deficiency; APOC3: apolipoprotein C3; BACH1: BTB domain and CNC homolog 1; CEBP: CCAAT enhancer binding protein; DDIT3/CHOP: DNA damage inducible transcript 3; EBSS: Earle's Balanced Salt Solution; EIF2AK4/GCN2: eukaryotic translation initiation factor 2 alpha kinase 4; ER: endoplasmic reticulum; HisOH: histidinol; ISR: integrated stress response; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MEF2D: myocyte enhancer factor 2D; MTOR: mechanistic target of rapamycin kinase; NR4A1: nuclear receptor subfamily 4 group A member 1; RETREG1/FAM134B: reticulophagy regulator 1; RTN2: reticulon 2, TF: transcription factor; TFEB: transcription factor EB; ZBTB10: zinc finger and BTB domain containing 10. 10.1080/15548627.2021.1968228
    Using data mining technology to explore homocysteine at low levels. Tseng Fei-Ching,Huang Tin-Chung Medicine ABSTRACT:A high homocysteine level is known to be an independent risk factor for cardiovascular diseases; however, whether or not low homocysteine level contributes to any damage to the body has not been extensively studied. Furthermore, acquiring healthy subject databases from domestic studies on homocysteine is not trivial. Therefore, we aimed to investigate the causality between serum homocysteine levels and health status and lifestyle factors, particularly with a focus on low serum homocysteine levels. Additionally, we discussed a systematic methodical platform for data collection and statistical analysis, using the descriptive analysis of the chi-square test, t test, multivariate analysis of variance, and logistic regression.This study was a cross-sectional analysis of 5864 subjects (i.e., clients of a health examination clinic) in Taipei, Taiwan during a general health check-up in 2017. The patients' personal information and associated links were excluded. A sample group was selected as per the health criteria defined for this research whose data were processed using SPSS for descriptive statistical analysis using chi-square test, t test, multivariate analysis of variance, and logistic regression analysis.Those working for >12 hours/day had a higher homocysteine level than those working for <12 hours/day (P < .001). The average serum homocysteine level was 7.9 and 8.6 mol/L for people with poor sleep quality and good sleep quality, respectively (P = .003). The homocysteine value of people known to have cancer was analyzed using the logistic regression analysis, revealing a Δodds value of 0.898. The percentage of subjects with a homocysteine value of ≤6.3 μmol/L, who perceived their health status as "not very good" or "very bad," was higher than those with a higher homocysteine level. The number of subjects who perceived their health as poor was higher than expected.The results suggest that the homocysteine level could be an effective health management indicator. We conclude that normal homocysteine level should not be ≤6.3 μmol/L. Moreover, homocysteine should not be considered as harmful and its fluctuations from the normal range could be utilized to infer a person's physical status for health management. 10.1097/MD.0000000000026893
    Associations of Homocysteine Metabolism With the Risk of Spinal Osteoarthritis Progression in Postmenopausal Women. Nakano Masaki,Nakamura Yukio,Urano Tomohiko,Miyazaki Akiko,Suzuki Takako,Watanabe Kazuki,Takahashi Jun,Shiraki Masataka The Journal of clinical endocrinology and metabolism CONTEXT:Although homocysteine accumulation is a reported risk factor for several age-related disorders, little is known about its relationship with osteoarthritis (OA). OBJECTIVE:We investigated for associations of homocysteine and C677T polymorphism in methylenetetrahydrofolate reductase (MTHFR), which is involved in homocysteine clearance, with the development and progression of spinal OA through a combined cross-sectional and longitudinal cohort study. METHODS:A total of 1306 Japanese postmenopausal outpatients participating in the Nagano Cohort Study were followed for a mean 9.7-year period. Cross-sectional multiple logistic regression for spinal OA prevalence at registration by serum homocysteine level was performed with adjustment for confounders. In addition to Kaplan-Meier analysis, multivariate Cox regression was employed to examine the independent risk of MTHFR C677T variant for spinal OA progression. RESULTS:Multivariate regression analysis revealed a significant association between homocysteine and spinal OA prevalence (odds ratio 1.38; 95% CI 1.14-1.68). Kaplan-Meier curves showed a gene dosage effect of the T allele in MTHFR C677T polymorphism on the accelerated progression of spinal OA severity (P = 0.003). A statistically significant independent risk of the T allele for spinal OA advancement was validated by Cox regression analysis. Respective adjusted hazard ratios for the CT/TT and TT genotypes were 1.68 (95% CI, 1.16-2.42) and 1.67 (95% CI, 1.23-2.28). CONCLUSION:Circulating homocysteine and C677T variant in MTHFR are associated with the prevalence rate and ensuing progression, respectively, of spinal OA. These factors may represent potential interventional targets to prevent OA development and improve clinical outcomes. 10.1210/clinem/dgab591