Modifications of serum levels of omentin-1 and other cardiovascular risk factors following weight loss secondary to a Mediterranean hypocaloric diet.

PubMed

Antonio de Luis, Daniel; Izaola, Olatz; Primo, David; Aller, R

2017-11-21

Omentin-1 might play a role on insulin resistance, dyslipidemia and obesity. The aim of this investigation was to evaluate the influence of weight loss on omentin-1 concentrations after a hypocaloric diet with Mediterranean pattern. A Caucasian sample of 67 obese patients was analyzed before and after 3 months on a hypocaloric diet. Anthropometric parameters, blood pressure, fasting blood glucose, C-reactive protein (CRP), fasting insulin, insulin resistance (HOMA-IR), lipid concentrations and omentin-1 were measured. Sixty-seven obese subjects were enrolled in the study. The mean age was 48.3 ± 8.0 years (range: 25-66) and the mean BMI 34.5 ± 4.8 kg/m 2 (range: 30.2-40.8). Gender distribution was 50 females (74.6%) and 17 males (25.4%). After dietary intervention and in males and females; body mass index, weight, fat mass, waist circumference, blood pressure, glucose, LDL cholesterol, insulin and HOMA-IR decreased. Omentin-1 levels increase after dietary intervention (males vs females) (delta basal vs 3 months: 10.0 ± 3.8 ng/dl: p = 0.01 vs 9.9 ± 4.1 ng/dl; p = 0.03). In the multiple regression analysis adjusted for age and sex; BMI and insulin remained independently associated with baseline and post-treatment levels of omentin-1. Our investigation showed a significant increase in omentin-1 levels after weight loss secondary to a hypocaloric diet with a Mediterranean pattern. Copyright © 2017 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.

Association between omentin levels and insulin resistance in pregnancy.

PubMed

Aktas, G; Alcelik, A; Ozlu, T; Tosun, M; Tekce, B K; Savli, H; Tekce, H; Dikbas, O

2014-03-01

Omentin is a new adipokine secreted mainly from visceral adipose tissue. Serum omentin is found to be reduced in patients with impaired glucose tolerance, type 2 diabetes mellitus, obesity and insulin resistant states. Despite the fact that pregnancy is also characterized with hyperinsulinemia, literature is lacking about data of omentin levels and its association with insulin resistance in pregnant women. We aimed to evaluate the association of omentin levels and insulin resistance in pregnant women and to compare these levels with those of non-pregnant, non-diabetic women. Uncomplicated pregnant women who admit to our outpatient clinics for routine follow-up were included in the study group. Non-pregnant women without diabetes mellitus were served as control group. Fasting glucose, insulin, omentin levels and HOMA IR were recorded. SPSS 15.0 for Windows was used for statistical analysis. There were 36 pregnant women in the study group and 37 healthy, non-pregnant women in the control group. Serum omentin and fasting glucose levels were significantly decreased and fasting insulin was significantly increased in the study group compared to control group. Omentin might be an indicator of insulin resistance in pregnant women. Larger prospective studies are needed to claim whether omentin can have a clinical use for diagnosis of gestational diabetes mellitus. © J. A. Barth Verlag in Georg Thieme Verlag KG Stuttgart · New York.

Effect of High-Intensity Interval Training on Plasma Omentin-1 Concentration in Overweight/Obese and Normal-Weight Youth

PubMed Central

Ouerghi, Nejmeddine; Fradj, Mohamed Kacem Ben; Bezrati, Ikram; Feki, Moncef; Kaabachi, Naziha; Bouassida, Anissa

2017-01-01

Objectives Omentin-1 is a recently discovered adipokine, mainly produced by visceral adipose tissue, which is thought to improve insulin sensitivity. The study aimed to assess the association of plasma omentin-1 with cardiometabolic traits and physical performance and to test its response to high-intensity interval training (HIIT) in obese and normal-weight subjects. Methods Nine overweight/obese (OG) and 9 normal-weight (NWG) young men performed an 8-week HIIT program. Body composition, physical performance, homeostasis model assessment index for insulin resistance (HOMA-IR) as well as plasma omentin-1and lipid levels were assessed before and after the HIIT program. Results Baseline plasma omentin-1 was lower in OG than NWG men (359 ± 138 vs. 470 ± 114 ng/ml; p = 0.052). Plasma omentin-1 was related to body fat (r = −0.57; p = 0.03) and LDL-cholesterol (r = −0.49; p = 0.04). There was a trend towards significant association of omentin-1 with BMI (r = −0.47; p = 0.06) and VO2max (r = 0.41; p = 0.09). However, no association was observed with HOMA-IR. Following the HIIT program, omentin-1 concentrations have significantly (p < 0.01) increased in OG (359 ± 138 to 455 ± 126 ng/ml) and NWG men (470 ± 114 to 572 ± 115 ng/ml). In parallel, the cardiometabolic profile has improved with a significant decrease of HOMA-IR in OG. Conclusions HIIT resulted in a plasma omentin-1 increase and an improvement with regard to cardiometabolic traits in the OG men, which may contribute to modulate insulin sensitivity. PMID:28787708

Effect of High-Intensity Interval Training on Plasma Omentin-1 Concentration in Overweight/Obese and Normal-Weight Youth.

PubMed

Ouerghi, Nejmeddine; Ben Fradj, Mohamed Kacem; Bezrati, Ikram; Feki, Moncef; Kaabachi, Naziha; Bouassida, Anissa

2017-01-01

Omentin-1 is a recently discovered adipokine, mainly produced by visceral adipose tissue, which is thought to improve insulin sensitivity. The study aimed to assess the association of plasma omentin-1 with cardiometabolic traits and physical performance and to test its response to high-intensity interval training (HIIT) in obese and normal-weight subjects. Nine overweight/obese (OG) and 9 normal-weight (NWG) young men performed an 8-week HIIT program. Body composition, physical performance, homeostasis model assessment index for insulin resistance (HOMA-IR) as well as plasma omentin-1and lipid levels were assessed before and after the HIIT program. Baseline plasma omentin-1 was lower in OG than NWG men (359 ± 138 vs. 470 ± 114 ng/ml; p = 0.052). Plasma omentin-1 was related to body fat (r = -0.57; p = 0.03) and LDL-cholesterol (r = -0.49; p = 0.04). There was a trend towards significant association of omentin-1 with BMI (r = -0.47; p = 0.06) and VO2max (r = 0.41; p = 0.09). However, no association was observed with HOMA-IR. Following the HIIT program, omentin-1 concentrations have significantly (p < 0.01) increased in OG (359 ± 138 to 455 ± 126 ng/ml) and NWG men (470 ± 114 to 572 ± 115 ng/ml). In parallel, the cardiometabolic profile has improved with a significant decrease of HOMA-IR in OG. HIIT resulted in a plasma omentin-1 increase and an improvement with regard to cardiometabolic traits in the OG men, which may contribute to modulate insulin sensitivity. © 2017 The Author(s) Published by S. Karger GmbH, Freiburg.

Association of single Nucleotide Missence Polymorphism Val109Asp of Omentin-1 gene and coronary artery disease in Pakistani population: Multicenter study

PubMed Central

Nazar, Shazia; Zehra, Sitwat; Azhar, Abid

2017-01-01

Background & Objective: Coronary artery disease (CAD) is a most important cause of morbidity and mortality worldwide as well as in Pakistan. Recent studies have shown that the combination of obesity, insulin resistance and fluctuation in circulating adipocytokines levels is associated with the pathogenesis of coronary artery disease. Omentin-1 is recently found adipocytokine that is highly expressed in visceral adipose tissue. It has anti- inflammatory properties and is negatively correlated with ischemic heart disease. Therefore, this study was designed to investigate the relationship between omentin-1 Val109Asp polymorphism and CAD in Pakistani population. Methods: A total of 350 subjects were included in the study. Two hundred fifty were diagnosed with coronary artery disease while 100 served as healthy controls. PCR-RFLP was performed at Dr. A Q. Khan Institute of Biotechnology (KIBGE) to analyze Val109Asp polymorphism. In this, case control study SPSS software version 16 (Chicago, IL, USA) was used for data analysis. Continuous variables and categorical variables were presented as mean±SD or in percentage. Independent sample test and chi-square test was performed to compare the differences in means between cases and controls. Genotype distribution was analyzed by chi-square test and results were presented as percentage and frequency. Multivarible regression analysis indicated that Val109Asp SNP might be an independent risk factor for CAD susceptibility after adjustment for some well- known CAD risk factors including age, gender, body mass index, smoking, hypertension, diabetes mellitus and lipid abnormalities. There was estimation of odd ratios (OR) and 95% confidence intervals (CIs) to determine the correlation between genotypes and the risk of CAD. (p> 0.05). Genotype frequencies were compared by Chi-square test. Results: There was prevalence of Omentin-1 Val109Asp polymorphism in both case and control groups. However, Val/Asp (heterozygous mutant) genotype was detected more frequently in patients with CAD, OR(95%)=1.921; CI=1.173-3.1469 in comparison of Asp/Asp and Val/Val genotypes. Conclusion: Individuals having Val/Asp heterozygous gemotype of omentin-1 gene polymorphism are at more risk of developing CAD in Pakistani population, further studies are required in different populations and ethnicities to confirm our findings. PMID:29142551

Omentin inhibits TNF-{alpha}-induced expression of adhesion molecules in endothelial cells via ERK/NF-{kappa}B pathway

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zhong, Xia, E-mail: zhongxia1977@126.com; Li, Xiaonan; Liu, Fuli

2012-08-24

Highlights: Black-Right-Pointing-Pointer Omentin inhibited TNF-{alpha}-induced adhesion of THP-1 cells to HUVECs. Black-Right-Pointing-Pointer Omentin reduces expression of ICAM-1 and VCAM-1 induced by TNF-{alpha} in HUVECs. Black-Right-Pointing-Pointer Omentin inhibits TNF-{alpha}-induced ERK and NF-{kappa}B activation in HUVECs. Black-Right-Pointing-Pointer Omentin supreeses TNF-{alpha}-induced expression of ICAM-1 and VCAM-1 via ERK/NF-{kappa}B pathway. -- Abstract: In the present study, we investigated whether omentin affected the expression of intracellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) in tumor necrosis factor-{alpha} (TNF-{alpha}) induced human umbilical vein endothelial cells (HUVECs). Our data showed that omentin decreased TNF-{alpha}-induced expression of ICAM-1 and VCAM-1 in HUVECs. In addition, omentin inhibitedmore » TNF-{alpha}-induced adhesion of THP-1 cells to HUVECs. Further, we found that omentin inhibited TNF-{alpha}-activated signal pathway of nuclear factor-{kappa}B (NF-{kappa}B) by preventing NF-{kappa}B inhibitory protein (I{kappa}B{alpha}) degradation and NF-{kappa}B/DNA binding activity. Omentin pretreatment significantly inhibited TNF-{alpha}-induced ERK activity and ERK phosphorylation in HUVECs. Pretreatment with PD98059 suppressed TNF-{alpha}-induced NF-{kappa}B activity. Omentin, NF-kB inhibitor (BAY11-7082) and ERK inhibitor (PD98059) reduced the up-regulation of ICAM-1 and VCAM-1 induced by TNF-{alpha}. These results suggest that omentin may inhibit TNF-{alpha}-induced expression of adhesion molecules in endothelial cells via blocking ERK/NF-{kappa}B pathway.« less

Role of Omentin, Vaspin, Cardiotrophin-1, TWEAK and NOV/CCN3 in Obesity and Diabetes Development

PubMed Central

Escoté, Xavier; Gómez-Zorita, Saioa; López-Yoldi, Miguel; Fernández-Quintela, Alfredo; Moreno-Aliaga, María J.; Portillo, María P.

2017-01-01

Adipose tissue releases bioactive mediators called adipokines. This review focuses on the effects of omentin, vaspin, cardiotrophin-1, Tumor necrosis factor-like Weak Inducer of Apoptosis (TWEAK) and nephroblastoma overexpressed (NOV/CCN3) on obesity and diabetes. Omentin is produced by the stromal-vascular fraction of visceral adipose tissue. Obesity reduces omentin serum concentrations and adipose tissue secretion in adults and adolescents. This adipokine regulates insulin sensitivity, but its clinical relevance has to be confirmed. Vaspin is produced by visceral and subcutaneous adipose tissues. Vaspin levels are higher in obese subjects, as well as in subjects showing insulin resistance or type 2 diabetes. Cardiotrophin-1 is an adipokine with a similar structure as cytokines from interleukin-6 family. There is some controversy regarding the regulation of cardiotrophin-1 levels in obese -subjects, but gene expression levels of cardiotrophin-1 are down-regulated in white adipose tissue from diet-induced obese mice. It also shows anti-obesity and hypoglycemic properties. TWEAK is a potential regulator of the low-grade chronic inflammation characteristic of obesity. TWEAK levels seem not to be directly related to adiposity, and metabolic factors play a critical role in its regulation. Finally, a strong correlation has been found between plasma NOV/CCN3 concentration and fat mass. This adipokine improves insulin actions. PMID:28809783

Omentin concentrations are independently associated with those of matrix metalloproteinase-3 in patients with mild but not severe rheumatoid arthritis.

PubMed

Robinson, Chanel; Tsang, Linda; Solomon, Ahmed; Woodiwiss, Angela J; Gunter, Sule; Millen, Aletta M E; Norton, Gavin R; Fernandez-Lopez, Maria J; Hollan, Ivana; Dessein, Patrick H

2017-01-01

Omentin is an adipokine that reportedly protects against cardiometabolic risk. We investigated the relationships between omentin concentrations and subclinical cardiovascular disease in rheumatoid arthritis (RA). Omentin concentrations were measured in 213 (104 black; 109 white) RA patients. Relationships of omentin levels with those of endothelial activation markers, ultrasound determined carotid intima-media thickness and plaque, and matrix metalloproteinase (MMP)-2, -3 and -9 that mediate altered plaque stability, were identified in confounder adjusted multivariate regression models. Omentin concentrations were inversely associated with MMP-3 levels [β = -364 (0.113), p = 0.002]. This relationship was influenced by population origin, RA activity and the erythrocyte sedimentation rate and joint deformity count (interaction p value = 0.009, 0.04, 0.04 and 0.007, respectively). Accordingly, the omentin-MMP-3 concentration relationship was reproduced in white [β (SE) = -0.450 (0.153), p = 0.0004)] but not black patients [β (SE) = -0.099 (0.195), p = 0.6)], in participants with disease remission or mild disease activity [β (SE) = -0.411 (0.139), p = 0.004] but not with moderate or severe RA activity [β (SE) = -0.286 (0.202), p = 0.2], and in those with a small [β (SE) = -0.534 (0.161), p = 0.001] but not large erythrocyte sedimentation rate [-0.212 (0.168), p = 0.2] and without [β (SE) = -0.554 (0.165), p = 0.0001] but not with large joint deformity counts [-0.110 (0.173), p = 0.5]. Omentin levels were unrelated to endothelial activation and atherosclerosis. Among patients with RA, a lack of plaque stabilizing effects by omentin may contribute to the reported link between severe disease and increased cardiovascular risk. The association between concentrations of omentin and MMP-3 is population specific in RA.

High plasma omentin predicts cardiovascular events independently from the presence and extent of angiographically determined atherosclerosis.

PubMed

Saely, Christoph H; Leiherer, Andreas; Muendlein, Axel; Vonbank, Alexander; Rein, Philipp; Geiger, Kathrin; Malin, Cornelia; Drexel, Heinz

2016-01-01

No prospective data on the power of the adipocytokine omentin to predict cardiovascular events are available. We aimed at investigating i) the association of plasma omentin with cardiometabolic risk markers, ii) its association with angiographically determined coronary atherosclerosis, and iii) its power to predict cardiovascular events. We measured plasma omentin in 295 patients undergoing coronary angiography for the evaluation of established or suspected stable coronary artery disease (CAD), of whom 161 had significant CAD with coronary artery stenoses ≥50% and 134 did not have significant CAD. Over 3.5 years, 17.6% of our patients suffered cardiovascular events, corresponding to an annual event rate of 5.0%. At baseline, plasma omentin was not significantly associated with metabolic syndrome stigmata and did not differ significantly between patients with and subjects without significant CAD (17.2 ± 13.6 ng/ml vs. 17.5 ± 15.1 ng/ml; p = 0.783). Prospectively, however, cardiovascular event risk significantly increased over tertiles of omentin (12.1%, 13.8%, and 29.5%, for tertiles 1 through 3; ptrend = 0.003), and omentin as a continuous variable significantly predicted cardiovascular events after adjustment for age, gender, BMI, diabetes, hypertension, LDL cholesterol, HDL cholesterol, and smoking (standardized adjusted hazard ratio (HR) 1.41 [95% CI 1.16-1.72]; p < 0.001), as well as after additional adjustment for the presence and extent of significant CAD at baseline (HR 1.59 [95% CI 1.29-1.97, p < 0.001). From this first prospective evaluation of the cardiovascular risk associated with omentin we conclude that elevated plasma omentin significantly predicts cardiovascular events independently from the presence and extent of angiographically determined baseline CAD. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

[Biological role of fetuin A and its potential importance for prediction of cardiovascular risk in patients with type 2 diabetes mellitus].

PubMed

Horshuns'ka, M Iu; Karachentsev, Iu I; Kravchun, N O; Ĭensen, É; Leshchenko, Zh A; Hladkykh, O I; Krasova, N S; Tyzhnenko, T V; Opaleĭko, Iu A; Poltorak, V V

2013-01-01

The authors' data and those from literature concerning biological role of fetuin A glycoprotein have been generalized in the article. A direct correlation has been established between fetuin A and some adipokines involved in the formation of insulin resistance and atherogenesis (progranulin, omentin-1), and osteoprotegerin (the novel cardiovascular risk factor) as well as an increase of circulating levels of fetuin A in patients with type 2 diabetes mellitus with high cardiovascular risk metabolic pattern but without manifestations of macrovascular complications. This substantiates the involvement of fetuin A in the complex of biomarkers of subclinical atherosclerosis.

Effects of rhythmic aerobic exercise plus core stability training on serum omentin, chemerin and vaspin levels and insulin resistance of overweight women.

PubMed

Faramarzi, Mohammad; Banitalebi, Ebrahim; Nori, Saba; Farzin, Shiva; Taghavian, Zohreh

2016-04-01

Omentin, chemerin and vaspin are novel adipokines that are secreted from adipose tissue and improved insulin sensitive. The purpose of this study was to examine the effects of rhythmic aerobic exercise plus core stability training on serum omentin, chemerin and vaspin levels and insulin resistance (IR) of overweight women. Forty aged healthy women (age; 25-45 years old, waist circumference [WC]>88 cm; Body Mass Index (BMI)>25 kg/m2) were selected purposely and divided in two control (N.=16) and experimental (N.=19) groups. Five dropped out during the study. The experimental group trained 12 weeks (3 sessions per week, one hr/session). The exercise program consisted of rhythmic aerobic exercise (55-85% maximum heart rate) along with core stability training. Serum chemerin, omentin, vaspin and insulin concentration were assayed by commercially ELISA kit. IR was evaluated according to the Homeostasis Model Assessment of Insulin Resistance Index (HOMA-IR). Data were analyzed by dependent and independent t-test to compare pre-test and post-test in each group and to compare the amount of changes in experimental and control training groups after twelve weeks. The result showed that exercise training had significant effect on BMI (P=0.00), WC (P=0.00), body fat (P=0.05), chemerin (P=0.041) and vaspin (P=0.045). But, this training had non-significant effect on plasma omentin level (P=0.090), plasma glucose level (P=0.670), insulin (P=0.11) and IR (P=0.07). Despite the fact that this kind of intervention could be an effective treatment to improve some adipokine levels and was accompanied by decreased body fat and waist circumference. However, more intense training is required to significantly change IR and serum omentin level in overweight women.

Does 8 weeks of strenuous bicycle exercise improve diabetes-related inflammatory cytokines and free fatty acids in type 2 diabetes patients and individuals at high-risk of metabolic syndrome?

PubMed

Madsen, Søren Møller; Thorup, Anne Cathrine; Bjerre, Mette; Jeppesen, Per Bendix

2015-01-01

In the present study, the effects of 8 weeks of low volume high intensity interval training (HIIT) was investigated on circulating diabetes-related cytokines and free fatty acids (FFA) in adults with type 2 diabetes (T2D) and matched controls (CON). Participants exercised for 8 weeks (3 weekly sessions: 10 × 60 sec HIIT) on a cycle ergometer supervised by medical staff. Prior to the intervention and after the last HIIT session, venous blood samples were collected. Circulating omentin-1 concentrations increased significantly in both the CON-group (p = 0.003) and in the T2D-group (p = 0.002). Pentraxin-3 (p = 0.010) and IL-1ra (p = 0.031) levels increased significantly in the CON-group. Plasma FFA in the T2D-group was significantly reduced after 60 min (p = 0.011). Post HIIT area under curve of circulating FFAs was reduced by -17.73 ± 6.99% (p = 0.041) in the T2D-group. We observed only modest exercise-induced improvements of multiple diabetes-related cytokines. Circulating levels of FFAs were significantly lowered in the T2D-group.

The effect of Stevia rebaudiana on serum omentin and visfatin level in STZ-induced diabetic rats.

PubMed

Akbarzadeh, Samad; Eskandari, Fatemeh; Tangestani, Hadis; Bagherinejad, Somaieh Tangerami; Bargahi, Afshar; Bazzi, Parviz; Daneshi, Adel; Sahrapoor, Azam; O'Connor, William J; Rahbar, Ali Reza

2015-03-01

Recently the role of adipocytokines in relationship to incidence of diabetes has been demonstrated. One of the medicinal plants that are used in the treatment of diabetes is stevia. This study investigates the effect of stevia on serum omentin and visfatin levels as novel adipocytokines in diabetic induced rats to find potential mechanisms for the anti hyperglycemic effect of stevia. Forty male wistar rats weighing 180-250 g were induced with diabetes by intraperitoneal injection of streptozotocin (STZ). The animals were divided into 5 groups of 8. Rats in group 1 (non-diabetic control) and group 2 (diabetic control) were treated with distilled water, and the rats in the treated groups, group 3 (T250), group 4 (T500), and group 5 (T750) were treated with stevia, gavaged every day at 9 a.m. in doses of 250, 500, and 750 mg/kg, respectively. At the end of the study significant reductions in fasting blood sugar (FBS), the homeostasis model assessment insulin resistance (HOMA-IR), triglyceride (TG), alkaline phosphatase (ALP), and Omentin level were found in groups 3 and 4 in comparison with group 2. Pancreatic histopathology slides demonstrated that stevia extract did not induce any increase in the number of β-cells. The conclusion is that prescription of stevia in the doses of 250 and 500 mg/kg/d decreases the omentin level indirectly via activating insulin sensitivity and lowering blood glucose in STZ-induced diabetic rats.

Differential Effects of Oral and Intravenous Lipid Administration on Key Molecules Related to Energy Homeostasis

PubMed Central

Vamvini, Maria T.; Hamnvik, Ole-Petter; Sahin-Efe, Ayse; Gavrieli, Anna; Dincer, Fadime; Farr, Olivia M.

2016-01-01

Context: The spectrum of lipid-induced changes in the secretion of hormones important in energy homeostasis has not yet been fully elucidated. Objective: To identify potential incretin-like effects in response to lipid administration, we examined the short-term effect of iv vs oral lipids on key molecules regulating energy homeostasis. Design, Intervention, and Participants: After a 10-hour overnight fast, 26 subjects were randomized to receive an oral lipid load, a 10% iv lipid emulsion, a 20% iv lipid emulsion, or an iv saline infusion. We obtained blood samples at 30-minute intervals for the first 2 hours and hourly thereafter for a total of 6 hours. Main Outcome Measures: Circulating levels of insulin, glucose, c-peptide, free fatty acids, incretins (glucagon-like peptide-1, gastric inhibitory polypeptide), glucagon, peptide YY, ghrelin, fibroblast growth factor 21, fetuin A, irisin, omentin, and adiponectin were measured. Results: Oral lipid ingestion resulted in higher glucagon-like peptide-1, gastric inhibitory polypeptide, glucagon, and peptide YY levels, compared with the other three groups (incremental area under the curve P = .003, P < .001, P < .001, P < .001, respectively). The 20% lipid emulsion, leading to higher free fatty acid levels, resulted in greater insulin, c-peptide, and fibroblast growth factor 21 responses compared with placebo and the other two groups (incremental area under the curve P = .002, P = .005, P < .001, P < .001, respectively). Omentin, adiponectin, fetuin A, and irisin levels were not affected by either mode of lipid administration. Conclusions: Metabolic responses to lipids depend on the route of administration. Only iv lipids trigger a dose-dependent fibroblast growth factor 21 secretion, which is nonglucagon mediated. Intravenous lipids also induce hyperinsulinemia without concurrent decreases in glucose, a phenomenon observed in insulin-resistant states. Orally administered lipids mostly affect gastrointestinal tract-secreted molecules important in glucose and energy homeostasis such as glucagon, incretins, and peptide YY. PMID:26964729

New insights into adipokines as potential biomarkers for type-2 diabetes mellitus.

PubMed

Olivera Santa-Catalina, Marta; Redondo, Pedro C; Cantonero, C; Granados, Maria P; Sanchez-Collado, Jose; Albarran, Letizia; Lopez, Jose Javier

2017-12-05

A large number of studies have been focused on investigating serum biomarkers associated with risk or diagnosis of type-2 diabetes mellitus. In the last decade, promising studies have shown that circulating levels of adipokines could be used as a relevant biomarker for diabetes mellitus progression as well as therapeutic future targets. Here we discuss the possible use of recent described adipokines, including apelin, omentin-1, resistin, FGF-21, neuregulin-4 and visfatin, as early biomarkers for diabetes. In addition, we also include recent findings of other well know adipokines such as leptin and adiponectin. In conclusion, further studies are needed to clarify the pathophysiological significance and clinical value of these biological factors as potential biomarkers in type-2 diabetes and related dysfunctions. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

[Omentin: Role in insulin resistance, inflammation and cardiovascular protection].

PubMed

Hernández-Díaz, Adrián; Arana-Martínez, Julio C; Carbó, Roxana; Espinosa-Cervantes, Román; Sánchez-Muñoz, Fausto

2016-01-01

The omentin is an adipokine, which role is due to the capacity of regulate metabolic (insulin sensitivity) and anti-inflammatory activities, thus conferring vascular protection during obesity and diabetes mellitus type 2. By this, it is important to know the mechanisms by which omentin confers cardiovascular protection, with the purpose of establish omentin a possible therapeutic target or molecule on this scenario. Copyright © 2015 Instituto Nacional de Cardiología Ignacio Chávez. Publicado por Masson Doyma México S.A. All rights reserved.

Serum adiposity-induced biomarkers in obese and lean children with recently diagnosed autoimmune type 1 diabetes.

PubMed

Redondo, M J; Rodriguez, L M; Haymond, M W; Hampe, C S; Smith, E O; Balasubramanyam, A; Devaraj, S

2014-12-01

Obesity increases the risk of cardiovascular disease and diabetic complications in type 1 diabetes. Adipokines, which regulate obesity-induced inflammation, may contribute to this association. We compared serum adipokines and inflammatory cytokines in obese and lean children with new-onset autoimmune type 1 diabetes. We prospectively studied 32 lean and 18 obese children (age range: 2-18 yr) with new-onset autoimmune type 1 diabetes and followed them for up to 2 yr. Serum adipokines [leptin, total and high molecular weight (HMW) adiponectin, omentin, resistin, chemerin, visfatin], cytokines [interferon (IFN)-gamma, interleukin (IL)-10, IL-12, IL-6, IL-8, and tumor necrosis factor (TNF)-alpha] and C-reactive protein (CRP) were measured at a median of 7 wk after diagnosis (range: 3-16 wk). Lean children were 71.9% non-Hispanic White, 21.9% Hispanic, and 6.3% African-American, compared with 27.8, 55.6, and 16.7%, respectively, for obese children (p = 0.01). Compared with lean children, obese children had significantly higher serum leptin, visfatin, chemerin, TNF-alpha and CRP, and lower total adiponectin and omentin after adjustment for race/ethnicity and Tanner stage. African-American race was independently associated with higher leptin among youth ≥10 yr (p = 0.007). Leptin levels at onset positively correlated with hemoglobin A1c after 1-2 yr (p = 0.0001) independently of body mass index, race/ethnicity, and diabetes duration. Higher TNF-alpha was associated with obesity and female gender, after adjustment for race/ethnicity (p = 0.0003). Obese children with new-onset autoimmune type 1 diabetes have a proinflammatory profile of circulating adipokines and cytokines that may contribute to the development of cardiovascular disease and diabetic complications. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Leptin Is Associated With Persistence of Hyperglycemia in Acute Pancreatitis

PubMed Central

Kennedy, James I.C.; Askelund, Kathryn J.; Premkumar, Rakesh; Phillips, Anthony R.J.; Murphy, Rinki; Windsor, John A.; Petrov, Maxim S.

2016-01-01

Abstract Adipokines have many homeostatic roles, including modulation of glucose metabolism, but their role in the pathophysiology of hyperglycemia associated with acute and critical illnesses in general, and acute pancreatitis (AP) in particular, is largely unknown. This study aimed to investigate the relationship between a panel of adipokines and hyperglycemia in the early course of AP, as well as the role of adipokines as predictors of AP severity. Adiponectin, leptin, omentin, resistin, and visfatin were measured on a daily basis in the first 72 hours after hospital admission. A first set of analyses was undertaken with admission glycemia stratified by severity, and a second set of analyses was undertaken based on persistence of early hyperglycemia. All of the analyses were adjusted for confounders. A total of 32 patients with AP were included in this study. None of the studied adipokines was significantly associated with glucose level on admission. Leptin was significantly (P = 0.003) increased in patients with persistent hyperglycemia. Adiponectin was significantly associated with the Acute Physiology and Chronic Health Evaluation II (APACHE II) score in patients with persistent hyperglycemia (P = 0.015), visfatin with APACHE II score in patients with persistent hyperglycemia (P = 0.014), and omentin with APACHE II score in all of the patients regardless of the presence or absence of hyperglycemia (P = 0.021). Leptin is significantly associated with persistent hyperglycemia in the early course of AP. Omentin has a potential to become an accurate predictor of AP severity. PMID:26871770

Insulin resistance, adipokine profile and hepatic expression of SOCS-3 gene in chronic hepatitis C.

PubMed

Wójcik, Kamila; Jabłonowska, Elżbieta; Omulecka, Aleksandra; Piekarska, Anna

2014-08-14

To analyze adipokine concentrations, insulin resistance and hepatic expression of suppressor of cytokine signaling 3 (SOCS-3) in patients with chronic hepatitis C genotype 1 with normal body weight, glucose and lipid profile. The study group consisted of 31 patients with chronic hepatitis C and 9 healthy subjects. Total levels of adiponectin, leptin, resistin, visfatin, omentin, osteopontin and insulin were measured using an ELISA kit. The hepatic expression of SOCS-3 was determined by the use of the reverse transcription polymerase chain reaction method. Homeostasis model assessment for insulin resistance (HOMA-IR) values were significantly higher in hepatitis C virus (HCV) infected patients without metabolic disorders compared to healthy controls (2.24 vs 0.59, P = 0.0003). Hepatic steatosis was observed in 32.2% of patients with HCV infection and was found in patients with increased HOMA-IR index (2.81 vs 1.99, P = 0.05) and reduced adiponectin level (5.96 vs 8.37, P = 0.04). Inflammatory activity (G ≥ 2) was related to increased osteopontin concentration (34.04 vs 23.35, P = 0.03). Advanced liver fibrosis (S ≥ 2) was associated with increased levels of omentin and osteopontin (436.94 vs 360.09, P = 0.03 and 32.84 vs 20.29, P = 0.03) and reduced resistin concentration (1.40 vs 1.74, P = 0.047). No correlations were reported between adipokine profile, HOMA-IR values and hepatic expression of the SOCS-3 gene. We speculated that no relationship between adipokines and HOMA-IR values may indicate that HCV can induce insulin resistance itself. Some adipokines appear to be biochemical markers of steatosis, inflammation and fibrosis in patients with chronic HCV infection. © 2014 Baishideng Publishing Group Inc. All rights reserved.

Resistin, visfatin, leptin and omentin are differently related to hormonal and metabolic parameters in growth hormone-deficient children.

PubMed

Ciresi, A; Pizzolanti, G; Leotta, M; Guarnotta, V; Teresi, G; Giordano, C

2016-09-01

The effect of growth hormone (GH) on adipose tissue and the role of adipokines in modulating metabolism are documented, but with discordant data. Our aim was to evaluate the impact of GH treatment on a series of selected adipokines known to have a metabolic role and poorly investigated in this setting. This is a prospective study. Thirty-one prepubertal children (25 M, 6 F; aged 8.5 ± 1.6 years) with isolated GH deficiency treated with GH for at least 12 months and 30 matched controls were evaluated. Auxological and metabolic parameters, insulin sensitivity indexes, leptin, soluble leptin receptor, adiponectin, visfatin, resistin, omentin, adipocyte fatty acid-binding protein and retinol-binding protein-4 were evaluated before and after 12 months of treatment. At baseline, no significant difference in metabolic parameters was found between GHD children and controls, except for higher LDL cholesterol (p = 0.004) in the first group. At multivariate analysis, LDL cholesterol was independently associated with resistin (B 0.531; p = 0.002), while IGF-I was the only variable independently associated with visfatin (B 0.688; p < 0.001). After 12 months, a significant increase in fasting insulin (p = 0.008), Homa-IR (p = 0.007) and visfatin (p < 0.001) was found, with a concomitant decrease in LDL cholesterol (p = 0.015), QUICKI (p = 0.001), ISI Matsuda (p = 0.006), leptin (p = 0.015) and omentin (p = 0.003)]. At multivariate analysis, BMI was the only variable independently associated with leptin (B 0.485; p = 0.040). GH treatment modifies adipokine secretion and the perturbation of some adipokine levels could contribute to the clinical and metabolic changes observed during the follow-up.

Effects of vitamin D-fortified low fat yogurt on glycemic status, anthropometric indexes, inflammation, and bone turnover in diabetic postmenopausal women: A randomised controlled clinical trial.

PubMed

Jafari, Tina; Faghihimani, Elham; Feizi, Awat; Iraj, Bijan; Javanmard, Shaghayegh Haghjooy; Esmaillzadeh, Ahmad; Fallah, Aziz A; Askari, Gholamreza

2016-02-01

Low levels of serum 25-hydroxy vitamin D (25(OH)D) are common in type 2 diabetic patients and cause several complications particularly, in postmenopausal women due to their senile and physiological conditions. This study aimed to assess the effects of vitamin D-fortified low fat yogurt on glycemic status, anthropometric indexes, inflammation, and bone turnover in diabetic postmenopausal women. In a randomized, placebo-controlled, double-blind parallel-group clinical trial, 59 postmenopausal women with type 2 diabetes received fortified yogurt (FY; 2000 IU vitamin D in 100 g/day) or plain yogurt (PY) for 12 weeks. Glycemic markers, anthropometric indexes, inflammatory, and bone turnover markers were assessed at baseline and after 12 weeks. After intervention, in FY group (vs PY group), were observed: significant increase in serum 25(OH)D and decrease of PTH (stable values in PY); significant improvement in serum fasting insulin, HOMA-IR, HOMA-B, QUICKI, and no changes in serum fasting glucose and HbA1c (significant worsening of all indexes in PY); significant improvement in WC, WHR, FM, and no change in weight and BMI (stable values in PY); significant increase of omentin (stable in PY) and decrease of sNTX (significant increase in PY). Final values of glycemic markers (except HbA1c), omentin, and bone turnover markers significantly improved in FY group compared to PY group. Regarding final values of serum 25(OH)D in FY group, subjects were classified in insufficient and sufficient categories. Glycemic status improved more significantly in the insufficient rather than sufficient category; whereas the other parameters had more amelioration in the sufficient category. Daily consumption of 2000 IU vitamin D-fortified yogurt for 12 weeks improved glycemic markers (except HbA1c), anthropometric indexes, inflammation, and bone turnover markers in postmenopausal women with type 2 diabetes. www.irct.ir (IRCT2013110515294N1). Copyright © 2015 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.

Pharmacodynamic Effects of Low-Dose Pioglitazone in Patients with the Metabolic Syndrome without Diabetes Mellitus.

PubMed

Vu, Anh; Kosmiski, Lisa A; Beitelshees, Amber L; Prigeon, Ronald; Sidhom, Maha S; Bredbeck, Brooke; Predhomme, Julie; Deininger, Kimberly M; Aquilante, Christina L

2016-03-01

To determine the effects of low-dose pioglitazone on plasma adipocyte-derived cytokines, high-sensitivity C-reactive protein (hs-CRP), and components of the metabolic syndrome in adults with the metabolic syndrome without diabetes mellitus. Prospective, randomized, double-blind, placebo-controlled study. University of Colorado Clinical and Translational Research Center. Thirty-two men and women, aged 30-60 years, without diabetes who had a clinical diagnosis of the metabolic syndrome, as defined by the American Heart Association/National Heart, Lung, and Blood Institute criteria. Patients were randomly assigned to receive oral pioglitazone 7.5 mg daily or matching placebo for 8 weeks. The primary end point was the change in plasma high-molecular-weight (HMW) adiponectin level from baseline to week 8. Other end points were changes in plasma total adiponectin, omentin, and hs-CRP levels, and changes in components of the metabolic syndrome (e.g., insulin sensitivity) from baseline to week 8. Pioglitazone was associated with a significant increase in plasma HMW adiponectin from baseline to week 8 compared with placebo (+47% vs -10%, p<0.001). Insulin sensitivity increased significantly from baseline to week 8 in the pioglitazone group (+88%, p=0.02) but not in the placebo group (+15%, p=0.14). Change in HMW adiponectin was significantly correlated with the change in insulin sensitivity in the pioglitazone group (r = 0.784, p=0.003). No significant differences in mean percentage changes in plasma total adiponectin, omentin, and hs-CRP levels were observed between the pioglitazone and placebo groups. Likewise, changes in body weight, insulin sensitivity, glucose, lipids, and blood pressure did not differ significantly between the groups. Low-dose pioglitazone favorably modulates plasma HMW adiponectin, which was associated with an improvement in insulin sensitivity, in patients with the metabolic syndrome without diabetes. © 2016 Pharmacotherapy Publications, Inc.

Adipokines in human reproduction.

PubMed

Dupont, Joëlle; Pollet-Villard, Xavier; Reverchon, Maxime; Mellouk, Namya; Levy, Rachel

2015-10-01

Adipose tissue communicates with other central and peripheral organs by the synthesis and release of substances called adipokines. The most studied adipokine is leptin but others have been recently identified including resistin, adiponectin, chemerin, omentin and visfatin. These adipokines have a critical role in the development of obesity-related complications and inflammatory conditions. However, they are also involved in other functions in the organism including reproductive functions. Indeed, many groups have demonstrated that adipokine receptors, such as adiponectin and chemerin, but also adipokines themselves (adiponectin, chemerin, resistin, visfatin and omentin) are expressed in human peripheral reproductive tissues and that these adipokines are likely to exert direct effects on these tissues. After a brief description of these new adipokines, an overview of their actions in different human reproductive organs (hypothalamus, pituitary, ovary, testis, uterus and placenta) will be presented. Finally, comments will be made on the eventual alterations of these adipokines in reproductive disorders, with special attention to polycystic ovary syndrome, a disease characterized by dysfunction of gonadal axis and systemic nerve endocrine metabolic network with a prevalence of up to 10% in women of reproductive age.

Genetic Determination of Serum Levels of Diabetes-Associated Adipokines

PubMed Central

Schleinitz, Dorit

2015-01-01

Adipose tissue secretes an abundance of proteins. Some of these proteins are known as adipokines and adipose-derived hormones which have been linked with metabolic disorders, including type 2 diabetes, and even with cancer. Variance in serum adipokine concentration is often closely associated with an increase (obesity) or decrease (lipodystrophy) in fat tissue mass, and it is affected by age, gender, and localization of the adipose tissue. However, there may be genetic variants which, in consequence, influence the serum concentration of a certain adipokine, and thereby promote metabolic disturbances or, with regard to the “protective” allele, exert beneficial effects. This review focuses on the genetic determination of serum levels of the following adipokines: adiponectin, chemerin, leptin, progranulin, resistin, retinol binding protein 4, vaspin, adipsin, apelin, and omentin. The article reports on the latest findings from genome-wide association studies (GWAS) and candidate gene studies, showing variants located in/nearby the adipokine genes and other (non-receptor) genes. An extra chapter highlights adipokine-receptor variants. Epigenetic studies on adipokines are also addressed. PMID:26859657

Adipose Tissue as an Endocrine Organ: An Update on Pro-inflammatory and Anti-inflammatory Microenvironment.

PubMed

Smitka, Kvido; Marešová, Dana

2015-01-01

Adipose tissue is recognized as an active endocrine organ that produces a number of endocrine substances referred to as "adipokines" including leptin, adiponectin, adipolin, visfatin, omentin, tumour necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), resistin, pigment epithelium-derived factor (PEDF), and progranulin (PGRN) which play an important role in the food intake regulation and significantly influence insulin sensitivity and in some cases directly affect insulin resistance in skeletal muscle, liver, and adipose tissue. The review summarizes current knowledge about adipose tissue-derived hormones and their influence on energy homeostasis regulation. The possible therapeutic potential of these adipokines in the treatment of insulin resistance, endothelial dysfunction, a pro-inflammatory response, obesity, eating disorders, progression of atherosclerosis, type 1 diabetes, and type 2 diabetes is discussed.

Determination of Viremia and Concentration of Circulating Nonstructural Protein 1 in Patients Infected with Dengue Virus in Mexico

PubMed Central

de la Cruz-Hernández, Sergio I.; Flores-Aguilar, Hilario; González-Mateos, Silvia; López-Martinez, Irma; Alpuche-Aranda, Celia; Ludert, Juan E.; del Angel, Rosa M.

2013-01-01

Higher levels of viremia and circulating nonstructural protein 1 (NS1) have been associated with dengue disease severity. In this study, viremia and circulating NS1 levels were determined in 225 serum samples collected from patients in Mexico infected with dengue virus serotypes 1 and 2 (DENV-1 and DENV-2). Patients with dengue hemorrhagic fever (DHF) who were infected with DENV-1 showed higher levels of circulating NS1 than patients with dengue fever (DF) (P = 0.0175). Moreover, NS1 levels were higher in patients with primary infections with DENV-1 than in patient infected with DENV-2 (P < 0.0001) and in patients with primary infections with DENV-2 than in patients with secondary infections with DENV-2 (P = 0.0051). Unexpectedly, viremia levels were higher in patients with DF than in those with DHF infected with either DENV-1 or DENV-2 (P = 0.0019 and P = 0.001, respectively) and in patients with primary infections than those with secondary DENV-2 infections (P < 0.0001). Results indicate that levels of circulating NS1 vary according to the infecting serotype, immunologic status (primary or secondary infection), and dengue disease severity. PMID:23339203

Determination of viremia and concentration of circulating nonstructural protein 1 in patients infected with dengue virus in Mexico.

PubMed

de la Cruz-Hernández, Sergio I; Flores-Aguilar, Hilario; González-Mateos, Silvia; López-Martinez, Irma; Alpuche-Aranda, Celia; Ludert, Juan E; del Angel, Rosa M

2013-03-01

Higher levels of viremia and circulating nonstructural protein 1 (NS1) have been associated with dengue disease severity. In this study, viremia and circulating NS1 levels were determined in 225 serum samples collected from patients in Mexico infected with dengue virus serotypes 1 and 2 (DENV-1 and DENV-2). Patients with dengue hemorrhagic fever (DHF) who were infected with DENV-1 showed higher levels of circulating NS1 than patients with dengue fever (DF) (P = 0.0175). Moreover, NS1 levels were higher in patients with primary infections with DENV-1 than in patient infected with DENV-2 (P < 0.0001) and in patients with primary infections with DENV-2 than in patients with secondary infections with DENV-2 (P = 0.0051). Unexpectedly, viremia levels were higher in patients with DF than in those with DHF infected with either DENV-1 or DENV-2 (P = 0.0019 and P = 0.001, respectively) and in patients with primary infections than those with secondary DENV-2 infections (P < 0.0001). Results indicate that levels of circulating NS1 vary according to the infecting serotype, immunologic status (primary or secondary infection), and dengue disease severity.

Circulating levels of C-reactive protein, interleukin-6 and tumor necrosis factor-α and risk of colorectal adenomas: a meta-analysis.

PubMed

Zhang, Xiaoqian; Liu, Shanglong; Zhou, Yanbing

2016-09-27

Results from publications on inflammatory markers of C-reactive protein (CRP), interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) and risk of colorectal adenomas are not consistent. A meta-analysis was conducted to explore the above-mentioned associations. Relevant studies were identified by a search of Embase, Medline and PubMed through February 2016. A random effect model was adopted to combine study-specific odds ratio (OR) and 95% confidence interval (95% CI). Between-study heterogeneity and publications bias were assessed. Dose-response relationships were assessed by restricted cubic splines. Nineteen observational studies were included. For highest vs. lowest levels, results from this meta-analysis did not support an association between circulating levels of CRP [OR (95% CI): 1.15 (0.94-1.40)], IL-6 [1.17 (0.94-1.46)] and TNF-α [0.99 (0.75-1.31)] and risk of colorectal adenomas, respectively. The findings were supported by sensitivity analysis and subgroup analysis. In dose-response analysis, the risk of colorectal adenomas increased by 2% [1.02 (0.97-1.08)] for each 1 mg/L increment in circulation CRP levels, 9% [1.09 (0.91-1.31)] for each 1 ng/L increment in circulation IL-6 levels, and 6% [1.06 (0.93-1.21)] for each 1 pg/mL increment in circulation TNF-α levels. Moderate between-study heterogeneity was found. No evidence of publication bias was found. Circulation levels of CRP, IL-6 and TNF-α might be not useful biomarkers for identifying colorectal adenomas, respectively.

Lower Circulating Irisin Level in Patients with Diabetes Mellitus: A Systematic Review and Meta-Analysis.

PubMed

Du, X-L; Jiang, W-X; Lv, Z-T

2016-09-01

Studies measuring circulating irisin levels in patients with insulin resistance conditions such as type 2 diabetes mellitus (T2DM) and gestational diabetes mellitus (GDM) have achieved controversial results. Our systematic review and meta-analysis aim to assess the circulating irisin levels in patients with diabetes mellitus. Pubmed, EMBASE, CENTRAL, ISI Web of Science, and CNKI were searched to identify observational studies of circulating irisin levels in patients with diabetes mellitus. Two reviewers independently searched the databases and screened studies according to the inclusion criteria. Data were extracted using a standardized collection form. Meta-analysis was performed. A total of 23 studies (17 cross-sectional and 6 case control) involving 1 745 diabetic patients and 1 337 non-diabetic controls were selected. Compared with non-diabetic controls, circulating irisin concentrations were significantly lower in patients with T2DM (SMD -1.72, 95%CI -2.49, -0.96; p<0.00001) and GDM (SMD -0.76, 95CI -1.31, -0.22; p=0.006), but 30 percent higher in patients with T1DM. Circulating irisin in Asian diabetic patients decreased more than European patients. The findings of our current review suggest that circulating irisin levels were decreased in patients with T2DM and GDM, but not in patients with T1DM. © Georg Thieme Verlag KG Stuttgart · New York.

Circulating levels of dickkopf-1, osteoprotegerin and sclerostin are higher in old compared with young men and women and positively associated with whole-body bone mineral density in older adults.

PubMed

Coulson, J; Bagley, L; Barnouin, Y; Bradburn, S; Butler-Browne, G; Gapeyeva, H; Hogrel, J-Y; Maden-Wilkinson, T; Maier, A B; Meskers, C; Murgatroyd, C; Narici, M; Pääsuke, M; Sassano, L; Sipilä, S; Al-Shanti, N; Stenroth, L; Jones, D A; McPhee, J S

2017-09-01

Bone mineral density declines with increasing older age. We examined the levels of circulating factors known to regulate bone metabolism in healthy young and older adults. The circulating levels of dickkopf-1, osteocalcin, osteoprotegerin and sclerostin were positively associated with whole-body bone mineral density (WBMD) in older adults, despite the average WBMD being lower and circulating dickkopf-1, osteoprotegerin and sclerostin being higher in old than young. This study aims to investigate the relationship between whole-body bone mineral density (WBMD) and levels of circulating factors with known roles in bone remodelling during 'healthy' ageing. WBMD and fasting plasma concentrations of dickkopf-1, fibroblast growth factor-23, osteocalcin, osteoprotegerin, osteopontin and sclerostin were measured in 272 older subjects (69 to 81 years; 52% female) and 171 younger subjects (18-30 years; 53% female). WBMD was lower in old than young. Circulating osteocalcin was lower in old compared with young, while dickkopf-1, osteoprotegerin and sclerostin were higher in old compared with young. These circulating factors were each positively associated with WBMD in the older adults and the relationships remained after adjustment for covariates (r values ranging from 0.174 to 0.254, all p < 0.01). In multivariate regression, the body mass index, circulating sclerostin and whole-body lean mass together accounted for 13.8% of the variation with WBMD in the older adults. In young adults, dickkopf-1 and body mass index together accounted for 7.7% of variation in WBMD. Circulating levels of dickkopf-1, osteocalcin, osteoprotegerin and sclerostin are positively associated with WBMD in community-dwelling older adults, despite the average WBMD being lower and circulating dickkopf-1, osteoprotegerin and sclerostin being higher in old than young.

High T3, Low T4 Serum Levels in Mct8 Deficiency Are Not Caused by Increased Hepatic Conversion through Type I Deiodinase

PubMed Central

Wirth, Eva K.; Rijntjes, Eddy; Meyer, Franziska; Köhrle, Josef; Schweizer, Ulrich

2015-01-01

Background The Allan-Herndon-Dudley syndrome is a severe psychomotor retardation accompanied by specific changes in circulating thyroid hormone levels (high T3, low T4). These are caused by mutations in the thyroid hormone transmembrane transport protein monocarboxylate transporter 8 (MCT8). Objective: To test the hypothesis that circulating low T4 and high T3 levels are caused by enhanced conversion of T4 via increased activity of hepatic type I deiodinase (Dio1). Methods We crossed mice deficient in Mct8 with mice lacking Dio1 activity in hepatocytes. Translation of the selenoenzyme Dio1 was abrogated by hepatocyte-specific inactivation of selenoprotein biosynthesis. Results Inactivation of Dio1 activity in the livers of global Mct8-deficient mice does not restore normal circulating thyroid hormone levels. Conclusions Our data suggest that although hepatic Dio1 activity is increased in Mct8-deficient mice, it does not cause the observed abnormal circulating thyroid hormone levels. Since global inactivation of Dio1 in Mct8-deficient mice does normalize circulating thyroid hormone levels, the underlying mechanism and relevant tissues involved remain to be elucidated. PMID:26601078

High T3, Low T4 Serum Levels in Mct8 Deficiency Are Not Caused by Increased Hepatic Conversion through Type I Deiodinase.

PubMed

Wirth, Eva K; Rijntjes, Eddy; Meyer, Franziska; Köhrle, Josef; Schweizer, Ulrich

2015-09-01

The Allan-Herndon-Dudley syndrome is a severe psychomotor retardation accompanied by specific changes in circulating thyroid hormone levels (high T3, low T4). These are caused by mutations in the thyroid hormone transmembrane transport protein monocarboxylate transporter 8 (MCT8). To test the hypothesis that circulating low T4 and high T3 levels are caused by enhanced conversion of T4 via increased activity of hepatic type I deiodinase (Dio1). We crossed mice deficient in Mct8 with mice lacking Dio1 activity in hepatocytes. Translation of the selenoenzyme Dio1 was abrogated by hepatocyte-specific inactivation of selenoprotein biosynthesis. Inactivation of Dio1 activity in the livers of global Mct8-deficient mice does not restore normal circulating thyroid hormone levels. Our data suggest that although hepatic Dio1 activity is increased in Mct8-deficient mice, it does not cause the observed abnormal circulating thyroid hormone levels. Since global inactivation of Dio1 in Mct8-deficient mice does normalize circulating thyroid hormone levels, the underlying mechanism and relevant tissues involved remain to be elucidated.

Tuberculosis-diabetes co-morbidity is characterized by heightened systemic levels of circulating angiogenic factors

PubMed Central

Kumar, Nathella Pavan; Moideen, Kadar; Sivakumar, Shanmugam; Menon, Pradeep A; Viswanathan, Vijay; Kornfeld, Hardy; Babu, Subash

2016-01-01

Background Tuberculosis-diabetes co-morbidity (TB-DM) is characterized by increased inflammation with elevated circulating levels of inflammatory cytokines and other factors. Circulating angiogenic factors are intricately involved in the angiogenesis-inflammation nexus. Methods To study the association of angiogenic factors with TB-DM, we examined the systemic levels of VEGF-A, VEGF-C, VEGF-D, VEGF-R1, VEGF-R2, VEGF-R3 in individuals with either TB-DM (n=44) or TB alone (n=44). Results Circulating levels of VEGF-A, C, D, R1, R2 and R3 were significantly higher in TB-DM compared to TB individuals. Moreover, the levels of VEGF-A, C, R2 and/or R3 were significantly higher in TB-DM with bilateral or cavitary disease or with hemoptysis, suggesing an association with both disease severity and adverse clinical presentation. The levels of these factors also exhibited a significant positive relationship with bacterial burdens and HbA1c levels. In addition, VEGF-A, C and R2 levels were signifantly higher (at 2 months of treatment) in culture positive compared to culture negative TB-DM individuals. Finally, the circulating levels of VEGF-A, C, D, R1, R2 and R3 were significantly reduced following successful chemotherapy at 6 months. Conclusion Our data demonstrate that TB-DM is associated with heightened levels of circulating angiogenic factors, possibly reflecting both dysregulated angiogenesis and exaggerated inflammation. PMID:27717783

Genetic and Dietary Determinants of Insulin-Like Growth Factor (IGF)-1 and IGF Binding Protein (BP)-3 Levels among Chinese Women

PubMed Central

Li, Hui; McCullough, Lauren E.; Qi, Ya-na; Li, Jia-yuan; Zhang, Jing; Miller, Erline; Yang, Chun-xia; Smith, Jennifer S.

2014-01-01

Background Higher insulin-like growth factor (IGF)-1 and lower IGF binding protein (BP)-3 levels have been associated with higher commoncancer risk, including breast cancer. Dietary factors, genetic polymorphisms, and the combination of both may influence circulating IGF-1 and IGFBP-3 serum concentrations. Methods From September 2011 to July 2012, we collected demographic, reproductive and dietary data on 143 women (≥40 years). We genotyped IGF-1 rs1520220 and IGFBP-3 rs2854744 and measured circulating IGF-1 and IGFBP-3 levels in serum. Covariance analyses were used to estimate the associations of serum levels of IGF-1 and IGFBP-3, and the molar ratio of IGF-1to IGFBP-3 with IGF-1 rs1520220 and IGFBP-3 rs2854744 genotypes. We subsequently assessed the combined influence of genetics and diet (daily intake of protein, fat and soy isoflavones) on IGF-1 and IGFBP-3 levels. Results Among women aged less than 50 years, circulating IGF-1 serum levels were significantly lower for those with CC genotype for IGF-1 rs1520220 than levels for those with the GC or GG genotypes (in recessive model: P = 0.007).In gene-diet analyses among these women, we found carrying CC genotype for IGF-1 rs1520220 and high soy isoflavone intake tend to be associated with lower circulating IGF-1 levels synthetically (P = 0.002). Women with GG or GC genotypes for IGF-1 rs1520220 and with low intake of soy isoflavones had the highest levels of circulating IGF-1 (geometric mean [95% CI]: 195 [37, 1021] µg/L). Comparatively, women with both the CC genotype and high soy intake had the lowest levels of circulating IGF-1 (geometric mean [95% CI]: 120 [38,378] µg/L). Conclusions IGF-1 serum levels are significantly lower among women with the CC genotype for IGF-1-rs1520220. High soy isoflavone intake may interact with carrying CC genotype for IGF-1-rs1520220 to lower women's serum IGF-1 levels more. PMID:25285521

Circulating metastasis associated in colon cancer 1 transcripts in gastric cancer patient plasma as diagnostic and prognostic biomarker

PubMed Central

Burock, Susen; Herrmann, Pia; Wendler, Ina; Niederstrasser, Markus; Wernecke, Klaus-Dieter; Stein, Ulrike

2015-01-01

AIM: To evaluate the diagnostic and prognostic value of circulating Metastasis Associated in Colon Cancer 1 (MACC1) transcripts in plasma of gastric cancer patients. METHODS: We provide for the first time a blood-based assay for transcript quantification of the metastasis inducer MACC1 in a prospective study of gastric cancer patient plasma. MACC1 is a strong prognostic biomarker for tumor progression and metastasis in a variety of solid cancers. We conducted a study to define the diagnostic and prognostic power of MACC1 transcripts using 76 plasma samples from gastric cancer patients, either newly diagnosed with gastric cancer, newly diagnosed with metachronous metastasis of gastric cancer, as well as follow-up patients. Findings were controlled by using plasma samples from 54 tumor-free volunteers. Plasma was separated, RNA was isolated, and levels of MACC1 as well as S100A4 transcripts were determined by quantitative RT-PCR. RESULTS: Based on the levels of circulating MACC1 transcripts in plasma we significantly discriminated tumor-free volunteers and gastric cancer patients (P < 0.001). Levels of circulating MACC1 transcripts were increased in gastric cancer patients of each disease stage, compared to tumor-free volunteers: patients with tumors without metastasis (P = 0.005), with synchronous metastasis (P = 0.002), with metachronous metastasis (P = 0.005), and patients during follow-up (P = 0.021). Sensitivity was 0.68 (95%CI: 0.45-0.85) and specificity was 0.89 (95%CI: 0.77-0.95), respectively. Importantly, gastric cancer patients with high circulating MACC1 transcript levels in plasma demonstrated significantly shorter survival when compared with patients demonstrating low MACC1 levels (P = 0.0015). Furthermore, gastric cancer patients with high circulating transcript levels of MACC1 as well as of S100A4 in plasma demonstrated significantly shorter survival when compared with patients demonstrating low levels of both biomarkers or with only one biomarker elevated (P = 0.001). CONCLUSION: Levels of circulating MACC1 transcripts in plasma of gastric cancer patients are of diagnostic value and are prognostic for patient survival in a prospective study. PMID:25574109

Prognostic value of circulating VEGFR2+ bone marrow-derived progenitor cells in patients with advanced cancer.

PubMed

Massard, Christophe; Borget, Isabelle; Le Deley, Marie Cécile; Taylor, Melissa; Gomez-Roca, Carlos; Soria, Jean Charles; Farace, Françoise

2012-06-01

We hypothesised that host-related markers, possibly reflecting tumour aggressiveness, such as circulating endothelial cells (CEC) and circulating VEGFR2(+) bone marrow-derived (BMD) progenitor cells, could have prognostic value in patients with advanced cancer enrolled in early anticancer drug development trials. Baseline CECs (CD45(-)CD31(+)CD146(+)7AAD(-) cells) and circulating VEGFR2(+)-BMD progenitor cells (defined as CD45(dim)CD34(+)VEGFR2(+)7AAD(-) cells) were measured by flow-cytometry in 71 and 58 patients included in phase 1 trials testing novel anti-vascular or anti-angiogenic agents. Correlations between levels of CECs, circulating VEGFR2(+)-BMD progenitor cells, clinical and biological prognostic factors (i.e. the Royal Marsden Hospital (RMH) score), and overall survival (OS) were studied. The median value of CECs was 12 CEC/ml (range 0-154/ml). The median level of VEGFR2(+)-BMD progenitor cells was 1.3% (range 0-32.5%) of circulating BMD-CD34(+) progenitors. While OS was not correlated with CEC levels, it was significantly worse in patients with high VEGFR2(+)-BMD progenitor levels (>1%) (median OS 9.0 versus 17.0 months), and with a RMH prognostic score >0 (median OS 9.0 versus 24.2 months). The prognostic value of VEGFR2(+)-BMD progenitor levels remained significant (hazard ratio (HR) = 2.3, 95% confidence interval (CI), 1.1-4.6, p = 0.02) after multivariate analysis. A composite VEGFR2(+)-BMD progenitor level/RHM score ≥ 2 was significantly associated with an increased risk of death compared to scores of 0 or 1 (median OS 9.0 versus 18.4 months, HR = 2.6 (95%CI, 1.2-5.8, p = 0.02)). High circulating VEGFR2(+)-BMD progenitor levels are associated with poor prognostics and when combined to classical clinical and biological parameters could provide a new tool for patient selection in early anticancer drug trials. Copyright © 2012 Elsevier Ltd. All rights reserved.

IGF-1, IGFBP-1, and IGFBP-3 polymorphisms predict circulating IGF levels but not breast cancer risk: findings from the Breast and Prostate Cancer Cohort Consortium (BPC3).

PubMed

Patel, Alpa V; Cheng, Iona; Canzian, Federico; Le Marchand, Loïc; Thun, Michael J; Berg, Christine D; Buring, Julie; Calle, Eugenia E; Chanock, Stephen; Clavel-Chapelon, Francoise; Cox, David G; Dorronsoro, Miren; Dossus, Laure; Haiman, Christopher A; Hankinson, Susan E; Henderson, Brian E; Hoover, Robert; Hunter, David J; Kaaks, Rudolf; Kolonel, Laurence N; Kraft, Peter; Linseisen, Jakob; Lund, Eiliv; Manjer, Jonas; McCarty, Catherine; Peeters, Petra H M; Pike, Malcolm C; Pollak, Michael; Riboli, Elio; Stram, Daniel O; Tjonneland, Anne; Travis, Ruth C; Trichopoulos, Dimitrios; Tumino, Rosario; Yeager, Meredith; Ziegler, Regina G; Feigelson, Heather Spencer

2008-07-02

IGF-1 has been shown to promote proliferation of normal epithelial breast cells, and the IGF pathway has also been linked to mammary carcinogenesis in animal models. We comprehensively examined the association between common genetic variation in the IGF1, IGFBP1, and IGFBP3 genes in relation to circulating IGF-I and IGFBP-3 levels and breast cancer risk within the NCI Breast and Prostate Cancer Cohort Consortium (BPC3). This analysis included 6,912 breast cancer cases and 8,891 matched controls (n = 6,410 for circulating IGF-I and 6,275 for circulating IGFBP-3 analyses) comprised primarily of Caucasian women drawn from six large cohorts. Linkage disequilibrium and haplotype patterns were characterized in the regions surrounding IGF1 and the genes coding for two of its binding proteins, IGFBP1 and IGFBP3. In total, thirty haplotype-tagging single nucleotide polymorphisms (htSNP) were selected to provide high coverage of common haplotypes; the haplotype structure was defined across four haplotype blocks for IGF1 and three for IGFBP1 and IGFBP3. Specific IGF1 SNPs individually accounted for up to 5% change in circulating IGF-I levels and individual IGFBP3 SNPs were associated up to 12% change in circulating IGFBP-3 levels, but no associations were observed between these polymorphisms and breast cancer risk. Logistic regression analyses found no associations between breast cancer and any htSNPs or haplotypes in IGF1, IGFBP1, or IGFBP3. No effect modification was observed in analyses stratified by menopausal status, family history of breast cancer, body mass index, or postmenopausal hormone therapy, or for analyses stratified by stage at diagnosis or hormone receptor status. In summary, the impact of genetic variation in IGF1 and IGFBP3 on circulating IGF levels does not appear to substantially influence breast cancer risk substantially among primarily Caucasian postmenopausal women.

Serum levels of leptin and high molecular weight adiponectin are inversely associated with radiographic spinal progression in patients with ankylosing spondylitis: results from the ENRADAS trial.

PubMed

Hartl, Agnes; Sieper, Joachim; Syrbe, Uta; Listing, Joachim; Hermann, Kay-Geert; Rudwaleit, Martin; Poddubnyy, Denis

2017-06-15

Previous research indicates a role of adipokines in inflammation and osteogenesis. Hence adipokines might also have a pathophysiological role in inflammation and new bone formation in patients with ankylosing spondylitis (AS). The aim of this study was to investigate the role of adipokine serum levels as predictors of radiographic spinal progression in patients with AS. A total of 120 patients with definite AS who completed a 2-year follow up in the ENRADAS trial were included in the current study. Radiographic spinal progression was defined as: (1) worsening of the modified Stoke Ankylosing Spondylitis spine (mSASSS) score by ≥2 points and/or (2) new syndesmophyte formation or progression of existing syndesmophytes after 2 years. Serum levels of adipokines (adiponectin (APN) and its high molecular weight form (HMW-APN), chemerin, leptin, lipocalin-2, omentin, resistin, visfatin) were measured using enzyme-linked immunosorbent assays. There was a significant association between radiographic spinal progression and both leptin and HMW-APN. Baseline serum levels of both adipokines were lower in patients who showed radiographic spinal progression after 2 years. This association was especially evident in men; they had generally lower leptin and HMW-APN serum levels as compared to women. The inverse association between adipokines and radiographic spinal progression was confirmed in the logistic regression analysis: the odds ratios (OR) for the outcome "no mSASSS progression ≥2 points" were 1.16 (95% CI 1.03 to 1.29) and 1.17 (95% CI 0.99 to 1.38), for leptin and HMW-APN, respectively; for "no syndesmophyte formation/progression" the respective OR were 1.29 (95% CI 1.11 to 1.50) and 1.18 (95% CI 0.98 to 1.42), adjusted for the presence of syndesmophytes at baseline, C-reactive protein at baseline, sex, body mass index (BMI), non-steroidal anti-inflammatory drugs intake score over 2 years, and smoking status at baseline. Serum leptin and HMW-APN predict protection from spinal radiographic progression in patients with AS. Women generally have higher leptin and HMW-APN serum levels that might explain why they have less structural damage in the spine as compared to male patients with AS. EudraCT: 2007-007637-39. ClinicalTrials.gov, NCT00715091 . Registered on 14 July 2008.

Circulating vascular cell adhesion molecule-1 in pre-eclampsia, gestational hypertension, and normal pregnancy: evidence of selective dysregulation of vascular cell adhesion molecule-1 homeostasis in pre-eclampsia.

PubMed

Higgins, J R; Papayianni, A; Brady, H R; Darling, M R; Walshe, J J

1998-08-01

Our purpose was to investigate circulating levels of vascular cell adhesion molecule-1 in the peripheral and uteroplacental circulations during normotensive and hypertensive pregnancies. This prospective observational study involved 2 patient groups. Group 1 consisted of 22 women with pre-eclampsia and 30 normotensive women followed up longitudinally through pregnancy and post partum. There were an additional 13 women with established gestational hypertension. Group 2 consisted of 20 women with established pre-eclampsia and 19 normotensive control subjects undergoing cesarean delivery. Plasma levels of vascular cell adhesion molecule-1 were measured in blood drawn from the antecubital vein (group 1) and from both the antecubital and uterine veins (group 2). Data were analyzed by analysis of variance. In group 1 vascular cell adhesion molecule-1 levels did not change significantly throughout normal pregnancy and post partum. Women with established pre-eclampsia had increased vascular cell adhesion molecule-1 levels compared with the normotensive pregnancy group (P = .01). Vascular cell adhesion molecule-1 levels were not elevated in women with established gestational hypertension. In group 2 significantly higher levels of vascular cell adhesion molecule-1 were detected in the uteroplacental (P < .0001) and peripheral (P < .0001) circulations of pre-eclamptic women by comparison with normotensive women. In the pre-eclamptic group there was a tendency toward higher vascular cell adhesion molecule-1 levels in the peripheral circulation than in the uteroplacental circulation (P = .06). In contrast to vascular cell adhesion molecule-1, circulating levels of E-selectin and intercellular adhesion molecule-1, other major leukocyte adhesion molecules expressed by the endothelium, were not different in pre-eclamptic and normotensive pregnancies. Established pre-eclampsia is characterized by selective dysregulation of vascular cell adhesion molecule-1 homeostasis. This event is not an early preclinical feature of pre-eclampsia, does not persist post partum, is not a feature of nonproteinuric gestational hypertension, and is not observed with other major leukocyte adhesion molecules. Induction of vascular cell adhesion molecule-1 expression in pre-eclampsia may contribute to leukocyte-mediated tissue injury in this condition or may reflect perturbation of other, previously unrecognized, functions of this molecule in pregnancy.

CCR7(lo)PD-1(hi) CXCR5(+) CD4(+) T cells are positively correlated with levels of IL-21 in active and transitional cystic echinococcosis patients.

PubMed

Zhang, Fengbo; Pang, Nannan; Zhu, Yuejie; Zhou, Dexian; Zhao, Hui; Hu, Jinwei; Ma, Xiumin; Li, Jun; Wen, Hao; Samten, Buka; Fan, Haining; Ding, Jianbing

2015-10-26

In our study, we investigated whether circulating T follicular helper (Tfh) and the related cytokines are involved in human cystic echinococcosis (CE). A total of 64 patients with CE and 30 healthy controls were enrolled in this study. Percentages of CCR7(lo)PD-1(hi) cells within CXCR5(+) CD4(+) T cells (circulating Tfh cells) were detected by flow cytometry. Levels of IL-21 and IL-4 in peripheral blood were detected by cytometric bead array. The mRNA expression of IL-21, IL-4, Bcl-6, and Blimp-1 in peripheral blood mononuclear cells (PBMCs) were measured by real-time PCR. Levels of IgG1, IgG2, IgG3, and IgG4 in the patients' sera were measured using enzyme-linked immunosorbent assay. Percentages of circulating Tfh cells were significantly increased in the CE1, CE2, and CE3 groups (p < 0.05). The concentrations of IL-21 and IL-4 in the serum were significantly increased in CE1, CE2, and CE3 groups (p < 0.05). IL-21 was positively correlated with circulating Tfh cells in CE3 group (r = 0.779, p < 0.05). The mRNA levels of IL-21, IL-4, and Bcl-6 were increased in CE1, CE2, and CE3 groups. Levels of IgG1 and IgG4 in patients' sera were increased in CE1, CE2, and CE3 groups. Levels of IgG2 and IgG3 were increased in CE4-5 group. Additionally, after stimulation with hydatid fluid in vitro, the levels of circulating Tfh cells, IL-21 and IL-4 in PBMCs isolated from CE patients were significantly increased (p < 0.05). The levels of circulating Tfh and related cytokines were significantly increased in CE patients, suggesting that they are involved in human CE.

Diversity in the representation of large-scale circulation associated with ENSO-Indian summer monsoon teleconnections in CMIP5 models

NASA Astrophysics Data System (ADS)

Ramu, Dandi A.; Chowdary, Jasti S.; Ramakrishna, S. S. V. S.; Kumar, O. S. R. U. B.

2018-04-01

Realistic simulation of large-scale circulation patterns associated with El Niño-Southern Oscillation (ENSO) is vital in coupled models in order to represent teleconnections to different regions of globe. The diversity in representing large-scale circulation patterns associated with ENSO-Indian summer monsoon (ISM) teleconnections in 23 Coupled Model Intercomparison Project Phase 5 (CMIP5) models is examined. CMIP5 models have been classified into three groups based on the correlation between Niño3.4 sea surface temperature (SST) index and ISM rainfall anomalies, models in group 1 (G1) overestimated El Niño-ISM teleconections and group 3 (G3) models underestimated it, whereas these teleconnections are better represented in group 2 (G2) models. Results show that in G1 models, El Niño-induced Tropical Indian Ocean (TIO) SST anomalies are not well represented. Anomalous low-level anticyclonic circulation anomalies over the southeastern TIO and western subtropical northwest Pacific (WSNP) cyclonic circulation are shifted too far west to 60° E and 120° E, respectively. This bias in circulation patterns implies dry wind advection from extratropics/midlatitudes to Indian subcontinent. In addition to this, large-scale upper level convergence together with lower level divergence over ISM region corresponding to El Niño are stronger in G1 models than in observations. Thus, unrealistic shift in low-level circulation centers corroborated by upper level circulation changes are responsible for overestimation of ENSO-ISM teleconnections in G1 models. Warm Pacific SST anomalies associated with El Niño are shifted too far west in many G3 models unlike in the observations. Further large-scale circulation anomalies over the Pacific and ISM region are misrepresented during El Niño years in G3 models. Too strong upper-level convergence away from Indian subcontinent and too weak WSNP cyclonic circulation are prominent in most of G3 models in which ENSO-ISM teleconnections are underestimated. On the other hand, many G2 models are able to represent most of large-scale circulation over Indo-Pacific region associated with El Niño and hence provide more realistic ENSO-ISM teleconnections. Therefore, this study advocates the importance of representation/simulation of large-scale circulation patterns during El Niño years in coupled models in order to capture El Niño-monsoon teleconnections well.

Circulating levels of FAS/APO-1 in patients with the systemic inflammatory response syndrome.

PubMed

Torre, Donato; Tambini, Roberto; Manfredi, Mariangela; Mangani, Valerio; Livi, Paola; Maldifassi, Viviana; Campi, Paolo; Speranza, Filippo

2003-04-01

Resolution of inflammation/infection involves removal of neutrophils and other inflammatory cells by the induction of apoptosis. Fas/Apo-1 is a widely occurring apoptotic signal receptor molecule expressed by almost any type of cell, which is also released in a soluble circulating form. In this study we investigated the role of circulating Fas/Apo-1 in patients with systemic inflammatory response syndrome (SIRS). We evaluated 57 critically ill patients, 34 with infectious SIRS (sepsis and septic shock), and 23 patients with noninfectious SIRS. Circulating Fas/Apo-1 was determined by a commercially available immunoassay. Our results clearly show that levels of Fas/Apo-1 were significantly elevated in patients with infectious and noninfectious SIRS (10.4 +/- 8.1 pg/mL, controls: 5.0 +/- 0.7 pg/mL; p < 0.0001). In addition, Fas/Apo-1 levels were not able in predicting in predicting poor outcome of patients with SIRS. In conclusion, these results show that increased levels of Fas/Apo-1 from patients with SIRS is a mechanism which contribute to inflammatory response through accumulation of neutrophils at sites of inflammation/infection.

Genetic evidence of a causal effect of insulin resistance on branched-chain amino acid levels.

PubMed

Mahendran, Yuvaraj; Jonsson, Anna; Have, Christian T; Allin, Kristine H; Witte, Daniel R; Jørgensen, Marit E; Grarup, Niels; Pedersen, Oluf; Kilpeläinen, Tuomas O; Hansen, Torben

2017-05-01

Fasting plasma levels of branched-chain amino acids (BCAAs) are associated with insulin resistance, but it remains unclear whether there is a causal relation between the two. We aimed to disentangle the causal relations by performing a Mendelian randomisation study using genetic variants associated with circulating BCAA levels and insulin resistance as instrumental variables. We measured circulating BCAA levels in blood plasma by NMR spectroscopy in 1,321 individuals from the ADDITION-PRO cohort. We complemented our analyses by using previously published genome-wide association study (GWAS) results from the Meta-Analyses of Glucose and Insulin-related traits Consortium (MAGIC) (n = 46,186) and from a GWAS of serum BCAA levels (n = 24,925). We used a genetic risk score (GRS), calculated using ten established fasting serum insulin associated variants, as an instrumental variable for insulin resistance. A GRS of three variants increasing circulating BCAA levels was used as an instrumental variable for circulating BCAA levels. Fasting plasma BCAA levels were associated with higher HOMA-IR in ADDITION-PRO (β 0.137 [95% CI 0.08, 0.19] p = 6 × 10 -7 ). However, the GRS for circulating BCAA levels was not associated with fasting insulin levels or HOMA-IR in ADDITION-PRO (β -0.011 [95% CI -0.053, 0.032] p = 0.6 and β -0.011 [95% CI -0.054, 0.031] p = 0.6, respectively) or in GWAS results for HOMA-IR from MAGIC (β for valine-increasing GRS -0.012 [95% CI -0.069, 0.045] p = 0.7). By contrast, the insulin-resistance-increasing GRS was significantly associated with increased BCAA levels in ADDITION-PRO (β 0.027 [95% CI 0.005, 0.048] p = 0.01) and in GWAS results for serum BCAA levels (β 1.22 [95% CI 0.71, 1.73] p = 4 × 10 -6 , β 0.96 [95% CI 0.45, 1.47] p = 3 × 10 -4 , and β 0.67 [95% CI 0.16, 1.18] p = 0.01 for isoleucine, leucine and valine levels, respectively) and instrumental variable analyses in ADDITION-PRO indicated that HOMA-IR is causally related to higher circulating fasting BCAA levels (β 0.73 [95% CI 0.26, 1.19] p = 0.002). Our results suggest that higher BCAA levels do not have a causal effect on insulin resistance while increased insulin resistance drives higher circulating fasting BCAA levels.

Circulating Influenza Virus and Adverse Pregnancy Outcomes: A Time-Series Study.

PubMed

Fell, Deshayne B; Buckeridge, David L; Platt, Robert W; Kaufman, Jay S; Basso, Olga; Wilson, Kumanan

2016-08-01

Individual-level epidemiologic studies of pregnancy outcomes after maternal influenza are limited in number and quality and have produced inconsistent results. We used a time-series design to investigate whether fluctuation in influenza virus circulation was associated with short-term variation in population-level rates of preterm birth, stillbirth, and perinatal death in Ontario between 2003 and 2012. Using Poisson regression, we assessed the association between weekly levels of circulating influenza virus and counts of outcomes offset by the number of at-risk gestations during 3 gestational exposure windows. The rate of preterm birth was not associated with circulating influenza level in the week preceding birth (adjusted rate ratio = 1.01, 95% confidence interval: 1.00, 1.02) or in any other exposure window. These findings were robust to alternate specifications of the model and adjustment for potential confounding. Stillbirth and perinatal death rates were similarly not associated with gestational exposure to influenza circulation during late pregnancy. We could not assess mortality outcomes relative to early gestational exposure because of missing dates of conception for many stillbirths. In this time-series study, population-level influenza circulation was not associated with short-term variation in rates of preterm birth, stillbirth, or perinatal death. © The Author 2016. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Circulating Mesenchymal Stem Cells Microparticles in Patients with Cerebrovascular Disease

PubMed Central

Cho, Yeon Hee; Kang, Ho Young; Hyung, Na Kyum; Kim, Donghee; Lee, Ji Hyun; Nam, Ji Yoon; Bang, Oh Young

2012-01-01

Preclinical and clinical studies have shown that the application of CD105+ mesenchymal stem cells (MSCs) is feasible and may lead to recovery after stroke. In addition, circulating microparticles are reportedly functional in various disease conditions. We tested the levels of circulating CD105+ microparticles in patients with acute ischemic stroke. The expression of CD105 (a surface marker of MSCs) and CXCR4 (a CXC chemokine receptor for MSC homing) on circulating microparticles was evaluated by flow cytometry of samples from 111 patients and 50 healthy subjects. The percentage of apoptotic CD105 microparticles was determined based on annexin V (AV) expression. The relationship between serum levels of CD105+/AV− microparticles, stromal cells derived factor-1α (SDF-1α), and the extensiveness of cerebral infarcts was also evaluated. CD105+/AV− microparticles were higher in stroke patients than control subjects. Correlation analysis showed that the levels of CD105+/AV− microparticles increased as the baseline stroke severity increased. Multivariate testing showed that the initial severity of stroke was independently associated with circulating CD105+/AV− microparticles (OR, 1.103 for 1 point increase in the NIHSS score on admission; 95% CI, 1.032–1.178) after adjusting for other variables. The levels of CD105+/CXCR4+/AV− microparticles were also increased in patients with severe disability (r = 0.192, p = 0.046 for NIHSS score on admission), but were decreased with time after stroke onset (r = −0.204, p = 0.036). Risk factor profiles were not associated with the levels of circulating microparticles or SDF-1α. In conclusion, our data showed that stroke triggers the mobilization of MSC-derived microparticles, especially in patients with extensive ischemic stroke. PMID:22615882

Usefulness of Circulating Decoy Receptor 3 in Predicting Coronary Artery Disease Severity and Future Major Adverse Cardiovascular Events in Patients With Multivessel Coronary Artery Disease.

PubMed

Chang, Ting-Yung; Hsu, Chien-Yi; Huang, Po-Hsun; Chiang, Chia-Hung; Leu, Hsin-Bang; Huang, Chin-Chou; Chen, Jaw-Wen; Lin, Shing-Jong

2015-10-01

Decoy receptor 3 (DcR3), a member of the tumor necrosis factor receptor superfamily, is an antiapoptotic soluble receptor considered to play an important role in immune modulation and has pro-inflammatory functions. This study was designed to test whether circulating DcR3 levels are associated with coronary artery disease (CAD) severity and predict future major adverse cardiovascular events (MACEs) in patients with CAD. Circulating DcR3 levels and the Syntax score (SXscore) were determined in patients with multivessel CAD. The primary end point was the MACE within 12 months. In total, 152 consecutive patients with angiographically confirmed multivessel CAD who had received percutaneous coronary intervention were enrolled and were divided into 3 groups according to CAD lesion severity. Group 1 was defined as low SXscore (≤13), group 2 as intermediate SXscore (>13 and ≤22), and group 3 as high SXscore (>22). DcR3 levels were significantly higher in the high SXscore group than the other 2 groups (13,602 ± 7,256 vs 8,025 ± 7,789 vs 4,637 ± 4,403 pg/ml, p <0.001). By multivariate analysis, circulating DcR3 levels were identified as an independent predictor for high SXscore (adjusted odds ratio 1.15, 95% confidence interval 1.09 to 1.21; p <0.001). The Kaplan-Meier analysis showed that increased circulating DcR3 levels are associated with enhanced 1-year MACE in patients with multivessel CAD (log-rank p <0.001). In conclusion, increased circulating DcR3 levels are associated with CAD severity and predict future MACE in patients with multivessel CAD. Copyright © 2015 Elsevier Inc. All rights reserved.

Circulating leptin level in rheumatoid arthritis and its correlation with disease activity: a meta-analysis.

PubMed

Lee, Y H; Bae, S-C

2016-12-01

This study aimed to evaluate the relationship between the circulating serum leptin level and rheumatoid arthritis (RA) and to establish a correlation between serum leptin levels and RA activity. We searched the PUBMED, EMBASE, and Cochrane databases. A meta-analysis was performed, comparing the serum/plasma leptin levels in patients with RA and healthy controls. Correlation coefficients between serum leptin level and either disease activity score 28 (DAS28) or C‑reactive protein (CRP) in RA patients were also examined. Thirteen studies with a total of 648 RA patients and 426 controls were included in this meta-analysis. Circulating leptin level was significantly higher in the RA group than in the control group (SMD = 1.056, 95 % CI = 0.647-1.465, p = 4.2 × 10 -7 ). In addition, stratification by ethnicity showed a significantly elevated leptin level in the RA group in Caucasian, Turkish, and Arab populations (SMD = 0.813, 95 % CI = 0.137-1.490, p = 0.018, SMD = 0.981, 95 % CI = 0.307-1.655, p = 0.004, and SMD = 1.469, 95 % CI = 0.443-2.495, p = 0.005 respectively). A meta-analysis of correlation coefficients showed a small but significantly positive correlation between the circulating leptin level and either DAS28 (correlation coefficient = 0.275, 95 % CI = 0.076-0.452, p = 0.007) or CRP (correlation coefficient = 0.274, 95 % CI = 0.068-0.458, p = 0.010). Our meta-analysis demonstrated that the circulating leptin level is significantly higher in patients with RA and that a small but significantly positive correlation exists between leptin levels and RA activity.

Groundwater-saline lakes interaction - The contribution of saline groundwater circulation to solute budget of saline lakes: a lesson from the Dead Sea

NASA Astrophysics Data System (ADS)

Kiro, Yael; Weinstein, Yishai; Starinsky, Abraham; Yechieli, Yoseph

2013-04-01

Saline lakes act as base level for both surface water and groundwater. Thus, a change in lake levels is expected to result in changes in the hydrogeological system in its vicinity, exhibited in groundwater levels, location of the fresh-saline water interface, sub-lacustrine groundwater discharge (SGD) and saline water circulation. All these processes were observed in the declining Dead Sea system, whose water level dropped by ~35 meters in the last 50 years. This work focuses mainly on the effect of circulation of Dead Sea water in the aquifer, which continues even in this very rapid base level drop. In general, seawater circulation in coastal aquifers is now recognized as a major process affecting trace element mass balances in coastal areas. Estimates of submarine groundwater discharge (SGD) vary over several orders of magnitude (1-1000000 m3/yr per meter shoreline). These estimates are sensitive to fresh-saline SGD ratios and to the temporal and spatial scales of the circulation. The Dead Sea system is an excellent natural field lab for studying seawater-groundwater interaction and large-scale circulation due to the absence of tides and to the minor role played by waves. During Dead Sea water circulation in the aquifer several geochemical reactions occur, ranging from short-term adsorption-desorption reactions and up to long-term precipitation and dissolution reactions. These processes affect the trace element distribution in the saline groundwater. Barite and celestine, which are supersaturated in the lake water, precipitate during circulation in the aquifer, reducing barium (from 5 to 1.5 mg/L), strontium (from 350 to 300 mg/L) and the long-lived 226Ra (from 145 to 60 dpm/L) in the saline groundwater. Redox-controlled reactions cause a decrease in uranium from 2.4 to 0.1 μg/L, and an increase in iron from 1 to 13 mg/L. 228Ra (t1/2=5.75 yr) activity in the Dead Sea is ~1 dpm/L and increase gradually as the saline water flows further inland until reaching steady-state activities (~27 dpm/L) with the aquifer sediments. The decrease in 226Ra and increase in 228Ra in the circulation process provide a robust method for calculating the amount of Dead Sea water circulating in the aquifer. This process can affect trace element concentrations in the Dead Sea and emphasize the potential of long-term seawater circulation in mass balances of saline water bodies.

Circulating tocopherols and risk of coronary artery disease: A systematic review and meta-analysis.

PubMed

Li, Guangxiao; Li, Ying; Chen, Xin; Sun, Hao; Hou, Xiaowen; Shi, Jingpu

2016-05-01

Circulating level of tocopherols was supposed to be associated with risk of coronary artery disease. However, the results from previous studies remain controversial. Therefore, we conducted a meta-analysis based on observational studies to evaluate the association between circulating tocopherols and coronary artery disease risk for the first time. Meta-analysis. PubMed, Embase and Cochrane databases were searched to retrieve articles published during January 1995 and May 2015. Articles were included if they provided sufficient information to calculate the weighted mean difference and its corresponding 95% confidence interval. Circulating level of total tocopherols was significantly lower in coronary artery disease patients than that in controls (weighted mean difference -4.33 μmol/l, 95% confidence interval -6.74 to -1.91, P < 0.01). However, circulating α-tocopherol alone was not significantly associated with coronary artery disease risk. Results from subgroup analyses showed that a lower level of circulating total tocopherols was merely associated with higher coronary artery disease risk in studies with higher sex ratio in cases (<2, weighted mean difference -0.07 μmol/l, 95% confidence interval -1.15 to 1.00, P = 0.90; ≥ 2, weighted mean difference -6.00 μmol/l, 95% confidence interval -9.76 to -2.22, P < 0.01). Similarly, a lower level of circulating total tocopherols was associated with early onset coronary artery disease rather than late onset coronary artery disease (<60 years, weighted mean difference -5.40 μmol/l, 95% confidence interval -9.22 to -1.57, P < 0.01; ≥ 60 years, weighted mean difference -1.37 μmol/l, 95% confidence interval -3.48 to 0.74, P = 0.20). We also found some discrepancies in circulating total tocopherols when the studies were stratified by matching status and assay methods. Our findings suggest that a deficiency in circulating total tocopherols might be associated with higher coronary artery disease risk. Whereas circulating α-tocopherol alone could not protect us from developing coronary artery disease. Further prospective studies were warranted to confirm our findings. © The European Society of Cardiology 2015.

Potential beneficial effect of some adipokines positively correlated with the adipose tissue content on the cardiovascular system.

PubMed

Sawicka, Magdalena; Janowska, Joanna; Chudek, Jerzy

2016-11-01

Obesity is a risk factor of cardiovascular diseases. However, in the case of heart failure, obese and overweight patients have a more favourable prognosis compared to patients who have a normal body weight. This phenomenon is referred to as the "obesity paradox," and it is explained by, among others, a positive effect of adipokines produced by adipose tissue, particularly by the tissue located in the direct vicinity of the heart and blood vessels. The favourable effect on the cardiovascular system is mostly associated with adiponectin and omentin, but the levels of these substances are reduced in obese patients. Among the adipokines which levels are positively correlated with the adipose tissue content, favourable activity is demonstrated by apelin, progranulin, chemerin, TNF-α (tumour necrosis factor-)α, CTRP-3 (C1q/tumour necrosis factor (TNF) related protein), leptin, visfatin and vaspin. This activity is associated with the promotion of regeneration processes in the damaged myocardium, formation of new blood vessels, reduction of the afterload, improvement of metabolic processes in cardiomyocytes and myocardial contractile function, inhibition of apoptosis and fibrosis of the myocardium, as well as anti-inflammatory and anti-atheromatous effects. The potential use of these properties in the treatment of heart failure and ischaemic heart disease, as well as in pulmonary hypertension, arterial hypertension and the limitation of the loss of cardiomyocytes during cardioplegia-requiring cardiosurgical procedures, is studied. The most advanced studies focus on analogues of apelin and progranulin. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Genome-wide meta-analysis uncovers novel loci influencing circulating leptin levels.

PubMed

Kilpeläinen, Tuomas O; Carli, Jayne F Martin; Skowronski, Alicja A; Sun, Qi; Kriebel, Jennifer; Feitosa, Mary F; Hedman, Åsa K; Drong, Alexander W; Hayes, James E; Zhao, Jinghua; Pers, Tune H; Schick, Ursula; Grarup, Niels; Kutalik, Zoltán; Trompet, Stella; Mangino, Massimo; Kristiansson, Kati; Beekman, Marian; Lyytikäinen, Leo-Pekka; Eriksson, Joel; Henneman, Peter; Lahti, Jari; Tanaka, Toshiko; Luan, Jian'an; Del Greco M, Fabiola; Pasko, Dorota; Renström, Frida; Willems, Sara M; Mahajan, Anubha; Rose, Lynda M; Guo, Xiuqing; Liu, Yongmei; Kleber, Marcus E; Pérusse, Louis; Gaunt, Tom; Ahluwalia, Tarunveer S; Ju Sung, Yun; Ramos, Yolande F; Amin, Najaf; Amuzu, Antoinette; Barroso, Inês; Bellis, Claire; Blangero, John; Buckley, Brendan M; Böhringer, Stefan; I Chen, Yii-Der; de Craen, Anton J N; Crosslin, David R; Dale, Caroline E; Dastani, Zari; Day, Felix R; Deelen, Joris; Delgado, Graciela E; Demirkan, Ayse; Finucane, Francis M; Ford, Ian; Garcia, Melissa E; Gieger, Christian; Gustafsson, Stefan; Hallmans, Göran; Hankinson, Susan E; Havulinna, Aki S; Herder, Christian; Hernandez, Dena; Hicks, Andrew A; Hunter, David J; Illig, Thomas; Ingelsson, Erik; Ioan-Facsinay, Andreea; Jansson, John-Olov; Jenny, Nancy S; Jørgensen, Marit E; Jørgensen, Torben; Karlsson, Magnus; Koenig, Wolfgang; Kraft, Peter; Kwekkeboom, Joanneke; Laatikainen, Tiina; Ladwig, Karl-Heinz; LeDuc, Charles A; Lowe, Gordon; Lu, Yingchang; Marques-Vidal, Pedro; Meisinger, Christa; Menni, Cristina; Morris, Andrew P; Myers, Richard H; Männistö, Satu; Nalls, Mike A; Paternoster, Lavinia; Peters, Annette; Pradhan, Aruna D; Rankinen, Tuomo; Rasmussen-Torvik, Laura J; Rathmann, Wolfgang; Rice, Treva K; Brent Richards, J; Ridker, Paul M; Sattar, Naveed; Savage, David B; Söderberg, Stefan; Timpson, Nicholas J; Vandenput, Liesbeth; van Heemst, Diana; Uh, Hae-Won; Vohl, Marie-Claude; Walker, Mark; Wichmann, Heinz-Erich; Widén, Elisabeth; Wood, Andrew R; Yao, Jie; Zeller, Tanja; Zhang, Yiying; Meulenbelt, Ingrid; Kloppenburg, Margreet; Astrup, Arne; Sørensen, Thorkild I A; Sarzynski, Mark A; Rao, D C; Jousilahti, Pekka; Vartiainen, Erkki; Hofman, Albert; Rivadeneira, Fernando; Uitterlinden, André G; Kajantie, Eero; Osmond, Clive; Palotie, Aarno; Eriksson, Johan G; Heliövaara, Markku; Knekt, Paul B; Koskinen, Seppo; Jula, Antti; Perola, Markus; Huupponen, Risto K; Viikari, Jorma S; Kähönen, Mika; Lehtimäki, Terho; Raitakari, Olli T; Mellström, Dan; Lorentzon, Mattias; Casas, Juan P; Bandinelli, Stefanie; März, Winfried; Isaacs, Aaron; van Dijk, Ko W; van Duijn, Cornelia M; Harris, Tamara B; Bouchard, Claude; Allison, Matthew A; Chasman, Daniel I; Ohlsson, Claes; Lind, Lars; Scott, Robert A; Langenberg, Claudia; Wareham, Nicholas J; Ferrucci, Luigi; Frayling, Timothy M; Pramstaller, Peter P; Borecki, Ingrid B; Waterworth, Dawn M; Bergmann, Sven; Waeber, Gérard; Vollenweider, Peter; Vestergaard, Henrik; Hansen, Torben; Pedersen, Oluf; Hu, Frank B; Eline Slagboom, P; Grallert, Harald; Spector, Tim D; Jukema, J W; Klein, Robert J; Schadt, Erik E; Franks, Paul W; Lindgren, Cecilia M; Leibel, Rudolph L; Loos, Ruth J F

2016-02-01

Leptin is an adipocyte-secreted hormone, the circulating levels of which correlate closely with overall adiposity. Although rare mutations in the leptin (LEP) gene are well known to cause leptin deficiency and severe obesity, no common loci regulating circulating leptin levels have been uncovered. Therefore, we performed a genome-wide association study (GWAS) of circulating leptin levels from 32,161 individuals and followed up loci reaching P<10(-6) in 19,979 additional individuals. We identify five loci robustly associated (P<5 × 10(-8)) with leptin levels in/near LEP, SLC32A1, GCKR, CCNL1 and FTO. Although the association of the FTO obesity locus with leptin levels is abolished by adjustment for BMI, associations of the four other loci are independent of adiposity. The GCKR locus was found associated with multiple metabolic traits in previous GWAS and the CCNL1 locus with birth weight. Knockdown experiments in mouse adipose tissue explants show convincing evidence for adipogenin, a regulator of adipocyte differentiation, as the novel causal gene in the SLC32A1 locus influencing leptin levels. Our findings provide novel insights into the regulation of leptin production by adipose tissue and open new avenues for examining the influence of variation in leptin levels on adiposity and metabolic health.

Circulating prolactin level in systemic lupus erythematosus and its correlation with disease activity: a meta-analysis.

PubMed

Song, G G; Lee, Y H

2017-10-01

Objective This study aimed to evaluate the relationship between circulating prolactin level and systemic lupus erythematosus (SLE), and to establish a correlation between plasma/serum prolactin levels and SLE activity. Methods We performed a meta-analysis comparing the plasma/serum prolactin levels in patients with SLE to controls, and examined correlation coefficients between circulating prolactin level and SLE disease activity. Results Twenty-five studies with a total of 1056 SLE patients and 426 controls were included. Prolactin levels were significantly higher overall in the SLE group than in the control group (standardized mean difference (SMD) = 0.987, 95% CI = 0.512-1.463, p = 4.7 × 10 -5 ). Stratification by ethnicity showed significantly elevated prolactin levels in the SLE group in Asian, Latin American, and mixed populations (SMD = 0.813, 95% CI = 0.137-1.490, p = 0.018; SMD = 0.981, 95% CI = 0.307-1.655, p = 0.004; SMD = 1.469, 95% CI = 0.443-2.495, p = 0.005, respectively), but not in the European population. Subgroup analysis by sample size showed significantly higher prolactin levels in the SLE group by small ( n < 30) and large sample numbers ( n > 30). Meta-analysis of correlation coefficients showed a significantly positive correlation between circulating prolactin level and SLE activity (correlation coefficient = 0.379, 95% CI = 0.026-0.487, p = 4.0 × 10 -9 ). Circulating prolactin levels were positively associated with SLE activity in European, Asian, and mixed populations (SMD = 0.532, 95% CI = 0.443-0.609  p < 1.0 × 10 -8 ; SMD = 0.427, 95% CI = 0.240-0.583, p = 2.4 × 10 -5 ; SMD = 0.433, 95% CI = 0.212-0.591, p = 2.7 × 10 -5 , respectively). Conclusions Our meta-analysis demonstrated that circulating prolactin levels are higher in patients with SLE, and that a significantly positive correlation exists between prolactin levels and SLE activity.

Genome-wide association meta-analysis of circulating odd-numbered chain saturated fatty acids: Results from the CHARGE Consortium

PubMed Central

King, Irena B.; Wu, Jason H. Y.; Manichaikul, Ani; Rich, Stephen S.; Tsai, Michael Y.; Chen, Y. D.; Fornage, Myriam; Weihua, Guan; Aslibekyan, Stella; Irvin, Marguerite R.; Kabagambe, Edmond K.; Arnett, Donna K.; Jensen, Majken K.; McKnight, Barbara; Psaty, Bruce M.; Steffen, Lyn M.; Smith, Caren E.; Risérus, Ulf; Lind, Lars; Hu, Frank B.; Rimm, Eric B.; Siscovick, David S.; Mozaffarian, Dariush

2018-01-01

Background Odd-numbered chain saturated fatty acids (OCSFA) have been associated with potential health benefits. Although some OCSFA (e.g., C15:0 and C17:0) are found in meats and dairy products, sources and metabolism of C19:0 and C23:0 are relatively unknown, and the influence of non-dietary determinants, including genetic factors, on circulating levels of OCSFA is not established. Objective To elucidate the biological processes that influence circulating levels of OCSFA by investigating associations between genetic variation and OCSFA. Design We performed a meta-analysis of genome-wide association studies (GWAS) of plasma phospholipid/erythrocyte levels of C15:0, C17:0, C19:0, and C23:0 among 11,494 individuals of European descent. We also investigated relationships between specific single nucleotide polymorphisms (SNPs) in the lactase (LCT) gene, associated with adult-onset lactase intolerance, with circulating levels of dairy-derived OCSFA, and evaluated associations of candidate sphingolipid genes with C23:0 levels. Results We found no genome-wide significant evidence that common genetic variation is associated with circulating levels of C15:0 or C23:0. In two cohorts with available data, we identified one intronic SNP (rs13361131) in myosin X gene (MYO10) associated with C17:0 level (P = 1.37×10−8), and two intronic SNP (rs12874278 and rs17363566) in deleted in lymphocytic leukemia 1 (DLEU1) region associated with C19:0 level (P = 7.07×10−9). In contrast, when using a candidate-gene approach, we found evidence that three SNPs in LCT (rs11884924, rs16832067, and rs3816088) are associated with circulating C17:0 level (adjusted P = 4×10−2). In addition, nine SNPs in the ceramide synthase 4 (CERS4) region were associated with circulating C23:0 levels (adjusted P<5×10−2). Conclusions Our findings suggest that circulating levels of OCSFA may be predominantly influenced by non-genetic factors. SNPs associated with C17:0 level in the LCT gene may reflect genetic influence in dairy consumption or in metabolism of dairy foods. SNPs associated with C23:0 may reflect a role of genetic factors in the synthesis of sphingomyelin. PMID:29738550

Circulating magnesium levels and incidence of coronary heart diseases, hypertension, and type 2 diabetes mellitus: a meta-analysis of prospective cohort studies.

PubMed

Wu, Jiang; Xun, Pengcheng; Tang, Qingya; Cai, Wei; He, Ka

2017-09-19

Data on the associations between circulating magnesium (Mg) levels and incidence of coronary heart diseases (CHD), hypertension, and type 2 diabetes mellitus (T2DM) are inconsistent and inconclusive. The aim of this study was to examine circulating Mg levels in relation to incidence of CHD, hypertension, and T2DM. Prospective cohort studies published before May 2017 were searched through PubMed, EmBase, SCOPUS, and Google Scholar. A total of 11 studies that reported multivariable-adjusted associations of interest were identified. Information on the characteristics of study and participants, exposure, main outcomes, risk estimates, and cofounders was extracted and analyzed. Of the 11 included studies, 5 reported results on CHD (38,808 individuals [4437 cases] with an average 10.5-year follow-up), 3 on hypertension (14,876 participants [3149 cases] with a 6.7-year follow-up), and 4 on T2DM (31,284 participants [2680 cases] with an 8.8-year follow-up). Comparing the highest to the lowest category of circulating Mg concentration, the pooled relative risks [RRs] (95% confidence intervals [CIs]) were 0.86 (0.74, 0.996), 0.91 (0.80, 1.02), and 0.64 (0.50, 0.81) for incidence of CHD, hypertension, and T2DM, respectively. Every 0.1 mmol/L increment in circulating Mg levels was associated with 4% (RR, 0.96; 95% CI: 0.94, 0.99) reduction in hypertension incidence. No significant linear association was found between circulating Mg levels and incidence of CHD (RR, 0.89; 95% CI: 0.77, 1.03) and T2DM (RR, 0.90; 95% CI: 0.81, 1.002). The observed associations of interest were sensitive to exclusion of individual studies. Findings in this meta-analysis suggest that circulating Mg levels are inversely associated with incidence of CHD, hypertension, and T2DM. Additional studies are needed to provide more solid evidence and identify the optimal range of circulating Mg concentration with respect to primary prevention of CHD, hypertension, and T2DM.

Association of serum uric acid with high-sensitivity C-reactive protein in postmenopausal women.

PubMed

Raeisi, A; Ostovar, A; Vahdat, K; Rezaei, P; Darabi, H; Moshtaghi, D; Nabipour, I

2017-02-01

To explore the independent correlation between serum uric acid and low-grade inflammation (measured by high-sensitivity C-reactive protein, hs-CRP) in postmenopausal women. A total of 378 healthy Iranian postmenopausal women were randomly selected in a population-based study. Circulating hs-CRP levels were measured by highly specific enzyme-linked immunosorbent assay method and an enzymatic calorimetric method was used to measure serum levels of uric acid. Pearson correlation coefficient, multiple linear regression and logistic regression models were used to analyze the association between uric acid and hs-CRP levels. A statistically significant correlation was seen between serum levels of uric acid and log-transformed circulating hs-CRP (r = 0.25, p < 0.001). After adjustment for age and cardiovascular risk factors (according to NCEP ATP III criteria), circulating hs-CRP levels were significantly associated with serum uric acid levels (β = 0.20, p < 0.001). After adjustment for age and cardiovascular risk factors, hs-CRP levels ≥3 mg/l were significantly associated with higher uric acid levels (odds ratio =1.52, 95% confidence interval 1.18-1.96). Higher serum uric acid levels were positively and independently associated with circulating hs-CRP in healthy postmenopausal women.

Mendelian Randomization Studies Do Not Support a Role for Raised Circulating Triglyceride Levels Influencing Type 2 Diabetes, Glucose Levels, or Insulin Resistance

PubMed Central

De Silva, N. Maneka G.; Freathy, Rachel M.; Palmer, Tom M.; Donnelly, Louise A.; Luan, Jian'an; Gaunt, Tom; Langenberg, Claudia; Weedon, Michael N.; Shields, Beverley; Knight, Beatrice A.; Ward, Kirsten J.; Sandhu, Manjinder S.; Harbord, Roger M.; McCarthy, Mark I.; Smith, George Davey; Ebrahim, Shah; Hattersley, Andrew T.; Wareham, Nicholas; Lawlor, Debbie A.; Morris, Andrew D.; Palmer, Colin N.A.; Frayling, Timothy M.

2011-01-01

OBJECTIVE The causal nature of associations between circulating triglycerides, insulin resistance, and type 2 diabetes is unclear. We aimed to use Mendelian randomization to test the hypothesis that raised circulating triglyceride levels causally influence the risk of type 2 diabetes and raise normal fasting glucose levels and hepatic insulin resistance. RESEARCH DESIGN AND METHODS We tested 10 common genetic variants robustly associated with circulating triglyceride levels against the type 2 diabetes status in 5,637 case and 6,860 control subjects and four continuous outcomes (reflecting glycemia and hepatic insulin resistance) in 8,271 nondiabetic individuals from four studies. RESULTS Individuals carrying greater numbers of triglyceride-raising alleles had increased circulating triglyceride levels (SD 0.59 [95% CI 0.52–0.65] difference between the 20% of individuals with the most alleles and the 20% with the fewest alleles). There was no evidence that the carriers of greater numbers of triglyceride-raising alleles were at increased risk of type 2 diabetes (per weighted allele odds ratio [OR] 0.99 [95% CI 0.97–1.01]; P = 0.26). In nondiabetic individuals, there was no evidence that carriers of greater numbers of triglyceride-raising alleles had increased fasting insulin levels (SD 0.00 per weighted allele [95% CI −0.01 to 0.02]; P = 0.72) or increased fasting glucose levels (0.00 [−0.01 to 0.01]; P = 0.88). Instrumental variable analyses confirmed that genetically raised circulating triglyceride levels were not associated with increased diabetes risk, fasting glucose, or fasting insulin and, for diabetes, showed a trend toward a protective association (OR per 1-SD increase in log10 triglycerides: 0.61 [95% CI 0.45–0.83]; P = 0.002). CONCLUSIONS Genetically raised circulating triglyceride levels do not increase the risk of type 2 diabetes or raise fasting glucose or fasting insulin levels in nondiabetic individuals. One explanation for our results is that raised circulating triglycerides are predominantly secondary to the diabetes disease process rather than causal. PMID:21282362

Mendelian randomization studies do not support a role for raised circulating triglyceride levels influencing type 2 diabetes, glucose levels, or insulin resistance.

PubMed

De Silva, N Maneka G; Freathy, Rachel M; Palmer, Tom M; Donnelly, Louise A; Luan, Jian'an; Gaunt, Tom; Langenberg, Claudia; Weedon, Michael N; Shields, Beverley; Knight, Beatrice A; Ward, Kirsten J; Sandhu, Manjinder S; Harbord, Roger M; McCarthy, Mark I; Smith, George Davey; Ebrahim, Shah; Hattersley, Andrew T; Wareham, Nicholas; Lawlor, Debbie A; Morris, Andrew D; Palmer, Colin N A; Frayling, Timothy M

2011-03-01

The causal nature of associations between circulating triglycerides, insulin resistance, and type 2 diabetes is unclear. We aimed to use Mendelian randomization to test the hypothesis that raised circulating triglyceride levels causally influence the risk of type 2 diabetes and raise normal fasting glucose levels and hepatic insulin resistance. We tested 10 common genetic variants robustly associated with circulating triglyceride levels against the type 2 diabetes status in 5,637 case and 6,860 control subjects and four continuous outcomes (reflecting glycemia and hepatic insulin resistance) in 8,271 nondiabetic individuals from four studies. Individuals carrying greater numbers of triglyceride-raising alleles had increased circulating triglyceride levels (SD 0.59 [95% CI 0.52-0.65] difference between the 20% of individuals with the most alleles and the 20% with the fewest alleles). There was no evidence that the carriers of greater numbers of triglyceride-raising alleles were at increased risk of type 2 diabetes (per weighted allele odds ratio [OR] 0.99 [95% CI 0.97-1.01]; P = 0.26). In nondiabetic individuals, there was no evidence that carriers of greater numbers of triglyceride-raising alleles had increased fasting insulin levels (SD 0.00 per weighted allele [95% CI -0.01 to 0.02]; P = 0.72) or increased fasting glucose levels (0.00 [-0.01 to 0.01]; P = 0.88). Instrumental variable analyses confirmed that genetically raised circulating triglyceride levels were not associated with increased diabetes risk, fasting glucose, or fasting insulin and, for diabetes, showed a trend toward a protective association (OR per 1-SD increase in log(10) triglycerides: 0.61 [95% CI 0.45-0.83]; P = 0.002). Genetically raised circulating triglyceride levels do not increase the risk of type 2 diabetes or raise fasting glucose or fasting insulin levels in nondiabetic individuals. One explanation for our results is that raised circulating triglycerides are predominantly secondary to the diabetes disease process rather than causal.

Levels of free fatty acids (FFA) are associated with insulin resistance but do not explain the relationship between adiposity and insulin resistance in Hispanic Americans: the IRAS Family Study.

PubMed

Miller, Melissa R; Pereira, Rocio I; Langefeld, Carl D; Lorenzo, Carlos; Rotter, Jerome I; Chen, Yii-Der Ida; Bergman, Richard N; Wagenknecht, Lynne E; Norris, Jill M; Fingerlin, Tasha E

2012-09-01

We investigated whether free fatty acids (FFA) mediate the association between adiposity and insulin resistance in the Hispanic-American families of the Insulin Resistance Atherosclerosis Family Study. In 815 Hispanic individuals in the Insulin Resistance Atherosclerosis Family Study, we tested for association between the following: 1) levels of adiposity [body mass index (BMI), visceral and sc adipose tissue area (VAT and SAT)] and circulating levels of FFA; 2) levels of circulating FFA and insulin sensitivity (S(I)); and 3) levels of adiposity and S(I), additionally testing to see whether levels of FFA mediated or modified the relationship between adiposity and S(I.) After adjusting for age, sex, clinic site, and admixture, increasing levels of BMI, VAT, and SAT were weakly associated with increasing levels of circulating FFA (BMI: P = 0.024; VAT: P = 2.33 × 10(-3); SAT: P = 0.018; percent variation explained: ∼1.00%). Increasing levels of circulating FFA were associated with decreasing S(I) (P = 8.10 × 10(-11)). Increasing BMI, VAT, and SAT were also associated with decreasing S(I) (BMI: P = 4.98 × 10(-71); VAT: P = 1.48 × 10(-64); SAT: P = 4.21 × 10(-62)), but this relationship was not significantly mediated by FFA. VAT, but not BMI or SAT, interacts with levels of FFA to influence S(I) (P = 0.021). Although levels of circulating FFA are associated both with increasing adiposity and decreasing S(I), they do not appear to mediate the association between levels of adiposity and S(I) in this large cohort of Hispanic-Americans. These results may indicate that FFA contribute to insulin resistance independent of adiposity.

Assessing water quality of the Chesapeake Bay by the impact of sea level rise and warming

NASA Astrophysics Data System (ADS)

Wang, P.; Linker, L.; Wang, H.; Bhatt, G.; Yactayo, G.; Hinson, K.; Tian, R.

2017-08-01

The influence of sea level rise and warming on circulation and water quality of the Chesapeake Bay under projected climate conditions in 2050 were estimated by computer simulation. Four estuarine circulation scenarios in the estuary were run using the same watershed load in 1991-2000 period. They are, 1) the Base Scenario, which represents the current climate condition, 2) a Sea Level Rise Scenario, 3) a Warming Scenario, and 4) a combined Sea Level Rise and Warming Scenario. With a 1.6-1.9°C increase in monthly air temperatures in the Warming Scenario, water temperature in the Bay is estimated to increase by 0.8-1°C. Summer average anoxic volume is estimated to increase 1.4 percent compared to the Base Scenario, because of an increase in algal blooms in the spring and summer, promotion of oxygen consumptive processes, and an increase of stratification. However, a 0.5-meter Sea Level Rise Scenario results in a 12 percent reduction of anoxic volume. This is mainly due to increased estuarine circulation that promotes oxygen-rich sea water intrusion in lower layers. The combined Sea Level Rise and Warming Scenario results in a 10.8 percent reduction of anoxic volume. Global warming increases precipitation and consequently increases nutrient loads from the watershed by approximately 5-7 percent. A scenario that used a 10 percent increase in watershed loads and current estuarine circulation patterns yielded a 19 percent increase in summer anoxic volume, while a scenario that used a 10 percent increase in watershed loads and modified estuarine circulation patterns by the aforementioned sea level rise and warming yielded a 6 percent increase in summer anoxic volume. Impacts on phytoplankton, sediments, and water clarity were also analysed.

Circulating Betatrophin Levels and Gestational Diabetes Mellitus: A Systematic Review and Meta-Analysis.

PubMed

Kong, Fei-Juan; Ma, Lei-Lei; Li, Ge; Chen, Yi-Xin; Zhou, Jia-Qiang

2017-01-01

The association between circulating betatrophin levels and gestational diabetes mellitus (GDM) is controversial. The aim of our study was to systematically review available literature linking betatrophin to GDM for a comprehensive understanding of the relationship between circulating betatrophin levels and GDM in human. PubMed, The Cochrane Library, Medline and CNKI were searched for studies published up to August 2016. Manual searches of references of the relevant original studies were conducted. Pooled estimates were measured using the fixed or random effect model. Overall effect was reported in a standard mean difference (SMD). All data were analyzed with Review Manager 5.3 and Stata 12.0. Of 25 references reviewed, 8 studies met our inclusion criteria and contributed to meta-analysis. All the studies were used to evaluate the relationship between betatrophin levels in blood and GDM. Betatrophin levels were significantly elevated in women with GDM compared with those without GDM (SMD = 1.05; 95% CI: 0.41-1.68, P = 0.001). This evidence was more consistent among women with betatrophin blood draw during the third trimester (SMD = 1.3, 95% CI: 1-1.61, P < 0.001) and for women BMI ≥ 28 kg/m2 (SMD = 1.53, 95% CI: 1.30-1.75, P < 0.001). The evidences from this meta-analysis indicated that the levels of circulating betatrophin were significantly elevated among women with GDM compared with women with normal glucose tolerance, especially with BMI ≥ 28 kg/m2 and in the third trimester.

High levels of circulating TNFR1 increase the risk of all-cause mortality and progression of renal disease in type 2 diabetic nephropathy.

PubMed

Fernández-Juárez, Gema; Villacorta Perez, Javier; Luño Fernández, José Luis; Martinez-Martinez, Ernesto; Cachofeiro, Victoria; Barrio Lucia, Vicente; Tato Ribera, Ana M; Mendez Abreu, Angel; Cordon, Alfredo; Oliva Dominguez, Jesus Angel; Praga Terente, Manuel

2017-05-01

Several studies have demonstrated that levels of circulating inflammatory markers such as tumour necrosis factorα (TNFα), are associated with early progression of diabetic nephropathy (DN). The aim of this study was to investigate whether there is an association between circulating TNFα receptor and disease progression in patients with advanced type 2 DN and severe proteinuria. Between 2006 and 2011, we measured levels of circulating soluble TNFα receptor 1 (TNFR1) and soluble TNFα receptor 2 (TNFR2) at baseline and 4 and 12 months in 101 patients included in a multicenter randomized controlled trial to compare the effect of optimal doses of renin-angiotensin system blockers in monotherapy or in combination (dual blockade) to slow progression of established type 2 DN. The primary composite endpoint was a >50% increase in baseline serum creatinine, end-stage renal disease, or death. The median follow-up was 32 months (IQR, 18-48), during which time 28 patients (22.7%) achieved the primary endpoint. The TNFR1 level, but not the TNFR2 level, was correlated with other inflammatory markers. Cox regression analysis showed that the highest TNFR1 levels (HR, 2.60; 95%CI, 1.11-86.34) and baseline proteinuria (HR 1.32; 95%CI 1.15-1.52) were associated with the primary endpoint. The mixed model analysis revealed that TNFR1 and the TNFR2 levels did not change after starting treatment with renin-angiotensin system blockers. Our results show that the highest levels of TNFR1 are independently associated with progression of renal disease and death in type 2 DN. The renin angiotensin blockers have no effect on these inflammatory markers. © 2016 Asian Pacific Society of Nephrology.

Effects of polychlorinated biphenyl (PCB) on regulation of thyroid-, growth-, and neurochemically related developmental processes in young rats

DOE Office of Scientific and Technical Information (OSTI.GOV)

Juarez de Ku, L.M.

1992-01-01

Neonatal exposure to the toxic chemical polychlorinated biphenyl (PCB) induces hypothyroidism and retarded growth. Neonatal rats made hypothyroid by chemical or surgical means experience retarded growth and subnormal activity of choline acetyltransferase (ChAT) This study compared thyroid-, growth-, and neurochemically-related processes altered by hypothyroidism induced by other means, with PCB-induced hypothyroidism: (1) titers of thyroid stimulating hormone (TSH); (2) titers of hormones that regulate growth [growth hormone (GH), insulin-growth like factor-I (IGF-1), growth hormone releasing hormone (GHRH) and somatostatin (SS)]; or (3) brain ChAT activity. Whether PCB-induced growth retardation and other alterations are secondary to accompanying hypothyroidism rather than ormore » in addition to a direct effect of PCB was also examined. Pregnant rats were fed chow containing 0 (controls), 62.5, 125, or 250 ppm PCB (entering offspring through placenta and milk) throughout pregnancy and lactation. Neonates exposed to PCB displayed many alterations similar to those made hypothyroid by other means: depression of overall and skeletal growth, circulating by other means: depression of overall and skeletal growth, circulating T[sub 4] levels and ChAT activity, and no change in hypothalamic GHRH and SS concentrations. Differences included a paradoxical increase in circulating GH levels, and no significant alteration of circulation IGF-1 and TSH levels and pituitary GH and TSH levels (although trends were in the expected direction). Thus, PCB-induced hypothyroidism may partially cause altered skeletal growth, circulating GH and TSH concentrations, and ChAT activity. Both T[sub 4] and T[sub 3] injections returned circulating TSH and GH levels and pituitary TSH content toward control levels; T[sub 3] restored skeletal, but not overall growth; and T[sub 4] elevated ChAT activity.« less

The effects of graded levels of calorie restriction: VI. Impact of short-term graded calorie restriction on transcriptomic responses of the hypothalamic hunger and circadian signaling pathways.

PubMed

Derous, Davina; Mitchell, Sharon E; Green, Cara L; Chen, Luonan; Han, Jing-Dong J; Wang, Yingchun; Promislow, Daniel E L; Lusseau, David; Speakman, John R; Douglas, Alex

2016-04-01

Food intake and circadian rhythms are regulated by hypothalamic neuropeptides and circulating hormones, which could mediate the anti-ageing effect of calorie restriction (CR). We tested whether these two signaling pathways mediate CR by quantifying hypothalamic transcripts of male C57BL/6 mice exposed to graded levels of CR (10 % to 40 %) for 3 months. We found that the graded CR manipulation resulted in upregulation of core circadian rhythm genes, which correlated negatively with circulating levels of leptin, insulin-like growth factor 1 (IGF-1), insulin, and tumor necrosis factor alpha (TNF-α). In addition, key components in the hunger signaling pathway were expressed in a manner reflecting elevated hunger at greater levels of restriction, and which also correlated negatively with circulating levels of insulin, TNF-α, leptin and IGF-1. Lastly, phenotypes, such as food anticipatory activity and body temperature, were associated with expression levels of both hunger genes and core clock genes. Our results suggest modulation of the hunger and circadian signaling pathways in response to altered levels of circulating hormones, that are themselves downstream of morphological changes resulting from CR treatment, may be important elements in the response to CR, driving some of the key phenotypic outcomes.

The effects of graded levels of calorie restriction: VI. Impact of short-term graded calorie restriction on transcriptomic responses of the hypothalamic hunger and circadian signaling pathways

PubMed Central

Green, Cara L.; Chen, Luonan; Han, Jing‐Dong J.; Wang, Yingchun; Promislow, Daniel E.L.; Lusseau, David; Speakman, John R.; Douglas, Alex

2016-01-01

Food intake and circadian rhythms are regulated by hypothalamic neuropeptides and circulating hormones, which could mediate the anti‐ageing effect of calorie restriction (CR). We tested whether these two signaling pathways mediate CR by quantifying hypothalamic transcripts of male C57BL/6 mice exposed to graded levels of CR (10 % to 40 %) for 3 months. We found that the graded CR manipulation resulted in upregulation of core circadian rhythm genes, which correlated negatively with circulating levels of leptin, insulin‐like growth factor 1 (IGF‐1), insulin, and tumor necrosis factor alpha (TNF‐α). In addition, key components in the hunger signaling pathway were expressed in a manner reflecting elevated hunger at greater levels of restriction, and which also correlated negatively with circulating levels of insulin, TNF‐α, leptin and IGF‐1. Lastly, phenotypes, such as food anticipatory activity and body temperature, were associated with expression levels of both hunger genes and core clock genes. Our results suggest modulation of the hunger and circadian signaling pathways in response to altered levels of circulating hormones, that are themselves downstream of morphological changes resulting from CR treatment, may be important elements in the response to CR, driving some of the key phenotypic outcomes. PMID:26945906

Impact of Tumour Epithelial Subtype on Circulating microRNAs in Breast Cancer Patients

PubMed Central

Brougham, Cathy; Glynn, Claire L.; Wall, Deirdre; Hyland, Peter; Duignan, Maria; McLoughlin, Mark; Newell, John; Kerin, Michael J.

2014-01-01

While a range of miRNAs have been shown to be dysregulated in the circulation of patients with breast cancer, little is known about the relationship between circulating levels and tumour characteristics. The aim of this study was to analyse alterations in circulating miRNA expression during tumour progression in a murine model of breast cancer, and to detemine the clinical relevance of identified miRNAs at both tissue and circulating level in patient samples. Athymic nude mice received a subcutaneous or mammary fat pad injection of MDA-MB-231 cells. Blood sampling was performed at weeks 1, 3 and 6 following tumour induction, and microRNA extracted. MicroRNA microArray analysis was performed comparing samples harvested at week 1 to those collected at week 6 from the same animals. Significantly altered miRNAs were validated across all murine samples by RQ-PCR (n = 45). Three miRNAs of interest were then quantified in the circulation(n = 166) and tissue (n = 100) of breast cancer patients and healthy control individuals. MicroArray-based analysis of murine blood samples revealed levels of 77 circulating microRNAs to be changed during disease progression, with 44 demonstrating changes >2-fold. Validation across all samples revealed miR-138 to be significantly elevated in the circulation of animals during disease development, with miR-191 and miR-106a levels significantly decreased. Analysis of patient tissue and blood samples revealed miR-138 to be significantly up-regulated in the circulation of patients with breast cancer, with no change observed in the tissue setting. While not significantly changed overall in breast cancer patients compared to controls, circulating miR-106a and miR-191 were significantly decreased in patients with basal breast cancer. In tissue, both miRNAs were significantly elevated in breast cancer compared to normal breast tissue. The data demonstrates an impact of tumour epithelial subtype on circulating levels of miRNAs, and highlights divergent miRNA profiles between tissue and blood samples from breast cancer patients. PMID:24626163

Wind-induced circulation in a large tropical lagoon: Chetumal Bay

NASA Astrophysics Data System (ADS)

Palacios, E.; Carrillo, L.

2013-05-01

Chetumal Bay is a large tropical lagoon located at the Mesoamerican Reef System. Windinduced circulation in this basin was investigated by using direct measurements of current, sea level, and 2d barotropic numerical model. Acoustic Doppler Profiler (ADP) transects covering the north of Chetumal Bay during two campaigns September 2006 and March 2007 were used. The 2d barotropic numerical model was ROMs based and wind forced. Wind information was obtained from a meteorological station located at ECOSUR Chetumal. Sea level data was collected from a pressure sensor deployed in the lagoon. A seasonal pattern of circulation was observed. From observations, during September 2006, a northward flow was shown in most part of the bay and a southward flow in the eastern coast was observed with velocities ranged from 6 cm s-1 to 36 cm s-1. In March 2007, the current pattern was more complex; divergences and converges were identified. The dominant circulation was northward in eastern portion, and southward in the central and western zone. The average current speed was 6 cm s-1 with maximum values of 26 -34 cm s-1. During September 2006 predominant wind was easternsoutheastern and during March 2007, northerly wind events were recorded. Sea level amplitude responded quickly to changes in the magnitude and direction of the wind. Results of sea level and circulation from the 2d barotropic numerical model agreed with observations at first approximation.

Post-Effect of Air Quality Improvement on Biomarkers for Systemic Inflammation and Microparticles in Asthma Patients After the 2008 Beijing Olympic Games: a Pilot Study.

PubMed

Gao, Jinming; Xu, Xiaohua; Ying, Zhekang; Jiang, Lei; Zhong, Mianhua; Wang, Aixia; Chen, Lung-Chi; Lu, Bo; Sun, Qinghua

2017-08-01

This study's aim was to investigate the post-effect of an air quality improvement on systemic inflammation and circulating microparticles in asthmatic patients during, and 2 months after, the Beijing Olympics 2008. We measured the levels of circulating inflammatory cytokines and microparticles in the peripheral blood from asthma patients and healthy controls during (phase 1), and 2 months after (phase 2) the Beijing 2008 Olympic Games. The concentrations of circulating cytokines (including TNFα, IL-6, IL-8, and IL-10) were still seen reduced in phase 2 when compared with those in phase 1. The number of circulating endothelial cell-derived microparticles was significantly lower during the phase 2 than that during phase 1 in asthma patients. The level of plasma lipopolysaccharide-binding protein (LBP) was significantly decreased in asthmatics in phase 2. The level of norepinephrine was significantly higher in phase 2 than that in phase 1 in plasma from both asthma patients and healthy subjects. There were no significant differences in the gene profile for the toll-like receptor (TLR) signaling from peripheral blood mononuclear cells. In vitro, microvesicles from patients with asthma impaired the relaxation to bradykinin and contraction to acetylcholine, whereas microparticles from healthy subjects did not. These data suggested that reduction in systemic pro-inflammatory responses and circulating LBP and increased level of norepinephrine in asthma patients persisted even after 2 months of the air pollution intervention. These changes were independent of the TLR signaling pathway. Circulating microparticles might be associated with airway smooth muscle dysfunction.

Serum tissue inhibitor of matrix metalloproteinase-1 levels are associated with mortality in patients with malignant middle cerebral artery infarction.

PubMed

Lorente, Leonardo; Martín, María M; Ramos, Luis; Cáceres, Juan J; Solé-Violán, Jordi; Argueso, Mónica; Jiménez, Alejandro; Borreguero-León, Juan M; Orbe, Josune; Rodríguez, José A; Páramo, José A

2015-07-11

In the last years, circulating matrix metalloproteinases (MMP)-9 levels have been associated with functional outcome in ischemic stroke patients. However the prognostic value of circulating levels of tissue inhibitor of matrix metalloproteinases (TIMP)-1 and MMP-10 in functional outcome of ischemic stroke patients has been scarcely studied. In addition, to our knowledge, serum MMP-9, MMP-10 and TIMP-1 levels in patients with malignant middle cerebral artery infarction (MMCAI) for mortality prediction have not been studied, and these were the objectives of this study. This was a multicenter, observational and prospective study carried out in six Spanish Intensive Care Units. We included patients with severe MMCAI defined as Glasgow Coma Scale (GCS) lower than 9. We measured circulating levels of MMP-9, MMP-10, TIMP-1, in 50 patients with severe MMCAI at diagnosis and in 50 healthy subjects. Endpoint was 30-day mortality. Patients with severe MMCAI showed higher serum levels of MMP-9 (p = 0.001), MMP-10 (p < 0.001), and TIMP-1 (p = 0.02) than healthy subjects. Non-surviving MMCAI patients (n = 26) compared to survivor ones (n = 24) showed higher circulating levels of TIMP-1 (p < 0.001), MMP-10 (p = 0.02) and PAI-1(p = 0.02), and lower MMP-9 levels (p = 0.04). Multiple binomial logistic regression analysis showed that serum TIMP-1 levels > 239 ng/mL are associated with 30-day mortality (OR = 5.82; 95% CI = 1.37-24.73; P = 0.02) controlling for GCS and age. The area under the curve for TIMP-1 as predictor of 30-day mortality was 0.81 (95% CI = 0.67-0.91; P < 0.001). We found an association between circulating levels of TIMP-1 and MMP-10 (rho = 0.45; P = 0.001), plasminogen activator inhibitor (PAI)-1 (rho = 0.53; P < 0.001), and tumor necrosis factor (TNF)-alpha (rho = 0.70; P < 0.001). The most relevant and new findings of our study, were that serum TIMP-1 levels in MMCAI patients were associated with mortality, and could be used as a prognostic biomarker of mortality in MMCAI patients.

Arctic Climate and Atmospheric Planetary Waves

NASA Technical Reports Server (NTRS)

Cavalieri, D. J.; Haekkinen, S.

2000-01-01

Analysis of a fifty-year record (1946-1995) of monthly-averaged sea level pressure data provides a link between the phases of planetary-scale sea level pressure waves and Arctic Ocean and ice variability. Results of this analysis show: (1) a breakdown of the dominant wave I pattern in the late 1960's, (2) shifts in the mean phase of waves 1 and 2 since this breakdown, (3) an eastward shift in the phases of both waves 1 and 2 during the years of simulated cyclonic Arctic Ocean circulation relative to their phases during the years of anticyclonic circulation, (4) a strong decadal variability of wave phase associated with simulated Arctic Ocean circulation changes. Finally, the Arctic atmospheric circulation patterns that emerge when waves 1 and 2 are in their extreme eastern and western positions suggest an alternative approach to determine significant forcing patterns of sea ice and high-latitude variability.

Correlation of Higher Levels of Soluble TNF-R1 with a Shorter Survival, Independent of Age, in Recurrent Glioblastoma

PubMed Central

Ahluwalia, Manmeet S.; Bou-Anak, Stephanie; Burgett, Monica E.; Sarmey, Nehaw; Khosla, Divya; Dahiya, Saurabh; Weil, Robert J.; Bae, Eunnyung; Huang, Ping; McGraw, Mary; Grove, Lisa M.; Olman, Mitchell A.; Prayson, Richard A.; Suh, John H.; Gillespie, G. Yancey; Barnholtz-Sloan, Jill; Nowacki, Amy S.; Barnett, Gene H.; Gladson, Candece L.

2016-01-01

The circulating levels of soluble tumor necrosis factor receptor-1 (sTNF-R1) and sTNF-R2 are altered in numerous diseases, including several types of cancer. Correlations with the risk of progression in some cancers, as well as systemic manifestations of the disease and therapeutic side-effects, have been described. However, there is very little information on the levels of these soluble receptors in glioblastoma (GBM). Here, we report on an exploratory retrospective study of the levels of sTNF-Rs in the vascular circulation of patients with GBM. Banked samples were obtained from 112 GBM patients (66 untreated, newly-diagnosed patients and 46 with recurrent disease) from two institutions. The levels of sTNF-R1 in the plasma were significantly lower in patients with newly-diagnosed or recurrent GBM than apparently healthy individuals and correlated with the intensity of expression of TNF-R1 on the tumor-associated endothelial cells (ECs) in the corresponding biopsies. Elevated levels of sTNF-R1 in patients with recurrent, but not newly-diagnosed GBM, were significantly associated with a shorter survival, independent of age (p=0.02) or steroid medication. In contrast, the levels of circulating sTNF-R2 were significantly higher in recurrent GBM than healthy individuals and there was no significant correlation with expression of TNF-R2 on the tumor-associated ECs or survival time. The results indicate that larger, prospective studies are warranted to determine the predictive value of the levels of sTNF-R1 in patients with recurrent GBM and the factors that regulate the levels of sTNF-Rs in the circulation in GBM patients. PMID:27858267

Detection of circulating Bmi-1 mRNA in plasma and its potential diagnostic and prognostic value for uterine cervical cancer.

PubMed

Zhang, Xin; Wang, Chuanxin; Wang, Lili; Du, Lutao; Wang, Shun; Zheng, Guixi; Li, Wei; Zhuang, Xuewei; Zhang, Xuhua; Dong, Zhaogang

2012-07-01

Bmi-1 is overexpressed in uterine cervical cancer (UCC) and is found to be associated with adverse clinical characteristics and poor prognosis. However, little information is available on the status of circulating Bmi-1 mRNA in UCC. Because circulating cell-free nucleic acids have emerged as a novel class of markers for cancer detection, our research aims to address this question by detecting the circulating Bmi-1 mRNA and to assess its diagnostic and prognostic potential in UCC. Reverse transcription quantitative real-time PCR method was established to detect the circulating Bmi-1 mRNA in plasma of 109 patients with UCC, 138 patients with cervical intraepithelial neoplasia (CIN) and 80 healthy volunteers, and found that it was significantly increased in UCC compared with CINs and healthy controls (all at p < 0.001). Moreover, its high level was significantly correlated with advanced clinical stage (p < 0.001) and positive lymph nodes metastasis (p = 0.002). The area under the receiver operating characteristic curve (AUC) was 0.881, and the optimal cut-off value was 0.057, providing a sensitivity of 69.7% and a specificity of 95.9%. The AUC for circulating Bmi-1 mRNA showed higher diagnosis capability than that for SCC-Ag (p = 0.035) or CA125 (p < 0.001) currently utilized. Kaplan-Meier analysis demonstrated a correlation between increased circulating Bmi-1 mRNA level and reduced disease-free survival (DFS) (p = 0.001) and overall survival (OS) (p = 0.015). And, Cox analysis indicated that it was an independent prognostic factor for DFS and OS. We conclude that circulating Bmi-1 mRNA may be a potential noninvasive molecular marker for diagnosis and prognosis of UCC. Copyright © 2011 UICC.

Circulating miR-1, miR-133a, and miR-206 levels are increased after a half-marathon run.

PubMed

Gomes, Clarissa P C; Oliveira, Getúlio P; Madrid, Bibiano; Almeida, Jeeser A; Franco, Octávio L; Pereira, Rinaldo W

2014-11-01

Circulating miRNAs are potential biomarkers that can be important molecules driving cell-to-cell communication. To investigate circulating muscle-specific miRNAs in recreational athletes. Three miRNAs from whole plasma before and after a half-marathon were analyzed by qPCR. MiR-1, -133a, and -206 significantly increased after the race. Increased levels of miRNAs after exercise point to potential biomarkers and to the possibility of being functional players following endurance training. These miRNAs are potential biomarkers of muscle damage or adaptation to exercise.

Pleiotrophin levels are associated with improved coronary collateral circulation.

PubMed

Türker Duyuler, Pinar; Duyuler, Serkan; Gök, Murat; Kundi, Harun; Topçuoğlu, Canan; Güray, Ümit

2018-01-01

Elucidation of the underlying mechanisms of angiogenesis and arteriogenesis in coronary collateral formation is necessary for new therapies. Pleiotrophin is a secreted multifunctional cytokine and associated with the formation of functional cardiovascular neovascularization in a series of experimental animal models. We aimed to evaluate the serum levels of pleiotrophin in patients with chronic total coronary artery occlusion and poor or good collateral development. We included 88 consecutive patients (mean age of the entire population: 63.7±12.1 years, 68 male patients) with stable angina pectoris who underwent coronary angiography and had chronic total occlusion in at least one major coronary artery. Collateral grading was performed according to the Rentrop classification. After grading, patients were divided into poor collateral circulation (Rentrop grade 0 and 1) and good collateral circulation (Rentrop grades 2 and 3) groups. Serum pleiotrophin levels were measured using a commercial human ELISA kit. Fifty-eight patients had good and 30 patients had poor coronary collaterals. The good collateral group had higher serum pleiotrophin levels than the poor collateral group (690.1±187.9 vs. 415.3±165.9 ng/ml, P<0.001). Pleiotrophin levels were higher with higher Rentrop grade (P<0.001). In multivariate analysis, increased pleiotrophin was associated independently with good collateral development (odds ratio: 1.007; confidence interval: 1.003-1.012; P=0.002). This study showed that increased serum pleiotrophin levels are associated with better developed coronary collateral circulation. Further studies are needed to better understand the relationship.

Circulating monocyte chemoattractant protein‐1 (MCP‐1) is associated with cachexia in treatment‐naïve pancreatic cancer patients

PubMed Central

Talbert, Erin E.; Lewis, Heather L.; Farren, Matthew R.; Ramsey, Mitchell L.; Chakedis, Jeffery M.; Rajasekera, Priyani; Haverick, Ericka; Sarna, Angela; Bloomston, Mark; Pawlik, Timothy M.; Zimmers, Teresa A.; Lesinski, Gregory B.; Hart, Phil A.; Dillhoff, Mary E.; Schmidt, Carl R.

2018-01-01

Abstract Background Cancer‐associated wasting, termed cancer cachexia, has a profound effect on the morbidity and mortality of cancer patients but remains difficult to recognize and diagnose. While increases in circulating levels of a number of inflammatory cytokines have been associated with cancer cachexia, these associations were generally made in patients with advanced disease and thus may be associated with disease progression rather than directly with the cachexia syndrome. Thus, we sought to assess potential biomarkers of cancer‐induced cachexia in patients with earlier stages of disease. Methods A custom multiplex array was used to measure circulating levels of 25 soluble factors from 70 pancreatic cancer patients undergoing attempted tumour resections. A high‐sensitivity multiplex was used for increased sensitivity for nine cytokines. Results Resectable pancreatic cancer patients with cachexia had low levels of canonical pro‐inflammatory cytokines including interleukin‐6 (IL‐6), interleukin‐1β (IL‐1β), interferon‐γ (IFN‐γ), and tumour necrosis factor (TNF). Even in our more sensitive analysis, these cytokines were not associated with cancer cachexia. Of the 25 circulating factors tested, only monocyte chemoattractant protein‐1 (MCP‐1) was increased in treatment‐naïve cachectic patients compared with weight stable patients and identified as a potential biomarker for cancer cachexia. Although circulating levels of leptin and granulocyte‐macrophage colony‐stimulating factor (GM‐CSF) were found to be decreased in the same cohort of treatment‐naïve cachectic patients, these factors were closely associated with body mass index, limiting their utility as cancer cachexia biomarkers. Conclusions Unlike in advanced disease, it is possible that cachexia in patients with resectable pancreatic cancer is not associated with high levels of classical markers of systemic inflammation. However, cachectic, treatment‐naïve patients have higher levels of MCP‐1, suggesting that MCP‐1 may be useful as a biomarker of cancer cachexia. PMID:29316343

The Clinical Development of Thalildomide as an Angiogenesis Inhibitor Therapy for Prostate Cancer

DTIC Science & Technology

2005-10-01

regulation of cell adhesion molecules LFA-1 and ICAM-1 after in vitro treatment with the anti- TNF - alpha agent thalidomide . Settles B, Stevenson A...Plasma levels of circulating TNF -α and VEGF measured in 16 thalidomide treated patients seemed to increase after treatment (Table 2). Serum levels of...Logothetis, Christopher J. Page 6 Table 2. Levels of circulating VEGF, bFGF, TNF -α and IL-6 before and after thalidomide treatment. Comparison of

A Circadian Rhythm in both Complement Cascade (ComC) Activation and Sphingosine-1-Phosphate (S1P) Levels in Human Peripheral Blood Supports a Role for the ComC-S1P Axis in Circadian Changes in the Number of Stem Cells Circulating in Peripheral Blood.

PubMed

Budkowska, Marta; Ostrycharz, Ewa; Wojtowicz, Adrianna; Marcinowska, Zuzanna; Woźniak, Jarosław; Ratajczak, Mariusz Z; Dołęgowska, Barbara

2018-06-17

The number of hematopoietic stem/progenitor cells (HSPCs) circulating in peripheral blood (PB) is regulated by a circadian rhythm, and more HSPCs circulate in PB in the morning hours than at night. Different mechanisms have been proposed that might regulate this process, including changes in tonus of β-adrenergic innervation of bone marrow (BM) tissue. Our group reported that in mice circadian changes in the number of HSPCs circulating in PB correlates with diurnal activation of the complement cascade (ComC) and that the mice deficient in C5 component of ComC (C5-KO mice) do not show circadian changes in the number of circulating HSPCs in PB. We also reported the existence of a gradient between PB and BM of a bioactive phosphosphingolipid, sphingosine-1-phosphate (S1P), which is a major PB chemottractant for BM-residing HSPCs. Based on these observations, we investigated activation of the ComC and the level of S1P in the PB of 66 healthy volunteers. We found that both ComC activation and the S1P level undergo changes in a circadian cycle. While the ComC becomes highly activated during deep sleep at 2 am, S1P becomes activated later, and its highest level is observed at 8 am, which precedes circadian egress of HSPCs from BM into PB. In sum, circadian activation of the ComC-S1P axis releases HSPCs from BM into PB.

Elevated circulating level of osteopontin is associated with advanced disease state of non-small cell lung cancer.

PubMed

Chang, Yoon Soo; Kim, Hyung Jung; Chang, Joon; Ahn, Chul Min; Kim, Sung Kyu; Kim, Se Kyu

2007-09-01

Osteopontin (OPN) plays important roles in tumor progression and metastasis through binding to OPN receptors such as alpha(v)beta(beta) integrin and CD44, and its overexpression in tumor is associated poor clinical outcome of NSCLC patients. Circulating OPN levels, measured by ELISA in 130 NSCLC cases that had not been treated for cancer at the time of sampling, were analyzed according to clinical, pathologic parameters and single nucleotide polymorphisms (SNPs) in the OPN gene promoter. Advanced disease states had higher circulating levels of OPN (T4 versus T1-3, N3 versus N0-2, and M1 versus M0, P=.029, .001, and .001, respectively, Kruskal-Wallis H-test), reflected by higher level of OPN in stage IV than stage I-III (P=.029, Kruskal-Wallis H-test). Among the clinical and pathological parameters including age, gender, smoking status, histologic subtypes and grade of differentiation, smoking status influences circulating OPN level showing higher level of OPN in ex-smokers than current and non-smokers (P=.038, Kruskal-Wallis H-test). Variation at nucleotide (nt) -443 of the OPN gene promoter had no influence on circulating OPN levels, however, patients with G/G at nt -156 showed higher concentrations of OPN than those with G/GG or GG/GG (P=.003, Kruskal-Wallis H-test). A patient with G/G at nt -156 was more frequently diagnosed with advanced stage (IIIB-IV) than with early stage (I-IIIA) NSCLC (P=.048, Mantel-Haenszel-test). In multivariate analysis, stage is the only independent factor influencing circulating level of OPN. Although circulating level of OPN in the patients with bone metastasis was higher than in those without bone metastasis (P=.028, Mann-Whitney U-test), there was no difference in the OPN levels between bone metastasis group and non-bone metastasis group. Given that the elevated levels of OPN is associated with advanced stages of NSCLC, elucidating OPN regulatory mechanisms may contribute to the development of a new therapeutic modality for NSCLC.

The effect of acute exposure to coarse particulate matter air pollution in a rural location on circulating endothelial progenitor cells: results from a randomized controlled study

PubMed Central

Brook, Robert D.; Bard, Robert L.; Kaplan, Mariana J.; Yalavarthi, Srilakshmi; Morishita, Masako; Dvonch, J. Timothy; Wang, Lu; Yang, Hui-yu; Spino, Catherine; Mukherjee, Bhramar; Oral, Elif A.; Sun, Qinghua; Brook, Jeffrey R.; Harkema, Jack; Rajagopalan, Sanjay

2015-01-01

Context Fine particulate matter (PM) air pollution has been associated with alterations in circulating endothelial progenitor cell (EPC) levels, which may be one mechanism whereby exposures promote cardiovascular diseases. However, the impact of coarse PM on EPCs is unknown. Objective We aimed to determine the effect of acute exposure to coarse concentrated ambient particles (CAP) on circulating EPC levels. Methods Thirty-two adults (25.9±6.6 years) were exposed to coarse CAP (76.2±51.5 μgm−3) in a rural location and filtered air (FA) for 2 h in a randomized double-blind crossover study. Peripheral venous blood was collected 2 and 20 h post-exposures for circulating EPC (n=21), white blood cell (n=24) and vascular endothelial growth factor (VEGF) (n=16–19) levels. The changes between exposures were compared by matched Wilcoxon signed-rank tests. Results Circulating EPC levels were elevated 2 [108.29 (6.24–249.71) EPC mL−1; median (25th–75th percentiles), p=0.052] and 20 h [106.86 (52.91–278.35) EPC mL−1, p=0.008] post-CAP exposure compared to the same time points following FA [38.47 (0.00–84.83) and 50.16 (0.00–104.79) EPC mL−1]. VEGF and white blood cell (WBC) levels did not differ between exposures. Conclusions Brief inhalation of coarse PM from a rural location elicited an increase in EPCs that persisted for at least 20 h. The underlying mechanism responsible may reflect a systemic reaction to an acute “endothelial injury” and/or a circulating EPC response to sympathetic nervous system activation. PMID:23919441

Circulating testosterone and inhibin levels at different ages in the male beluga (Delphinapterus leucas).

PubMed

Katsumata, Etsuko; Ueda, Yoko; Arai, Kazutoshi; Katsumata, Hiroshi; Kishimoto, Miori; Watanabe, Gen; Taya, Kazuyoshi

2012-03-01

This study is the first report on circulating testosterone and inhibin levels in a species of whales, the beluga. Circulating testosterone and immunoreactive (ir-) inhibin levels in two captive male belugas ("Nack", originally from Canada and "Duke", from the Okhotsk Sea) were measured every month for 9 years between 1995 and 2003. Assuming that clearly increased testosterone levels in the circulation indicates that the belugas had reached sexual maturity, at the ages of 10 ("Nack") and 11 years old ("Duke"). Their testosterone levels before the significant increase (pre-pubertal) were 0.42 ± 0.07 ng/ml (n=18) and 0.35 ± 0.10 ng/ml (n=18) and, those of after the increase (maturity) were 1.65 ± 0.14 ng/m l (n=74) and 2.06 ± 0.14 ng/ml (n=74). Circulating ir-inhibin levels before sexual maturity were 0.78 ± 0.04 ng/ml (n=18) and 0.64 ± 0.04 ng/ml (n=15) and, after sexual maturity were 0.52 ± 0.02 ng/ml (n=56) and 0.43 ± 0.02 ng/ml (n=67). Seasonal changes were observed in the testosterone levels after sexual maturity and the levels increased during March and April in Canadian origin "Nack", and peaked in February in Okhotsk origin "Duke". Circulating ir-inhibin level gradually decreased as they aged. A negative correlation between the circulating testosterone and ir-inhibin was observed. No seasonal changes were observed in the ir-inhibin levels after sexual maturity. These data will surely correspond to clarification of endocrinology and the successful reproduction of the beluga.

Prognostic value of insulin-like growth factor 1 and insulin-like growth factor binding protein 3 blood levels in breast cancer.

PubMed

Hartog, H; Boezen, H M; de Jong, M M; Schaapveld, M; Wesseling, J; van der Graaf, W T A

2013-12-01

High circulating insulin-like growth factor 1 (IGF-1) levels are firmly established as a risk factor for developing breast cancer, especially estrogen positive tumors. The effect of circulating IGF-1 on prognosis once a tumor is established is unknown. The authors explored the effect of IGF-1 blood levels and of it's main binding protein, IGFBP-3, on overall survival and occurrence of second primary breast tumors in breast cancer patients, as well as reproductive and lifestyle factors that could modify this risk. Patients were accrued from six hospitals in the Netherlands between 1998 and 2003. Total IGF-1 and IGFBP-3 were measured in 582 plasma samples. No significant association between IGF-1 and IGFBP-3 plasma levels and overall survival was found. However, in a multivariate Cox regression model including standard prognostic variables high IGF-1 levels were related to worse overall survival in patients receiving endocrine therapy (HR = 1.37, 95% CI: 1.11, 1.69, P 0.004). These data at least indicate that higher IGF-1 levels, and as a consequence most likely IGF-1-induced signaling, are related to a less favorable overall survival in breast cancer patients treated with endocrine therapy. Interventions aimed at reducing circulating levels of IGF-1 in hormone receptor positive breast cancer may improve survival. Copyright © 2013 Elsevier Ltd. All rights reserved.

Normal growth and development in the absence of hepatic insulin-like growth factor I

PubMed Central

Yakar, Shoshana; Liu, Jun-Li; Stannard, Bethel; Butler, Andrew; Accili, Domenici; Sauer, Brian; LeRoith, Derek

1999-01-01

The somatomedin hypothesis proposed that insulin-like growth factor I (IGF-I) was a hepatically derived circulating mediator of growth hormone and is a crucial factor for postnatal growth and development. To reassess this hypothesis, we have used the Cre/loxP recombination system to delete the igf1 gene exclusively in the liver. igf1 gene deletion in the liver abrogated expression of igf1 mRNA and caused a dramatic reduction in circulating IGF-I levels. However, growth as determined by body weight, body length, and femoral length did not differ from wild-type littermates. Although our model proves that hepatic IGF-I is indeed the major contributor to circulating IGF-I levels in mice it challenges the concept that circulating IGF-I is crucial for normal postnatal growth. Rather, our model provides direct evidence for the importance of the autocrine/paracrine role of IGF-I. PMID:10377413

Elevated circulating irisin is associated with lower risk of insulin resistance: association and path analyses of obese Chinese adults.

PubMed

Shi, Xiulin; Lin, Mingzhu; Liu, Changqin; Xiao, Fangsen; Liu, Yongwen; Huang, Peiying; Zeng, Xin; Yan, Bing; Liu, Suhuan; Li, Xiaoying; Yang, Shuyu; Li, Xuejun; Li, Zhibin

2016-07-29

Evidence on the role of irisin in insulin resistance is limited and controversial, and pathways between them remain unknown. We aimed to examine the independent effects of circulating irisin and different adiposity measurements, as well as their potential interactions, on insulin resistance. We also aimed to explore possible pathways among circulating irisin, adiposity, glucose and insulin levels and insulin resistance. A cross-sectional study of 1,115 community- living obese Chinese adults, with data collection on clinical characteristics, glucose and lipid metabolic parameters and circulating irisin levels. Among the 1,115 subjects, 667 (59.8 %) were identified as insulin-resistance, and showed significantly decreased serum irisin than their controls (log-transformed irisin: 1.19 ± 2.34 v.s. 1.46 ± 2.05 ng/ml, p = 0.042). With adjustment for potential confounders, elevated circulating irisin was significantly associated with reduced risk of insulin resistance, with adjusted odds ratio per standard deviation increase of irisin of 0.871 (0.765-0.991, p = 0.036). As for different adiposity measurements, body fat percentage, but neither BMI nor waist, was significantly associated with increased risk of insulin resistance (OR: 1.152 (1.041-1.275), p = 0.006). No significant interaction effect between serum irisin and adiposity on insulin resistance was found. A one pathway model about the relationship between serum irisin and insulin resistance fits well (χ (2) = 44.09, p < 0.001; CFI-0.994; TLI =0.986; and RMSEA = 0.067), and shows that elevated circulating irisin might improve insulin resistance indirectly through lowering fasting insulin levels (standardized path coefficient = -0.046, p = 0.032). Elevated circulating irisin is associated with lower risk of insulin resistance indirectly through lowering fasting insulin.

Effect of long-term dietary sphingomyelin supplementation on atherosclerosis in mice

PubMed Central

Chung, Rosanna W. S.; Wang, Zeneng; Bursill, Christina A.; Wu, Ben J.; Barter, Philip J.

2017-01-01

Sphingomyelin (SM) levels in the circulation correlate positively with atherosclerosis burden. SM is a ubiquitous component of human diets, but it is unclear if dietary SM increases circulating SM levels. Dietary choline increases atherosclerosis by raising circulating trimethylamine N-oxide (TMAO) levels in mice and humans. As SM has a choline head group, we ask in this study if dietary SM accelerates atherosclerotic lesion development by increasing circulating SM and TMAO levels. Three studies were performed: (Study 1) C57BL/6 mice were maintained on a high fat diet with or without SM supplementation for 4 weeks prior to quantification of serum TMAO and SM levels; (Study 2) atherosclerosis was studied in apoE-/- mice after 16 weeks of a high fat diet without or with SM supplementation and (Study 3) apoE-/- mice were maintained on a chow diet for 19 weeks without or with SM supplementation and antibiotic treatment prior to quantification of atherosclerotic lesions and serum TMAO and SM levels. SM consumption did not increase circulating SM levels or atherosclerosis in high fat-fed apoE-/- mice. Serum TMAO levels in C57BL/6 mice were low and had no effect atherosclerosis lesion development. Dietary SM supplementation significantly reduced atherosclerotic lesion area in the aortic arch of chow-fed apoE-/- mice. This study establishes that dietary SM does not affect circulating SM levels or increase atherosclerosis in high fat-fed apoE-/- mice, but it is anti-atherogenic in chow-fed apoE-/- mice. PMID:29240800

Increased levels of circulating platelet-derived microparticles are associated with metastatic cutaneous melanoma.

PubMed

Moreau, Joséphine; Pelletier, Fabien; Biichle, Sabeha; Mourey, Guillaume; Puyraveau, Marc; Badet, Nicolas; Caubet, Matthieu; Laresche, Claire; Garnache-Ottou, Francine; Saas, Philippe; Seilles, Estelle; Aubin, François

2017-10-01

We investigated the plasma levels of PMPs in patients with 45 stage III and 45 stage IV melanoma. PMPs were characterised by flow cytometry and their thrombogenic activity. We also investigated the link between PMPs circulating levels and tumor burden. The circulating levels of PMPs were significantly higher in stage IV (8500 μL -1 ) than in patients with stage III (2041 μL -1 ) melanoma (P=.0001). We calculated a highly specific (93.3%) and predictive (91.7%) cut-off value (5311 μL -1 ) allowing the distinction between high-risk stage III and metastatic stage IV melanoma. The thrombogenic activity of PMPs was significantly higher in patients with stage IV melanoma (clotting time: 40.7 second vs 65 second, P=.0001). There was no significant association between the radiological tumoral syndrome and the plasma level of PMPs. Our data suggest the role of PMPs in metastatic progression of melanoma. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Circulating Endothelial Microparticles and Correlation of Serum 1,25-Dihydroxyvitamin D with Adiponectin, Nonesterified Fatty Acids, and Glycerol from Middle-Aged Men in China.

PubMed

Wan, Zhongxiao; Yu, Lugang; Cheng, Jinbo; Zhang, Zengli; Xu, Baohui; Pang, Xing; Zhou, Hui; Lei, Ting

2016-01-01

The aim of the present study is (1) to determine the correlation between circulating 1,25-dihydroxyvitamin D [25(OH)D] and adiponectin, nonesterified fatty acids (NEFAs), and glycerol and (2) to determine the alterations in circulating endothelial microparticles (EMPs) in Chinese male subjects with increased body mass index (BMI). A total of 45 male adults were enrolled with varied BMI [i.e., lean, overweight (OW), and obese (OB), N = 15 per group]. Blood samples were collected under overnight fasting condition, and plasma was isolated for the measurement of endothelial microparticles (EMPs), total and high-molecular weight (HMW) adiponectin, 25(OH)D, nonesterified fatty acids (NEFAs), and glycerol. Circulating 25(OH)D levels were inversely associated with total adiponectin, NEFA, and glycerol levels. There is no difference for CD62E+ or CD31+/CD42b- EMPs among 3 groups. In Chinese male adults with varied BMI, an inverse correlation existed between 25(OH)D levels and total adiponectin, NEFA, and glycerol levels; and there is no significant difference for CD62E+ or CD31+/CD42b- EMPs among lean, overweight, and obese subjects.

Circulating Endothelial Microparticles and Correlation of Serum 1,25-Dihydroxyvitamin D with Adiponectin, Nonesterified Fatty Acids, and Glycerol from Middle-Aged Men in China

PubMed Central

Wan, Zhongxiao; Yu, Lugang; Cheng, Jinbo; Zhang, Zengli; Xu, Baohui; Pang, Xing; Zhou, Hui; Lei, Ting

2016-01-01

The aim of the present study is (1) to determine the correlation between circulating 1,25-dihydroxyvitamin D [25(OH)D] and adiponectin, nonesterified fatty acids (NEFAs), and glycerol and (2) to determine the alterations in circulating endothelial microparticles (EMPs) in Chinese male subjects with increased body mass index (BMI). A total of 45 male adults were enrolled with varied BMI [i.e., lean, overweight (OW), and obese (OB), N = 15 per group]. Blood samples were collected under overnight fasting condition, and plasma was isolated for the measurement of endothelial microparticles (EMPs), total and high-molecular weight (HMW) adiponectin, 25(OH)D, nonesterified fatty acids (NEFAs), and glycerol. Circulating 25(OH)D levels were inversely associated with total adiponectin, NEFA, and glycerol levels. There is no difference for CD62E+ or CD31+/CD42b− EMPs among 3 groups. In Chinese male adults with varied BMI, an inverse correlation existed between 25(OH)D levels and total adiponectin, NEFA, and glycerol levels; and there is no significant difference for CD62E+ or CD31+/CD42b− EMPs among lean, overweight, and obese subjects. PMID:27314039

IGF-1 REGULATES VERTEBRAL BONE AGING THROUGH SEX-SPECIFIC AND TIME-DEPENDENT MECHANISMS

PubMed Central

Ashpole, Nicole M; Herron, Jacquelyn C; Mitschelen, Matthew C; Farley, Julie A; Logan, Sreemathi; Yan, Han; Ungvari, Zoltan; Hodges, Erik L.; Csiszar, Anna; Ikeno, Yuji; Humphrey, Mary Beth; Sonntag, William E

2016-01-01

Advanced aging is associated with increased risk of bone fracture, especially within the vertebrae, which exhibit significant reductions in trabecular bone structure. Aging is also associated with a reduction in circulating levels of insulin-like growth factor (IGF-1). Studies have suggested that the reduction in IGF-1 compromises healthspan, while others report that loss of IGF-1 is beneficial as it increases healthspan and lifespan. To date, the effect of decreases in circulating IGF-1 on vertebral bone aging has not been thoroughly investigated. Here, we delineate the consequences of a loss of circulating IGF-1 on vertebral bone aging in male and female Igff/f mice. IGF-1 was reduced at multiple specific time points during the mouse lifespan- early in postnatal development (crossing albumin-Cre mice with Igff/f mice), or early adulthood, and late adulthood using hepatic-specific viral vectors (AAV8-TBG-Cre). Vertebrae bone structure was analyzed at 27 months of age using microCT and quantitative bone histomorphometry. Consistent with previous studies, both male and female mice exhibited age-related reductions in vertebral bone structure. In male mice, reduction of circulating IGF-1 induced at any age did not diminish vertebral bone loss. Interestingly, early-life loss of IGF-1 in females resulted in a 67% increase in vertebral bone volume fraction, as well as increased connectivity density and increased trabecular number. The maintenance of bone structure in the early-life IGF-1-deficient females was associated with increased osteoblast surface and an increased ratio of osteoprotegerin/receptor-activator of NFkB-ligand levels in circulation. Within 3 months of a loss of IGF-1, there was a 2.2 fold increase in insulin receptor expression within the vertebral bones of our female mice, suggesting that local signaling may compensate for the loss of circulating IGF-1. Together, these data suggest the age-related loss of vertebral bone density in females can be reduced by modifying circulating IGF-1 levels early in life. PMID:26260312

IGF-1 Regulates Vertebral Bone Aging Through Sex-Specific and Time-Dependent Mechanisms.

PubMed

Ashpole, Nicole M; Herron, Jacquelyn C; Mitschelen, Matthew C; Farley, Julie A; Logan, Sreemathi; Yan, Han; Ungvari, Zoltan; Hodges, Erik L; Csiszar, Anna; Ikeno, Yuji; Humphrey, Mary Beth; Sonntag, William E

2016-02-01

Advanced aging is associated with increased risk of bone fracture, especially within the vertebrae, which exhibit significant reductions in trabecular bone structure. Aging is also associated with a reduction in circulating levels of insulin-like growth factor (IGF-1). Studies have suggested that the reduction in IGF-1 compromises healthspan, whereas others report that loss of IGF-1 is beneficial because it increases healthspan and lifespan. To date, the effect of decreases in circulating IGF-1 on vertebral bone aging has not been thoroughly investigated. Here, we delineate the consequences of a loss of circulating IGF-1 on vertebral bone aging in male and female Igf(f/f) mice. IGF-1 was reduced at multiple specific time points during the mouse lifespan: early in postnatal development (crossing albumin-cyclic recombinase [Cre] mice with Igf(f/f) mice); and in early adulthood and in late adulthood using hepatic-specific viral vectors (AAV8-TBG-Cre). Vertebrae bone structure was analyzed at 27 months of age using micro-computed tomography (μCT) and quantitative bone histomorphometry. Consistent with previous studies, both male and female mice exhibited age-related reductions in vertebral bone structure. In male mice, reduction of circulating IGF-1 induced at any age did not diminish vertebral bone loss. Interestingly, early-life loss of IGF-1 in females resulted in a 67% increase in vertebral bone volume fraction, as well as increased connectivity density and increased trabecular number. The maintenance of bone structure in the early-life IGF-1-deficient females was associated with increased osteoblast surface and an increased ratio of osteoprotegerin/receptor-activator of NF-κB-ligand (RANKL) levels in circulation. Within 3 months of a loss of IGF-1, there was a 2.2-fold increase in insulin receptor expression within the vertebral bones of our female mice, suggesting that local signaling may compensate for the loss of circulating IGF-1. Together, these data suggest the age-related loss of vertebral bone density in females can be reduced by modifying circulating IGF-1 levels early in life. © 2015 American Society for Bone and Mineral Research.

Dietary intake of phytoestrogen is associated with increased circulating endothelial progenitor cells in patients with cardiovascular disease.

PubMed

Chan, Yap-Hang; Lam, Tai-Hing; Lau, Kui-Kai; Yiu, Kai-Hang; Siu, Chung-Wah; Li, Sheung-Wai; Chan, Hiu-Ting; Tam, Sidney; Lau, Chu-Pak; Tse, Hung-Fat

2011-06-01

Endogenous estrogen is known to positively influence the level and functionality of endothelial progenitor cells (EPC). However, the effect of phytoestrogen on EPC is unknown. Isoflavone is a major component of phytoestrogen. This study aims to investigate if the intake of isoflavone has any impact on the circulating level of EPC. We studied 102 consecutive patients (mean age: 66.5 ± 9.5 years, 78% male, all female post-menopausal) with cardiovascular disease (atherothrombotic stroke 62%, coronary artery disease 38%). Circulating levels of CD133(+) EPC were determined by flow cytometry. Non-invasive pulse wave velocity (PWV) was measured. Long-term intake of isoflavone was determined by a validated food frequency questionnaire. Isoflavone intake was positively associated with circulating CD133(+) EPC (r = 0.31, p = 0.001). Patients with circulating CD133(+) EPC <10th percentile had significantly lower isoflavone intake than patients with CD133(+)EPC ≥10th percentile (4.6 ± 3.7 mg/day versus 19.3 ± 30.2 mg/day, p < 0.001). A significant overall linear trend of circulating EPC across increasing tertiles of isoflavone intake was observed (p = 0.004). Adjusted for potential confounders, increased isoflavone intake from the 1st to the 3rd tertile independently predicted increased circulating CD133(+) EPC level by 221 cells/µl (95%CI: 71.4 to 369.8, relative increase 160%, p = 0.004). Gender was not a significant factor (p > 0.05). Furthermore, circulating CD133(+) EPC <10th percentile was independently predictive of increased PWV by 261.7 cm/s (95% CI: 37.1 to 486.2, p = 0.024). The study demonstrated that circulating EPC increased by more than one fold in patients with cardiovascular disease who had higher intake of isoflavone, suggesting that isoflavone may confer vascular protection through enhanced endothelial repair.

Comparative analysis of the Rotarix™ vaccine strain and G1P[8] rotaviruses detected before and after vaccine introduction in Belgium.

PubMed

Zeller, Mark; Heylen, Elisabeth; Tamim, Sana; McAllen, John K; Kirkness, Ewen F; Akopov, Asmik; De Coster, Sarah; Van Ranst, Marc; Matthijnssens, Jelle

2017-01-01

G1P[8] rotaviruses are responsible for the majority of human rotavirus infections worldwide. The effect of universal mass vaccination with rotavirus vaccines on circulating G1P[8] rotaviruses is still poorly understood. Therefore we analyzed the complete genomes of the Rotarix™ vaccine strain, and 70 G1P[8] rotaviruses, detected between 1999 and 2010 in Belgium (36 before and 34 after vaccine introduction) to investigate the impact of rotavirus vaccine introduction on circulating G1P[8] strains. All rotaviruses possessed a complete Wa-like genotype constellation, but frequent intra-genogroup reassortments were observed as well as multiple different cluster constellations circulating in a single season. In addition, identical cluster constellations were found to circulate persistently over multiple seasons. The Rotarix™ vaccine strain possessed a unique cluster constellation that was not present in currently circulating G1P[8] strains. At the nucleotide level, the VP6, VP2 and NSP2 gene segments of Rotarix™ were relatively distantly related to any Belgian G1P[8] strain, but other gene segments of Rotarix™ were found in clusters also containing circulating Belgian strains. At the amino acid level, the genetic distance between Rotarix™ and circulating Belgian strains was considerably lower, except for NSP1. When we compared the Belgian G1P[8] strains collected before and after vaccine introduction a reduction in the proportion of strains that were found in the same cluster as the Rotarix™ vaccine strain was observed for most gene segments. The reduction in the proportion of strains belonging to the same cluster may be the result of the vaccine introduction, although natural fluctuations cannot be ruled out.

Circulating betatrophin is elevated in patients with type 1 and type 2 diabetes.

PubMed

Yamada, Hodaka; Saito, Tomoyuki; Aoki, Atsushi; Asano, Tomoko; Yoshida, Masashi; Ikoma, Aki; Kusaka, Ikuyo; Toyoshima, Hideo; Kakei, Masafumi; Ishikawa, San-E

2015-01-01

There is evidence that betatrophin, a hormone derived from adipose tissue and liver, affects the proliferation of pancreatic beta cells in mice. The aim of this study was to examine circulating betatrophin concentrations in Japanese healthy controls and patients with type 1 and type 2 diabetes. A total of 76 subjects (12 healthy controls, 34 type 1 diabetes, 30 type 2 diabetes) were enrolled in the study. Circulating betatrophin was measured with an ELISA kit and clinical parameters related to betatrophin were analyzed statistically. Circulating betatrophin (Log transformed) was significantly increased in patients with diabetes compared with healthy subjects (healthy controls, 2.29 ± 0.51; type 1 diabetes, 2.94 ± 0.44; type 2 diabetes, 3.17 ± 0.18; p<0.001, 4.1 to 5.4 times in pg/mL order). Age, HbA1c, fasting plasma glucose and Log triglyceride were strongly associated with Log betatrophin in all subjects (n=76) in correlation analysis. In type 1 diabetes, there was a correlation between Log betatrophin and Log CPR. These results provide the first evidence that circulating betatrophin is significantly elevated in Japanese patients with diabetes. The findings of this pilot study also suggest a possibility of association between the level of betatrophin and the levels of glucose and triglycerides.

High levels of circulating extracellular vesicles with altered expression and function during pregnancy.

PubMed

Nardi, Fabiola da Silva; Michelon, Tatiana Ferreira; Neumann, Jorge; Manvailer, Luis Felipe Santos; Wagner, Bettina; Horn, Peter A; Bicalho, Maria da Graça; Rebmann, Vera

2016-07-01

Extracellular vesicles (EVs) are widely considered important modulators of cell-cell communication and may interact with target cells locally and on a systemic level. Several studies had shown that circulating EVs' levels are increased during pregnancy. However, EVs characteristics, composition and biological functions in pregnancy still need to be clarified. This study aims to determine if circulating EVs during pregnancy are modified regarding levels, markers and cytokine profile as well as their reactivity towards peripheral blood cells. 26 pregnant women (PW) being in the second gestational trimester and 59 non-pregnant women (NPW) were investigated. EVs enrichment was performed by ExoQuick™ or ultracentrifugation; nanoparticle tracking analysis, SDS-PAGE followed by Western Blotting and densitometry, and IFN-γ, IL-10 and TGF-β1 ELISA for EVs characterization; imaging flow cytometry to analyze EVs' uptake by peripheral blood cells and flow cytometry were performed to analyze EVs function regarding induction of caspase-3 activity. Circulating EVs' levels were increased during pregnancy [26.9×10(6)EVs/ml (range: 6.4-46.3); p=0.003] vs NPW [18.9×10(6)EVs/ml (range: 2.5-61.3)]. Importantly, the immunosuppressive TGF-β1 and IL-10 cytokine cargo were increased in EVs of PW even after normalization to 1 million EVs [TGF-β1: 0.25pg/10(6)EVs (range: 0.0-2.0); p<0.0001] and [IL-10: 0.21pg/10(6)EVs (range: 0.0-16.8); p=0.006] vs NPW. Although EVs derived from non-pregnant and pregnant women were taken up by NK cells, the latter exclusively enhanced the caspase-3 activity in CD56(dim) NK cells (8.2±0.9; p=0.02). The qualitative and quantitative pregnancy-related alterations of circulating EVs provide first hints for an immune modulating role of circulating EVs during pregnancy. Copyright © 2016 Elsevier GmbH. All rights reserved.

Matrix metalloproteinase-9 and tissue inhibitor of metalloproteinase-1 in hypertension and their relationship to cardiovascular risk and treatment: a substudy of the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT).

PubMed

Tayebjee, Muzahir H; Nadar, Sunil; Blann, Andrew D; Gareth Beevers, D; MacFadyen, Robert J; Lip, Gregory Y H

2004-09-01

Hypertension results in structural changes to the cardiac and vascular extracellular matrix (ECM). Matrix metalloproteinases (MMP) and their inhibitors (TIMP) may play a central role in the modulation of this matrix. We hypothesized that both MMP-9 and TIMP-1 would be abnormal in hypertension, reflecting alterations in ECM turnover, and that their circulating levels should be linked to cardiovascular (CHD) and stroke (CVA) risk scores using the Framingham equation. Second, we hypothesized that treatment would result in changes in ECM indices. Plasma MMP-9 and TIMP-1 were measured before and after treatment (median 3 years) from 96 patients with uncontrolled hypertension participating in the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT). Pretreatment values were compared to circulating MMP-9 and TIMP-1 levels in 45 age- and sex-matched healthy controls. Circulating pretreatment MMP-9 and TIMP-1 levels were significantly higher in patients with hypertension than in the normotensive controls (P =.0041 and P =.0166, respectively). Plasma MMP-9 levels decreased, and TIMP-1 levels increased after treatment (P =.035 and P =.005, respectively). Levels of MMP-9 correlated with CHD risk (r = 0.317, P =.007) and HDL cholesterol (r = -0.237, P =.022), but not CVA risk. There were no significant correlations between TIMP-1 and CVA or CHD scores. Increased circulating MMP-9 and TIMP-1 at baseline in patients with hypertension could reflect an increased deposition and retention of type I collagen at the expense of other components of ECM within the cardiac and vascular ECM. After cardiovascular risk management, MMP-9 levels decreased and TIMP-1 levels increased. Elevated levels of MMP-9 also appeared to be associated with higher Framingham cardiovascular risk scores. Our observations suggest a possible role for these surrogate markers of tissue ECM composition and the prognosis of cardiovascular events in hypertension. Copyright 2004 American Journal of Hypertension, Ltd.

A case of severe anorexia, excessive weight loss and high peptide YY levels after sleeve gastrectomy.

PubMed

Pucci, Andrea; Cheung, Wui Hang; Jones, Jenny; Manning, Sean; Kingett, Helen; Adamo, Marco; Elkalaawy, Mohamed; Jenkinson, Andrew; Finer, Nicholas; Doyle, Jacqueline; Hashemi, Majid; Batterham, Rachel L

2015-01-01

Sleeve gastrectomy (SG) is the second most commonly performed bariatric procedure worldwide. Altered circulating gut hormones have been suggested to contribute post-operatively to appetite suppression, decreased caloric intake and weight reduction. In the present study, we report a 22-year-old woman who underwent laparoscopic SG for obesity (BMI 46 kg/m(2)). Post-operatively, she reported marked appetite reduction, which resulted in excessive weight loss (1-year post-SG: BMI 22 kg/m(2), weight loss 52%, >99th centile of 1-year percentage of weight loss from 453 SG patients). Gastrointestinal (GI) imaging, GI physiology/motility studies and endoscopy revealed no anatomical cause for her symptoms, and psychological assessments excluded an eating disorder. Despite nutritional supplements and anti-emetics, her weight loss continued (BMI 19 kg/m(2)), and she required nasogastric feeding. A random gut hormone assessment revealed high plasma peptide YY (PYY) levels. She underwent a 3 h meal study following an overnight fast to assess her subjective appetite and circulating gut hormone levels. Her fasted nausea scores were high, with low hunger, and these worsened with nutrient ingestion. Compared to ten other post-SG female patients, her fasted circulating PYY and nutrient-stimulated PYY and active glucagon-like peptide 1 (GLP1) levels were markedly elevated. Octreotide treatment was associated with suppressed circulating PYY and GLP1 levels, increased appetite, increased caloric intake and weight gain (BMI 22 kg/m(2) after 6 months). The present case highlights the value of measuring gut hormones in patients following bariatric surgery who present with anorexia and excessive weight loss and suggests that octreotide treatment can produce symptomatic relief and weight regain in this setting. Roux-en-Y gastric bypass and SG produce marked sustained weight reduction. However, there is a marked individual variability in this reduction, and post-operative weight loss follows a normal distribution with extremes of 'good' and 'poor' response.Profound anorexia and excessive weight loss post-SG may be associated with markedly elevated circulating fasted PYY and post-meal PYY and GLP1 levels.Octreotide treatment can produce symptomatic relief and weight regain for post-SG patients that have an extreme anorectic and weight loss response.The present case highlights the value of measuring circulating gut hormone levels in patients with post-operative anorexia and extreme weight loss.

Morphology of ovaries in laron dwarf mice, with low circulating plasma levels of insulin-like growth factor-1 (IGF-1), and in bovine GH-transgenic mice, with high circulating plasma levels of IGF-1

PubMed Central

2012-01-01

Background It is well known that somatotrophic/insulin signaling affects lifespan in experimental animals, and one of the signs of aging is progressive gonadal dysfunction. Methods To study the effects of insulin-like growth factor-1 (IGF-1) plasma level on ovaries, we analyzed ovaries isolated from 2-year-old growth hormone receptor knockout (GHR-KO) Laron dwarf mice, with low circulating plasma levels of IGF-1, and 6-month-old bovine growth hormone transgenic (bGHTg) mice, with high circulating plasma levels of IGF-1. The ages of the Laron dwarf mutants employed in our studies were selected based on their overall survival (up to ~ 4 years for Laron dwarf mice and ~ 1 year for bGHTg mice). Results Morphological analysis of the ovaries of mice that reached ~50% of their maximal life span revealed a lower biological age for the ovaries isolated from 2-year-old Laron dwarf mice than their normal-lifespan wild type littermates. By contrast, the ovarian morphology of increased in size 6 month old bGHTg mice was generally normal. Conclusion Ovaries isolated from 2-year-old Laron dwarf mice exhibit a lower biological age compared with ovaries from normal WT littermates at the same age. At the same time, no morphological features of accelerated aging were found in 0.5-year-old bGHTg mice compared with ovaries from normal the same age-matched WT littermates. PMID:22747742

Association between circulating transforming growth factor-β1 level and polymorphisms in systemic lupus erythematosus and rheumatoid arthritis: A meta-analysis.

PubMed

Lee, Y H; Bae, S-C

2017-02-22

This study systemically reviewed evidence regarding the relationship between circulating blood transforming growth factor-β1 (TGF-β1) levels and systemic lupus erythematous (SLE) and rheumatoid arthritis (RA), and associations between TGF-β1 polymorphisms and susceptibility to SLE and RA.  We conducted a meta-analysis on the serum/plasma TGF-β1 levels in SLE and RA patients and healthy controls, and the associations between TGF-β1 +869 T/C, +915 C/G, and -509 T/C polymorphisms and SLE or RA risk. Twenty-eight studies were considered in this meta-analysis. Circulating TGF-β1 levels were significantly lower in the SLE group than in controls (SMD = -1.164, 95% CI = -2.257 - -0.070, P = 0.037). Serum/plasma TGF-β1 levels were not significantly different between RA and control groups (SMD = 0.699, 95% CI = -0.379 - 1.717, p = 0.211). No association between TGF-β1 +869 T/C polymorphism and SLE was found. However, meta-analysis showed an association between the TGF-β1 +869 T allele and RA in all subjects (OR = 1.282, 95% CI = 1.118-1.470, P = 3.8 x 10-4). Analysis after stratification by ethnicity indicated that the T allele was significantly associated with RA in Asians and Arabs (OR = 1.429, 95% CI = 1.179-1.733, P = 2.9 x 10-4; OR = 1.352, 95% CI = 1.097-1.668, P = 0.005), but not Europeans. However, no association was found between TGF-β1 +915 G/C or -509 C/T polymorphisms and RA or SLE. Meta-analysis revealed a significantly lower circulating TGF-β1 level in SLE patients, and a significant association between TGF-β1 +869 T/C polymorphism and RA development.

Increased Circulating FGF23 Does Not Lead to Cardiac Hypertrophy in the Male Hyp Mouse Model of XLH.

PubMed

Liu, Eva S; Thoonen, Robrecht; Petit, Elizabeth; Yu, Binglan; Buys, Emmanuel S; Scherrer-Crosbie, Marielle; Demay, Marie B

2018-05-01

Serum levels of fibroblast growth factor 23 (FGF23) markedly increase with renal impairment, with FGF23 levels correlating with the presence of left ventricular hypertrophy (LVH) and mortality in patients with chronic kidney disease (CKD). FGF23 activates calcineurin/nuclear factor of activated T cell (NFAT) signaling and induces hypertrophy in murine cardiomyocytes. X-linked hypophosphatemia (XLH) is characterized by high circulating levels of FGF23 but, in contrast to CKD, is associated with hypophosphatemia. The cardiac effects of high circulating levels of FGF23 in XLH are not well defined. Thus, studies were undertaken to define the cardiac phenotype in the mouse model of XLH (Hyp mice). Echocardiographic and histological analyses demonstrated that Hyp left ventricles (LVs) are smaller than those of wild-type mice. Messenger RNA expression of cardiac hypertrophy markers was not altered in the LV or right ventricle of Hyp mice. However, the Hyp LVs had increased expression of the NFAT target genes NFATc1 and RCAN1. To determine whether phosphate alone can induce markers of hypertrophy, differentiated C2C12 myocytes were treated with phosphate. Phosphate treatment increased expression of cardiac hypertrophy markers, supporting a primary role for phosphate in inducing LVH. Although previous studies showed that increased circulating FGF23 and phosphate levels are associated with LVH, our results demonstrated that in XLH, high circulating levels of FGF23 in the setting of hypophosphatemia do not induce cardiac hypertrophy.

Increased body fat mass explains the positive association between circulating estradiol and insulin resistance in postmenopausal women.

PubMed

Marchand, Geneviève B; Carreau, Anne-Marie; Weisnagel, S John; Bergeron, Jean; Labrie, Fernand; Lemieux, Simone; Tchernof, André

2018-05-01

The relationship between circulating estrogen levels and cardiometabolic risk factors such as insulin resistance is unclear in postmenopausal women. High estradiol (E 2 ) levels have been reported to predict increased risk of type 2 diabetes in this population. We aimed to examine associations among estrogen levels, adiposity measurements, and cardiometabolic risk variables including insulin resistance in postmenopausal women. One hundred-one healthy participants (mean ± SD: age 57 ± 4 yr, BMI 27.9 ± 4.8 kg/m 2 ) were included in the analysis. Fifteen plasma steroids or metabolites were measured by liquid chromatography-tandem mass spectrometry. Insulin sensitivity was assessed with a hyperinsulinemic-euglycemic clamp. Body composition and fat distribution were determined with hydrostatic weighing and computed tomography, respectively. Blood lipids and circulating cytokines were also measured. Circulating E 2 was positively correlated with all adiposity indexes ( r = 0.62 to 0.42, P < 0.0001) except waist-to-hip ratio. E 2 was positively correlated with VLDL-cholesterol, plasma-, VLDL-, and HDL-triglyceride levels ( r = 0.31 to 0.24, P < 0.02) as well as with hs-CRP and IL-6 ( r = 0.52 and 0.29, P < 0.005) and negatively with HDL-cholesterol, adiponectin, and insulin sensitivity ( r = -0.36 to -0.20, P < 0.02). With adjustments for percent body fat, correlations between E 2 and metabolic risk variables were no longer significant. Similar results were observed for circulating estrone (E 1 ) and estrone-sulfate (E 1 -S) levels. In conclusion, circulating estrogen concentrations are proportional to adipose mass in postmenopausal women, although they remain in the low range. Insulin resistance as well as altered blood lipids and cytokines are observed when circulating estrogen levels are high within that range, but these differences are explained by concomitant variation in total adiposity.

Increased Levels of Circulating Anti-ANXA1 IgG Antibody in Patients with Non-Small Cell Lung Cancer.

PubMed

Liang, Tingting; Han, Zhifeng; Zhao, Huan; Zhang, Xuan; Wang, Yao

2018-06-01

Our previous studies revealed that concentrations of circulating antibodies to annexin A1 (ANXA1) were increased in non-small lung cancer (NSCLC). This study was thus designed to replicate this initial finding with an independent sample set. An enzyme-linked immunosorbent assay (ELISA) was developed in-house to examine plasma antiANXA1 IgG levels in 220 patients with NSCLC and 200 control subjects. Mann-Whitney U test showed that patients with NSCLC had significantly higher anti-ANXA1 IgG levels than control subjects (Z = -4.02, p < 0.001); male patients appeared to mainly contribute to the increased antibody level (Z = -3.09, p = 0.002). Receiver operating characteristic (ROC) curve analysis showed an overall area under the ROC curve (AUC) of 0.61 (95% CI: 0.56 - 0.67), with sensitivity of 8% against a specificity of 95.0%. Spearman's correlation analysis failed to show a significant correlation between the anti-ANXA1 IgG levels and the expression of three tumor-associated antigens including p53 (r = 0.156, p = 0.027), Ki67 (r = -0.048, p = 0.489), and EGFR (r = 0.02, p = 0.782). Increased levels of circulating anti-ANXA1 IgG antibody may have a prognostic value for NSCLC.

Genetic and epigenetic regulation of YKL-40 in childhood.

PubMed

Guerra, Stefano; Melén, Erik; Sunyer, Jordi; Xu, Cheng-Jian; Lavi, Iris; Benet, Marta; Bustamante, Mariona; Carsin, Anne-Elie; Dobaño, Carlota; Guxens, Mònica; Tischer, Christina; Vrijheid, Martine; Kull, Inger; Bergström, Anna; Kumar, Ashish; Söderhäll, Cilla; Gehring, Ulrike; Dijkstra, Dorieke J; van der Vlies, Pieter; Wickman, Magnus; Bousquet, Jean; Postma, Dirkje S; Anto, Josep M; Koppelman, Gerard H

2018-03-01

Circulating levels of the chitinase-like protein YKL-40 are influenced by genetic variation in its encoding gene (chitinase 3-like 1 [CHI3L1]) and are increased in patients with several diseases, including asthma. Epigenetic regulation of circulating YKL-40 early in life is unknown. We sought to determine (1) whether methylation levels at CHI3L1 CpG sites mediate the association of CHI3L1 single nucleotide polymorphisms (SNPs) with YKL-40 levels in the blood and (2) whether these biomarkers (CHI3L1 SNPs, methylation profiles, and YKL-40 levels) are associated with asthma in early childhood. We used data from up to 2405 participants from the Spanish Infancia y Medio Ambiente; the Swedish Barn/Children, Allergy, Milieu, Stockholm, Epidemiological survey; and the Dutch Prevention and Incidence of Asthma and Mite Allergy birth cohorts. Associations between 68 CHI3L1 SNPs, methylation levels at 14 CHI3L1 CpG sites in whole-blood DNA, and circulating YKL-40 levels at 4 years of age were tested by using correlation analysis, multivariable regression, and mediation analysis. Each of these biomarkers was also tested for association with asthma at 4 years of age by using multivariable logistic regression. YKL-40 levels were significantly associated with 7 SNPs and with methylation at 5 CpG sites. Consistent associations between these 7 SNPs (particularly rs10399931 and rs4950928) and 5 CpG sites were observed. Alleles linked to lower YKL-40 levels were associated with higher methylation levels. Participants with high YKL-40 levels (defined as the highest YKL-40 tertile) had increased odds for asthma compared with subjects with low YKL-40 levels (meta-analyzed adjusted odds ratio, 1.90 [95% CI, 1.08-3.36]). In contrast, neither SNPs nor methylation levels at CpG sites in CHI3L1 were associated with asthma. The effects of CHI3L1 genetic variation on circulating YKL-40 levels are partly mediated by methylation profiles. In our study YKL-40 levels, but not CHI3L1 SNPs or methylation levels, were associated with childhood asthma. Copyright © 2017 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

Structural coloration signals condition, parental investment, and circulating hormone levels in Eastern bluebirds (Sialia sialis).

PubMed

Grindstaff, Jennifer L; Lovern, Matthew B; Burtka, Jennifer L; Hallmark-Sharber, Alesia

2012-08-01

Many of the brilliant plumage coloration displays of birds function as signals to conspecifics. One species in which the function of plumage ornaments has been assessed is the Eastern bluebird (Sialia sialis). Studies of a population breeding in Alabama (USA) have established that plumage ornaments signal quality, parental investment, and competitive ability in both sexes. Here we tested the additional hypotheses that (1) Eastern bluebird plumage ornamentation signals nest defense behavior in heterospecific competitive interactions and (2) individual variation in plumage ornamentation reflects underlying differences in circulating hormone levels. We also tested the potential for plumage ornaments to signal individual quality and parental investment in a population breeding in Oklahoma (USA). We found that Eastern bluebirds with more ornamented plumage are in better condition, initiate breeding earlier in the season, produce larger clutches, have higher circulating levels of the stress hormone corticosterone, and more ornamented males have lower circulating androgen levels. Plumage coloration was not related to nest defense behavior. Thus, plumage ornamentation may be used by both sexes to assess the physiological condition and parental investment of prospective mates. Experimental manipulations of circulating hormone levels during molt are needed to define the role of hormones in plumage ornamentation.

Enhanced risk profiling of implanted defibrillator shocks with circulating SCN5A mRNA splicing variants: a pilot trial

PubMed Central

Gao, Ge; Brahmanandam, Vikram; Raicu, Mihai; Gu, Lianzhi; Zhou, Li; Kasturirangan, Srinivasan; Shah, Anish; Negi, Smita I.; Wood, Melissa R.; Desai, Ankit A.; Tatooles, Antone; Schwartz, Alan; Dudley, Samuel C.

2014-01-01

Objectives The aim of this study was to determine the association of SCN5A cardiac sodium (Na+) channel mRNA splice variants in white blood cells (WBCs) with risk of arrhythmias in heart failure (HF). Background HF is associated with upregulation of two cardiac SCN5A mRNA splice variants. that encode prematurely truncated, nonfunctional Na+ channels. Since circulating WBCs demonstrate similar SCN5A splicing patterns, we hypothesized that these WBC-derived splice variants might further stratify HF patients at risk for arrhythmias. Methods Simultaneously obtained myocardial core samples and WBCs were compared for SCN5A variants C (VC) and D (VD). Circulating variant levels were compared between HF patients divided into three groups: HF without an implantable cardioverter-defibrillator (ICD), HF with an ICD without appropriate intervention, and HF with an ICD with appropriate intervention. Results Myocardial tissue-derived SCN5A variant expression levels strongly correlated with circulating WBC samples for both VC and VD variants (r = 0.78 and 0.75, respectively). After controlling for covariates, HF patients who had received an appropriate ICD intervention had higher expression levels of both WBC-derived SCN5A variants compared to HF patients with ICDs who had not (OR= 3.25 (95% CI 1.64–6.45; p=0.001)). Receiver operating characteristics analysis revealed that circulating SCN5A variants levels were highly associated with the risk for appropriate ICD intervention (area under the curve ≥ 0.97). Conclusions Circulating expression levels of SCN5A variants were strongly associated with myocardial tissue levels. Furthermore, circulating variant levels were correlative with arrhythmic risk as measured by ICD events in a HF population within one year. PMID:24703920

Circulating concentrations of insulin markers and coronary heart disease: a quantitative review of 19 Western prospective studies.

PubMed

Sarwar, Nadeem; Sattar, Naveed; Gudnason, Vilmundur; Danesh, John

2007-10-01

It is uncertain whether there are associations between circulating levels of insulin markers and coronary heart disease (CHD) risk. We report an updated meta-analysis of studies of circulating levels of three insulin markers (fasting insulin, non-fasting insulin, and pro-insulin) and CHD risk. Prospective studies based in Western populations that reported on associations between levels of fasting insulin, non-fasting insulin, and pro-insulin and incident CHD [defined as non-fatal myocardial infarction (MI) or coronary death] were identified by computer-based searches and by manual searches of the relevant literature. Nineteen relevant population-based studies were identified, of which 14 reported on fasting insulin levels involving 2649 CHD cases, eight reported on non-fasting insulin levels involving 1980 CHD cases and three reported on pro-insulin levels involving 413 CHD cases. In a comparison of individuals who had circulating levels of each of these markers in the top third with those in the bottom third of the population, the odds ratio for CHD was 1.12 [95% confidence interval (CI): 0.98-1.28] for raised fasting insulin, 1.35 (1.14-1.60) for raised non-fasting insulin, and 2.23 (1.65-3.00) for raised pro-insulin. There was no good evidence of heterogeneity in these estimates attributable to the several study characteristics recorded, including sex, assay methods used, or degree of adjustment of risk estimates, but the available data in many of these subgroups, particularly by sex, are sparse. Associations between CHD risk and fasting or non-fasting insulin levels are likely to be more modest than previously suspected. Preliminary data suggest that pro-insulin levels may be more strongly associated with CHD risk than are insulin levels, and this possibility should be evaluated in larger and more rigorous studies.

tPA-MMP-9 Axis Plays a Pivotal Role in Mobilization of Endothelial Progenitor Cells from Bone Marrow to Circulation and Ischemic Region for Angiogenesis

PubMed Central

Day, Yuan-Ji

2016-01-01

We examined the role of tissue plasminogen activator- (tPA-) matrix metalloproteinase- (MMP-) 9 in mobilizing endothelial progenitor cells (EPCs) from bone marrow to circulation and critical limb ischemia (CLI) region. Male C57BL/6J mice having been irradiated were categorized into wild-type mice (WT) receiving WT bone marrow cell (BMC) transfusion (group 1), WT mice receiving MMP-9 knockout (MMP-9−/−) BMC (group 2), MMP-9−/− receiving MMP-9−/− BMC (group 3), and MMP-9−/− receiving WT BMC (group 4), each of which was subdivided into sham control (SC), CLI, SC-tPA, and CLI-tPA. In groups 1 and 4, by post-CLI 18 h and day 14, circulating EPC (C-kit+/CD31+, Sca-1+/KDR+) levels were highest in CLI-tPA subgroup. In groups 2 and 3, EPC levels did not differ among all subgroups. The EPC levels in bone marrow were higher in groups 2 and 3 than those in groups 1 and 4. By day 14, in animals with CLI, expression levels of proangiogenic factors (CXCR4, SDF-1α, and VEGF) showed similar trends as circulating EPC levels. Moreover, the number of infiltrated neutrophils and macrophages in quadriceps was higher in groups 1 and 4 than groups in 2 and 3. In conclusion, tPA-MMP-9 axis plays a crucial role in EPC mobilization and angiogenesis in experimental CLI. PMID:27610138

Increased circulating heat shock protein 70 (HSPA1A) levels in gestational diabetes mellitus: a pilot study.

PubMed

Garamvölgyi, Zoltán; Prohászka, Zoltán; Rigó, János; Kecskeméti, András; Molvarec, Attila

2015-07-01

Recent data indicate that serum Hsp70 (HSPA1A) levels are increased in type 1 and 2 diabetes mellitus. However, there is no report in the literature on circulating Hsp70 levels in gestational diabetes mellitus. In this pilot study, we measured serum Hsp70 levels in 11 pregnant women with pregestational diabetes, 38 women with gestational diabetes, and 40 healthy pregnant women with ELISA. Plasma glucose levels, serum insulin concentrations, HbA1c values, and the Homeostatic Model Assessment-Insulin Resistance (HOMA-IR) index were also determined. According to our results, serum Hsp70 concentrations were significantly higher in women with pregestational and gestational diabetes mellitus than in healthy pregnant women. In addition, pregestational diabetic women had significantly higher Hsp70 levels than those with gestational diabetes. Furthermore, in the group of women with gestational diabetes mellitus, serum Hsp70 levels showed a significant positive correlation with HbA1c values. However, there was no other relationship between clinical features and metabolic parameters of the study subjects and their serum Hsp70 levels in either study group. In conclusion, we demonstrated for the first time in the literature that serum Hsp70 levels are increased and correlate with HbA1c values in women with gestational diabetes mellitus. Nevertheless, further studies are needed to determine whether circulating Hsp70 plays a causative role in the pathogenesis of gestational diabetes or elevated serum Hsp70 levels are only consequences of the disease.

Pro- and antiinflammatory cytokines in threatened miscarriages.

PubMed

Calleja-Agius, Jean; Muttukrishna, Shanthi; Pizzey, Arnold R; Jauniaux, Eric

2011-07-01

The purpose of this study was to evaluate circulating and intracellular levels of Th1 and Th2 cytokines in women with threatened miscarriage (TM) and subsequent outcome. Plasma levels of tumor necrosis factor (TNF)-receptors 1 and 2, TNFα, interferon gamma (IFNγ), and interleukins (IL) -6 and -10 were measured by flow cytometric bead assays in 80 women with TM: 53 women with normal outcome and 27 women who miscarried. Fluorescent antibody labeling was also performed on whole blood in a subgroup of 27 women of TM: 16 women with normal outcome and 11 women who miscarried. Monocyte expression of TNFα and circulating levels of TNFα, IFNγ, IL-10, IL-6, and TNF-R1 were significantly lower, whereas circulating levels of TNFα/IL-10, IFNγ/IL-10, and TNFα/IL-6 ratios were significantly higher, in women with TM who subsequently miscarried, compared with the women with normal outcome. An increased Th1 type of immune response, which was similar to that observed in preterm delivery, was found in TM cases that were complicated by a subsequent miscarriage. Copyright © 2011. Published by Mosby, Inc.

Association between circulating fibroblast growth factor 21 and mortality in end-stage renal disease.

PubMed

Kohara, Marina; Masuda, Takahiro; Shiizaki, Kazuhiro; Akimoto, Tetsu; Watanabe, Yuko; Honma, Sumiko; Sekiguchi, Chuji; Miyazawa, Yasuharu; Kusano, Eiji; Kanda, Yoshinobu; Asano, Yasushi; Kuro-O, Makoto; Nagata, Daisuke

2017-01-01

Fibroblast growth factor 21 (FGF21) is an endocrine factor that regulates glucose and lipid metabolism. Circulating FGF21 predicts cardiovascular events and mortality in type 2 diabetes mellitus, including early-stage chronic kidney disease, but its impact on clinical outcomes in end-stage renal disease (ESRD) patients remains unclear. This study enrolled 90 ESRD patients receiving chronic hemodialysis who were categorized into low- and high-FGF21 groups by the median value. We investigated the association between circulating FGF21 levels and the cardiovascular event and mortality during a median follow-up period of 64 months. A Kaplan-Meier analysis showed that the mortality rate was significantly higher in the high-FGF21 group than in the low-FGF21 group (28.3% vs. 9.1%, log-rank, P = 0.034), while the rate of cardiovascular events did not significantly differ between the two groups (30.4% vs. 22.7%, log-rank, P = 0.312). In multivariable Cox models adjusted a high FGF21 level was an independent predictor of all-cause mortality (hazard ratio: 3.98; 95% confidence interval: 1.39-14.27, P = 0.009). Higher circulating FGF21 levels were associated with a high mortality rate, but not cardiovascular events in patient with ESRD, suggesting that circulating FGF21 levels serve as a predictive marker for mortality in these subjects.

Circulating exosomes from patients with systemic lupus erythematosus induce an proinflammatory immune response.

PubMed

Lee, Joo Youn; Park, Jin Kyun; Lee, Eun Young; Lee, Eun Bong; Song, Yeong Wook

2016-11-16

Exosomes are involved in intercellular communication. The aim of this study was to investigate whether circulating exosomes effectively contribute to the inflammatory response in systemic lupus erythematosus (SLE). Exosomes were purified from SLE patients and healthy controls (HCs). Healthy peripheral blood mononuclear cells (PBMCs) were stimulated with exosomes isolated from SLE patients and HCs in the presence or absence of Toll-like receptor (TLR) inhibitors. Production of interferon (IFN)-α, tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6 were measured. Correlation between exosome levels and SLE disease activity was examined. The serum exosomes levels were significantly higher in SLE patients than in HCs. SLE exosomes induced a higher production of IFN-α, TNF-α, IL-1β, and IL-6 compared to healthy exosomes. SLE serum that was depleted of exosomes and SLE exosomes that were mechanically disrupted failed to induce any significant cytokine production. Exosome-mediated production of TNF-α, IL-1β, and IL-6 was decreased by the TLR4 antagonist, whereas that of IFN-α was suppressed by the TLR1/2, TLR7, and TLR9 antagonists. Exosome levels correlated with disease activity in SLE patients (rho = 0.846, p = 0.008). The circulating exosomes are immunologically active and their levels correlate with disease activity in SLE patients. The circulating exosomes might serve as novel biomarkers of SLE disease activity.

Circulating matrix metalloproteinase-9 and tissue inhibitors of metalloproteinases-1 and -2 levels in gestational hypertension.

PubMed

Tayebjee, Muzahir H; Karalis, Ioannis; Nadar, Sunil K; Beevers, D Gareth; MacFadyen, Robert J; Lip, Gregory Y H

2005-03-01

Gestational hypertension (GH) is dangerous to both mother and child. Arterial invasiveness and growth are dependent on successful extracellular matrix (ECM) breakdown, which may be abnormal in GH. We hypothesized abnormalities in circulating matrix metalloproteinase-9 (MMP-9) and tissue inhibitors of metalloproteinases-1 and -2 (TIMP-1 and TIMP-2, respectively) in patients with GH, when compared with normotensive women with normal pregnancies and healthy nonpregnant control subjects. Plasma MMP-9, TIMP-1, and TIMP-2 were measured by ELISA in 23 women with GH, 30 normotensive pregnant women, and 28 nonpregnant women who were matched for age, gestational age, and parity. Levels of circulating MMP-9, TIMP-1 and TIMP-2, and the MMP-9/TIMP-1 and MMP-9/TIMP-2 ratios were significantly different among the three groups (P = .026, P = .006, P = .007, P = .001 and P = .008 respectively). Within the GH group, MMP-9 and the MMP-9/TIMP-1 ratio correlated negatively with age (r = -0.581, P = .004 and r = -0.563, P = .005, respectively) and levels of diastolic blood pressure (r = -0.432, P = .040 and r = -0.461, P = .027, respectively). With multiple regression analysis, only age independently correlated with circulating levels of MMP-9 (P = .010); neither age nor levels of diastolic blood pressure had any effect on the MMP-9/TIMP-1 ratio. We have demonstrated altered MMP/TIMP ratios in maternal blood during GH. These observations suggest pregnancy-related changes in ECM breakdown and turnover. Given the importance of changes in ECM composition to vascular and cardiac structure in hypertension, we suggest that these observations may be related to the pathophysiology of human GH.

Association of circulating ANGPTL 3, 4, and 8 levels with medical status in a population undergoing routine medical checkups: A cross-sectional study.

PubMed

Morinaga, Jun; Zhao, Jiabin; Endo, Motoyoshi; Kadomatsu, Tsuyoshi; Miyata, Keishi; Sugizaki, Taichi; Okadome, Yusuke; Tian, Zhe; Horiguchi, Haruki; Miyashita, Kazuya; Maruyama, Nobuhiro; Mukoyama, Masashi; Oike, Yuichi

2018-01-01

Angiopoietin-like proteins (ANGPTLs) 3, 4, and 8 reportedly contribute to progression of metabolic disease, a risk factor for cardiovascular disease (CVD). The purpose of this study was to investigate whether circulating ANGPTL levels are associated with CVD risk after adjustment for potential confounding factors. We conducted a single center, cross-sectional study of 988 Japanese subjects undergoing routine health checks. Serum ANGPTL3, 4, and 8 levels were measured using an enzyme-linked immunosorbent assay. Using multiple regression analysis we evaluated potential association of circulating ANGPTL3, 4, and 8 levels with general medical status including age, sex, smoking, drinking, obesity, hypertension, impaired glycometabolism, dyslipidemia, hyperuricemia, hepatic impairment, chronic kidney disease, anemia, cardiac abnormality, and inflammation. Circulating ANGPTL3 levels were relatively high in health-related categories of hepatic impairment and inflammation. Circulating ANGPTL4 levels were also significantly high in impaired glycometabolism or hepatic impairment but decreased in inflammation. Finally, increased ANGPTL8 levels were observed in obesity, impaired glycometabolism and dyslipidemia. Particularly, increased levels of circulating ANGPTL8 were positively correlated with circulating triglycerides and LDL-cholesterol levels and inversely correlated with circulating HDL-cholesterol levels. Circulating ANGPTL3, 4, and 8 levels reflect some risk factors for CVD development.

Increased Obesity-Associated Circulating Levels of the Extracellular Matrix Proteins Osteopontin, Chitinase-3 Like-1 and Tenascin C Are Associated with Colon Cancer

PubMed Central

Catalán, Victoria; Gómez-Ambrosi, Javier; Rodríguez, Amaia; Ramírez, Beatriz; Izaguirre, Maitane; Hernández-Lizoain, José Luis; Baixauli, Jorge; Martí, Pablo; Valentí, Víctor; Moncada, Rafael; Silva, Camilo; Salvador, Javier; Frühbeck, Gema

2016-01-01

Background Excess adipose tissue represents a major risk factor for the development of colon cancer with inflammation and extracellular matrix (ECM) remodeling being proposed as plausible mechanisms. The aim of this study was to investigate whether obesity can influence circulating levels of inflammation-related extracellular matrix proteins in patients with colon cancer (CC), promoting a microenvironment favorable for tumor growth. Methods Serum samples obtained from 79 subjects [26 lean (LN) and 53 obese (OB)] were used in the study. Enrolled subjects were further subclassified according to the established diagnostic protocol for CC (44 without CC and 35 with CC). Anthropometric measurements as well as circulating metabolites and hormones were determined. Circulating concentrations of the ECM proteins osteopontin (OPN), chitinase-3-like protein 1 (YKL-40), tenascin C (TNC) and lipocalin-2 (LCN-2) were determined by ELISA. Results Significant differences in circulating OPN, YKL-40 and TNC concentrations between the experimental groups were observed, being significantly increased due to obesity (P<0.01) and colon cancer (P<0.05). LCN-2 levels were affected by obesity (P<0.05), but no differences were detected regarding the presence or not of CC. A positive association (P<0.05) with different inflammatory markers was also detected. Conclusions To our knowledge, we herein show for the first time that obese patients with CC exhibit increased circulating levels of OPN, YKL-40 and TNC providing further evidence for the influence of obesity on CC development via ECM proteins, representing promising diagnostic biomarkers or target molecules for therapeutics. PMID:27612200

Short-term administration of the GLP-1 analog liraglutide decreases circulating leptin and increases GIP levels and these changes are associated with alterations in CNS responses to food cues: A randomized, placebo-controlled, crossover study

PubMed Central

Farr, Olivia M.; Tsoukas, Michael A.; Triantafyllou, Georgios; Dincer, Fadime; Filippaios, Andreas; Ko, Byung-Joon; Mantzoros, Christos S.

2016-01-01

Background GLP-1 agonists, including liraglutide, have emerged as effective therapies for type 2 diabetes (DM) and obesity. Here, we attempted to delineate how liraglutide, at doses approved for DM, may impact circulating hormones influencing energy homeostasis in diabetics. Basic Procedures Using a randomized, placebo-controlled, double-blind, cross-over trial of 20 patients with type 2 diabetes, we examined the effects of liraglutide as compared to placebo on fasting levels of circulating hormones important to energy homeostasis, including leptin, ghrelin, PYY, and GIP. After 17 days (0.6 mg for 7 days, 1.2 mg for 7 days and 1.8 mg for 3 days) of treatment, we also studied changes in fMRI responses to food cues. Main Findings By design, to avoid any confounding by weight changes, subjects were studied for 17 days, i.e. before body weight changed. Participants on liraglutide had significantly increased GLP-1 levels (p<0.001), decreased percent change in leptin levels (p<0.01) and increased GIP levels (p<0.03) in comparison to placebo treated subjects. Whole brain regressions of functional activity in response to food cues reveal that increased GIP levels were associated with deactivation of the attention- and reward-related insula. Decreases in leptin levels were associated with activations in the reward-related midbrain, precuneus, and dorsolateral prefrontal cortex (DLPFC), and sensorimotor-related motor cortex and with deactivations in the attention-related parietal cortex and the cognitive control-related thalamus and pre-SMA. Principal Conclusions We demonstrate herein short-term changes to circulating levels of GIP and leptin in response to GLP-1 agonist liraglutide therapy. These findings suggest that liraglutide may alter the circulating levels of hormones important in energy homeostasis that, in turn, influence CNS perception of food cues. This could possibly lead to compensatory changes in energy homeostasis that would over time limit the efficacy of liraglutide to decrease body weight. These novel findings, which, pointing to the potential advantages of combination therapies, may have therapeutic implications, will need to be confirmed by larger and longer-term trials. PMID:27282865

Circulating levels of p,p'-DDE are related to prevalent hypertension in the elderly

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lind, P. Monica, E-mail: monica.lind@medsci.uu.se; Penell, Johanna; Salihovic, Samira

Background: Polychlorinated biphenyls (PCBs) and dioxin given to experimental animals increase the blood pressure. We therefore investigated if circulating levels of persistent organic pollutants (POPs) were related to hypertension in a population-based sample of men and women. Methods: One thousand and sixteen subjects aged 70 years were investigated in the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study. Twenty-three POPs were analyzed using high-resolution gas chromatography/high-resolution mass spectrometry (HRGC/HRMS). Hypertension was defined as a systolic blood pressure ≥140 mmHg or a diastolic blood pressure ≥90 mmHg, and/or use of antihypertensive medication. Results: Seven hundred and thirty-two subjects (72%)more » showed hypertension. When the POPs were treated as continuous variables and adjusted for gender only, two PCBs with a low number of chlorine atoms (PCB 105 and 118) were related to prevalent hypertension. Also the OC pesticide p,p'-DDE was related to hypertension. The strongest of these associations was seen for p,p'-DDE (OR 1.35 for a 1 SD change, 95% CI 1.17–1.56, p<0.0001). Following further adjustment also for BMI, smoking status, education level and exercise habits, only p,p'-DDE was still significantly related to hypertension (OR 1.23 for a 1 SD change, 95% CI 1.06–1.43, p=0.006). Conclusion: In this cross-sectional analysis of an elderly population, high levels of circulating levels of p,p'-DDE were associated with prevalent hypertension, further strengthening the experimental findings that POPs might influence blood pressure. - Highlights: • We evaluated the relation between POPs and hypertension. • Cross sectional data from a cohort of elderly men and women were analyzed. • The main exposure was circulating levels of 23 different POPs. • Hypertension was defined as ≥140/90 mmHg and/or antihypertensive treatment. • High levels of p,p'-DDE were associated with prevalent hypertension.« less

High levels of circulating VEGFR2+ Bone marrow-derived progenitor cells correlate with metastatic disease in patients with pediatric solid malignancies.

PubMed

Taylor, Melissa; Rössler, Jochen; Geoerger, Birgit; Laplanche, Agnès; Hartmann, Olivier; Vassal, Gilles; Farace, Françoise

2009-07-15

Pediatric solid malignancies display important angiogenic potential, and blocking tumor angiogenesis represents a new therapeutic approach for these patients. Recent studies have evidenced rare circulating cells with endothelial features contributing to tumor neovascularization and have shown the pivotal role of bone marrow-derived (BMD) progenitor cells in metastatic disease progression. We measured these cells in patients with pediatric solid malignancies as a prerequisite to clinical trials with antiangiogenic therapy. Peripheral blood was drawn from 45 patients with localized (n = 23) or metastatic (n = 22) disease, and 20 healthy subjects. Subsets of circulating vascular endothelial growth factor receptor (VEGFR)2+-BMD progenitor cells, defined as CD45-CD34+VEGFR2(KDR)+7AAD- and CD45(dim)CD34+VEGFR2+7AAD- events, were measured in progenitor-enriched fractions by flow cytometry. Mature circulating endothelial cells (CEC) were measured in whole blood as CD31+CD146+CD45-7AAD- viable events. Data were correlated with VEGF and sVEGFR2 plasma levels. The CD45-CD34+VEGFR2(KDR)+7AAD- subset represented <0.003% of circulating BMD progenitor cells (< or =0.05 cells/mL). However, the median level (range) of the CD45(dim)CD34+VEGFR2+7AAD- subset was higher in patients compared with healthy subjects, 1.5% (0%-10.3%) versus 0.3% (0%-1.6%) of circulating BMD progenitors (P < 0.0001), and differed significantly between patients with localized and metastatic disease, 0.7% (0%-8.6%) versus 2.9% (0.6%-10.3%) of circulating BMD progenitors (P < 0.001). Median CEC value was 7 cells/mL (0-152 cells/mL) and similar in all groups. Unlike VEGFR2+-BMD progenitors, neither CECs, VEGF, or sVEGFR2 plasma levels correlated with disease status. High levels of circulating VEGFR2+-BMD progenitor cells correlated with metastatic disease. Our study provides novel insights for angiogenesis mechanisms in pediatric solid malignancies for which antiangiogenic targeting of VEGFR2+-BMD progenitors could be of interest.

Higher Frequency of Circulating PD-1high CXCR5+CD4+ Tfh Cells in Patients with Chronic Schistosomiasis

PubMed Central

Zhang, Yumei; Jiang, Yanyan; Wang, Yanjuan; Liu, Hua; Shen, Yujuan; Yuan, Zhongying; Hu, Yuan; Xu, Yuxin; Cao, Jianping

2015-01-01

The current knowledge of immunological responses to schistosomiasis is insufficient for the development of vaccine and therapies. The role of T follicular helper (Tfh) cells in schistosome infections is not fully defined. The frequency of circulating Tfh cells and serum cytokine levels were analyzed in 11 patients with chronic schistosomiasis and 10 healthy controls (HC), who reside in an endemic area for Schistosomiasis japonicum. Significantly higher frequencies of circulating CXCR5+ CD4+ Tfh cells and higher expression levels of ICOS and PD-1 in CXCR5+ CD4+ Tfh cells were observed in patients with chronic schistosomiasis compared to HC. The levels of IL-21 in serum and the expression of IL-21 mRNA were higher in chronic schistosomiasis patients than in HC. Moreover, the frequency of circulating PD-1high CXCR5+ CD4+ Tfh cells positively correlated with the levels of IL-21 in serum from patients with chronic schistosomiasis. A positive correlation was also found between the frequency of PD-1high CXCR5+ CD4+ Tfh cells and the levels of soluble egg antigen (SEA)-specific antibodies in serum samples from the patient group. Our study is the first regarding Tfh cells in chronic human schistosomiasis and the finding indicate that PD-1high CXCR5+ CD4+Tfh cells might play an important role in the production of specific antibodies in schistosomiasis. This study contributes to the understanding of immune response to schistosomiasis and may provide helpful support in vaccine development. PMID:26221072

Higher Frequency of Circulating PD-1(high) CXCR5(+)CD4(+) Tfh Cells in Patients with Chronic Schistosomiasis.

PubMed

Zhang, Yumei; Jiang, Yanyan; Wang, Yanjuan; Liu, Hua; Shen, Yujuan; Yuan, Zhongying; Hu, Yuan; Xu, Yuxin; Cao, Jianping

2015-01-01

The current knowledge of immunological responses to schistosomiasis is insufficient for the development of vaccine and therapies. The role of T follicular helper (Tfh) cells in schistosome infections is not fully defined. The frequency of circulating Tfh cells and serum cytokine levels were analyzed in 11 patients with chronic schistosomiasis and 10 healthy controls (HC), who reside in an endemic area for Schistosomiasis japonicum. Significantly higher frequencies of circulating CXCR5(+) CD4(+) Tfh cells and higher expression levels of ICOS and PD-1 in CXCR5(+) CD4(+) Tfh cells were observed in patients with chronic schistosomiasis compared to HC. The levels of IL-21 in serum and the expression of IL-21 mRNA were higher in chronic schistosomiasis patients than in HC. Moreover, the frequency of circulating PD-1(high) CXCR5(+) CD4(+) Tfh cells positively correlated with the levels of IL-21 in serum from patients with chronic schistosomiasis. A positive correlation was also found between the frequency of PD-1(high) CXCR5(+) CD4(+) Tfh cells and the levels of soluble egg antigen (SEA)-specific antibodies in serum samples from the patient group. Our study is the first regarding Tfh cells in chronic human schistosomiasis and the finding indicate that PD-1(high) CXCR5(+) CD4(+)Tfh cells might play an important role in the production of specific antibodies in schistosomiasis. This study contributes to the understanding of immune response to schistosomiasis and may provide helpful support in vaccine development.

An exploratory study of inflammatory cytokines as prognostic biomarkers in patients with ductal pancreatic adenocarcinoma.

PubMed

Dima, Simona O; Tanase, Cristiana; Albulescu, Radu; Herlea, Vlad; Chivu-Economescu, Mihaela; Purnichescu-Purtan, Raluca; Dumitrascu, Traian; Duda, Dan G; Popescu, Irinel

2012-10-01

We measured the serum concentration of a panel of inflammatory cytokines and evaluated their association with circulating proangiogenic biomarkers and with outcome in patients with pancreatic ductal adenocarcinoma (PDAC). We collected serum samples from 36 patients with PDAC, 9 patients with chronic pancreatitis, and 22 healthy volunteers as a control. Inflammatory cytokines and proangiogenic biomarkers were measured using the multianalyte xMAP array and carcinoembryonic antigen (CEA) and carbohydrate 19-9 by immunoassay. Patients with PDAC had higher circulating levels of interleukin 6 (IL-6) than those of patients with pancreatitis or healthy individuals and higher levels of IL-10 and tumor necrosis factor α (TNF-α) compared with those of healthy individuals. In patients with PDAC, circulating IL-6, TNF-α, IL-1β, and IL-10 correlated with serum concentrations of vascular endothelial growth factor and basic fibroblast growth factor; circulating IL-6, IL-1β, and TNF-α correlated with carbohydrate 19-9; and IL-8, IL-10, and TNF-α correlated with CEA levels. Circulating IL-8, TNF-α, and CEA; tumor stage; and lymph node metastases were associated with a poor outcome. The results of this exploratory study indicate that inflammatory cytokines should be pursued as potential prognostic biomarkers as well as targets for therapy in larger studies in PDAC.

Gynaecomastia complicating the treatment of myeloma.

PubMed Central

Large, D. M.; Jones, J. M.; Shalet, S. M.; Scarffe, J. H.; Gibbs, A. C.

1983-01-01

The hormonal mechanisms involved in the development of gynaecomastia accompanying the treatment of multiple myeloma in adult men have been investigated by studying levels of circulating testosterone (T), oestrone (EI), oestradiol (E2), sex-hormone binding globulin (SHBG), prolactin (PRL) and the gonadotrophins LH and FSH, before, during and after development of gynaecomastia in 4 men. These have been compared with 5 closely matched men who did not develop gynaecomastia during similar treatment for myeloma. Levels of circulating T fell, and levels of E1 and E2 rose during treatment periods in all subjects, and the changes were statistically significant in subjects developing gynaecomastia, which resolved as levels of sex steroid returned towards normal following cessation of treatment. We conclude that treatment of adult men for myeloma results in testicular dysfunction with a reduction in circulating T and a rise in circulating oestrogens. These changes are most marked in subjects developing gynaecomastia in whom the normal breast tissue is stimulated by a subtle, transient oestrogen:androgen imbalance in favour of oestrogens. PMID:6409138

Culture and Characterization of Circulating Endothelial Progenitor Cells in Patients with Renal Cell Carcinoma.

PubMed

Gu, Wenyu; Sun, Wei; Guo, Changcheng; Yan, Yang; Liu, Min; Yao, Xudong; Yang, Bin; Zheng, Junhua

2015-07-01

Although emerging evidence demonstrates increased circulating endothelial progenitor cells in patients with solid tumors, to our knowledge it is still unknown whether such cells can be cultured from patients with highly angiogenic renal cell carcinoma. We cultured and characterized circulating endothelial progenitor cells from patients with renal cell carcinoma. The circulating endothelial progenitor cell level (percent of CD45(-)CD34(+) VEGF-R2(+) cells in total peripheral blood mononuclear cells) was quantified in 47 patients with renal cell carcinoma and 40 healthy controls. Peripheral blood mononuclear cells were then isolated from 33 patients with renal cell carcinoma and 30 healthy controls to culture and characterize circulating endothelial progenitor cells. The circulating endothelial progenitor cell level was significantly higher in patients with renal cell carcinoma than in healthy controls (0.276% vs 0.086%, p <0.001). A colony of circulating endothelial progenitor cells first emerged significantly earlier in patient than in control preparations (6.72 vs 14.67 days, p <0.001). The culture success rate (87.8% vs 40.0% of participants) and the number of colonies (10.06 vs 1.83) were significantly greater for patients than for controls (each p <0.001). The circulating endothelial progenitor cell level correlated positively with the number of patient colonies (r = 0.762, p <0.001). Cells cultured from patients and controls showed a similar growth pattern, immunophenotype, ability to uptake Ac-LDL and bind lectin, and form capillary tubes in vitro. However, significantly more VEGF-R2(+) circulating endothelial progenitor cells were found in preparations from patients with renal cell carcinoma than from healthy controls (21.1% vs 13.4%, p <0.001). Earlier emergence of circulating endothelial progenitor cell colonies, a higher cell culture success rate and more colonies were found for patients with renal cell carcinoma than for healthy controls. Results indicate the important significance of VEGF-R2(+) circulating endothelial progenitors in patients with renal cell carcinoma. Copyright © 2015 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.

Sex steroid-induced changes in circulating monocyte chemoattractant protein-1 levels may contribute to metabolic dysfunction in obese men.

PubMed

Ruige, Johannes B; Bekaert, Marlies; Lapauw, Bruno; Fiers, Tom; Lehr, Stefan; Hartwig, Sonja; Herzfeld de Wiza, Daniella; Schiller, Martina; Passlack, Waltraud; Van Nieuwenhove, Yves; Pattyn, Piet; Cuvelier, Claude; Taes, Youri E; Sell, Henrike; Eckel, Juergen; Kaufman, Jean-Marc; Ouwens, D Margriet

2012-07-01

Low testosterone accompanied by elevated estradiol associates with the development of metabolic dysfunction in men. The aim of the study was to explore the hypothesis that alterations in sex steroid levels induce metabolic dysfunction through adipokines. Circulating levels of sex steroids and 28 adipokines were determined in a cross-sectional study of morbidly obese men and aged-matched controls, as well as in a randomized clinical trial with healthy young men in which obesity-related alterations in sex steroid levels were mimicked by treatment with an aromatase inhibitor plus estradiol patches. Morbidly obese men had lower testosterone levels than normal-weight controls. Estradiol levels were increased in morbidly obese men (without DM2) as compared to normal-weight controls. Circulating levels of multiple proinflammatory cytokines, including IL-1Ra, IL-5, IL-6, IL-10, leptin, monocyte chemoattractant protein 1 (MCP1), and macrophage inflammatory protein 1α, positively associated with estradiol and negatively with testosterone. The associations with estradiol, but not with testosterone, remained significant after adjusting for adipocyte cell size. In a separate clinical trial, the direct adverse effects of lowering testosterone and raising estradiol on MCP1 were substantiated in vivo. Initial alterations in sex steroid levels may contribute to metabolic dysfunction through adverse effects on adipokine levels in obese men. The direct adverse effects on MCP1, a chemokine highly linked to the development of metabolic dysfunction, were substantiated in a trial mimicking obesity-related alterations of sex steroid levels in healthy young males.

Circulating IGF-I and IGFBP3 levels control human colonic stem cell function and are disrupted in diabetic enteropathy

PubMed Central

Maestroni, Anna; Jung, Peter; Orsenigo, Elena; Nasr, Moufida Ben; Tezza, Sara; Bassi, Roberto; Finzi, Giovanna; Marando, Alessandro; Vergani, Andrea; Frego, Roberto; Albarello, Luca; Andolfo, Annapaola; Manuguerra, Roberta; Viale, Edi; Staudacher, Carlo; Corradi, Domenico; Batlle, Eduard; Breault, David; Secchi, Antonio; Folli, Franco; Fiorina, Paolo

2016-01-01

Summary The role of circulating factors in regulating colonic stem cells (CoSCs) and colonic epithelial homeostasis is unclear. Individuals with long-standing type 1 diabetes (T1D) frequently have intestinal symptoms, termed diabetic enteropathy (DE), though its etiology is unknown. Here, we report T1D patients with DE exhibit abnormalities in their intestinal mucosa and CoSCs, which fail to generate in vitro mini-guts. Proteomic profiling of T1D+DE patient serum revealed altered levels of insulin-like growth factor 1 (IGF-1) and its binding protein-3 (IGFBP3). IGFBP3 prevented in vitro growth of patient-derived organoids via binding its receptor TMEM219, in an IGF-1-independent manner, and disrupted in vivo CoSC function in a preclinical DE model. Restoration of normoglycemia in patients with long-standing T1D via kidney-pancreas transplantation or in diabetic mice by treatment with an ecto-TMEM219 recombinant protein normalized circulating IGF-1/IGFBP3 levels and reestablished CoSC homeostasis. These findings demonstrate that peripheral IGF-1/IGFBP3 control CoSCs and their dysfunction in DE. PMID:26431183

Genome-Wide Association Analysis of Blood Biomarkers in Chronic Obstructive Pulmonary Disease

PubMed Central

Kim, Deog Kyeom; Cho, Michael H.; Hersh, Craig P.; Lomas, David A.; Miller, Bruce E.; Kong, Xiangyang; Bakke, Per; Gulsvik, Amund; Agustí, Alvar; Wouters, Emiel; Celli, Bartolome; Coxson, Harvey; Vestbo, Jørgen; MacNee, William; Yates, Julie C.; Rennard, Stephen; Litonjua, Augusto; Qiu, Weiliang; Beaty, Terri H.; Crapo, James D.; Riley, John H.; Tal-Singer, Ruth

2012-01-01

Rationale: A genome-wide association study (GWAS) for circulating chronic obstructive pulmonary disease (COPD) biomarkers could identify genetic determinants of biomarker levels and COPD susceptibility. Objectives: To identify genetic variants of circulating protein biomarkers and novel genetic determinants of COPD. Methods: GWAS was performed for two pneumoproteins, Clara cell secretory protein (CC16) and surfactant protein D (SP-D), and five systemic inflammatory markers (C-reactive protein, fibrinogen, IL-6, IL-8, and tumor necrosis factor-α) in 1,951 subjects with COPD. For genome-wide significant single nucleotide polymorphisms (SNPs) (P < 1 × 10−8), association with COPD susceptibility was tested in 2,939 cases with COPD and 1,380 smoking control subjects. The association of candidate SNPs with mRNA expression in induced sputum was also elucidated. Measurements and Main Results: Genome-wide significant susceptibility loci affecting biomarker levels were found only for the two pneumoproteins. Two discrete loci affecting CC16, one region near the CC16 coding gene (SCGB1A1) on chromosome 11 and another locus approximately 25 Mb away from SCGB1A1, were identified, whereas multiple SNPs on chromosomes 6 and 16, in addition to SNPs near SFTPD, had genome-wide significant associations with SP-D levels. Several SNPs affecting circulating CC16 levels were significantly associated with sputum mRNA expression of SCGB1A1 (P = 0.009–0.03). Several SNPs highly associated with CC16 or SP-D levels were nominally associated with COPD in a collaborative GWAS (P = 0.001–0.049), although these COPD associations were not replicated in two additional cohorts. Conclusions: Distant genetic loci and biomarker-coding genes affect circulating levels of COPD-related pneumoproteins. A subset of these protein quantitative trait loci may influence their gene expression in the lung and/or COPD susceptibility. Clinical trial registered with www.clinicaltrials.gov (NCT 00292552). PMID:23144326

Fibrocyte measurement in peripheral blood correlates with number of cultured mature fibrocytes in vitro and is a potential biomarker for interstitial lung disease in Rheumatoid Arthritis.

PubMed

Just, Søren Andreas; Lindegaard, Hanne; Hejbøl, Eva Kildall; Davidsen, Jesper Rømhild; Bjerring, Niels; Hansen, Søren Werner Karlskov; Schrøder, Henrik Daa; Hansen, Inger Marie Jensen; Barington, Torben; Nielsen, Christian

2017-07-18

Interstitial lung disease (ILD) can be a severe extra-articular disease manifestation in Rheumatoid Arthritis (RA). A potential role of fibrocytes in RA associated ILD (RA-ILD) has not previously been described. We present a modified faster method for measuring circulating fibrocytes, without intracellular staining. The results are compared to the traditional culture method, where the number of monocytes that differentiate into mature fibrocytes in vitro are counted. The results are following compared to disease activity in patients with severe asthma, ILD, RA (without diagnosed ILD) and RA with verified ILD (RA-ILD). CD45 + CD34 + CD11b + (7-AAD - CD3 - CD19 - CD294 - ) cells were isolated by cell sorting and stained for pro-collagen type 1. Thirty-nine patients (10 RA, 9 ILD and 10 with severe asthma, 10 with RA-ILD) and 10 healthy controls (HC) were included. Current medication, disease activity, pulmonary function test and radiographic data were collected. Circulating fibrocytes were quantified by flow cytometry. Peripheral blood mononuclear cells were isolated and cultured for 5 days and the numbers of mature fibrocytes were counted. 90.2% (mean, SD = 1.5%) of the sorted cells were pro-collagen type 1 positive and thereby fulfilled the criteria for being circulating fibrocytes. The ILD and RA-ILD groups had increased levels of circulating fibrocytes compared to HC (p < 0.05). Levels of circulating fibrocytes correlated overall to number of monocytes that subsequently in vitro differentiated to mature fibrocytes (r = 0.81, p < 0.001). RA patients with pathologically reduced diffusion capacity for carbon monoxide adjusted for hemoglobin (DLCO c ) in both the RA and in the combined RA + RA-ILD group, had significantly higher levels of both circulating and number of cultured mature fibrocytes (both p < 0.05). In both groups, the level of circulating fibrocytes and number of mature fibrocytes in culture also correlated to a reduction in DLCO c (r = -0.61 an r = -0.58 both p < 0.05). We presented a fast and valid method for measuring circulating fibrocytes using flow cytometry on lysed peripheral blood. Further, we showed for the first time, that the level of circulating fibrocytes correlated with the number of peripheral blood mononuclear cells, that differentiated into mature fibrocytes in vitro. Reduced DLCO c was correlated with high levels of circulating and mature fibrocytes in RA, which have not been reported previously. In such, this study suggests that fibrocytes may exhibit an important role in the pathogenesis of RA-ILD, which requires further clarification in future studies. ClinicalTrials.gov : NCT02711657 , registered 13/3-2016, retrospectively registered.

Insulin-like growth factor-1 and growth hormone (GH) levels in canine cerebrospinal fluid are unaffected by GH or GH secretagogue (MK-0677) administration.

PubMed

Prahalada, S; Block, G; Handt, L; DeBurlet, G; Cahill, M; Hoe, C M; van Zwieten, M J

1999-01-01

Elevation in circulating GH levels results in a dose-related increase in serum insulin-like growth factor-1 (IGF-1) levels in dogs. However, it is not known whether elevations in systemic IGF-1 and GH levels contribute to the cerebrospinal fluid (CSF) levels of these hormones. Therefore, a study was designed in dogs to determine if elevated circulating GH levels was a result of a GH secretagogue (MK-0677) or if exogenous GH administration resulted in increased IGF-1 and GH levels in the CSF of dogs. A total of 12 normal, young adult male dogs were randomized to three treatment groups (4 dogs/group) based on body weight. There were 4 vehicle control dogs. A group of 4 dogs were dosed orally with MK-0677 (5 mg/kg/day) dissolved in deionized water. A third group of 4 dogs received subcutaneous injections of porcine GH (pGH) at a dose of 0.1 IU/kg/day. From all dogs, blood and CSF samples were collected prior to the initiation of treatment and on days 7 and 15 of treatment. All samples were assayed using a validated radioimmunoassay. Administration of MK-0677 or pGH resulted in a statistically significant (P < or = 0.05) increased body weight gain and increased serum IGF-1 and GH levels. In contrast, administration of MK-0677 resulted in no significant (P > 0.05) increase in CSF IGF-1 or GH levels on days 7 or 15 of the study. The CSF IGF-1 values ranged from 1.2 to 2.0 ng/ml with minimal variation among three separate samples taken during the course of the study from each dog. Similarly, the CSF GH levels were very low (< 0.98 ng/ml to 2.4 ng/ml) in all dogs irrespective of treatment group. This study has demonstrated that there is no correlation between the circulating levels of IGF-1 or GH and the levels of these hormones in the CSF of normal dogs. An approximately 100-fold difference between serum and CSF IGF-1 levels in vehicle control dogs suggest that there is a blood-brain barrier for the circulating IGF-1. Similarly, failure to see an elevation in CSF GH levels despite increases in serum GH levels shows that there is a blood-brain barrier for GH in normal dogs. These results suggest that the likely source of GH and IGF-1 in the CSF of dogs is from the CNS.

Importance of 5α-reductase gene polymorphisms on circulating and intraprostatic androgens in prostate cancer.

PubMed

Lévesque, Éric; Laverdière, Isabelle; Lacombe, Louis; Caron, Patrick; Rouleau, Mélanie; Turcotte, Véronique; Têtu, Bernard; Fradet, Yves; Guillemette, Chantal

2014-02-01

Polymorphisms in the genes SRD5A1 and SRD5A2 encoding androgen biosynthetic 5α-reductase enzymes have been associated with an altered risk of biochemical recurrence after radical prostatectomy in localized prostate cancer. To gain potential insights into SRD5A biologic effects, we examined the relationship between SRD5A prognostic markers and endogenous sex-steroid levels measured by mass spectrometry in plasma samples and corresponding prostatic tissues of patients with prostate cancer. We report that five of the seven SRD5A markers differentially affect sex-steroid profiles of dihydrotestosterone and its metabolites in both the circulation and prostatic tissues of patients with prostate cancer. Remarkably, a 32% increase in intraprostatic testosterone levels was observed in the presence of the high-risk SRD5A rs2208532 polymorphism. Moreover, SRD5A2 markers were associated predominantly with circulating levels of inactive glucuronides. Indeed, the rs12470143 SRD5A2 protective allele was associated with high circulating androstane-3α, 17β-diol-17-glucuronide (3α-diol-17G) levels as opposed to lower levels of both 3α-diol-17G and androsterone-glucuronide observed with the rs2208532 SRD5A2 risk allele. Moreover, SRD5A2 rs676033 and rs523349 (V89L) risk variants, in strong linkage disequilibrium, were associated with higher circulating levels of 3α-diol-3G. The SRD5A2 rs676033 variant further correlated with enhanced intraprostatic exposure to 5α-reduced steroids (dihydrotestosterone and its metabolite 3β-diol). Similarly, the SRD5A1 rs166050C risk variant was associated with greater prostatic exposure to androsterone, whereas no association was noted with circulating steroids. Our data support the association of 5α-reductase germline polymorphisms with the hormonal milieu in patients with prostate cancer. Further studies are needed to evaluate if these variants influence 5α-reductase inhibitor efficacy. ©2013 AACR.

Circulating micrornas as potential biomarkers of muscle atrophy

NASA Astrophysics Data System (ADS)

Wang, Fei

2016-07-01

Noninvasive biomarkers with diagnostic value and prognostic applications have long been desired to replace muscle biopsy for muscle atrophy patients. Growing evidence indicates that circulating microRNAs are biomarkers to assess pathophysiological status. Here, we show that the medium levels of six muscle-specific miRNAs (miR-1/23a/206/133/499/208b, also known as myomiRs) were all elevated in the medium of starved C2C12 cell (P < 0.01). And, the level of miR-1 and miR-23a were all elevated in the serum of hindlimb unloaded mice (P < 0.01). miR-23a levels were negatively correlated with both muscle mass and muscle fiber cross section area in muscle atrophy patients, indicating that they might represent the degree of muscle atrophy. Collectively, our data indicated that circulating myomiRs could serve as promising biomarkers for muscle atrophy.

CCL11 (Eotaxin-1) Levels Predict Long-Term Functional Outcomes in Patients Following Ischemic Stroke.

PubMed

Roy-O'Reilly, Meaghan; Ritzel, Rodney M; Conway, Sarah E; Staff, Ilene; Fortunato, Gilbert; McCullough, Louise D

2017-12-01

Circulating levels of the pro-inflammatory cytokine C-C motif chemokine 11 (CCL11, also known as eotaxin-1) are increased in several animal models of neuroinflammation, including traumatic brain injury and Alzheimer's disease. Increased levels of CCL11 have also been linked to decreased neurogenesis in mice. We hypothesized that circulating CCL11 levels would increase following ischemic stroke in mice and humans, and that higher CCL11 levels would correlate with poor long-term recovery in patients. As predicted, circulating levels of CCL11 in both young and aged mice increased significantly 24 h after experimental stroke. However, ischemic stroke patients showed decreased CCL11 levels compared to controls 24 h after stroke. Interestingly, lower post-stroke CCL11 levels were predictive of increased stroke severity and independently predictive of poorer functional outcomes in patients 12 months after ischemic stroke. These results illustrate important differences in the peripheral inflammatory response to ischemic stroke between mice and human patients. In addition, it suggests CCL11 as a candidate biomarker for the prediction of acute and long-term functional outcomes in ischemic stroke patients.

Circulating retinol binding protein 4 levels in nonalcoholic fatty liver disease: a systematic review and meta-analysis.

PubMed

Zhou, Zhongwei; Chen, Hongmei; Ju, Huixiang; Sun, Mingzhong

2017-09-20

Retinol binding protein 4 (RBP4) is implicated in obesity, insulin resistance and type 2 diabetes mellitus that are closely associated with nonalcoholic fatty liver disease (NAFLD). However, recent investigations regarding circulating RBP4 levels in NAFLD are conflicting. This meta-analysis is to determine whether NAFLD, non-alcoholic steatohepatitis (NASH) and simple steatosis (SS) patients have altered RBP4 levels. We performed a systematic search in PubMed, EMBASE and The Cochrane Library up until 18 March 2017, and 12 studies comprising a total of 4247 participants (2271 NAFLD patients and 1976 controls) were included in the meta-analysis. There were no significant differences of circulating RBP4 levels in the following comparisons: (1) NAFLD patients vs controls (standardized mean differences [SMD]: 0.08; 95% CI: -0.21, 0.38); (2) NASH patients vs controls (SMD: -0.49; 95% CI: -1.09, 0.12); (3) SS patients vs controls (SMD: -0.72; 95% CI: -1.64, 0.20) and (4) NASH vs SS patients (SMD: -0.04; 95% CI: -0.32, 0.24). The results remained essentially unchanged in the comparisons between NAFLD patients and controls after excluding single individual study or bariatric studies (n = 2). No significant publication bias was detected. However, there was significant heterogeneity among studies and the subgroup and meta-regression analyses did not find the potential sources. Circulating RBP4 levels may not be associated with NAFLD. Further prospective cohort studies are required to confirm these findings.

Differential adipokine receptor expression on circulating leukocyte subsets in lean and obese children.

PubMed

Keustermans, Genoveva; van der Heijden, Laila B; Boer, Berlinda; Scholman, Rianne; Nuboer, Roos; Pasterkamp, Gerard; Prakken, Berent; de Jager, Wilco; Kalkhoven, Eric; Janse, Arieke J; Schipper, Henk S

2017-01-01

Childhood obesity prevalence has increased worldwide and is an important risk factor for type 2 diabetes (T2D) and cardiovascular disease (CVD). The production of inflammatory adipokines by obese adipose tissue contributes to the development of T2D and CVD. While levels of circulating adipokines such as adiponectin and leptin have been established in obese children and adults, the expression of adiponectin and leptin receptors on circulating immune cells can modulate adipokine signalling, but has not been studied so far. Here, we aim to establish the expression of adiponectin and leptin receptors on circulating immune cells in obese children pre and post-lifestyle intervention compared to normal weight control children. 13 obese children before and after a 1-year lifestyle intervention were compared with an age and sex-matched normal weight control group of 15 children. Next to routine clinical and biochemical parameters, circulating adipokines were measured, and flow cytometric analysis of adiponectin receptor 1 and 2 (AdipoR1, AdipoR2) and leptin receptor expression on peripheral blood mononuclear cell subsets was performed. Obese children exhibited typical clinical and biochemical characteristics compared to controls, including a higher BMI-SD, blood pressure and circulating leptin levels, combined with a lower insulin sensitivity index (QUICKI). The 1-year lifestyle intervention resulted in stabilization of their BMI-SD. Overall, circulating leukocyte subsets showed distinct adipokine receptor expression profiles. While monocytes expressed high levels of all adipokine receptors, NK and iNKT cells predominantly expressed AdipoR2, and B-lymphocytes and CD4+ and CD8+ T-lymphocyte subsets expressed AdipoR2 as well as leptin receptor. Strikingly though, leukocyte subset numbers and adipokine receptor expression profiles were largely similar in obese children and controls. Obese children showed higher naïve B-cell numbers, and pre-intervention also higher numbers of immature transition B-cells and intermediate CD14++CD16+ monocytes combined with lower total monocyte numbers, compared to controls. Furthermore, adiponectin receptor 1 expression on nonclassical CD14+CD16++ monocytes was consistently upregulated in obese children pre-intervention, compared to controls. However, none of the differences in leukocyte subset numbers and adipokine receptor expression profiles between obese children and controls remained significant after multiple testing correction. First, the distinct adipokine receptor profiles of circulating leukocyte subsets may partly explain the differential impact of adipokines on leukocyte subsets. Second, the similarities in adipokine receptor expression profiles between obese children and normal weight controls suggest that adipokine signaling in childhood obesity is primarily modulated by circulating adipokine levels, instead of adipokine receptor expression.

Circulating Estrogen Levels and Self-Reported Health and Mobility Limitation in Community-Dwelling Men of the Framingham Heart Study.

PubMed

Jasuja, Guneet Kaur; Travison, Thomas G; Murabito, Joanne M; Davda, Maithili N; Rose, Adam J; Basaria, Shehzad; Coviello, Andrea; Vasan, Ramachandran S; D'Agostino, Ralph; Bhasin, Shalender

2017-08-01

Self-rated health is a commonly used global indicator of health status. Few studies have examined the association of self-rated health and mobility with estrone and estradiol in men. Accordingly, we determined the cross-sectional, incident, and mediating relations between circulating estrone and estradiol levels with self-rated health, mobility limitation, and physical performance in community-dwelling men. The cross-sectional sample included 1,148 men, who attended Framingham Offspring Study Examinations 7 and 8. Estrone and estradiol levels were measured using liquid chromatography tandem mass spectrometry at Examination 7. Self-reported mobility limitation and self-rated health were assessed at Examinations 7 and 8. Additionally, short physical performance battery, usual walking speed, and grip strength were assessed at Examination 7. In incident analysis, estradiol levels at Examination 7 were associated with increased odds of fair or poor self-rated health at Examination 8, after adjusting for age, body mass index, comorbidities, and testosterone levels; in an individual with 50% greater estradiol than other, the odds of reporting "fair or poor" self-rated health increased by 1.78 (95% confidence interval: 1.25-2.55; p = .001). Neither estrone nor estradiol levels were associated with any physical performance measure at baseline. Higher circulating levels of estradiol are associated with increased risk of incident fair/poor self-rated health in community-dwelling men. The mechanisms by which circulating levels of estradiol are related to self-rated health in men need further investigation. Published by Oxford University Press on behalf of The Gerontological Society of America 2016. This work is written by (a) US Government employee(s) and is in the public domain in the US.

Circulating CTRP9 levels are increased in patients with newly diagnosed type 2 diabetes and correlated with insulin resistance.

PubMed

Jia, Yanjun; Luo, Xiaohe; Ji, Ying; Xie, Jingwen; Jiang, Han; Fu, Mao; Li, Xiaoqiang

2017-09-01

C1q/TNF-related protein-9 (CTRP9) is a novel adipokine that has been shown to promote lipid metabolism, enhance insulin sensitivity and protect against cardiovascular disease. However, previous studies in humans have produced controversial results regarding the association between CTRP9 and insulin resistance. The objective of this study was to evaluate the relationships between CTRP9 and insulin resistance in Chinese population. Subjects with normal glucose tolerance (NGT, n=108), impaired glucose tolerance (IGT, n=92), and newly diagnosed type 2 diabetes mellitus (nT2DM, n=106) were recruited to determining the circulating CTRP9 and adiponectin levels by enzyme linked immunosorbent assay. Anthropometric and biochemical measurements related to insulin resistance, adiposity and lipid profile were examined for all participants. Oral glucose tolerance test was performed in healthy subjects (17 male and 17 female). Circulating CTRP9 level was significantly higher in both IGT and nT2DM than in individuals with NGT. Overweight/obese subjects had much higher CTRP9 levels than lean individuals, and in all subjects, females also had higher CTRP9 levels than males. In addition, circulating CTRP9 level was positively correlated with markers of obesity and insulin resistance, including body mass index, fasting blood glucose, insulin, HbA1c, homeostasis model assessment of insulin resistance and low-density lipoprotein-cholesterol, while was inversely correlated with high-density lipoprotein-cholesterol and adiponectin. Moreover, hyperglycemia during an oral glucose challenge increased circulating CTRP9 concentrations. We conclude that CTRP9 was strongly associated with insulin resistance, suggesting that CTRP9 might be important in the development of type 2 diabetes. Copyright © 2017 Elsevier B.V. All rights reserved.

B Cell Depletion Therapy Normalizes Circulating Follicular Th Cells in Primary Sjögren Syndrome.

PubMed

Verstappen, Gwenny M; Kroese, Frans G M; Meiners, Petra M; Corneth, Odilia B; Huitema, Minke G; Haacke, Erlin A; van der Vegt, Bert; Arends, Suzanne; Vissink, Arjan; Bootsma, Hendrika; Abdulahad, Wayel H

2017-01-01

To assess the effect of B cell depletion therapy on effector CD4+ T cell homeostasis and its relation to objective measures of disease activity in patients with primary Sjögren syndrome (pSS). Twenty-four patients with pSS treated with rituximab (RTX) and 24 healthy controls (HC) were included. Frequencies of circulating effector CD4+ T cell subsets were examined by flow cytometry at baseline and 16, 24, 36, and 48 weeks after the first RTX infusion. Th1, Th2, follicular Th (TFH), and Th17 cells were discerned based on surface marker expression patterns. Additionally, intracellular cytokine staining was performed for interferon-γ, interleukin (IL)-4, IL-21, and IL-17 and serum levels of these cytokines were analyzed. In patients with pSS, frequencies of circulating TFH cells and Th17 cells were increased at baseline compared with HC, whereas frequencies of Th1 and Th2 cells were unchanged. B cell depletion therapy resulted in a pronounced decrease in circulating TFH cells, whereas Th17 cells were only slightly lowered. Frequencies of IL-21-producing and IL-17-producing CD4+ T cells and serum levels of IL-21 and IL-17 were also reduced. Importantly, the decrease in circulating TFH cells was associated with lower systemic disease activity over time, as measured by the European League Against Rheumatism Sjögren's Syndrome Disease Activity Index scores and serum IgG levels. B cell depletion therapy in patients with pSS results in normalization of the elevated levels of circulating TFH cells. This reduction is associated with improved objective clinical disease activity measures. Our observations illustrate the pivotal role of the crosstalk between B cells and TFH cells in the pathogenesis of pSS.

Angiopoietin-like protein 8/betatrophin as a new determinant of type 2 diabetes remission after bariatric surgery.

PubMed

Ejarque, Miriam; Borlaug, Marianne; Vilarrasa, Nuria; Martinez-Perez, Bruno; Llauradó, Gemma; Megía, Ana; Helland, Thomas; Gutierrez, Cristina; Serena, Carolina; Folkestad, Oddry; Nuñez-Roa, Catalina; Roche, Kelly; Casajoana, Ana; Fradera, Rosa; González-Clemente, José Miguel; López, Miguel; Mohn, Arne C; Nedrebø, Bjørn G; Nogueiras, Ruben; Mellgren, Gunnar; Fernø, Johan; Fernández-Veledo, Sonia; Vendrell, Joan

2017-06-01

This work aimed to explore the link between angiopoietin-like protein 8 (ANGPTL8) and weight loss after metabolic surgery. In the cross-sectional study (n = 100), circulating ANGPTL8 concentrations were significantly lower in morbidly obese than in lean subjects, and strikingly lower in morbidly obese patients with type 2 diabetes mellitus (T2DM). Conversely, ANGPTL8 expression in subcutaneous adipose tissue (SAT) was higher in morbidly obese patients, particularly in those with T2DM, whereas its expression in visceral adipose tissue was unchanged. The main predictors for circulating levels of ANGPTL8 were BMI and T2DM, whereas ANGPTL8 expression in SAT was determined by the presence of T2DM. The prospective cohort studies before and 1 year after bariatric surgery in morbidly obese patients with (n = 45) and without (n = 30) T2DM, revealed a significant increase of circulating ANGPTL8 levels 1 year after the bariatric surgery. Intriguingly, this increment, which was predicted by basal ANGPTL8 concentrations, appeared as a determinant of T2DM remission. In conclusion, circulating ANGPTL8 levels have an inverse relationship with SAT expression. Low basal levels of ANGPTL8 rebound after bariatric surgery. The increment in ANGPTL8 concentrations at 1 month of follow-up after weight loss emerged as a significant predictor of the T2DM remission at 1 year of follow-up. Copyright © 2017 Elsevier Inc. All rights reserved.

Type 2 diabetes mellitus coincident with pulmonary tuberculosis is associated with heightened systemic type 1, type 17, and other proinflammatory cytokines.

PubMed

Kumar, Nathella Pavan; Sridhar, Rathinam; Banurekha, Vaithilingam V; Jawahar, Mohideen S; Fay, Michael P; Nutman, Thomas B; Babu, Subash

2013-10-01

Type 2 diabetes mellitus is a major risk factor for the development of active tuberculosis, although the biological basis underlying this susceptibility remains poorly characterized. To identify the influence of coincident diabetes mellitus on cytokine levels in pulmonary tuberculosis, we examined circulating levels of a panel of cytokines and chemokines in the plasma of individuals with tuberculosis with diabetes and compared them with those of individuals without diabetes. Tuberculosis with diabetes is characterized by elevated circulating levels of type 1 (IFN-γ, tumor necrosis factor-α, and IL-2), type 2 (IL-5), and type 17 (IL-17A) cytokines but decreased circulating levels of IL-22. This was associated with increased systemic levels of other proinflammatory cytokines (IL-1β, IL-6, and IL-18) and an antiinflammatory cytokine (IL-10) but not type 1 IFNs. Moreover, tuberculosis antigen-stimulated whole blood also showed increased levels of proinflammatory cytokines. Finally, type 1 and type 17 cytokines in plasma exhibit a significant positive correlation with hemoglobin A1C levels, indicating that impaired control of diabetes is associated with this proinflammatory milieu. Multivariate analysis revealed that the association of proinflammatory cytokines with diabetes mellitus was not influenced by age, sex, or other metabolic parameters. Our data reveal that tuberculosis with diabetes is characterized by heightened cytokine responsiveness, indicating that chronic inflammation underlying type 2 diabetes potentially contributes to increased immune pathology and poor control in tuberculosis infection.

Could circulating fetuin A be a biomarker of aortic valve stenosis?

PubMed

Di Minno, Alessandro; Zanobini, Marco; Myasoedova, Veronika A; Valerio, Vincenza; Songia, Paola; Saccocci, Matteo; Di Minno, Matteo Nicola Dario; Tremoli, Elena; Poggio, Paolo

2017-12-15

Aortic valve stenosis (AVS) is a multifactorial-progressive pathological process. In the past decades, many studies have focus their attention on circulating biomarkers able to identify AVS and/or to predict its progression. One of the many biomarkers studied is the fetuin A. The aim of the present meta-analysis was to evaluate the correlation between fetuin A levels and end-stage AVS. A systematic search was performed in three electronic databases (PubMed, Web of Science and Scopus), looking for studies that compared control subjects with AVS patients and that have measured fetuin A circulating levels in both groups. The main outcome was to evaluate the difference in circulating fetuin A concentration in the two groups. Seven studies, enrolling 2283 AVS patients and 1549 controls, were included. Differences between control subjects and AVS patients were expressed as standardized mean difference (SMD) with pertinent 95% confidence intervals (95%CI) and standard deviation (SD), analysing the data using a random effect model. We found significantly lower circulating levels of fetuin A in AVS patients compared to healthy subjects (SMD: -0.96μg/mL, 95% CI: -1.62, -0.30; p=0.004). In addition, meta-regression analyses showed that several cardiovascular risk factors were significantly associated with circulating levels of fetuin A between patients affected by AVS and healthy controls. In conclusion, our meta-analysis shows that AVS patients have significant lower circulating levels of fetuin A compared to control subjects. However, dedicated studies with large and matched cohorts are needed to validate these findings, evaluating if there is a real link or just a mere association. Copyright © 2017 Elsevier B.V. All rights reserved.

Obesity suppresses circulating level and function of endothelial progenitor cells and heart function

PubMed Central

2012-01-01

Background and aim This study tested the hypothesis that obesity suppresses circulating number as well as the function of endothelial progenitor cells (EPCs) and left ventricular ejection fraction (LVEF). Methods High fat diet (45 Kcal% fat) was given to 8-week-old C57BL/6 J mice (n = 8) for 20 weeks to induce obesity (group 1). Another age-matched group (n = 8) were fed with control diet for 20 weeks as controls (group 2). The animals were sacrificed at the end of 20 weeks after obesity induction. Results By the end of study period, the heart weight, body weight, abdominal fat weight, serum levels of total cholesterol and fasting blood sugar were remarkably higher in group 1 than in group 2 (all p<0.01). The circulating level of EPCs (C-kit/CD31, Sca-1/KDR, CXCR4/CD34) was significantly lower in group 1 than in group 2 (p<0.03) at 18 h after critical limb ischemia induction. The angiogenesis and migratory ability of bone marrow-derived EPCs was remarkably impaired in group 1 compared to that in group 2 (all p<0.01). The repair ability of aortic endothelium damage by lipopolysaccharide was notably attenuated in group 1 compared with that in group 2 (p<0.01). Collagen deposition (Sirius red staining) and fibrotic area (Masson's Trichrome staining) in LV myocardium were notably increased in group 1 compared with group 2 (p<0.001). LVEF was notably lower, whereas LV end-diastolic and end-systolic dimensions were remarkably higher in group 1 than in group 2 (all p<0.001). Conclusions Obesity diminished circulating EPC level, impaired the recovery of damaged endothelium, suppressed EPC angiogenesis ability and LVEF, and increased LV remodeling. PMID:22747715

Circulating levels of hydrogen sulfide and substance P in patients with sepsis.

PubMed

Gaddam, Ravinder Reddy; Chambers, Stephen; Murdoch, David; Shaw, Geoffrey; Bhatia, Madhav

2017-10-01

To determine alterations of circulating levels of hydrogen sulfide and substance P in patients with sepsis compared to non-sepsis patients with similar disease severity and organ dysfunction. This study included 23 septic and 14 non-septic patients during 2015-16 study period at the Christchurch Hospital Intensive Care Unit, Christchurch, New Zealand. Blood samples were collected from the time of admission to 96 h, with collection at different time points (0 h, 12 h, 24 h, 48 h, 72 h and 96 h) and subjected to measurement of hydrogen sulfide, substance P, procalcitonin, C-reactive protein, interleukin-6 and lactate levels. Patients with sepsis showed higher circulating hydrogen sulfide and substance P levels compared to patients without sepsis. Hydrogen sulfide levels were significantly higher at 12 h (1.45 vs 0.75 μM; p < 0.05) and 24 h (1.11 vs 0.72 μM; p < 0.01), whereas substance P levels were higher at 48 h (0.55 vs 0.31 ng/mL; p < 0.05). Increased hydrogen sulfide and substance P levels in septic patients were associated with increased levels of inflammatory mediators - procalcitonin, C-reactive protein and interleukin-6. These results provide evidence that higher circulating levels of hydrogen sulfide and substance P are associated with increased inflammatory response in patients with sepsis. Copyright © 2017 The British Infection Association. Published by Elsevier Ltd. All rights reserved.

Impaired Cerebellar Maturation, Growth Restriction, and Circulating Insulin-Like Growth Factor 1 in Preterm Rabbit Pups

PubMed Central

Sveinsdóttir, Kristbjörg; Länsberg, John-Kalle; Sveinsdóttir, Snjólaug; Garwicz, Martin; Ohlsson, Lennart; Hellström, Ann; Smith, Lois; Gram, Magnus; Ley, David

2018-01-01

Cerebellar growth is impeded following very preterm birth in human infants and the observed reduction in cerebellar volume is associated with neurodevelopmental impairment. Decreased levels of circulating insulin-like growth factor 1 (IGF-1) are associated with decreased cerebellar volume. The relationship between preterm birth, circulating IGF-1, and key cell populations supporting cerebellar proliferation is unknown. The aim of this study was to evaluate the effect of preterm birth on postnatal growth, circulating IGF-1, and cerebellar maturation in a preterm rabbit pup model. Preterm rabbit pups (PT) were delivered by cesarean section at day 29 of gestation, cared for in closed incubators with humidified air, and gavage fed with formula. Control term pups (T) delivered by spontaneous vaginal delivery at day 32 of gestation were housed and fed by their lactating doe. In vivo perfusion-fixation for immunohistochemical evaluation of cerebellar proliferation, cell maturation, and apoptosis was performed at repeated time points in PT and T pups. Results show that the mean weight of the pups and circulating IGF-1 protein levels were lower in the PT group at all time points (p < 0.05) than in the T group. Postnatal weight development correlated with circulating IGF-1 (r2 = 0.89) independently of gestational age at birth and postnatal age. The proliferative (Ki-67-positive) portion of the external granular layer (EGL) was decreased in the PT group at postnatal day 2 (P2) compared to in the T group (p = 0.01). Purkinje cells exhibited decreased calbindin staining at P0 (p = 0.003), P2 (p = 0.004), and P5 (p = 0.04) in the PT group compared to in the T group. Staining for sonic hedgehog was positive in neuronal EGL progenitors and Purkinje cells at early time points but was restricted to a well-defined Purkinje cell monolayer at later time points. Preterm birth in rabbit pups is associated with lower circulating levels of IGF-1, decreased postnatal growth, and decreased cerebellar EGL proliferation and Purkinje cell maturation. The preterm rabbit pup model exhibits important characteristics of human preterm birth, and may thus be suitable for the evaluation of interventions aiming to modify growth and cerebellar development in the preterm population. PMID:28972955

Circulating Wnt inhibitory factor 1 levels are associated with development of cardiovascular disease.

PubMed

Ress, Claudia; Paulweber, Mariya; Goebel, Georg; Willeit, Karin; Rufinatscha, Kerstin; Strobl, Anna; Salzmann, Karin; Kedenko, Ludmilla; Tschoner, Alexander; Staudacher, Gabriele; Iglseder, Bernhard; Tilg, Herbert; Paulweber, Bernhard; Kaser, Susanne

2018-03-29

Wnt signaling is involved in atherosclerotic plaque formation directly and indirectly by modulating cardiovascular risk factors. We investigated whether circulating concentrations of Wnt inhibitors are associated with cardiovascular events in subjects with intermediate cardiovascular risk. 904 non-diabetic subjects participating in the SAPHIR study were assessed. In the SAPHIR study, middle-aged women without overt atherosclerotic disease at study entry were followed up for 10 years. 88 patients of our study cohort developed cardiovascular disease at follow-up (CVD group). Subjects of the CVD group were 1:2 case-control matched for age, sex, BMI and smoking behavior with subjects without overt cardiovascular disease after a 10 year-follow-up (control group). 18 patients of the CVD group and 19 subjects of the control group were retrospectively excluded due to fulfilling exclusion criteria. Baseline circulating sclerostin, dickkopf (DKK)-1, secreted frizzled-related protein (SFRP)-1 and Wnt inhibitory factor (WIF)-1 levels were assessed by ELISA. Baseline systemic SFRP-1 and WIF-1 levels were significantly higher in patients with cardiovascular events (n = 70) when compared to healthy controls (n = 157) while DKK-1 and sclerostin levels were similar in both groups. Logistic regression analysis revealed WIF-1 as a significant predictor of future cardiovascular events. Our data suggest that increased SFRP-1 and WIF-1 levels precede the development of symptomatic atherosclerotic disease. Assessment of systemic WIF-1 levels, which turned out to be independently associated with CVD, might help to early identify patients at intermediate cardiovascular risk. Copyright © 2018 Elsevier B.V. All rights reserved.

Impact of Hepatitis C Virus on the Circulating Levels of IL-7 in HIV-1 Coinfected Women.

PubMed

Kerzerho, Jerome; McIlvaine, Elizabeth J; Anthony, Patricia; Mack, Wendy J; Wang, Chia-Hao; Frederick, Toni; Operskalski, Eva; Chen, Zhi; Al-Harthi, Lena; Landay, Alan; Young, Mary A; Tien, Phyllis C; Augenbraun, Michael; Strickler, Howard D; Akbari, Omid; Golub, Elizabeth T; Sharp, Gerald B; Kovacs, Andrea

2016-02-01

Hepatitis C virus (HCV) infection causes an alteration in T-cell maturation and activation in patients coinfected with human immunodeficiency virus (HIV). Because interleukin 7 (IL-7) is a major cytokine controlling T-cell homeostasis, we analyzed the potential influence of HCV coinfection on circulating IL-7 levels in HIV-infected women before and after highly active antiretroviral therapy (HAART). This prospective study included 56 HIV monoinfected, 55 HIV/HCV coinfected without HCV viremia, 132 HIV/HCV coinfected with HCV viremia, and 61 HIV/HCV-uninfected women for whom plasma levels of IL-7 were determined by enzyme-linked immunosorbent assay at 1 or more follow-up visits before and after HAART. Cross-sectional analyses of the associations between plasma IL-7 levels and HCV infection, demographic, clinical, and immunologic characteristics were evaluated using univariate and multivariate linear regression models before and after HAART. In multivariate models, IL-7 levels were significantly higher in coinfected HCV viremic women than in HIV monoinfected women (multiplicative effect = 1.48; 95% confidence interval: 1.01 to 2.16; P = 0.04) before HAART, but were similar between these two groups among women after HAART. In addition to HCV viremia, higher IL-7 levels were associated with older age (P = 0.02), lower CD4(+) T-cell count (P = 0.0007), and higher natural killer T-cell count (P = 0.02) in women before HAART. Among HAART-treated women, only lower CD4(+) T-cell count was significantly associated with IL-7 level (P = 0.006). Our data demonstrate that in HIV-infected women, circulating levels of IL-7 are strongly associated with CD4 T-cell depletion both before and after HAART. Our data also demonstrate that HCV viremia increases circulating IL-7 levels before HAART but not after HAART in coinfected women. This suggests that the effect of HCV on lymphopenia is abrogated by HAART.

Circulating levels of sphingosine-1-phosphate are elevated in severe, but not mild psoriasis and are unresponsive to anti-TNF-α treatment

NASA Astrophysics Data System (ADS)

Checa, Antonio; Xu, Ning; Sar, Daniel G.; Haeggström, Jesper Z.; Ståhle, Mona; Wheelock, Craig E.

2015-07-01

Sphingolipids are bioactive molecules with a putative role in inflammation. Alterations in sphingolipids, in particular ceramides, have been consistently observed in psoriatic skin. Herein, we quantified the circulating sphingolipid profile in individuals with mild or severe psoriasis as well as healthy controls. In addition, the effects of anti-TNF-α treatment were determined. Levels of sphingoid bases, including sphingosine-1-phosphate (S1P), increased in severe (P < 0.001 n = 32), but not in mild (n = 32), psoriasis relative to healthy controls (n = 32). These alterations were not reversed in severe patients (n = 16) after anti-TNF-α treatment despite significant improvement in psoriasis lesions. Circulating levels of sphingomyelins and ceramides shifted in a fatty acid chain length-dependent manner. These alterations were also observed in psoriasis skin lesions and were associated with changes in mRNA levels of ceramide synthases. The lack of S1P response to treatment may have pathobiological implications due to its close relation to the vascular and immune systems. In particular, increased levels of sphingolipids and especially S1P in severe psoriasis patients requiring biological treatment may potentially be associated with cardiovascular comorbidities. The fact that shifts in S1P levels were not ameliorated by anti-TNF-α treatment, despite improvements in the skin lesions, further supports targeting S1P receptors as therapy for severe psoriasis.

Circulating plasma vascular endothelial growth factor and microvascular complications of type 1 diabetes mellitus: the influence of ACE inhibition.

PubMed

Chaturvedi, N; Fuller, J H; Pokras, F; Rottiers, R; Papazoglou, N; Aiello, L P

2001-04-01

To determine whether circulating plasma vascular endothelial growth factor (VEGF) is elevated in the presence of diabetic microvascular complications, and whether the impact of angiotensin-converting enzyme (ACE) inhibitors on these complications can be accounted for by changes in circulating VEGF. Samples (299/354 of those with retinal photographs) from the EUCLID placebo-controlled clinical trial of the ACE inhibitor lisinopril in mainly normoalbuminuric non-hypertensive Type 1 diabetic patients were used. Albumin excretion rate (AER) was measured 6 monthly. Geometric mean VEGF levels by baseline retinopathy status, change in retinopathy over 2 years, and by treatment with lisinopril were calculated. No significant correlation was observed between VEGF at baseline and age, diabetes duration, glycaemic control, blood pressure, smoking, fibrinogen and von Willebrand factor. Mean VEGF concentration at baseline was 11.5 (95% confidence interval 6.0--27.9) pg/ml in those without retinopathy, 12.9 (6.0--38.9) pg/ml in those with non-proliferative retinopathy, and 16.1 (8.1--33.5) pg/ml in those with proliferative retinopathy (P = 0.06 for trend). Baseline VEGF was 15.2 pg/ml in those who progressed by at least one level of retinopathy by 2 years compared to 11.8 pg/ml in those who did not (P = 0.3). VEGF levels were not altered by lisinopril treatment. Results were similar for AER. Circulating plasma VEGF concentration is not strongly correlated with risk factor status or microvascular disease in Type 1 diabetes, nor is it affected by ACE inhibition. Changes in circulating VEGF cannot account for the beneficial effect of ACE inhibition on retinopathy.

[Laboratory evaluation of remediation of nitrobenzene contaminated aquifer by using groundwater circulation well].

PubMed

Bai, Jing; Zhao, Yong-Sheng; Sun, Chao; Qin, Chuan-Yu; Yu, Ling

2014-10-01

A two-dimension simulated sand box was set up to investigate the influencing factors, such as the initial groundwater level, aeration rate and the initial groundwater rate, that affect groundwater circulation well (GCW) by determining the intensity of groundwater circulation which was characterized by the variation of groundwater level before and after aeration. The optimal operating parameters were used to remediate nitrobenzene contaminated aquifer. The results demonstrated that: GCW could be well operated under the conditions of 45 cm groundwater level, 0.7 m3 · h(-1) aeration rate. The effects of groundwater velocity less than 1.0 m · d(-1) could be ignored. The lateral mobility rate of nitrobenzene was faster than that of longitudinal. The average concentration of nitrobenzene was 246.97 mg · L(-1) on day 50 of leakage. During the remediation of circulation well, an efficient organics remediation region was gradually formed around the circulation well. The organics in this region was removed preferentially, and the concentration decreased continuously. Besides the efficient remediation region, there was a transient region, where the concentration of organics was influenced by the combined effects of adsorption/desorption and migration potential of organics. During the whole remediation process, the concentration of nitrobenzene went through three stages described as rapid removal, slow removal. After 14h aeration, the nitrobenzene average concentration was reduced to 71.19 mg L(-1). The residual nitrobenzene was distributed in regions far away from GCW. Therefore, nitrobenzene contaminated aquifer could be well remediated by GCW, and there were optimal operation conditions and appropriate remediation time which guaranteed the best remediation effect.

Oxidative stress and inflammatory response increase during coronary artery bypass grafting with extracorporeal circulation.

PubMed

Melek, Flora Eli; Baroncini, Liz Andréa Villela; Repka, João Carlos Domingus; Nascimento, Celso Soares; Précoma, Dalton Bertolim

2012-01-01

Thiobarbituric acid-reactive substance is a marker of oxidative stress and has cytotoxic and genotoxic actions. C- reactive protein is used to evaluate the acute phase of inflammatory response. To assess the thiobarbituric acid-reactive substance and C-reactive protein levels during extracorporeal circulation in patients submitted to cardiopulmonary bypass. Twenty-five consecutive surgical patients (16 men and nine women; mean age 61.2 ± 9.7 years) with severe coronary artery disease diagnosed by angiography scheduled for myocardial revascularization surgery with extracorporeal circulation were selected. Blood samples were collected immediately before initializing extracorporeal circulation, T0; in 10 minutes, T10; and in 30 minutes, T30. The thiobarbituric acid-reactive substance levels increased after extracorporeal circulation (P=0.001), with average values in T0=1.5 ± 0.07; in T10=5.54 ± 0.35; and in T30=3.36 ± 0.29 mmoles/mg of serum protein. The C-reactive protein levels in T0 were negative in all samples; in T10 average was 0.96 ± 0.7 mg/dl; and in T30 average was 0.99 ± 0.76 mg/dl. There were no significant differences between the dosages in T10 and T30 (P=0.83). C-reactive protein and thiobarbituric acid-reactive substance plasma levels progressively increased during extracorporeal circulation, with maximum values of thiobarbituric acid-reactive substance at 10 min and of C-reactive protein at 30 min. It suggests that there are an inflammatory response and oxidative stress during extracorporeal circulation.

The adaptation of the cerebral circulation to pregnancy: mechanisms and consequences

PubMed Central

Cipolla, Marilyn J

2013-01-01

The adaptation of the cerebral circulation to pregnancy is unique from other vascular beds. Most notably, the growth and vasodilatory response to high levels of circulating growth factors and cytokines that promote substantial hemodynamic changes in other vascular beds is limited in the cerebral circulation. This is accomplished through several mechanisms, including downregulation of key receptors and transcription factors, and production of circulating factors that counteract the vasodilatory effects of vascular endothelial growth factor (VEGF) and placental growth factor. Pregnancy both prevents and reverses hypertensive inward remodeling of cerebral arteries, possibly through downregulation of the angiotensin type 1 receptor. The blood–brain barrier (BBB) importantly adapts to pregnancy by preventing the passage of seizure provoking serum into the brain and limiting the permeability effects of VEGF that is more highly expressed in cerebral vasculature during pregnancy. While the adaptation of the cerebral circulation to pregnancy provides for relatively normal cerebral blood flow and BBB properties in the face of substantial cardiovascular changes and high levels of circulating factors, under pathologic conditions, these adaptations appear to promote greater brain injury, including edema formation during acute hypertension, and greater sensitivity to bacterial endotoxin. PMID:23321787

T cell Bim levels reflect responses to anti–PD-1 cancer therapy

PubMed Central

Dronca, Roxana S.; Liu, Xin; Harrington, Susan M.; Chen, Lingling; Cao, Siyu; Kottschade, Lisa A.; McWilliams, Robert R.; Block, Matthew S.; Nevala, Wendy K.; Thompson, Michael A.; Mansfield, Aaron S.; Park, Sean S.; Markovic, Svetomir N.

2016-01-01

Immune checkpoint therapy with PD-1 blockade has emerged as an effective therapy for many advanced cancers; however, only a small fraction of patients achieve durable responses. To date, there is no validated blood-based means of predicting the response to PD-1 blockade. We report that Bim is a downstream signaling molecule of the PD-1 pathway, and its detection in T cells is significantly associated with expression of PD-1 and effector T cell markers. High levels of Bim in circulating tumor-reactive (PD-1+CD11ahiCD8+) T cells were prognostic of poor survival in patients with metastatic melanoma who did not receive anti–PD-1 therapy and were also predictive of clinical benefit in patients with metastatic melanoma who were treated with anti–PD-1 therapy. Moreover, this circulating tumor-reactive T cell population significantly decreased after successful anti–PD-1 therapy. Our study supports a crucial role of Bim in both T cell activation and apoptosis as regulated by PD-1 and PD-L1 interactions in effector CD8+ T cells. Measurement of Bim levels in circulating T cells of patients with cancer may provide a less invasive strategy to predict and monitor responses to anti–PD-1 therapy, although future prospective analyses are needed to validate its utility. PMID:27182556

Genetically elevated levels of circulating triglycerides and brachial-ankle pulse wave velocity in a Chinese population.

PubMed

Yao, W-M; Zhang, H-F; Zhu, Z-Y; Zhou, Y-L; Liang, N-X; Xu, D-J; Zhou, F; Sheng, Y-H; Yang, R; Gong, L; Yin, Z-J; Chen, F-K; Cao, K-J; Li, X-L

2013-04-01

Elevated levels of circulating triglycerides and increased arterial stiffness are associated with cardiovascular disease. Numerous studies have reported an association between levels of circulating triglycerides and arterial stiffness. We used Mendelian randomization to test whether this association is causal. We investigated the association between circulating triglyceride levels, the apolipoprotein A-V (ApoA5) -1131T>C single nucleotide polymorphism and brachial-ankle pulse wave velocity (baPWV) by examining data from 4421 subjects aged 18-74 years who were recruited from the Chinese population. baPWV was significantly associated with the levels of circulating triglycerides after adjusting for age, sex, body mass index (BMI), systolic blood pressure, heart rate, waist-to-hip ratio, antihypertensive treatment and diabetes mellitus status. The -1131C allele was associated with a 5% (95% confidence interval 3-8%) increase in circulating triglycerides (adjusted for age, sex, BMI, waist-to-hip ratio, diabetes mellitus and antihypertensive treatment). Instrumental variable analysis showed that genetically elevated levels of circulating triglycerides were not associated with increased baPWV. These results do not support the hypothesis that levels of circulating triglycerides have a causal role in the development of arterial stiffness.

HIV-1/HAART-Related Lipodystrophy Syndrome (HALS) Is Associated with Decreased Circulating sTWEAK Levels.

PubMed

López-Dupla, Miguel; Maymó-Masip, Elsa; Martínez, Esteban; Domingo, Pere; Leal, Manuel; Peraire, Joaquim; Viladés, Consuelo; Veloso, Sergi; Arnedo, Mireia; Ferrando-Martínez, Sara; Beltrán-Debón, Raúl; Alba, Verónica; Gatell, Josep Ma; Vendrell, Joan; Vidal, Francesc; Chacón, Matilde R

2015-01-01

Obesity and HIV-1/HAART-associated lipodystrophy syndrome (HALS) share clinical, pathological and mechanistic features. Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) is a multifunctional cytokine that plays an important role in obesity and related diseases. We sought to explore the relationship between HALS and circulating levels of soluble (s) TWEAK and its scavenger receptor sCD163. This was a cross-sectional multicenter study of 120 HIV-1-infected patients treated with a stable HAART regimen; 56 with overt HALS and 64 without HALS. Epidemiological and clinical variables were determined. Serum levels of sTWEAK and sCD163 levels were measured by ELISA. Results were analyzed with Student's t-test, Mann-Whitney U and χ2 test. Pearson and Spearman correlation were used to estimate the strength of association between variables. Circulating sTWEAK was significantly decreased in HALS patients compared with non-HALS patients (2.81±0.2 vs. 2.94±0.28 pg/mL, p = 0.018). No changes were observed in sCD163 levels in the studied cohorts. On multivariate analysis, a lower log sTWEAK concentration was independently associated with the presence of HALS (OR 0.027, 95% CI 0.001-0.521, p = 0.027). HALS is associated with decreased sTWEAK levels.

Regulatory peptides in the plasma of patients with chronic cardiac failure at rest and during exercise.

PubMed

Nicholls, D P; Riley, M; Elborn, J S; Stanford, C F; Shaw, C; McKillop, J M; Buchanan, K D

1992-10-01

The levels of several regulatory peptides were measured in peripheral plasma samples from individuals with chronic cardiac failure (CCF) and matched controls in both the resting state and during a short period of maximal exercise. Basal levels of noradrenaline (NA; 705 +/- 114 vs 195 +/- 54 ng.l-1; mean +/- SEM; P < 0.05), plasma renin activity (PRA; 12.9 +/- 2.9 vs 2.1 +/- 0.3 ng AI ml-1.h-1; P < 0.05) and aldosterone (ALDO; 325 +/- 49 vs 87 +/- 8 ng.l-1; P < 0.05) were all raised in the patients with CCF, and increased further with exercise. Basal circulating levels of atrial natriuretic peptide (ANP) were also significantly higher in the CCF group compared to controls (136 +/- 35 vs 27 +/- 5 ng.l-1; P < 0.01), but the response to exercise was attenuated, so that at peak exercise, no significant difference was observed. Basal circulating levels of gastrin-releasing peptide (GRP) (29 +/- 4 vs 40 +/- 4 ng.l-1; P < 0.05) and secretin (13 +/- 1 vs 32 +/- 4 ng.l-1; P < 0.05) were significantly lower in the CCF group when compared to controls and there was no significant change in the levels of either peptide with exercise. Levels of neurokinin A (NKA), neuropeptide Y (NPY) and neurotensin (NT) were somewhat higher in patients, but the differences were not significant, and there were no changes during exercise. There were also no significant differences in the levels of vasoactive intestinal peptide (VIP), glucose-dependent insulinotropic polypeptide (GIP), insulin or glucagon in either experimental group both before and during exercise. We have therefore identified different circulating levels of certain regulatory peptides in patients with CCF, but the significance of these remains unclear.

Levels of circulating CD45dimCD34+VEGFR2+ progenitor cells correlate with outcome in metastatic renal cell carcinoma patients treated with tyrosine kinase inhibitors

PubMed Central

Farace, F; Gross-Goupil, M; Tournay, E; Taylor, M; Vimond, N; Jacques, N; Billiot, F; Mauguen, A; Hill, C; Escudier, B

2011-01-01

Background: Predicting the efficacy of antiangiogenic therapy would be of clinical value in patients (pts) with metastatic renal cell carcinoma (mRCC). We tested the hypothesis that circulating endothelial cell (CEC), bone marrow-derived CD45dimCD34+VEGFR2+ progenitor cell or plasma angiogenic factor levels are associated with clinical outcome in mRCC pts undergoing treatment with tyrosine kinase inhibitors (TKI). Methods: Fifty-five mRCC pts were prospectively monitored at baseline (day 1) and day 14 during treatment (46 pts received sunitinib and 9 pts received sorafenib). Circulating endothelial cells (CD45−CD31+CD146+7-amino-actinomycin (7AAD)− cells) were measured in 1 ml whole blood using four-color flow cytometry (FCM). Circulating CD45dimCD34+VEGFR2+7AAD− progenitor cells were measured in progenitor-enriched fractions by four-color FCM. Plasma VEGF, sVEGFR2, SDF-1α and sVCAM-1 levels were determined by ELISA. Correlations between baseline CEC, CD45dimCD34+VEGFR2+7AAD− progenitor cells, plasma factors, as well as day 1–day 14 changes in CEC, CD45dimCD34+VEGFR2+7AAD− progenitor, plasma factor levels, and response to TKI, progression-free survival (PFS) and overall survival (OS) were examined. Results: No significant correlation between markers and response to TKI was observed. No association between baseline CEC, plasma VEGF, sVEGFR-2, SDF-1α, sVCAM-1 levels with PFS and OS was observed. However, baseline CD45dimCD34+VEGFR2+7AAD− progenitor cell levels were associated with PFS (P=0.01) and OS (P=0.006). Changes in this population and in SDF-1α levels between day 1 and day 14 were associated with PFS (P=0.03, P=0.002). Changes in VEGF and SDF-1α levels were associated with OS (P=0.02, P=0.007). Conclusion: Monitoring CD45dimCD34+VEGFR2+ progenitor cells, plasma VEGF and SDF-1α levels could be of clinical interest in TKI-treated mRCC pts to predict outcome. PMID:21386843

Circulating IGF-I and IGFBP3 Levels Control Human Colonic Stem Cell Function and Are Disrupted in Diabetic Enteropathy.

PubMed

D'Addio, Francesca; La Rosa, Stefano; Maestroni, Anna; Jung, Peter; Orsenigo, Elena; Ben Nasr, Moufida; Tezza, Sara; Bassi, Roberto; Finzi, Giovanna; Marando, Alessandro; Vergani, Andrea; Frego, Roberto; Albarello, Luca; Andolfo, Annapaola; Manuguerra, Roberta; Viale, Edi; Staudacher, Carlo; Corradi, Domenico; Batlle, Eduard; Breault, David; Secchi, Antonio; Folli, Franco; Fiorina, Paolo

2015-10-01

The role of circulating factors in regulating colonic stem cells (CoSCs) and colonic epithelial homeostasis is unclear. Individuals with long-standing type 1 diabetes (T1D) frequently have intestinal symptoms, termed diabetic enteropathy (DE), though its etiology is unknown. Here, we report that T1D patients with DE exhibit abnormalities in their intestinal mucosa and CoSCs, which fail to generate in vitro mini-guts. Proteomic profiling of T1D+DE patient serum revealed altered levels of insulin-like growth factor 1 (IGF-I) and its binding protein 3 (IGFBP3). IGFBP3 prevented in vitro growth of patient-derived organoids via binding its receptor TMEM219, in an IGF-I-independent manner, and disrupted in vivo CoSC function in a preclinical DE model. Restoration of normoglycemia in patients with long-standing T1D via kidney-pancreas transplantation or in diabetic mice by treatment with an ecto-TMEM219 recombinant protein normalized circulating IGF-I/IGFBP3 levels and reestablished CoSC homeostasis. These findings demonstrate that peripheral IGF-I/IGFBP3 controls CoSCs and their dysfunction in DE. Copyright © 2015 Elsevier Inc. All rights reserved.

Irisin in response to exercise in humans with and without metabolic syndrome.

PubMed

Huh, Joo Young; Siopi, Aikaterina; Mougios, Vassilis; Park, Kyung Hee; Mantzoros, Christos S

2015-03-01

Irisin is a recently identified exercise-induced myokine. However, the circulating levels of irisin in response to different types of exercise in subjects with metabolic syndrome are unknown. This study aimed to study the levels of irisin in healthy males and subjects with metabolic syndrome at baseline and in response to exercise. Each individual completed high-intensity interval exercise (HIIE), continuous moderate-intensity exercise (CME), and resistance exercise (RE) sessions in a random, crossover design. Percentage change in circulating irisin levels was examined. Two different irisin assays were used to compare the results of the RE study. Circulating irisin increased immediately after HIIE, CME, and RE and declined 1 hour later. The increase was greater in response to resistance compared with either high-intensity intermittent exercise or CME. Change in irisin in response to exercise did not differ between individuals with and without metabolic syndrome. Exercise is able to increase circulating irisin levels in individuals with the metabolic syndrome as well as healthy individuals. Whether this increase may contribute to the beneficial effects of exercise on patients with the metabolic syndrome remains to be studied further.

Clarifying the Dynamics of the General Circulation: Phillips's 1956 Experiment.

NASA Astrophysics Data System (ADS)

Lewis, John M.

1998-01-01

In the mid-1950s, amid heated debate over the physical mechanisms that controlled the known features of the atmosphere's general circulation, Norman Phillips simulated hemispheric motion on the high-speed computer at the Institute for Advanced Study. A simple energetically consistent model was integrated for a simulated time of approximately 1 month. Analysis of the model results clarified the respective roles of the synoptic-scale eddies (cyclones-anticyclones) and mean meridional circulation in the maintenance of the upper-level westerlies and the surface wind regimes. Furthermore, the modeled cyclones clearly linked surface frontogenesis with the upper-level Charney-Eady wave. In addition to discussing the model results in light of the controversy and ferment that surrounded general circulation theory in the 1940s-1950s, an effort is made to follow Phillips's scientific path to the experiment.

Association of Sepsis-Related Mortality with Early Increase of TIMP-1/MMP-9 Ratio

PubMed Central

Lorente, Leonardo; Martín, María M.; Solé-Violán, Jordi; Blanquer, José; Labarta, Lorenzo; Díaz, César; Borreguero-León, Juan M.; Orbe, Josune; Rodríguez, José A.; Jiménez, Alejandro; Páramo, José A.

2014-01-01

Objective Higher circulating levels of tissue inhibitor of matrix metalloproteinases (TIMP)-1 at the time of severe sepsis diagnosis have been reported in nonsurviving than in surviving patients. However, the following questions remain unanswered: 1) Does TIMP-1/MMP-9 ratio differ throughout the first week of intensive care between surviving and non-surviving patients? 2) Is there an association between TIMP-1/MMP-9 ratio and sepsis severity and mortality during such period? 3) Could TIMP-1/MMP-9 ratio during the first week be used as an early biomarker of sepsis outcome? 4) Is there an association between TIMP-1/MMP-9 ratio and coagulation state and circulating cytokine levels during the first week of intensive care in these patients? The present study sought to answer these questions. Methods Multicenter, observational and prospective study carried out in six Spanish Intensive Care Units (ICUs) of 295 patients with severe sepsis. Were measured circulating levels of TIMP-1, MMP-9, tumour necrosis factor (TNF)-alpha, interleukin (IL)-10 and plasminogen activator inhibitor (PAI)-1 at day 1, 4 and 8. End-point was 30-day mortality. Results We found higher TIMP-1/MMP-9 ratio during the first week in non-surviving (n = 98) than in surviving patients (n = 197) (p<0.01). Logistic regression analyses showed that TIMP-1/MMP-9 ratio at days 1, 4 and 8 was associated with mortality. Receiver operating characteristic (ROC) curves showed that TIMP-1/MMP-9 ratio at days 1, 4 and 8 could predict mortality. There was an association between TIMP-1/MMP-9 ratio and TNF-alpha, IL-10, PAI-1 and lactic acid levels, SOFA score and platelet count at days 1, 4 and 8. Conclusions The novel findings of our study were that non-surviving septic patients showed persistently higher TIMP-1/MMP-9 ratio than survivors ones during the first week, which was associated with severity, coagulation state, circulating cytokine levels and mortality; thus representing a new biomarker of sepsis outcome. PMID:24727739

Association of sepsis-related mortality with early increase of TIMP-1/MMP-9 ratio.

PubMed

Lorente, Leonardo; Martín, María M; Solé-Violán, Jordi; Blanquer, José; Labarta, Lorenzo; Díaz, César; Borreguero-León, Juan M; Orbe, Josune; Rodríguez, José A; Jiménez, Alejandro; Páramo, José A

2014-01-01

Higher circulating levels of tissue inhibitor of matrix metalloproteinases (TIMP)-1 at the time of severe sepsis diagnosis have been reported in nonsurviving than in surviving patients. However, the following questions remain unanswered: 1) Does TIMP-1/MMP-9 ratio differ throughout the first week of intensive care between surviving and non-surviving patients? 2) Is there an association between TIMP-1/MMP-9 ratio and sepsis severity and mortality during such period? 3) Could TIMP-1/MMP-9 ratio during the first week be used as an early biomarker of sepsis outcome? 4) Is there an association between TIMP-1/MMP-9 ratio and coagulation state and circulating cytokine levels during the first week of intensive care in these patients? The present study sought to answer these questions. Multicenter, observational and prospective study carried out in six Spanish Intensive Care Units (ICUs) of 295 patients with severe sepsis. Were measured circulating levels of TIMP-1, MMP-9, tumour necrosis factor (TNF)-alpha, interleukin (IL)-10 and plasminogen activator inhibitor (PAI)-1 at day 1, 4 and 8. End-point was 30-day mortality. We found higher TIMP-1/MMP-9 ratio during the first week in non-surviving (n = 98) than in surviving patients (n = 197) (p<0.01). Logistic regression analyses showed that TIMP-1/MMP-9 ratio at days 1, 4 and 8 was associated with mortality. Receiver operating characteristic (ROC) curves showed that TIMP-1/MMP-9 ratio at days 1, 4 and 8 could predict mortality. There was an association between TIMP-1/MMP-9 ratio and TNF-alpha, IL-10, PAI-1 and lactic acid levels, SOFA score and platelet count at days 1, 4 and 8. The novel findings of our study were that non-surviving septic patients showed persistently higher TIMP-1/MMP-9 ratio than survivors ones during the first week, which was associated with severity, coagulation state, circulating cytokine levels and mortality; thus representing a new biomarker of sepsis outcome.

From tissue iron retention to low systemic haemoglobin levels, new pathophysiological biomarkers of human abdominal aortic aneurysm.

PubMed

Martinez-Pinna, R; Lindholt, J S; Madrigal-Matute, J; Blanco-Colio, L M; Esteban-Salan, M; Torres-Fonseca, M M; Lefebvre, T; Delbosc, S; Laustsen, J; Driss, F; Vega de Ceniga, M; Gouya, L; Weiss, G; Egido, J; Meilhac, O; Michel, J-B; Martin-Ventura, J

2014-07-03

Iron deposits are observed in tissue of abdominal aortic aneurysm (AAA) patients, although the underlying mechanisms are not completely elucidated. Therefore we explored circulating markers of iron metabolism in AAA patients, and tested if they could serve as biomarkers of AAA. Increased red blood cell (RBC)-borne iron retention and transferrin, transferrin receptor and ferritin expression was observed in AAA tissue compared to control aorta (immunohistochemistry and western blot). In contrast, decreased circulating iron, transferrin, mean corpuscular haemoglobin concentration (MCHC) and haemoglobin concentration, along with circulating RBC count, were observed in AAA patients (aortic diameter >3 cm, n=114) compared to controls (aortic diameter <3 cm, n=88) (ELISA), whereas hepcidin concentrations were increased in AAA subjects (MS/MS assay). Moreover, iron, transferrin and haemoglobin levels were negatively, and hepcidin positively, correlated with aortic diameter in AAA patients. The association of low haemoglobin with AAA presence or aortic diameter was independent of specific risk factors. Moreover, MCHC negatively correlated with thrombus area in another cohort of AAA patients (aortic diameter 3-5 cm, n=357). We found that anaemia was significantly more prevalent in AAA patients (aortic diameter >5 cm, n=8,912) compared to those in patients with atherosclerotic aorto-iliac occlusive disease (n=17,737) [adjusted odds ratio=1.77 (95% confidence interval: 1.61;1.93)]. Finally, the mortality risk among AAA patients with anaemia was increased by almost 30% [adjusted hazard ratio: 1.29 (95% confidence interval: 1.16;1.44)] as compared to AAA subjects without anaemia. In conclusion, local iron retention and altered iron recycling associated to high hepcidin and low transferrin systemic concentrations could lead to reduced circulating haemoglobin levels in AAA patients. Low haemoglobin levels are independently associated to AAA presence and clinical outcome.

Impact of moisture variations on the circulation of the south-west monsoon

NASA Astrophysics Data System (ADS)

Kishtawal, C. M.; Pal, P. K.; Narayanan, M. S.; Manna, S. K.; Sharma, O. P.; Agarwal, Sangeeta; Upadhyaya, H. C.

1993-12-01

The impact of moisture anomalies on the circulation of the south-west Indian monsoon has been studied with a general circulation model. Newtonian relaxation is adopted to subject the model atmosphere under sustained moisture anomalies. The impact of negative anomalies of moisture was seen as a divergent circulation anomaly, while the positive anomaly was a stronger convergent anomaly. Although the humidity fields display a resilient behaviour, and relax back to normal patterns 1-2 days after the forcing terms in humidity are withdrawn, the circulation anomalies created by the moisture variation keeps growing. A feedback between positive moisture anomalies and low level convergence exists, which is terminated in the absence of external forcings.

Predictors of variation in serum IGF1 and IGFBP3 levels in healthy African American and white men.

PubMed

Hoyo, Cathrine; Grubber, Janet; Demark-Wahnefried, Wendy; Lobaugh, Bruce; Jeffreys, Amy S; Grambow, Steven C; Marks, Jeffrey R; Keku, Temitope O; Walther, Phillip J; Schildkraut, Joellen M

2009-07-01

Individual variation in circulating insulinlike growth factor-1 (IGF1) and its major binding protein, insulinlike growth factor binding protein-3 (IGFBP3), have been etiologically linked to several chronic diseases, including some cancers. Factors associated with variation in circulating levels of these peptide hormones remain unclear. Multiple linear regression models were used to determine the extent to which sociodemographic characteristics, lifestyle factors, personal and family history of chronic disease, and common genetic variants, the (CA)n repeat polymorphism in the IGF1 promoter and the IGFBP3-202 A/C polymorphism (rs2854744) predict variation in IGF1 or IGFBP3 serum levels in 33 otherwise healthy African American and 37 white males recruited from Durham Veterans Administration Medical Center. Predictors of serum IGF1, IGFBP3, and the IGF1:IGFBP3 molar ratio varied by race. In African Americans, 17% and 28% of the variation in serum IGF1 and the IGF1:IGFBP3 molar ratio, were explained by cigarette smoking and carrying the IGF1 (CA)19 repeat allele, respectively. Not carrying at least 1 IGF1 (CA)19 repeat allele and a high body mass index explained 8% and 14%, respectively, of the variation IGFBP3 levels. These factors did not predict variation of these peptides in whites. If successfully replicated in larger studies, these findings would add to recent evidence, suggesting known genetic and lifestyle chronic disease risk factors influence IGF1 and IGFBP3 circulating levels differently in African Americans and whites.

A Single Sphingomyelin Species Promotes Exosomal Release of Endoglin into the Maternal Circulation in Preeclampsia.

PubMed

Ermini, Leonardo; Ausman, Jonathan; Melland-Smith, Megan; Yeganeh, Behzad; Rolfo, Alessandro; Litvack, Michael L; Todros, Tullia; Letarte, Michelle; Post, Martin; Caniggia, Isabella

2017-09-22

Preeclampsia (PE), an hypertensive disorder of pregnancy, exhibits increased circulating levels of a short form of the auxillary TGF-beta (TGFB) receptor endoglin (sENG). Until now, its release and functionality in PE remains poorly understood. Here we show that ENG selectively interacts with sphingomyelin(SM)-18:0 which promotes its clustering with metalloproteinase 14 (MMP14) in SM-18:0 enriched lipid rafts of the apical syncytial membranes from PE placenta where ENG is cleaved by MMP14 into sENG. The SM-18:0 enriched lipid rafts also contain type 1 and 2 TGFB receptors (TGFBR1 and TGFBR2), but not soluble fms-like tyrosine kinase 1 (sFLT1), another protein secreted in excess in the circulation of women with PE. The truncated ENG is then released into the maternal circulation via SM-18:0 enriched exosomes together with TGFBR1 and 2. Such an exosomal TGFB receptor complex could be functionally active and block the vascular effects of TGFB in the circulation of PE women.

The potential predictive value of circulating immune cell ratio and tumor marker in atezolizumab treated advanced non-small cell lung cancer patients.

PubMed

Zhuo, Minglei; Chen, Hanxiao; Zhang, Tianzhuo; Yang, Xue; Zhong, Jia; Wang, Yuyan; An, Tongtong; Wu, Meina; Wang, Ziping; Huang, Jing; Zhao, Jun

2018-05-04

The PD-L1 antibody atezolizumab has shown promising efficacy in patients with advanced non-small cell lung cancer. But the predictive marker of clinical benefit has not been identified. This study aimed to search for potential predictive factors in circulating blood of patients receiving atezolizumab. Ten patients diagnosed with advanced non-small cell lung cancer were enrolled in this open-label observing study. Circulating immune cells and plasma tumor markers were examined in peripheral blood from these patients before and after atezolizumab treatment respectively. Relation between changes in circulating factors and anti-tumor efficacy were analyzed. Blood routine test showed that atezolizumab therapy induced slightly elevation of white blood cells count generally. The lymphocyte ratio was increased slightly in disease controlled patients but decreased prominently in disease progressed patients in response to atezolizumab therapy. Flow cytometric analysis revealed changes in percentage of various immune cell types, including CD4+ T cell, CD8+ T cell, myeloid-derived suppressor cell, regulatory T cell and PD-1 expressing T cell after atezolizumab. Levels of plasma tumor marker CEA, CA125 and CA199 were also altered after anti-PD-L1 therapy. In comparison with baseline, the disease progressed patients showed sharp increase in tumor marker levels, while those disease controlled patients were seen with decreased regulatory T cell and myeloid-derived suppressor cell ratios. The circulating immune cell ratios and plasma tumor marker levels were related with clinical efficacy of atezolizumab therapy. These factors could be potential predictive marker for anti-PD-L1 therapy in advanced non-small cell lung cancer.

Microparticle Shedding by Erythrocytes, Monocytes and Vascular Smooth Muscular Cells Is Reduced by Aspirin in Diabetic Patients.

PubMed

Chiva-Blanch, Gemma; Suades, Rosa; Padró, Teresa; Vilahur, Gemma; Peña, Esther; Ybarra, Juan; Pou, Jose M; Badimon, Lina

2016-07-01

Diabetes mellitus is associated with an enhanced risk for cardiovascular disease and its prevalence is increasing. Diabetes induces metabolic stress on blood and vascular cells, promoting platelet activation and vascular dysfunction. The level of vascular cell activation can be measured by the number and phenotype of microparticles found in the circulation. The aim of this study was to investigate the effect of a platelet-inhibitory dose of aspirin on the number and type of microparticles shed to the circulation. Forty-three diabetic patients were enrolled in the study and received a daily dose of 100mg of aspirin for 10 days to cover the average platelet life-span in the circulation. Before and after the intervention period, circulating microparticles were characterized and quantified by flow cytometry. Type 1 diabetic patients had about twice the number of tissue factor-positive circulating microparticles (derived both from platelets and monocytes) and endothelial-derived E-selectin positive microparticles than type 2 diabetic patients. Aspirin therapy significantly inhibited platelets since cyclooxygenase 1 derived thromboxane generation levels were reduced by 99%. Microparticles derived from erythrocytes, activated monocytes, and smooth muscle cells were significantly reduced after 10 days of aspirin administration. These results indicate that: a) vascular and blood cells in type 1 diabetic patients are exposed to more sustained stress shown by their specific microparticle origin and levels; b) aspirin therapy inhibits vascular wall cell activation and microparticle shedding, and c) the effects of aspirin are similar in type 1 and 2 diabetes. Copyright © 2016 Sociedad Española de Cardiología. Published by Elsevier España, S.L.U. All rights reserved.

Endocan is a predictor of increased cardiovascular risk in women with polycystic ovary syndrome.

PubMed

Bicer, Merve; Guler, Aslı; Unal Kocabas, Gokcen; Imamoglu, Cetin; Baloglu, Ali; Bilgir, Oktay; Yuksel, Arif; Bozkaya, Giray; Calan, Mehmet

2017-05-01

Endocan is a proteoglycan secreted mainly from endothelial cells. It has been implicated that there is a link between endocan and endothelial dysfunction. Polycystic ovary syndrome (PCOS) is a reproductive and metabolic disease associated with increased risk of cardiovascular events. The aims of this study were to ascertain whether circulating endocan levels are altered in women with PCOS, and whether there is an association between endocan and carotid intima media thickness (cIMT). This cross-sectional study included 80 women with PCOS and 80 age- and BMI-matched controls without PCOS. Circulating endocan levels were measured using ELISA. Metabolic, hormonal parameters and cIMT were determined. 2-h oral glucose tolerance test (2-h OGTT) was performed on all women. Circulating endocan levels were significantly elevated in women with PCOS compared with controls (5.99 ± 2.37 vs. 3.66 ± 1.79 ng/ml, P < 0.001). Endocan levels positively correlated with BMI, homeostasis model assessment of insulin resistance (HOMA-IR), free androgen index (FAI), high-sensitivity C-reactive protein (hs-CRP), and cIMT in both PCOS and control groups. Endocan levels did not correlate with fasting blood glucose, 2-h OGTT, A1 C and lipid parameters. Multiple linear regression analysis revealed that endocan is an independent predictor for cIMT (β = 0.128, 95% CI = 0.118-0.138, P = 0.011). Circulating endocan levels are significantly higher in women with PCOS and endocan is independently associated with cIMT. Elevated endocan levels can be a predictor of increased cardiovascular risk in PCOS subjects.

Circulating levels of environmental contaminants are associated with dietary patterns in older adults.

PubMed

Ax, Erika; Lampa, Erik; Lind, Lars; Salihovic, Samira; van Bavel, Bert; Cederholm, Tommy; Sjögren, Per; Lind, P Monica

2015-02-01

Food intake contributes substantially to our exposure to environmental contaminants. Still, little is known about our dietary habits' contribution to exposure variability. The aim of this study was to assess circulating levels of environmental contaminants in relation to predefined dietary patterns in an elderly Swedish population. Dietary data and serum concentrations of environmental contaminants were obtained from 844 70-year-old Swedish subjects (50% women) in the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study. Dietary data from 7-day food records was used to assess adherence to a Mediterranean-like diet, a low carbohydrate-high protein diet and the WHO dietary recommendations. Circulating levels of 6 polychlorinated biphenyl markers, 3 organochlorine pesticides, 1 dioxin and 1 polybrominated diphenyl ether, the metals cadmium, lead, mercury and aluminum and serum levels of bisphenol A and 4 phthalate metabolites were investigated in relation to dietary patterns in multivariate linear regression models. A Mediterranean-like diet was positively associated with levels of several polychlorinated biphenyls (118, 126, 153, and 209), trans-nonachlor and mercury. A low carbohydrate-high protein diet was positively associated with polychlorinated biphenyls 118 and 153, trans-nonachlor, hexachlorobenzene and p, p'-dichlorodiphenyldichloroethylene, mercury and lead. The WHO recommended diet was negatively related to levels of dioxin and lead, and borderline positively to polychlorinated biphenyl 118 and trans-nonachlor. Dietary patterns were associated in diverse manners with circulating levels of environmental contaminants in this elderly Swedish population. Following the WHO dietary recommendations seems to be associated with a lower burden of environmental contaminants. Copyright © 2014 Elsevier Ltd. All rights reserved.

Angiopoietin-2, its soluble receptor Tie-2 and subclinical cardiovascular disease in a population-based sample.

PubMed

Lorbeer, Roberto; Baumeister, Sebastian E; Dörr, Marcus; Felix, Stephan B; Nauck, Matthias; Grotevendt, Anne; Markus, Marcello R P; von Sarnowski, Bettina; Völzke, Henry; Vasan, Ramachandran S; Wallaschofski, Henri; Lieb, Wolfgang

2015-02-01

Higher circulating Angiopoietin-2 (Ang-2) levels predict cardiovascular events and mortality in clinical samples and in the general population. To better understand the underlying mechanisms, we investigated the association of circulating Ang-2 and sTie-2 (the soluble form of the Ang-2 receptor) levels with various measures of subclinical cardiovascular disease. Cross-sectional data of 3204 participants (1654 women) aged 25-88 years from the population-based Study of Health in Pomerania were analysed. LV mass (LVM) and fractional shortening were determined echocardiographically as indices of cardiac structure and function, respectively. Intima media thickness (IMT) of the common carotid artery, the number of carotid plaques and flow-mediated dilation (FMD) were used to characterise large and medium-sized arterial structure and function. Multivariable-adjusted linear and negative binomial regression models revealed an inverse association of circulating Ang-2 levels (independent variable) with fractional shortening (ß=-0.51 per 1 SD increment; 95% CI -0.86 to -0.16, p=0.005) and a positive association with number of carotid plaques (rate ratio=1.04 95% CI 1.01 to 1.07, p=0.019). No associations of Ang-2 or sTie-2 with LVM, IMT and FMD were found. Circulating Ang-2 levels were associated with select subclinical cardiovascular disease traits, consistent with the notion that the Ang-2-pathway plays a role in mediating cardiovascular morbidity. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

Increased numbers of circulating ICOS⁺ follicular helper T and CD38⁺ plasma cells in patients with newly diagnosed primary biliary cirrhosis.

PubMed

Wang, Li; Sun, Xiguang; Qiu, Jinpeng; Cai, Yanjun; Ma, Liang; Zhao, Pingwei; Jiang, Yanfang

2015-02-01

Aberrant activation of follicular helper T (TFH) and B cells is associated with the development of autoimmune diseases. However, little is known about the potential role of these cells in the development of primary biliary cirrhosis (PBC). This study aimed at characterizing the numbers of different subsets of circulating Tfh and B cells as well as evaluating their potential association with the levels of immunoglobulins and autoantibodies in newly diagnosed PBC patients. The numbers of circulating CD27(+), CD38(+), CD86(+) and CD95(+) B cells as well as inducible T cell costimulator (ICOS)(+) and programmed death-1 (PD-1)(+), IL-21(+) TFH cells were examined in 58 patients with newly diagnosed PBC and 30 matched healthy controls (HCs). The numbers of circulating CD38(+)CD19(+), CD86(+)CD19(+), and CD95(+)CD19(+) B cells; CD3(+)CD4(+)CXCR5(+)ICOS(+) and CD3(+)CD4(+)CXCR5(+)PD-1(+) Tfh cells; and the levels of serum IL-21 in the PBC patients were significantly greater, but the numbers of CD27(+)CD19(+) B cells were significantly less than those in the HCs (p < 0.05). The numbers of CD3(+)CD4(+)CXCR5(+)ICOS(+) Tfh cells were positively correlated with the numbers of CD38(+)CD19(+) and CD86(+)CD38(+)CD19(+) B cells and the levels of serum anti-mitochondrial antibodies against M2 antigen (AMA-M2), AMA and immunolgubin M (IgM) in the PBC patients. The levels of serum IL-21 were positively correlated with the levels of serum AMA-M2, AMA, IgG and IgM, but negatively with the numbers of CD27(+)CD19(+) B cells in the PBC patients. Increased numbers of circulating ICOS(+) and IL-21(+) Tfh and CD38(+) plasma cells may be exhibited by patients with recent diagnoses of PBC.

Effect of human body weight changes on circulating levels of peptide YY and peptide YY3-36.

PubMed

Pfluger, P T; Kampe, J; Castaneda, T R; Vahl, T; D'Alessio, D A; Kruthaupt, T; Benoit, S C; Cuntz, U; Rochlitz, H J; Moehlig, M; Pfeiffer, A F H; Koebnick, C; Weickert, M O; Otto, B; Spranger, J; Tschöp, M H

2007-02-01

Recent findings suggest that low plasma peptide YY (PYY) levels may contribute to diet-induced human obesity and justify PYY replacement therapy. Although the pharmacological value of PYY is controversial, further study of the secretion of the precursor PYY(1-36) and the pharmacologically active PYY(3-36) is indicated to determine the potential role in energy balance regulation. Our objective was to determine the effects of acute and chronic changes in human body weight on circulating levels of the putative satiety hormone peptide YY. Total plasma PYY levels (PYY(1-36) + PYY(3-36)) were measured in 66 lean, 18 anorectic, 63 obese, and 16 morbidly obese humans. In addition, total PYY was measured in 17 of the obese patients after weight loss and in the 18 anorectic patients after weight gain. Fasting PYY(3-36) levels were measured in 17 lean and 15 obese individuals. Fasting total plasma PYY levels were highest in patients with anorexia nervosa (80.9 +/- 12.9 pg/ml, P < 0.05) compared with lean (52.4 +/- 4.6 pg/ml), obese (43.9 +/- 3.8 pg/ml), or morbidly obese (45.6 +/- 11.2 pg/ml) subjects. In obese patients, weight loss of 5.4% was associated with a 30% decrease in fasting total PYY plasma levels. In anorectic patients, weight gain had no effect on fasting PYY. PYY(3-36) levels did not differ between lean (96.2 +/- 8.6 pg/ml) and obese (91.5 +/- 6.9 pg/ml) subjects. Our findings do not support a role for abnormal circulating PYY in human obesity. We conclude that circulating PYY levels in humans are significantly elevated in anorexia nervosa and, given the controversially discussed anorectic effect of PYY, could theoretically contribute to that syndrome.

Indomethacin Inhibits Circulating PGE2 and Reverses Postexercise Suppression of Natural Killer Cell Activity

DTIC Science & Technology

1999-01-01

after the oral administration of a placebo, the PG inhibitor indomethacin (75 mg/day for 5 days), or naltrexone (reported elsewhere). Circulating...which blocks PGE2 biosynthe- sis via inhibition of cyclooxygenase activity (57). Maxi- mal suppression of PG production occurs with doses between 50...and 150 mg (1). In addition to the indepen- dent effects of PGE2 on NKCA, low circulating levels of PGE2 can synergize with endogenous glucocorticoids

A Non-Lethal Traumatic/Hemorrhagic Insult Strongly Modulates the Compartment-Specific PAI-1 Response in the Subsequent Polymicrobial Sepsis

PubMed Central

Raeven, Pierre; Salibasic, Alma; Drechsler, Susanne; Weixelbaumer, Katrin Maria; Jafarmadar, Mohammad; van Griensven, Martijn; Bahrami, Soheyl; Osuchowski, Marcin Filip

2013-01-01

Introduction Plasminogen activator inhibitor 1 (PAI-1) is a key factor in trauma- and sepsis-induced coagulopathy. We examined how trauma-hemorrhage (TH) modulates PAI-1 responses in subsequent cecal ligation and puncture (CLP)-induced sepsis, and the association of PAI-1 with septic outcomes. Methods Mice underwent TH and CLP 48 h later in three separate experiments. In experiment 1, mice were sacrificed pre- and post-CLP to characterize the trajectory of PAI-1 in plasma (protein) and tissues (mRNA). Post-CLP dynamics in TH-CLP (this study) and CLP-Only mice (prior study) were then compared for modulatory effects of TH. In experiment 2, to relate PAI-1 changes to outcome, mice underwent TH-CLP and were sampled daily and followed for 14 days to compare non-survivors (DEAD) and survivors (SUR). In experiment 3, plasma and tissue PAI-1 expression were compared between mice predicted to die (P-DIE) and to live (P-LIVE). Results In experiment 1, an early post-TH rise of circulating PAI-1 was contrasted by a delayed (post-TH) decrease of PAI-1 mRNA in organs. In the post-CLP phase, profiles of circulating PAI-1 were similar between TH-CLP and CLP-Only mice. Conversely, PAI-1 mRNA declined in the liver and heart of TH-CLP mice versus CLP-Only. In experiment 2, there were no DEAD/SUR differences in circulating PAI-1 prior to CLP. Post-CLP, circulating PAI-1 in DEAD was 2–4-fold higher than in SUR. PAI-1 increase heralded septic deaths up to 48 h prior but DEAD/SUR thrombomodulin (endothelial injury marker) levels were identical. In experiment 3, levels of circulating PAI-1 and its hepatic gene expression were higher in P-DIE versus P-LIVE mice and those increases closely correlated with liver dysfunction. Conclusions Trauma modulated septic PAI-1 responses in a compartment-specific fashion. Only post-CLP increases in circulating PAI-1 predicted septic outcomes. In posttraumatic sepsis, pre-lethal release of PAI-1 was mostly of hepatic origin and was independent of endothelial injury. PMID:23408987

Reduction of circulating FABP4 level by treatment with omega-3 fatty acid ethyl esters.

PubMed

Furuhashi, Masato; Hiramitsu, Shinya; Mita, Tomohiro; Omori, Akina; Fuseya, Takahiro; Ishimura, Shutaro; Watanabe, Yuki; Hoshina, Kyoko; Matsumoto, Megumi; Tanaka, Marenao; Moniwa, Norihito; Yoshida, Hideaki; Ishii, Junnichi; Miura, Tetsuji

2016-01-12

Fatty acid-binding protein 4 (FABP4/A-FABP/aP2) mainly expressed in adipocytes is secreted and acts as an adipokine. Increased circulating FABP4 level is associated with obesity, insulin resistance and atherosclerosis. However, little is known about the modulation of serum FABP4 level by drugs including anti-dyslipidemic agents. Patients with dyslipidemia were treated with omega-3 fatty acid ethyl esters (4 g/day; n = 14) containing eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) for 4 weeks. Serum FABP4 level was measured before and after treatment. Expression and secretion of FABP4 were also examined in mouse 3T3-L1 adipocytes treated with EPA or DHA. Treatment with omega-3 fatty acid ethyl esters significantly decreased triglycerides and serum FABP4 level (13.5 ± 1.5 vs. 11.5 ± 1.1 ng/ml, P = 0.017). Change in FABP4 level by omega-3 fatty acids was negatively correlated with change in levels of EPA + DHA (r = -0.643, P = 0.013), EPA (r = -0.540, P = 0.046) and DHA (r = -0.650, P = 0.011) but not change in the level of triglycerides or other fatty acid composition. Treatment of 3T3-L1 adipocytes with EPA or DHA had no effect on short-term (2 h) secretion of FABP4. However, gene expression and long-term (24 h) secretion of FABP4 were significantly reduced by treatment with EPA or DHA. Omega-3 fatty acids decrease circulating FABP4 level, possibly by reducing expression and consecutive secretion of FABP4 in adipocytes. Reducing FABP4 level might be involved in suppression of cardiovascular events by omega-3 fatty acids.

Cytokine profiling of docetaxel-resistant castration-resistant prostate cancer.

PubMed

Mahon, K L; Lin, H-M; Castillo, L; Lee, B Y; Lee-Ng, M; Chatfield, M D; Chiam, K; Breit, S N; Brown, D A; Molloy, M P; Marx, G M; Pavlakis, N; Boyer, M J; Stockler, M R; Daly, R J; Henshall, S M; Horvath, L G

2015-04-14

Docetaxel improves symptoms and survival in metastatic castration-resistant prostate cancer (CRPC). However, ∼50% of patients are chemoresistant. This study examined whether changes in cytokine levels predict for docetaxel resistance in vitro and in a clinical cohort. PC3 cells or their docetaxel-resistant subline (PC3Rx) were co-cultured with U937 monocytes, with and without docetaxel treatment, and cytokine levels were measured. The circulating levels of 28 cytokines were measured pre-/post cycle 1 of docetaxel from 55 men with CRPC, and compared with prostate-specific antigen (PSA) response. PC3Rx-U937 co-culture expressed more cytokines, chiefly markers of alternative macrophage differentiation, compared with PC3-U937 co-culture. Docetaxel treatment enhanced cytokine production by PC3Rx-U937 co-culture, while reducing cytokine levels in PC3-U937. In patients, changes in the levels of seven circulating cytokines (macrophage inhibitory cytokine 1 (MIC1), interleukin (IL)-1ra, IL-1β, IL-4, IL-6, IL-12 and IFNγ) after cycle 1 of docetaxel were associated with progressive disease (all P<0.05). The combination of changes in MIC1, IL-4 and IL-6 most strongly predicted PSA response (P=0.002). In vitro studies suggest docetaxel resistance is mediated, at least in part, by cytokines induced by the interaction between the docetaxel-resistant tumour cells and macrophages. Early changes in circulating cytokine levels were associated with docetaxel resistance in CRPC patients. When considered together, these data suggest a significant role for the inflammatory response and macrophages in the development of docetaxel resistance in CRPC.

Therapeutic mild hypothermia improves early outcomes in rats subjected to severe sepsis.

PubMed

Ding, Wu; Shen, Yuehong; Li, Qiang; Jiang, Shouyin; Shen, Huahao

2018-04-15

Therapeutic hypothermia has shown beneficial effects in sepsis. This study focused on its mechanism. Sixteen male Sprague-Dawley rats underwent cecal ligation and perforation and subsequently were treated with either hypothermia (HT; body temperature cooled and maintained at 34 °C by ice pad for 10 h; n = 8) or normothermia (NT; n = 8). Three additional rats underwent sham surgery. The body temperatures of the sham-operated and NT groups were maintained at 38 °C with a thermal pad. After the hypothermia treatment, the HT rats were rewarmed for 2 h. The groups were compared for circulating cytokines (IL-6, IL-10), lactate, high mobility group box-1 protein (HMGB1), and lung and intestinal lesions. Animals were observed for 24 h. Compared with the sham-operated group, the 2 sepsis group rats had significantly higher circulating IL-6, HMGB1, and lactate levels, and tissue injury. In the HT rats, the levels of IL-6, HMGB1, and lactate, the lung wet-to-dry ratio, and lung and intestinal damage were significantly lower than that of the NT group. Circulating IL-10 levels increased significantly after 12 h in the sepsis groups compared with sham animals, while that of the NT and HT groups were comparable. The survival rates of the NT and HT rats were also comparable. Therapeutic hypothermia in a rat model of sepsis was associated with lower levels of circulating IL-6 and HMGB1, and less capillary leakage and tissue edema. These results suggest that mild hypothermia has potential as a therapy in sepsis. Copyright © 2018 Elsevier Inc. All rights reserved.

A Novel Splice-Site Mutation in Angiotensin I-Converting Enzyme (ACE) Gene, c.3691+1G>A (IVS25+1G>A), Causes a Dramatic Increase in Circulating ACE through Deletion of the Transmembrane Anchor

PubMed Central

Persu, Alexandre; Lambert, Michel; Deinum, Jaap; Cossu, Marta; de Visscher, Nathalie; Irenge, Leonid; Ambroise, Jerôme; Minon, Jean-Marc; Nesterovitch, Andrew B.; Churbanov, Alexander; Popova, Isolda A.; Danilov, Sergei M.; Danser, A. H. Jan; Gala, Jean-Luc

2013-01-01

Background Angiotensin-converting enzyme (ACE) (EC 4.15.1) metabolizes many biologically active peptides and plays a key role in blood pressure regulation and vascular remodeling. Elevated ACE levels are associated with different cardiovascular and respiratory diseases. Methods and Results Two Belgian families with a 8-16-fold increase in blood ACE level were incidentally identified. A novel heterozygous splice site mutation of intron 25 - IVS25+1G>A (c.3691+1G>A) - cosegregating with elevated plasma ACE was identified in both pedigrees. Messenger RNA analysis revealed that the mutation led to the retention of intron 25 and Premature Termination Codon generation. Subjects harboring the mutation were mostly normotensive, had no left ventricular hypertrophy or cardiovascular disease. The levels of renin-angiotensin-aldosterone system components in the mutated cases and wild-type controls were similar, both at baseline and after 50 mg captopril. Compared with non-affected members, quantification of ACE surface expression and shedding using flow cytometry assay of dendritic cells derived from peripheral blood monocytes of affected members, demonstrated a 50% decrease and 3-fold increase, respectively. Together with a dramatic increase in circulating ACE levels, these findings argue in favor of deletion of transmembrane anchor, leading to direct secretion of ACE out of cells. Conclusions We describe a novel mutation of the ACE gene associated with a major familial elevation of circulating ACE, without evidence of activation of the renin-angiotensin system, target organ damage or cardiovascular complications. These data are consistent with the hypothesis that membrane-bound ACE, rather than circulating ACE, is responsible for Angiotensin II generation and its cardiovascular consequences. PMID:23560051

Predictors of variation in serum IGFI and IGFBP3 levels in healthy African-American and white men

PubMed Central

Grubber, Janet; Demark-Wahnefried, Wendy; Lobaugh, Bruce; Jeffreys, Amy S.; Grambow, Steven C.; Marks, Jeffrey R.; Keku, Temitope O.; Walther, Phillip J.; Schildkraut, Joellen M.

2010-01-01

Background Individual variation in circulating insulin-like growth factor-I (IGF1) and its major binding protein, insulin-like growth factor binding protein-3 (IGFBP3) have been etiologically linked to several chronic diseases, including some cancers. Factors associated with variation in circulating levels of these peptide hormones remain unclear. Methods Multiple linear regression models were used to determine the extent to which socio-demographic characteristics, lifestyle factors, personal and family history of chronic disease, and common genetic variants, the (CA)n repeat polymorphism in the IGF1 promoter and the IGFBP3 -202 A/C polymorphism (rs2854744) predict variation in IGF1 or IGFBP3 serum levels in 33 otherwise healthy African American and 37 white males recruited from Durham Veterans Administration Medical Center. Results Predictors of serum IGF1, IGFBP3 and the IGF1:IGFBP3 molar ratio varied by race. In African Americans, 17% and 28% of the variation in serum IGF1 and the IGF1:IGFBP3 molar ratio, respectively, was explained by cigarette smoking and carrying the IGF1 (CA)19 repeat allele, respectively. Not carrying at least one IGF1 (CA)19 repeat allele and a high BMI explained 8% and 14%, respectively, of the variation IGFBP3 levels. These factors did not predict variation of these peptides in whites. Conclusion If successfully replicated in larger studies, these findings add to recent evidence suggesting known genetic and lifestyle chronic disease risk factors influence IGF1 and IGFBP3 circulating levels differently in African Americans and whites. PMID:19634593

4G/5G polymorphism modulates PAI-1 circulating levels in obese women.

PubMed

Fernandes, Karla S; Sandrim, Valéria C

2012-05-01

The increase in plasminogen activator inhibitor type 1 (PAI-1) has been described as a risk factor to thrombosis-related diseases. In addition, it has been demonstrated that the variant 4G of polymorphism 4G/5G located in promoter region of PAI-1 gene is associated with higher PAI-1 levels. We investigate the role of this polymorphism on circulating PAI-1 concentration in a population of 57 obese women (23%, 4G/4G; 49%, 4G/5G and 28%, 5G/5G genotypes). Our results demonstrate a genotype-specific modulation on PAI-1 levels in obese women, thus 5G/5G genotype presented significantly lower levels of plasma PAI-1 when compared to 4G/4G group (46 ± 19 ng/mL vs. 63 ± 13 ng/mL, respectively). Our findings indicate that obese carriers of 4G/4G genotype may have increased risk to develop thrombotic diseases.

[Agammaglobulinemia with the absence of circulating B-lymphocytes. 9 cases].

PubMed

Bejaoui, M; Barbouche, M R; Mellouli, F; Tirellil, N; Dellagi, K

1998-03-28

Agammaglobulinemia with absence of circulating B lymphocytes is a rare genetically transmitted immunodeficiency that appears in early childhood and affect mainly boys. The clinical manifestations of the disease are rather heterogeneous. Nine patients (7 boys and 2 girls) were diagnosed as suffering from agammaglobulinemia with absence of circulating B lymphocytes, over a period of 6 years. Quantitation of immunoglobulins and search for circulating B lymphocytes were respectively performed by the Mancini method and immunofluorescence using T specific (anti-CD3, anti-CD4 and anti-CD8) and B (anti-CD19) monoclonal antibody. The disease started to manifest clinically at the mean age of 8.7 months (4-16 months). The mean age at diagnosis is 4 years (1-11 years). The clinical manifestations were essentially recurrent infections of the lung and the gastrointestinal tract. However, bacterial meningitidis was observed in 3 patients. Severe complications such as an echovirus 27 meningoencephalitis and a chronic active hepatitis (1 patient) and a pericarditis (1 patient) were observed. All of our patients lacked circulating B lymphocytes and had low or null immunoglobulin levels. Five patients were treated by intravenous immunoglobulin (Ig) and 3 were treated by intramuscular immunoglobulin with a residual IgG level respectively of 5.5 g/l and 3.3 g/l. Recurrent infections are the principal manifestation of the agammaglobulinemia, early Ig treatment is the only therapy allowing improved.

Leisure-time physical activity and circulating 25-hydroxyvitamin D levels in cancer survivors: a cross-sectional analysis using data from the US National Health and Nutrition Examination Survey.

PubMed

Yang, Lin; Toriola, Adetunji T

2017-07-10

Circulating 25-hydroxyvitamin D (25-OHD) is associated with improved cancer prognosis in some studies, yet it may be a surrogate marker for physical activity. We investigated the associations of leisure-time physical activity (LTPA) with circulating 25-OHD levels in cancer survivors, and determined whether associations differ by indoor and outdoor activity. Cross-sectional study. The US National Health and Nutrition Examination Survey (NHANES). Cancer survivors with available data on demographic information, measures of adiposity, smoking history, self-reported LTPA and circulating 25-OHD levels in five waves of NHANES (2001-2010). Circulating 25-OHD levels. Multivariable linear regression and logistic regression models were used to evaluate the associations of self-reported LTPA with 25-OHD, adjusting for potential confounders. Due to the differences in LTPA measure, the analyses were conducted separately for 2001-2006 and 2007-2010 data. We further estimated associations by indoor and outdoor activity in the 2001-2006 data. There were 1530 cancer survivors (mean age=60.5 years, mean body mass index=28.6 kg/m 2 ). The prevalent cancer sites were breast (19.3%), prostate (18.8%), cervix (10.4%) and colon (8.6%). Compared with inactive cancer survivors, being physically active was associated with higher circulating 25-OHD levels (8.07 nmol/L, 95% CI 4.63 to 11.52) for 2001-2006 data. In the mutually adjusted model, higher outdoor activity (5.83 nmol/L, 95% CI 1.64 to 10.01), but not indoor activity (2.93 nmol/L, 95% CI -1.80 to 7.66), was associated with statistically significantly higher 25-OHD levels. The interaction between indoor and outdoor activities was, however, not significant (p=0.29). The only statistically significant association seen in the 2007-2010 data was among obese cancer survivors. Physical activity, particularly outdoor activity, is associated with higher 25-OHD levels in cancer survivors. In view of the possible beneficial effects of vitamin D on cancer prognosis, engaging in outdoor physical activity could provide clinically meaningful increases in 25-OHD levels among cancer survivors. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Multifocal clonal evolution characterized using circulating tumour DNA in a case of metastatic breast cancer

PubMed Central

Murtaza, Muhammed; Dawson, Sarah-Jane; Pogrebniak, Katherine; Rueda, Oscar M.; Provenzano, Elena; Grant, John; Chin, Suet-Feung; Tsui, Dana W. Y.; Marass, Francesco; Gale, Davina; Ali, H. Raza; Shah, Pankti; Contente-Cuomo, Tania; Farahani, Hossein; Shumansky, Karey; Kingsbury, Zoya; Humphray, Sean; Bentley, David; Shah, Sohrab P.; Wallis, Matthew; Rosenfeld, Nitzan; Caldas, Carlos

2015-01-01

Circulating tumour DNA analysis can be used to track tumour burden and analyse cancer genomes non-invasively but the extent to which it represents metastatic heterogeneity is unknown. Here we follow a patient with metastatic ER-positive and HER2-positive breast cancer receiving two lines of targeted therapy over 3 years. We characterize genomic architecture and infer clonal evolution in eight tumour biopsies and nine plasma samples collected over 1,193 days of clinical follow-up using exome and targeted amplicon sequencing. Mutation levels in the plasma samples reflect the clonal hierarchy inferred from sequencing of tumour biopsies. Serial changes in circulating levels of sub-clonal private mutations correlate with different treatment responses between metastatic sites. This comparison of biopsy and plasma samples in a single patient with metastatic breast cancer shows that circulating tumour DNA can allow real-time sampling of multifocal clonal evolution. PMID:26530965

Multifocal clonal evolution characterized using circulating tumour DNA in a case of metastatic breast cancer.

PubMed

Murtaza, Muhammed; Dawson, Sarah-Jane; Pogrebniak, Katherine; Rueda, Oscar M; Provenzano, Elena; Grant, John; Chin, Suet-Feung; Tsui, Dana W Y; Marass, Francesco; Gale, Davina; Ali, H Raza; Shah, Pankti; Contente-Cuomo, Tania; Farahani, Hossein; Shumansky, Karey; Kingsbury, Zoya; Humphray, Sean; Bentley, David; Shah, Sohrab P; Wallis, Matthew; Rosenfeld, Nitzan; Caldas, Carlos

2015-11-04

Circulating tumour DNA analysis can be used to track tumour burden and analyse cancer genomes non-invasively but the extent to which it represents metastatic heterogeneity is unknown. Here we follow a patient with metastatic ER-positive and HER2-positive breast cancer receiving two lines of targeted therapy over 3 years. We characterize genomic architecture and infer clonal evolution in eight tumour biopsies and nine plasma samples collected over 1,193 days of clinical follow-up using exome and targeted amplicon sequencing. Mutation levels in the plasma samples reflect the clonal hierarchy inferred from sequencing of tumour biopsies. Serial changes in circulating levels of sub-clonal private mutations correlate with different treatment responses between metastatic sites. This comparison of biopsy and plasma samples in a single patient with metastatic breast cancer shows that circulating tumour DNA can allow real-time sampling of multifocal clonal evolution.

Hydroxylated polychlorinated biphenyls decrease circulating steroids in female polar bears (Ursus maritimus).

PubMed

Gustavson, Lisa; Ciesielski, Tomasz M; Bytingsvik, Jenny; Styrishave, Bjarne; Hansen, Martin; Lie, Elisabeth; Aars, Jon; Jenssen, Bjørn M

2015-04-01

As a top predator in the Arctic food chain, polar bears (Ursus maritimus) are exposed to high levels of persistent organic pollutants (POPs). Because several of these compounds have been reported to alter endocrine pathways, such as the steroidogenesis, potential disruption of the sex steroid synthesis by POPs may cause implications for reproduction by interfering with ovulation, implantation and fertility. Blood samples were collected from 15 female polar bears in Svalbard (Norway) in April 2008. The concentrations of nine circulating steroid hormones; dehydroepiandrosterone (DHEA), androstenedione (AN), testosterone (TS), dihydrotestosterone (DHT), estrone (E1), 17α-estradiol (αE2), 17β-estradiol (βE2), pregnenolone (PRE) and progesterone (PRO) were determined. The aim of the study was to investigate associations among circulating levels of specific POP compounds and POP-metabolites (hydroxylated PCBs [OH-PCBs] and hydroxylated PBDEs [OH-PBDEs]), steroid hormones, biological and capture variables in female polar bears. Inverse correlations were found between circulating levels of PRE and AN, and circulating levels of OH-PCBs. There were no significant relationships between the steroid concentrations and other analyzed POPs or the variables capture date and capture location (latitude and longitude), lipid content, condition and body mass. Although statistical associations do not necessarily represent direct cause-effect relationships, the present study indicate that OH-PCBs may affect the circulating levels of AN and PRE in female polar bears and that OH-PCBs thus may interfere with the steroid homeostasis. Increase in PRO and a decrease in AN concentrations suggest that the enzyme CYP17 may be a potential target for OH-PCBs. In combination with natural stressors, ongoing climate change and contaminant exposure, it is possible that OH-PCBs may disturb the reproductive potential of polar bears. Copyright © 2015 Elsevier Inc. All rights reserved.

Cell–specific Variation in E-selectin Ligand Expression Among Human Peripheral Blood Mononuclear Cells: Implications for Immunosurveillance and Pathobiology

PubMed Central

Silva, Mariana; Fung, Ronald Kam Fai; Donnelly, Conor Brian; Videira, Paula Alexandra; Sackstein, Robert

2017-01-01

Both host defense and immunopathology are shaped by the ordered recruitment of circulating leukocytes to affected sites, a process initiated by binding of blood-borne cells to E-selectin displayed at target endothelial beds. Accordingly, knowledge of the expression and function of leukocyte E-selectin ligands is key to understanding the tempo and specificity of immunoreactivity. Here, we performed E-selectin adherence assays under hemodynamic flow conditions coupled with flow cytometry and western blot analysis to elucidate the function and structural biology of glycoprotein E-selectin ligands expressed on human peripheral blood mononuclear cells (PBMCs). Circulating monocytes uniformly express high levels of the canonical E-selectin binding determinant sLeX and display markedly greater adhesive interactions with E-selectin than do circulating lymphocytes, which exhibit variable E-selectin binding among CD4+ and CD8+ T-cells but no binding by B-cells. Monocytes prominently present sLeX decorations on an array of protein scaffolds including PSGL-1, CD43, and CD44 (rendering the E-selectin ligands CLA, CD43E, and HCELL, respectively), and B-cells altogether lack E-selectin ligands. Quantitative PCR gene expression studies of glycosyltransferases that regulate display of sLeX reveal high transcript levels among circulating monocytes and low levels among circulating B-cells, and, commensurately, cell surface α(1,3)-fucosylation reveals that acceptor sialyllactosaminyl glycans convertible into sLeX are abundantly expressed on human monocytes yet are relatively deficient on B-cells. Collectively, these findings unveil distinct cell-specific patterns of E-selectin ligand expression among human PBMCs, indicating that circulating monocytes are specialized to engage E-selectin and providing key insights into the molecular effectors mediating recruitment of these cells at inflammatory sites. PMID:28330896

Effects of centrifugation stress on pituitary-gonadal function in male rats

NASA Technical Reports Server (NTRS)

Gray, G. D.; Smith, E. R.; Damassa, D. A.; Davidson, J. M.

1980-01-01

The effects of centrifugation for various lengths of time on circulating levels of luteinizing hormone (LH) and testosterone in male rats were investigated. In a chronic 52-day experiment, centrifugation at 4.1 G significantly reduced LH and testosterone levels for the entire period. Centrifugation at 2.3 G had less effect inasmuch as LH levels were not significantly decreased and testosterone levels were significantly reduced only during the first few days of centrifugation. In more acute experiments, centrifugation at 4.1 G for 4 h resulted in reduced testosterone levels, whereas centrifugation for 15 min did not significantly alter the hormone levels. These results indicate that centrifugation can decrease circulating LH and testosterone levels if the gravitational force is of sufficient magnitude and is maintained for a period of hours. Chronic centrifugation may also inhibit the acute excitatory response of LH to handling and ether stress.

Diagnostic Value of Circulating CXC Chemokines in Non-small Cell Lung Cancer.

PubMed

Spaks, Artjoms; Jaunalksne, Inta; Spaka, Irina; Chudasama, Dimple; Pirtnieks, Ainis; Krievins, Dainis

2015-12-01

To evaluate the diagnostic value of circulating CXC chemokines as biomarkers for non-small cell lung cancer and compare them against a standard panel of already existing cancer biomarkers. A total of 90 individuals were enrolled in the study. We analyzed 30 patients with stage IA-IIB carcinoma of the lung who underwent pulmonary resection, 30 patients with metastatic NSCLC, and 30 healthy volunteers. The biomarkers levels were measured in plasma blood samples, by ELISA and immunoassays. The levels of circulating CXCL4, CXCL8, CXCL9, CXCL10 and CXCL11 were higher and those of circulating CXCL1 were lower in patients with early-stage NSCLC compared to metastatic NSCLC patients and controls (p<0.05). CXCL4, CXCL9 and CXCL11 were included in the panel that showed a sensitivity of 100% versus 60% for CEA, CA125 and CYFRA21-1 (p<0.001). Combination of CXCL4, CXCL9 and CXCL11 has a high diagnostic value. Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

Effects of physical activity on the link between PGC-1a and FNDC5 in muscle, circulating Ιrisin and UCP1 of white adipocytes in humans: A systematic review

PubMed Central

Dinas, Petros C.; Lahart, Ian M.; Timmons, James A.; Svensson, Per-Arne; Koutedakis, Yiannis; Flouris, Andreas D.; Metsios, George S.

2017-01-01

Background: Exercise may activate a brown adipose-like phenotype in white adipose tissue. The aim of this systematic review was to identify the effects of physical activity on the link between peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1a) and fibronectin type III domain-containing protein 5 (FNDC5) in muscle, circulating Irisin and uncoupling protein one (UCP1) of white adipocytes in humans. Methods: Two databases (PubMed 1966 to 08/2016 and EMBASE 1974 to 08/2016) were searched using an appropriate algorithm. We included articles that examined physical activity and/or exercise in humans that met the following criteria: a) PGC-1a in conjunction with FNDC5 measurements, and b) FNDC5 and/or circulating Irisin and/or UCP1 levels in white adipocytes. Results: We included 51 studies (12 randomised controlled trials) with 2474 participants. Out of the 51 studies, 16 examined PGC-1a and FNDC5 in response to exercise, and only four found increases in both PGC-1a and FNDC5 mRNA and one showed increased FNDC5 mRNA. In total, 22 out of 45 studies that examined circulating Irisin in response to exercise showed increased concentrations when ELISA techniques were used; two studies also revealed increased Irisin levels measured via mass spectrometry. Three studies showed a positive association of circulating Irisin with physical activity levels. One study found no exercise effects on UCP1 mRNA in white adipocytes. Conclusions: The effects of physical activity on the link between PGC-1a, FNDC5 mRNA in muscle and UCP1 in white human adipocytes has attracted little scientific attention. Current methods for Irisin identification lack precision and, therefore, the existing evidence does not allow for conclusions to be made regarding Irisin responses to physical activity. We found a contrast between standardised review methods and accuracy of the measurements used. This should be considered in future systematic reviews. PMID:28620456

Increased Circulating Levels of Vitamin D Binding Protein in MS Patients

PubMed Central

Rinaldi, Arturo Ottavio; Sanseverino, Isabella; Purificato, Cristina; Cortese, Antonio; Mechelli, Rosella; Francisci, Silvia; Salvetti, Marco; Millefiorini, Enrico; Gessani, Sandra; Gauzzi, Maria Cristina

2015-01-01

Vitamin D (vitD) low status is currently considered a main environmental factor in multiple sclerosis (MS) etiology and pathogenesis. VitD and its metabolites are highly hydrophobic and circulate mostly bound to the vitamin D binding protein (DBP) and with lower affinity to albumin, while less than 1% are in a free form. The aim of this study was to investigate whether the circulating levels of either of the two vitD plasma carriers and/or their relationship are altered in MS. We measured DBP and albumin plasma levels in 28 MS patients and 24 healthy controls. MS patients were found to have higher DBP levels than healthy subjects. Concomitant interferon beta therapy did not influence DBP concentration, and the difference with the control group was significant in both females and males. No significant correlation between DBP and albumin levels was observed either in healthy controls or in patients. These observations suggest the involvement of DBP in the patho-physiology of MS. PMID:25590278

HIV-1/HAART-Related Lipodystrophy Syndrome (HALS) Is Associated with Decreased Circulating sTWEAK Levels

PubMed Central

López-Dupla, Miguel; Maymó-Masip, Elsa; Martínez, Esteban; Domingo, Pere; Leal, Manuel; Peraire, Joaquim; Viladés, Consuelo; Veloso, Sergi; Arnedo, Mireia; Ferrando-Martínez, Sara; Beltrán-Debón, Raúl; Alba, Verónica; Gatell, Josep Mª; Vendrell, Joan; Vidal, Francesc; Chacón, Matilde R.

2015-01-01

Background and Objectives Obesity and HIV-1/HAART–associated lipodystrophy syndrome (HALS) share clinical, pathological and mechanistic features. Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) is a multifunctional cytokine that plays an important role in obesity and related diseases. We sought to explore the relationship between HALS and circulating levels of soluble (s) TWEAK and its scavenger receptor sCD163. Methods This was a cross-sectional multicenter study of 120 HIV-1-infected patients treated with a stable HAART regimen; 56 with overt HALS and 64 without HALS. Epidemiological and clinical variables were determined. Serum levels of sTWEAK and sCD163 levels were measured by ELISA. Results were analyzed with Student’s t-test, Mann-Whitney U and χ2 test. Pearson and Spearman correlation were used to estimate the strength of association between variables. Results Circulating sTWEAK was significantly decreased in HALS patients compared with non-HALS patients (2.81±0.2 vs. 2.94±0.28 pg/mL, p = 0.018). No changes were observed in sCD163 levels in the studied cohorts. On multivariate analysis, a lower log sTWEAK concentration was independently associated with the presence of HALS (OR 0.027, 95% CI 0.001–0.521, p = 0.027). Conclusions HALS is associated with decreased sTWEAK levels. PMID:26658801

Apoptosis-related deregulation of proteolytic activities and high serum levels of circulating nucleosomes and DNA in blood correlate with breast cancer progression.

PubMed

Roth, Carina; Pantel, Klaus; Müller, Volkmar; Rack, Brigitte; Kasimir-Bauer, Sabine; Janni, Wolfgang; Schwarzenbach, Heidi

2011-01-06

As cell-free circulating DNA exists predominantly as mono- and oligonucleosomes, the focus of the current study was to examine the interplay of circulating nucleosomes, DNA, proteases and caspases in blood of patients with benign and malignant breast diseases. The concentrations of cell-free DNA and nucleosomes as well as the protease and caspase activities were measured in serum of patients with benign breast disease (n = 20), primary breast cancer (M0, n = 31), metastatic breast cancer (M1, n = 32), and healthy individuals (n = 28) by PicoGreen, Cell Death Detection ELISA, Protease Fluorescent Detection Kit and Caspase-Glo®3/7 Assay, respectively. Patients with benign and malignant tumors had significantly higher levels of circulating nucleic acids in their blood than healthy individuals (p = 0.001, p = 0.0001), whereas these levels could not discriminate between benign and malignant lesions. Our analyses of all serum samples revealed significant correlations of circulating nucleosome with DNA concentrations (p = 0.001), nucleosome concentrations with caspase activities (p = 0.008), and caspase with protease activities (p = 0.0001). High serum levels of protease and caspase activities associated with advanced tumor stages (p = 0.009). Patients with lymph node-positive breast cancer had significantly higher nucleosome levels in their blood than node-negative patients (p = 0.004). The presence of distant metastases associated with a significant increase in serum nucleosome (p = 0.01) and DNA levels (p = 0.04), and protease activities (p = 0.008). Our findings demonstrate that high circulating nucleic acid concentrations in blood are no indicators of a malignant breast tumor. However, the observed changes in apoptosis-related deregulation of proteolytic activities along with the elevated serum levels of nucleosomes and DNA in blood are linked to breast cancer progression.

Increased circulating fibrocytes are associated with higher reticulocyte percent in children with sickle cell anemia.

PubMed

Karafin, Matthew S; Dogra, Shibani; Rodeghier, Mark; Burdick, Marie; Mehrad, Borna; Rose, C Edward; Strieter, Robert M; DeBaun, Michael R; Strunk, Robert C; Field, Joshua J

2016-03-01

Interstitial lung disease is common in patients with sickle cell anemia (SCA). Fibrocytes are circulating cells implicated in the pathogenesis of pulmonary fibrosis and airway remodeling in asthma. In this study, we tested the hypotheses that fibrocyte levels are: (1) increased in children with SCA compared to healthy controls, and (2) associated with pulmonary disease. Cross-sectional cohort study of children with SCA who participated in the Sleep Asthma Cohort Study. Fibrocyte levels were obtained from 45 children with SCA and 24 controls. Mean age of SCA cases was 14 years and 53% were female. In children with SCA, levels of circulating fibrocytes were greater than controls (P < 0.01). The fibrocytes expressed a hierarchy of chemokine receptors, with CXCR4 expressed on the majority of cells and CCR2 and CCR7 expressed on a smaller subset. Almost half of fibrocytes demonstrated α-smooth muscle actin activation. Increased fibrocyte levels were associated with a higher reticulocyte count (P = 0.03) and older age (P = 0.048) in children with SCA. However, children with increased levels of fibrocytes were not more likely to have asthma or lower percent predicted forced expiratory volume in 1 sec/forced vital capacity (FEV1 /FVC) or FEV1 than those with lower fibrocyte levels. Higher levels of fibrocytes in children with SCA compared to controls may be due to hemolysis. Longitudinal studies may be able to better assess the relationship between fibrocyte level and pulmonary dysfunction. © 2015 Wiley Periodicals, Inc.

Circulating FABP4 and FABP5 Levels Are Differently Linked to OSA Severity and Treatment

PubMed Central

Català, Raquel; Cabré, Anna; Hernández-Flix, Salvador; Ferré, Raimón; Sangenís, Sandra; Plana, Núria; Texidó, Anna; Masana, Lluís

2013-01-01

Objective: To evaluate circulating adipocyte and epidermal fatty acid-binding protein (FABP4 and FABP5) concentrations in patients with obstructive sleep apnea (OSA), as well as the effects of continuous positive airway pressure (CPAP) treatment. Methods: Our cross-sectional study included 125 patients. After polysomnography, 58 participants met the criteria for CPAP treatment and were included in a closed cohort study of 8 weeks of CPAP treatment. General anthropometric and biochemical data and circulating FABP4 and FABP5 levels were determined in all patients at baseline and after CPAP treatment in those receiving this therapy. Results Circulating FABP4 but not FABP5 levels were higher in patients with OSA (P = 0.003). FABP4 but not FABP5 values were associated with parameters of OSA severity independently of age, gender, adiposity and insulin resistance (P < 0.05). FABP4 but not FABP5 concentrations were determinants of OSA presence (OR: 1.11, P = 0.010) and severity (OR: 1.06, P = 0.020). After CPAP treatment, FABP4 levels decreased in the more severe patients (P = 0.019), while FABP5 levels increased in all patients (P < 0.001). Conclusions FABP4 is directly associated with obstructive sleep apnea severity and did not change with continuous positive airway pressure treatment, while FABP5 was not associated with obstructive sleep apnea severity and increased with continuous positive airway pressure treatment. FABP4 and FABP5 have different associations with obstructive sleep apnea. FABP4 but not FABP5 could be considered a marker of metabolic alterations in obstructive sleep apnea patients. Citation: Català R; Cabré A; Hernández-Flix S; Ferré R; Sangenís S; Plana N; Texidó A; Masana L. Circulating FABP4 and FABP5 levels are differently linked to OSA severity and treatment. SLEEP 2013;36(12):1831-1837. PMID:24293757

Presence of irregularity in region between -1115 and -784 nt in P1 promoter of insulin-like growth factor-1 gene may indicate beneficial effect on coronary arteries in a group of patients with stable angina: preliminary data.

PubMed

Burchardt, Pawel; Nowak, Witold; Gozdzicka-Jozefiak, Anna; Link, Rafal; Grotowski, Tomasz; Wisniecka, Anna; Siminiak, Tomasz

2009-07-01

Insulin-like growth factor-1 (IGF-1) plays an important role in arterial homeostasis. Its properties seem to depend on circulating IGF-1 level changes. The various IGF-1 levels are caused by varied expression of IGF-1 gene, due to the polymorphic structure of IGF-1 gene or its regulatory sequences. We examined the P1 promoter, being responsible for most IGF-1 transcripts, in patients with stable angina, to evaluate its sequence changes and to assess its influence on protein synthesis as well as on the degree of arteriosclerosis. For that purpose we evaluated the DNA isolated from blood cells. The DNA was amplified by using polymerase chain reaction (PCR), then analyzed using the SSCP (single-strand conformation polymorphism) technique. Products of every stage were verified by electrophoresis on agarose gel. In addition, every patient had coronary angiography performed and IGF-1, IGFBP3, and lipid levels measured. The SSCP in the region between -1115 and -784 nt was less commonly observed among subjects with positive MI (myocardial infarction) familial history (P = 0.0008) and with MI history (P = 0.012) than in patients without these conditions. Subjects with this irregularity tended towards higher circulating IGF-1 levels. In addition high Gensini scores - over 95th percentile, 105 points in our study - were more frequent in SSCP patients (P = 0.03). We presume that presence of SSCP in the P1 region between -1115 and -784 nt may positively affect coronary arteries by increasing circulating IGF-1 levels, but its clinical importance requires molecular verification and further studies.

Relationship between circulating visfatin/NAMPT, nutritional status and insulin resistance in an elderly population - results from the PolSenior substudy.

PubMed

Olszanecka-Glinianowicz, Magdalena; Owczarek, Aleksander; Bożentowicz-Wikarek, Maria; Brzozowska, Aniceta; Mossakowska, Małgorzata; Zdrojewski, Tomasz; Grodzicki, Tomasz; Więcek, Andrzej; Chudek, Jerzy

2014-11-01

Circulating visfatin/nicotinamide phosphoribosyltransferase (visfatin/NAMPT) levels according to some studies are related to nutritional status and insulin resistance. These associations have not been studied in large elderly populations. Therefore, the aim of our study was to assess the relationships between circulating visfatin/NAMPT levels, nutritional status, and insulin resistance in a large population of the elderly. Concentrations of glucose, albumin, creatinine, CRP, interleukin-6, insulin, and visfatin/NAMPT (by ELISA) were assessed, and HOMA-IR calculated in 3050 elderly participants of the PolSenior study. The highest plasma visfatin/NAMPT levels were observed in obese, as well as in non-diabetic insulin resistant subjects; however there were only significant differences found in women. The regression models showed that plasma visfatin/NAMPT levels decline with age and increased with waist circumference, BMI, and hs-CRP. Waist circumference was better correlated than BMI for visfatin/NAMPT levels in statistical models not adjusted by sex, and just the opposite in models which were. We demonstrated a 0.023ng/mL increase of Visfatin/NAMPT levels for 1mg/L increase of hs-CRP, and a 0.007ng/mL decline for each year of age. Our study revealed that in elderly subjects, circulating visfatin/NAMPT levels are related to age, nutritional status, especially visceral obesity, and inflammation. Copyright © 2014 Elsevier Inc. All rights reserved.

Low-dose endotoxemia and human neuropsychological functions.

PubMed

Krabbe, Karen Suárez; Reichenberg, Abraham; Yirmiya, Raz; Smed, Annelise; Pedersen, Bente Klarlund; Bruunsgaard, Helle

2005-09-01

Epidemiological data demonstrate an association between systemic low-grade inflammation defined as 2- to 3-fold increases in circulating inflammatory mediators and age-related decline in cognitive function. However, it is not known whether small elevations of circulating cytokine levels cause direct effects on human neuropsychological functions. We investigated changes in emotional, cognitive, and inflammatory parameters in an experimental in vivo model of low-grade inflammation. In a double-blind crossover study, 12 healthy young males completed neuropsychological tests before as well as 1.5, 6, and 24 h after an intravenous injection of Escherichia coli endotoxin (0.2 ng/kg) or saline in two experimental sessions. Endotoxin administration had no effect on body temperature, cortisol levels, blood pressure or heart rate, but circulating levels of tumor necrosis factor (TNF) and interleukin (IL)-6 increased 2- and 7-fold, respectively, reaching peak values at 3 h, whereas soluble TNF-receptors and IL-1 receptor antagonist peaked at 4.5 h. The neutrophil count increased and the lymphocyte count declined. In this model, low-dose endotoxemia did not affect cognitive performance significantly but declarative memory performance was inversely correlated with cytokine increases. In conclusion, our findings demonstrate a negative association between circulating IL-6 and memory functions during very low-dose endotoxemia independently of physical stress symptoms, and the hypothalamo-pituitary-adrenal axis.

Ciculating miRNA-21 as a Biomarker Predicts Polycystic Ovary Syndrome (PCOS) in Patients.

PubMed

Jiang, Liyan; Li, Wei; Wu, Minmin; Cao, Sifan

2015-01-01

Polycystic ovary syndrome (PCOS) is characterized by hyperandrogenism, hyperinsulinemia, and infertility. In PCOS, abnormal regulation of relevant genes is required for follicular development. By binding to the 3' untranslated region (3'URT), microRNAs (miRNAs) are widely involved in posttranscriptional gene regulation. However, few studies have been conducted on circulating miRNA expression in PCOS. This study aims to describe altered expression of circulating miR-21 in PCOS. The expression of serum miRNAs of PCOS patients were explored using the TaqMan Low Density Array followed by individual quantitative reverse transcription polymerase chain reaction assays. The protein level of LATS1 was determined using Western blot. To validate whether miR-21 targeted LATS1, the luciferase assay was applied. In comparison with normal subjects, the circulating level of miRNA-21 was significantly enhanced in PCOS patients. In PCOS patients, the expression levels of MST1/2, LATS1/2, TAZ were much lower than the control subjects. Luciferase reporter assay revealed that LATS1 was a downstream target of miR-21. In comparison with normal subjects, serum miR-21 is obviously increased in PCOS patients. Through targeting LATS1, miR-21 could prompt PCOS progression and could act as a novel non-invasive biomarker for diagnosis of PCOS.

PSA-alpha-2-macroglobulin complex is enzymatically active in the serum of patients with advanced prostate cancer and can degrade circulating peptide hormones.

PubMed

Kostova, Maya B; Brennen, William Nathaniel; Lopez, David; Anthony, Lizamma; Wang, Hao; Platz, Elizabeth; Denmeade, Samuel R

2018-08-01

Prostate cancer cells produce high levels of the serine protease Prostate-Specific Antigen (PSA). PSA is enzymatically active in the tumor microenvironment but is presumed to be enzymatically inactive in the blood due to complex formation with serum protease inhibitors α-1-antichymotrypsin and α-2-macroglobulin (A2M). PSA-A2M complexes cannot be measured by standard ELISA assays and are also rapidly cleared from the circulation. Thus the exact magnitude of PSA production by prostate cancer cells is not easily measured. The PSA complexed to A2M is unable to cleave proteins but maintains the ability to cleave small peptide substrates. Thus, in advanced prostate cancer, sufficient PSA-A2M may be in circulation to effect total A2M levels, levels of cytokines bound to A2M and hydrolyze small circulating peptide hormones. Total A2M levels in men with advanced prostate cancer and PSA levels above 1000 ng/mL were measured by ELISA and compared to controls. Additional ELISA assays were used to measure levels of IL-6 and TGF-beta which can bind to A2M. The ability of PSA-A2M complexes to hydrolyze protein and peptide substrates was analyzed ± PSA inhibitor. Enzymatic activity of PSA-A2M in serum of men with high PSA levels was also assayed. Serum A2M levels are inversely correlated with PSA levels in men with advanced prostate cancer. Il-6 Levels are significantly elevated in men with PSA >1000 ng/mL compared to controls with PSA <0.1 ng/mL. PSA-A2M complex in serum of men with PSA levels >1000 ng/mL can hydrolyze small fluorescently labeled peptide substrates but not large proteins that are PSA substrates. PSA can hydrolyze small peptide hormones like PTHrP and osteocalcin. PSA complexed to A2M retains the ability to degrade PTHrP. In advanced prostate cancer with PSA levels >1000 ng/mL, sufficient PSA-A2M is present in circulation to produce enzymatic activity against circulating small peptide hormones. Sufficient PSA is produced in advanced prostate cancer to alter total A2M levels, which can potentially alter levels of a variety of growth factors such as IL-6, TGF-beta, basic FGF, and PDGF. Alterations in levels of these cytokines and proteolytic degradation of small peptide hormones may have profound effect on host-cancer interaction. © 2018 Wiley Periodicals, Inc.

Anticipatory and consummatory effects of (hedonic) chocolate intake are associated with increased circulating levels of the orexigenic peptide ghrelin and endocannabinoids in obese adults.

PubMed

Rigamonti, Antonello E; Piscitelli, Fabiana; Aveta, Teresa; Agosti, Fiorenza; De Col, Alessandra; Bini, Silvia; Cella, Silvano G; Di Marzo, Vincenzo; Sartorio, Alessandro

2015-01-01

Hedonic hunger refers to consumption of food just for pleasure and not to maintain energy homeostasis. Recently, consumption of food for pleasure was reported to be associated with increased circulating levels of both the orexigenic peptide ghrelin and the endocannabinoid 2-arachidonoyl-glycerol (2-AG) in normal-weight subjects. To date, the effects of hedonic hunger, and in particular of chocolate craving, on these mediators in obese subjects are still unknown. To explore the role of some gastrointestinal orexigenic and anorexigenic peptides and endocannabinoids (and some related congeners) in chocolate consumption, we measured changes in circulating levels of ghrelin, glucagon-like peptide 1 (GLP-1), peptide YY (PYY), anandamide (AEA), 2-AG, palmitoylethanolamide (PEA), and oleoylethanolamide (OEA) in 10 satiated severely obese subjects after consumption of chocolate and, on a separate day, of a non-palatable isocaloric food with the same bromatologic composition. Evaluation of hunger and satiety was also performed by visual analogic scale. The anticipatory phase and the consumption of food for pleasure were associated with increased circulating levels of ghrelin, AEA, 2-AG, and OEA. In contrast, the levels of GLP-1, PYY, and PEA did not differ before and after the exposure/ingestion of either chocolate or non-palatable foods. Hunger and satiety were higher and lower, respectively, in the hedonic session than in the non-palatable one. When motivation to eat is generated by exposure to, and consumption of, chocolate a peripheral activation of specific endogenous rewarding chemical signals, including ghrelin, AEA, and 2-AG, is observed in obese subjects. Although preliminary, these findings predict the effectiveness of ghrelin and endocannabinoid antagonists in the treatment of obesity.

Anticipatory and consummatory effects of (hedonic) chocolate intake are associated with increased circulating levels of the orexigenic peptide ghrelin and endocannabinoids in obese adults

PubMed Central

Rigamonti, Antonello E.; Piscitelli, Fabiana; Aveta, Teresa; Agosti, Fiorenza; De Col, Alessandra; Bini, Silvia; Cella, Silvano G.; Di Marzo, Vincenzo; Sartorio, Alessandro

2015-01-01

Background Hedonic hunger refers to consumption of food just for pleasure and not to maintain energy homeostasis. Recently, consumption of food for pleasure was reported to be associated with increased circulating levels of both the orexigenic peptide ghrelin and the endocannabinoid 2-arachidonoyl-glycerol (2-AG) in normal-weight subjects. To date, the effects of hedonic hunger, and in particular of chocolate craving, on these mediators in obese subjects are still unknown. Methods To explore the role of some gastrointestinal orexigenic and anorexigenic peptides and endocannabinoids (and some related congeners) in chocolate consumption, we measured changes in circulating levels of ghrelin, glucagon-like peptide 1 (GLP-1), peptide YY (PYY), anandamide (AEA), 2-AG, palmitoylethanolamide (PEA), and oleoylethanolamide (OEA) in 10 satiated severely obese subjects after consumption of chocolate and, on a separate day, of a non-palatable isocaloric food with the same bromatologic composition. Evaluation of hunger and satiety was also performed by visual analogic scale. Results The anticipatory phase and the consumption of food for pleasure were associated with increased circulating levels of ghrelin, AEA, 2-AG, and OEA. In contrast, the levels of GLP-1, PYY, and PEA did not differ before and after the exposure/ingestion of either chocolate or non-palatable foods. Hunger and satiety were higher and lower, respectively, in the hedonic session than in the non-palatable one. Conclusions When motivation to eat is generated by exposure to, and consumption of, chocolate a peripheral activation of specific endogenous rewarding chemical signals, including ghrelin, AEA, and 2-AG, is observed in obese subjects. Although preliminary, these findings predict the effectiveness of ghrelin and endocannabinoid antagonists in the treatment of obesity. PMID:26546790

[The physiology of the isolated dog pancreas--the influence of the actual blood glucose level on the blood circulation in the pancreas].

PubMed

Hempfling, H; Husemann, B

1975-06-01

1. Glucose loading tests were undertaken on isolated pancreas or pancreas-duodenal preparations. 2. In 75% of cases a vasodilatation can be observed which leads to enhanced blood circulation under constant pressure in the isolated organ. 3. This vasodilatation persists until the level of blood sugar has normalized. 4. The experiment being carried out on an isolated organ, external factors such as the vagus nerve, do not become active.

Association of circulating levels of nicotinamide phosphoribosyltransferase (NAMPT/Visfatin) and of a frequent polymorphism in the promoter of the NAMPT gene with coronary artery disease in diabetic and non-diabetic subjects

PubMed Central

2013-01-01

Background Nicotinamide phosphoribosyltransferase (NAMPT) is the limiting enzyme in one of pathways of synthesis of Nicotinamide Adenine Dinucleotide, a redox coenzyme. NAMPT is considered as an insulin-mimetic factor and a potential regulatory factor in inflammatory and immune processes. Associations of circulating NAMPT levels with cardiovascular disease (CVD) and insulin resistance have been reported. We investigated association of circulating NAMPT levels and the rs9770242 NAMPT gene polymorphism with coronary artery disease (CAD). Methods We studied 594 Brazilian subjects undergoing a coronary angiography (49% of whom had type 2 diabetes). CAD, defined as stenosis greater than 50% in one major coronary vessel or branch, was observed in 68% of subjects. Genetic studies were also performed in 858 North-American Non-Hispanic White subjects with type 2 diabetes (49% with CAD). Results We observed an interaction between glycemic and CAD status on the comparison of NAMPT levels by CAD status. NAMPT levels were higher in type 2 diabetic patients with CAD as compared to those without CAD: 5.27 ± 2.93 ng/ml vs. 4.43 ± 2.94 ng/ml, p = 0.006 (mean ± SD). NAMPT levels were not significantly different in non-diabetic subjects with or without CAD. The T-allele of rs9770242 was associated with CAD in the Brazilian cohort (OR 1.46, 95% CI 1.06 - 2.01, p = 0.02) while no association was observed in the North-American cohort. Conclusions Our data suggest that circulating NAMPT levels are associated with CAD in type 2 diabetic patients. NAMPT rs9770242 polymorphism may be associated with CAD in some populations. PMID:23968400

Hepatic IGF-1R overexpression combined with the activation of GSK-3β and FOXO3a in the development of liver cirrhosis.

PubMed

Liu, Wentao; Li, Jing; Cai, Yan; Wu, Qiong; Pan, Yue; Chen, Yang; Chen, Yujing; Zheng, Xiao; Li, Wei; Zhang, Xuewen; E, Changyong

2016-02-15

Liver cirrhosis is the common pathological histology manifest among a number of chronic liver diseases and liver cancer. Circulating levels of insulin growth factor-1 (IGF-1) have been recently linked to liver cirrhosis and the development of liver cancer. Herein, we hypothesized that IGF-1R overexpression combining the activation of GSK-3β and FOXO3a were involved in the development of human and murine chronic liver cirrhosis. Liver samples of patients were screened from the Tissue Bank of the China-Japan Union Hospital of Jilin University. Mice liver fibrosis model was performed using intraperitoneal injection of carbon tetrachloride (CCl4) for 12weeks. Serum IGF-1 levels were detected by enzyme-linked immunosorbent assays (ELISA). Microscopical examination of liver parenchyma was performed using conventional H&E and Masson's staining. Moreover, we investigated the IGF-1 receptor (IGF-1R) signaling pathway at different period after CCl4 administration. Serum IGF-1 levels were significantly decreased in patients with liver cirrhosis, which is concomitant with the declined circulating levels of IGF-1 in 8 to 12weeks CCl4-treated mice. Furthermore, the expression of IGF-1R was significantly higher at 12w compared with control group. In addition, activation of the GSK-3β and FOXO3a were activated during the process of murine chronic liver injury. The present study demonstrates that decreased circulating IGF-1 levels are involved in human and murine chronic liver disease. Interestingly, overexpression of the IGF-1R, and activation of GSK3β and FOXO3a might be the molecular mechanisms underlying the development of liver cirrhosis. Copyright © 2016 Elsevier Inc. All rights reserved.

Impaired Endothelial Progenitor Cell Mobilization and Dysfunctional Bone Marrow Stroma in Diabetes Mellitus

PubMed Central

Rafii, Shahin; Jaspers, Janneke E.; White, Ian A.; Hooper, Andrea T.; Doevendans, Pieter A.; Verhaar, Marianne C.

2013-01-01

Background Circulating Endothelial Progenitor Cell (EPC) levels are reduced in diabetes mellitus. This may be a consequence of impaired mobilization of EPC from the bone marrow. We hypothesized that under diabetic conditions, mobilization of EPC from the bone marrow to the circulation is impaired –at least partly– due to dysfunction of the bone marrow stromal compartment. Methods Diabetes was induced in mice by streptozotocin injection. Circulating Sca-1+Flk-1+ EPC were characterized and quantified by flow cytometry at baseline and after mobilization with G-CSF/SCF injections. In vivo hemangiogenic recovery was tested by 5-FU challenge. Interaction within the bone marrow environment between CD34+ hematopoietic progenitor cells (HPC) and supporting stroma was assessed by co-cultures. To study progenitor cell–endothelial cell interaction under normoglycemic and hyperglycemic conditions, a co-culture model using E4Orf1-transfected human endothelial cells was employed. Results In diabetic mice, bone marrow EPC levels were unaffected. However, circulating EPC levels in blood were lower at baseline and mobilization was attenuated. Diabetic mice failed to recover and repopulate from 5-FU injection. In vitro, primary cultured bone marrow stroma from diabetic mice was impaired in its capacity to support human CFU-forming HPC. Finally, hyperglycemia hampered the HPC supportive function of endothelial cells in vitro. Conclusion EPC mobilization is impaired under experimental diabetic conditions and our data suggest that diabetes induces alterations in the progenitor cell supportive capacity of the bone marrow stroma, which could be partially responsible for the attenuated EPC mobilization and reduced EPC levels observed in diabetic patients. PMID:23555959

Impaired endothelial progenitor cell mobilization and dysfunctional bone marrow stroma in diabetes mellitus.

PubMed

Westerweel, Peter E; Teraa, Martin; Rafii, Shahin; Jaspers, Janneke E; White, Ian A; Hooper, Andrea T; Doevendans, Pieter A; Verhaar, Marianne C

2013-01-01

Circulating Endothelial Progenitor Cell (EPC) levels are reduced in diabetes mellitus. This may be a consequence of impaired mobilization of EPC from the bone marrow. We hypothesized that under diabetic conditions, mobilization of EPC from the bone marrow to the circulation is impaired -at least partly- due to dysfunction of the bone marrow stromal compartment. Diabetes was induced in mice by streptozotocin injection. Circulating Sca-1(+)Flk-1(+) EPC were characterized and quantified by flow cytometry at baseline and after mobilization with G-CSF/SCF injections. In vivo hemangiogenic recovery was tested by 5-FU challenge. Interaction within the bone marrow environment between CD34(+) hematopoietic progenitor cells (HPC) and supporting stroma was assessed by co-cultures. To study progenitor cell-endothelial cell interaction under normoglycemic and hyperglycemic conditions, a co-culture model using E4Orf1-transfected human endothelial cells was employed. In diabetic mice, bone marrow EPC levels were unaffected. However, circulating EPC levels in blood were lower at baseline and mobilization was attenuated. Diabetic mice failed to recover and repopulate from 5-FU injection. In vitro, primary cultured bone marrow stroma from diabetic mice was impaired in its capacity to support human CFU-forming HPC. Finally, hyperglycemia hampered the HPC supportive function of endothelial cells in vitro. EPC mobilization is impaired under experimental diabetic conditions and our data suggest that diabetes induces alterations in the progenitor cell supportive capacity of the bone marrow stroma, which could be partially responsible for the attenuated EPC mobilization and reduced EPC levels observed in diabetic patients.

Systematic review and meta-analysis of randomised controlled trials on the effects of potassium supplements on serum potassium and creatinine.

PubMed

Cappuccio, Francesco P; Buchanan, Laura A; Ji, Chen; Siani, Alfonso; Miller, Michelle A

2016-08-26

High potassium intake could prevent stroke, but supplementation is considered hazardous. We assessed the effect of oral potassium supplementation on serum or plasma potassium levels and renal function. We updated a systematic review of the effects of potassium supplementation in randomised clinical trials carried out worldwide, published in 2013, extending it to July 2015. We followed the PRISMA guidelines. Any individual taking part in a potassium supplementation randomised clinical trial. Studies included met the following criteria: randomised clinical trials, potassium supplement given and circulating potassium levels reported. Oral potassium supplementation. Serum or plasma potassium and serum or plasma creatinine. A total of 20 trials (21 independent groups) were included (1216 participants from 12 different countries). All but 2 were controlled (placebo n=16, control n=2). Of these trials, 15 were crossover, 4 had a parallel group and 1 was sequential. The duration of supplementation varied from 2 to 24 weeks and the amount of potassium given from 22 to 140 mmol/day. In the pooled analysis, potassium supplementation caused a small but significant increase in circulating potassium levels (weighted mean difference (WMD) 0.14 mmol/L, 95% CI 0.09 to 0.19, p<1×10(-5)), not associated with dose or duration of treatment. The average increase in urinary potassium excretion was 45.75 mmol/24 hours, 95% CI 38.81 to 53.69, p<1×10(-5). Potassium supplementation did not cause any change in circulating creatinine levels (WMD 0.30 µmol/L, 95% CI -1.19 to 1.78, p=0.70). In short-term studies of relatively healthy persons, a moderate oral potassium supplement resulted in a small increase in circulating potassium levels and no change in renal function. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

Dose-and gender-specific effects of resistance training on circulating levels of brain derived neurotrophic factor (BDNF) in community-dwelling older adults.

PubMed

Forti, Louis Nuvagah; Van Roie, Evelien; Njemini, Rose; Coudyzer, Walter; Beyer, Ingo; Delecluse, Christophe; Bautmans, Ivan

2015-10-01

BDNF is known to induce neuroplasticity and low circulating levels have been related to neuronal loss in older persons. Physical exercise is thought to trigger BDNF-induced neuroplasticity, but conflicting observations have been reported regarding the effects of resistance training on circulating BDNF in the elderly. These conflicting observations might reflect dose-and gender-specific differences. Fifty-six apparently healthy elderly (68 ± 5 years) participants were randomized to 12 weeks of resistance training (3×/week) at either high-resistance (HIGH, 8 Males, 10 Females, 2 × 10-15 repetitions at 80% 1 RM), low-resistance (LOW, 9 Males, 10 Females, 1 × 80-100 repetitions at 20% 1 RM), or mixed low-resistance (LOW+, 9 Males, 10 Females, 1 × 60 repetitions at 20% 1 RM followed by 1 × 10-20 repetitions at 40% 1 RM). Serum was collected for BDNF assay at baseline and after 12 weeks (24 h-48 h after the last training). 12 weeks of LOW+ exercise significantly increased BDNF levels in male (from 34.9 ± 10.7 ng/mL to 42.9 ± 11.9 ng/mL, time × group interaction p=0.013), but not in female participants. No significant change was observed in HIGH or LOW, neither in male nor female subjects. Our results show that only the mixed-low-resistance training program with a very high number of repetitions at a sufficiently high external resistance was able to increase circulating BDNF in older male participants. Training to volitional fatigue might be necessary to obtain optimal results. Additional studies are needed to unravel the underlying mechanisms, as well as to confirm the observed gender difference. Copyright © 2015 Elsevier Inc. All rights reserved.

Metabolic factors, adipose tissue, and plasminogen activator inhibitor-1 levels in Type 2 diabetes

USDA-ARS?s Scientific Manuscript database

Plasminogen activator inhibitor-1 (PAI-1) production by adipose tissue is increased in obesity, and its circulating levels are high in type 2 diabetes. PAI-1 increases cardiovascular risk by favoring clot stability, interfering with vascular remodeling, or both. We investigated in obese diabetic per...

Relationships between hormones and aggressive behavior in green anole lizards: an analysis using structural equation modeling.

PubMed

Yang, Eun-Jin; Wilczynski, Walter

2002-09-01

We investigated the relationship between aggressive behavior and circulating androgens in the context of agonistic social interaction and examined the effect of this interaction on the androgen-aggression relationship in response to a subsequent social challenge in male Anolis carolinensis lizards. Individuals comprising an aggressive encounter group were exposed to an aggressive conspecific male for 10 min per day during a 5-day encounter period, while controls were exposed to a neutral stimulus for the same period. On the sixth day, their responses to an intruder test were observed. At intervals, individuals were sacrificed to monitor plasma androgen levels. Structural equation modeling (SEM) was used to test three a priori interaction models of the relationship between social stimulus, aggressive behavior, and androgen. Model 1 posits that exposure to a social stimulus influences androgen and aggressive behavior independently. In Model 2, a social stimulus triggers aggressive behavior, which in turn increases circulating levels of androgen. In Model 3, exposure to a social stimulus influences circulating androgen levels, which in turn triggers aggressive behavior. During the 5 days of the encounter period, circulating testosterone (T) levels of the aggressive encounter group followed the same pattern as their aggressive behavioral responses, while the control group did not show significant changes in their aggressive behavior or T level. Our SEM results supported Model 2. A means analysis showed that during the intruder test, animals with 5 days of aggressive encounters showed more aggressive responses than did control animals, while their circulating androgen levels did not differ. This further supports Model 2, suggesting that an animal's own aggressive behavior may trigger increases in levels of plasma androgen. Copyright 2002 Elsevier Science (USA)

Long-term deficiency of circulating and hippocampal insulin-like growth factor I induces depressive behavior in adult mice: A potential model of geriatric depression

PubMed Central

Mitschelen, Matthew; Yan, Han; Farley, Julie A.; Warrington, Junie P.; Han, Song; Hereñú, Claudia B.; Csiszar, Anna; Ungvari, Zoltan; Bailey-Downs, Lora C.; Bass, Caroline E.; Sonntag, William E.

2011-01-01

Numerous studies support the hypothesis that deficiency of insulin-like growth factor I (IGF-1) in adults contributes to depression, but direct evidence is limited. Many psychological and pro-cognitive effects have been attributed to IGF-1, but appropriate animal models of adult-onset IGF-1 deficiency are lacking. In this study, we use a viral-mediated Cre-loxP system to knockout the Igf1 gene in either the liver, neurons of the CA1 region of the hippocampus, or both. Knockout of liver Igf1 reduced serum IGF-1 levels by 40% and hippocampal IGF-1 levels by 26%. Knockout of Igf1 in CA1 reduced hippocampal IGF-1 levels by 13%. The most severe reduction in hippocampal IGF-1 occurred in the group with knockouts in both liver and CA1 (36% reduction), and was associated with a 3.5-fold increase in immobility in the forced swim test. Reduction of either circulating or hippocampal IGF-1 levels did not alter anxiety measured in an open field and elevated plus maze, nor locomotion in the open field. Furthermore, local compensation for deficiencies in circulating IGF-1 did not occur in the hippocampus, nor were serum levels of IGF-1 upregulated in response to the moderate decline of hippocampal IGF-1 caused by the knockouts in CA1. We conclude that adult-onset IGF-1 deficiency alone is sufficient to induce a depressive phenotype in mice. Furthermore, our results suggest that individuals with low brain levels of IGF-1 are at increased risk for depression and these behavioral effects are not ameliorated by increased local IGF-1 production or transport. Our study supports the hypothesis that the natural IGF-1 decline in aging humans may contribute to geriatric depression. PMID:21524689

Elevation of soluble intercellular adhesion molecule-1 levels, but not angiopoietin 2, in the plasma of human immunodeficiency virus-infected African women with clinical Kaposi sarcoma.

PubMed

Graham, Susan M; Rajwans, Nimerta; Richardson, Barbra A; Jaoko, Walter; McClelland, R Scott; Overbaugh, Julie; Liles, W Conrad

2014-10-01

Circulating levels of endothelial activation biomarkers are elevated in during infection with human immunodeficiency virus 1 (HIV-1) and may also be increased in Kaposi sarcoma (KS). We compared 23 HIV-1-seropositive women with clinically diagnosed KS with 46 randomly selected controls matched for visit year, CD4 count, and antiretroviral therapy status. Conditional logistic regression was used to identify differences between cases and controls. The odds of clinical KS increased with increasing plasma viral load and with intercellular adhesion molecule 1 (ICAM-1) levels above or equal to the median. There was a borderline association between increasing plasma angiopoietin 2 levels and KS. In multivariable modeling including plasma viral load, angiopoietin 2, and ICAM-1, plasma ICAM-1 levels above or equal to the median remained associated with clinical KS (odds ratio = 14.2, 95% confidence interval = 2.3-87.7). Circulating ICAM-1 levels should be evaluated as a potential biomarker for disease progression and treatment response among HIV-infected KS patients. © The American Society of Tropical Medicine and Hygiene.

B Cell Response and Hemagglutinin Stalk-Reactive Antibody Production in Different Age Cohorts following 2009 H1N1 Influenza Virus Vaccination

PubMed Central

Baer, Jane; Santiago, Felix W.; Fitzgerald, Theresa; Ilyushina, Natalia A.; Sundararajan, Aarthi; Henn, Alicia D.; Krammer, Florian; Yang, Hongmei; Luke, Catherine J.; Zand, Martin S.; Wright, Peter F.; Treanor, John J.; Topham, David J.

2013-01-01

The 2009 pandemic H1N1 (pH1N1) influenza virus carried a swine-origin hemagglutinin (HA) that was closely related to the HAs of pre-1947 H1N1 viruses but highly divergent from the HAs of recently circulating H1N1 strains. Consequently, prior exposure to pH1N1-like viruses was mostly limited to individuals over the age of about 60 years. We related age and associated differences in immune history to the B cell response to an inactivated monovalent pH1N1 vaccine given intramuscularly to subjects in three age cohorts: 18 to 32 years, 60 to 69 years, and ≥70 years. The day 0 pH1N1-specific hemagglutination inhibition (HAI) and microneutralization (MN) titers were generally higher in the older cohorts, consistent with greater prevaccination exposure to pH1N1-like viruses. Most subjects in each cohort responded well to vaccination, with early formation of circulating virus-specific antibody (Ab)-secreting cells and ≥4-fold increases in HAI and MN titers. However, the response was strongest in the 18- to 32-year cohort. Circulating levels of HA stalk-reactive Abs were increased after vaccination, especially in the 18- to 32-year cohort, raising the possibility of elevated levels of cross-reactive neutralizing Abs. In the young cohort, an increase in MN activity against the seasonal influenza virus A/Brisbane/59/07 after vaccination was generally associated with an increase in the anti-Brisbane/59/07 HAI titer, suggesting an effect mediated primarily by HA head-reactive rather than stalk-reactive Abs. Our findings support recent proposals that immunization with a relatively novel HA favors the induction of Abs against conserved epitopes. They also emphasize the need to clarify how the level of circulating stalk-reactive Abs relates to resistance to influenza. PMID:23576673

Pharmacodynamic effects of C-domain-specific ACE inhibitors on the renin-angiotensin system in myocardial infarcted rats.

PubMed

Sharp, Sarah; Poglitsch, Marko; Zilla, Peter; Davies, Neil H; Sturrock, Edward D

2015-12-01

The renin-angiotensin system (RAS) is a dynamic network that plays a critical role in blood pressure regulation and fluid and electrolyte homeostasis. Modulators of the RAS, such as angiotensin-converting enzyme (ACE) inhibitors, are widely used to treat hypertension, heart failure and myocardial infarction. The effect of ACE inhibitors (lisinopril and C-domain-selective LisW-S) on the constituent peptides of the RAS following myocardial infarction was examined in rats. Ten angiotensin peptides were analysed using a sensitive LC-MS/MS-based assay to examine both the circulating and equilibrium levels of these peptides. Administration of lisinopril or LisW-S caused a significant decrease in Ang 1-8/Ang 1-10 ratios as determined by circulating and equilibrium peptide level analysis. Furthermore, Ang 1-7 levels were elevated by both ACE inhibitors, but only lisinopril decreased the Ang 1-5/Ang 1-7 ratio. This indicates LisW-S C-domain specificity as Ang 1-5 is generated by hydrolysis of Ang 1-7 by the N-domain. Further corroboration of LisW-S C-domain specificity is that only lisinopril increased the circulating levels of the N-domain ACE substrate Ac-SDKP. LisW-S is able to effectively block ACE in vivo by C-domain-selective inhibition. The LC-MS/MS-based assay allows the evaluation of the pharmacologic impact of RAS inhibitors in different pathophysiological conditions. © The Author(s) 2015.

H pylori status and angiogenesis factors in human gastric carcinoma

PubMed Central

Mangia, Anita; Chiriatti, Annalisa; Ranieri, Girolamo; Abbate, Ines; Coviello, Maria; Simone, Giovanni; Zito, Francesco Alfredo; Montemurro, Severino; Rucci, Antonello; Leo, Alfredo Di; Tommasi, Stefania; Berloco, Pasquale; Xu, Jian Ming; Paradiso, Angelo

2006-01-01

AIM: To investigate H pylori expression in gastric cancer patients in relation to primary tumor angiogenic markers, such as microvessel density (MVD), thymidine phosphorylase (TP), vascular endothelial growth factor receptor-1 (VEGF-R1), p53 and circulating VEGF levels. METHODS: Angiogenic markers were analyzed immunohistochemically in 56 primary gastric cancers. H pylori cytotoxin (vacA) and the cytotoxin-associated gene (cagA) amplification were evaluated using PCR assay. Serum H pylori IgG antibodies and serum/plasma circulating VEGF levels were detected in 39 and 38 patients by ELISA, respectively. RESULTS: A total of 69% of patients were positive for circulating IgG antibodies against H pylori. cagA-positive H pylori strains were found in 41% of gastric patients. vacA was found in 50% of patients; s1 strains were more highly expressed among vacA-positive patients. The presence of the s1 strain was significantly associated with cagA (P = 0.0001). MVD was significantly correlated with both tumor VEGF expression (r = 0.361, P = 0.009) and serum VEGF levels (r = -0.347, P = 0.041). Conversely, neither VEGF-R1 expression nor MVD was related to p53 expression. However, H pylori was not related to any angiogenic markers except for the plasma VEGF level (P = 0.026). CONCLUSION: H pylori antigen is related to higher plasma VEGF levels, but not to angiogenic characteristics. It can be hypothesized that the toxic effects of H pylori on angiogenesis occurs in early preclinical disease phase or in long-lasting aggressive infections, but only when high H pylori IgG levels are persistent. PMID:17006982

Estimated Prestroke Peak VO2 Is Related to Circulating IGF-1 Levels During Acute Stroke.

PubMed

Mattlage, Anna E; Rippee, Michael A; Abraham, Michael G; Sandt, Janice; Billinger, Sandra A

2017-01-01

Background Insulin-like growth factor-1 (IGF-1) is neuroprotective after stroke and is regulated by insulin-like binding protein-3 (IGFBP-3). In healthy individuals, exercise and improved aerobic fitness (peak oxygen uptake; peak VO 2 ) increases IGF-1 in circulation. Understanding the relationship between estimated prestroke aerobic fitness and IGF-1 and IGFBP-3 after stroke may provide insight into the benefits of exercise and aerobic fitness on stroke recovery. Objective The purpose of this study was to determine the relationship of IGF-1 and IGFBP-3 to estimated prestroke peak VO 2 in individuals with acute stroke. We hypothesized that (1) estimated prestroke peak VO 2 would be related to IGF-1 and IGFBP-3 and (2) individuals with higher than median IGF-1 levels will have higher estimated prestroke peak VO 2 compared to those with lower than median levels. Methods Fifteen individuals with acute stroke had blood sampled within 72 hours of hospital admission. Prestroke peak VO 2 was estimated using a nonexercise prediction equation. IGF-1 and IGFBP-3 levels were quantified using enzyme-linked immunoassay. Results Estimated prestroke peak VO 2 was significantly related to circulating IGF-1 levels (r = .60; P = .02) but not IGFBP-3. Individuals with higher than median IGF-1 (117.9 ng/mL) had significantly better estimated aerobic fitness (32.4 ± 6.9 mL kg -1 min -1 ) than those with lower than median IGF-1 (20.7 ± 7.8 mL kg -1 min -1 ; P = .03). Conclusions Improving aerobic fitness prior to stroke may be beneficial by increasing baseline IGF-1 levels. These results set the groundwork for future clinical trials to determine whether high IGF-1 and aerobic fitness are beneficial to stroke recovery by providing neuroprotection and improving function. © The Author(s) 2016.

Development of the probability of return of spontaneous circulation in intervals without chest compressions during out-of-hospital cardiac arrest: an observational study.

PubMed

Gundersen, Kenneth; Kvaløy, Jan Terje; Kramer-Johansen, Jo; Steen, Petter Andreas; Eftestøl, Trygve

2009-02-06

One of the factors that limits survival from out-of-hospital cardiac arrest is the interruption of chest compressions. During ventricular fibrillation and tachycardia the electrocardiogram reflects the probability of return of spontaneous circulation associated with defibrillation. We have used this in the current study to quantify in detail the effects of interrupting chest compressions. From an electrocardiogram database we identified all intervals without chest compressions that followed an interval with compressions, and where the patients had ventricular fibrillation or tachycardia. By calculating the mean-slope (a predictor of the return of spontaneous circulation) of the electrocardiogram for each 2-second window, and using a linear mixed-effects statistical model, we quantified the decline of mean-slope with time. Further, a mapping from mean-slope to probability of return of spontaneous circulation was obtained from a second dataset and using this we were able to estimate the expected development of the probability of return of spontaneous circulation for cases at different levels. From 911 intervals without chest compressions, 5138 analysis windows were identified. The results show that cases with the probability of return of spontaneous circulation values 0.35, 0.1 and 0.05, 3 seconds into an interval in the mean will have probability of return of spontaneous circulation values 0.26 (0.24-0.29), 0.077 (0.070-0.085) and 0.040(0.036-0.045), respectively, 27 seconds into the interval (95% confidence intervals in parenthesis). During pre-shock pauses in chest compressions mean probability of return of spontaneous circulation decreases in a steady manner for cases at all initial levels. Regardless of initial level there is a relative decrease in the probability of return of spontaneous circulation of about 23% from 3 to 27 seconds into such a pause.

Uncoupled iron homeostasis in type 2 diabetes mellitus.

PubMed

Altamura, Sandro; Kopf, Stefan; Schmidt, Julia; Müdder, Katja; da Silva, Ana Rita; Nawroth, Peter; Muckenthaler, Martina U

2017-12-01

Diabetes mellitus is frequently associated with iron overload conditions, such as primary and secondary hemochromatosis. Conversely, patients affected by type 2 diabetes mellitus (T2DM) show elevated ferritin levels, a biomarker for increased body iron stores. Despite these documented associations between dysregulated iron metabolism and T2DM, the underlying mechanisms are poorly understood. Here, we show that T2DM patients have reduced serum levels of hepcidin, the iron-regulated hormone that maintains systemic iron homeostasis. Consistent with this finding, we also observed an increase in circulating iron and ferritin levels. Our analysis of db/db mice demonstrates that this model recapitulates the systemic alterations observed in patients. Interestingly, db/db mice show an overall hepatic iron deficiency despite unaltered expression of ferritin and the iron importer TfR1. In addition, the liver correctly senses increased circulating iron levels by activating the BMP/SMAD signaling pathway even though hepcidin expression is decreased. We show that increased AKT phosphorylation may override active BMP/SMAD signaling and decrease hepcidin expression in 10-week old db/db mice. We conclude that the metabolic alterations occurring in T2DM impact on the regulation of iron homeostasis on multiple levels. As a result, metabolic perturbations induce an "iron resistance" phenotype, whereby signals that translate increased circulating iron levels into hepcidin production, are dysregulated. T2DM patients show increased circulating iron levels. T2DM is associated with inappropriately low hepcidin levels. Metabolic alterations in T2DM induce an "iron resistance" phenotype.

[THE ROLE OF ANGIOGENIC FACTORS IN THE DIAGNOSTICS OF PREGNANCY COMPLICATED WITH PREECLAMPSIA].

PubMed

Tagiyeva, I; Aliyeva, S; Bagirova, S; Shamsadinskaya, N; Agaeva, K

2017-01-01

The pathophysiology of preeclampsia remains largely unknown. It has been hypothesized that placental ischemia is an early event, leading to placental production of a soluble factor or factors that cause maternal endothelial dysfunction, resulting in the clinical findings of hypertension, proteinuria, and edema. Here, we confirm that placental soluble fms-like tyrosine kinase 1 (sFlt1), an antagonist of vascular growth factor (VEGF) and placental growth factor (PIGF), is upregulated in preeclampsia, leading to increased systemic levels of sFlt1. Our research demonstrate that increased circulating sFlt1 in III trimester in patients with preeclampsia is associated with decreased circulating levels of free VEGF and PIGF, resulting in endothelial dysfunction, comparing with control group. These observations suggest that excess circulating sFlt1 contributes to the pathogenesis of preeclampsia. 45 pregnant women with preeclampsia of different severity degrees were under observation. Control group included 20 healthy pregnant. Pregnant women with preeclampsia were subdivided into 2 groups. There were 11 (24,4%) pregnant with severe degree of preeclamsia (I group), the II group included 34 pregnant with mild degree of preeclampsia. Increased expression of soluble tyrosine kinase-1 (sFlt-1), together with decreased PIGF and VEGF signaling, were first abnormalities described. Thus, determination of levels angiogenic factors: PIGF, VEGF and sFlt-1 is very important for prediction severity of preeclampsia.

Somatostatin-14 modulates postprandial glucose levels and release of gastrointestinal and pancreatic hormones.

PubMed

O'Shaughnessy, D J; Long, R G; Adrian, T E; Christofides, N D; Ghatei, M A; Sarson, D L; Bloom, S R

1985-01-01

Ingestion of a 4,500-kcal mixed meal by healthy volunteers resulted in a significant rise of plasma somatostatin-14-like immunoreactivity (9 +/- 1 pmol l-1. Whether this peptide has a role as a humoral agent or not is still controversial and, until recently, most studies investigating its effects by exogenous administration have produced vastly supraphysiological circulating plasma levels. In order to reproduce the rise obtained following the large meal, synthetic somatostatin-14 was infused at a dose of 0.8 pmol kg-1 min-1 before and during a 530-kcal test breakfast. This resulted in a rise of 8 + 2 pmol l-1 in the peripheral circulation. This infusion produced a significant reduction in the postprandial release of insulin, gastric inhibitory polypeptide, pancreatic polypeptide and in the preprandial motilin levels. In contrast, blood glucose levels following the breakfast were elevated when compared to the control saline infusion. This suggests that somatostatin possesses true endocrine functions and is capable of profoundly altering the postprandial glucose and hormone response.

Measurement of lipocortin 1 levels in murine peripheral blood leukocytes by flow cytometry: modulation by glucocorticoids and inflammation.

PubMed

Perretti, M; Flower, R J

1996-06-01

1. Lipocortin 1 (LC1) immunoreactivity in murine peripheral blood leukocytes was quantified by use of a flow cytometric technique associated with a permeabilisation protocol with saponin. Using specific antisera raised against the whole protein or against its N-terminus peptide, cell-associated LC1-like immunoreactivity was easily detected in circulating neutrophils and monocytes, whereas very low levels were found in lymphocytes. Of the total protein measured 17.6% and 36% were associated with the external plasma membrane in neutrophils and monocytes, as assessed in the absence of cell permeabilisation, whereas no signal was detected on lymphocyte plasma membrane. 2. Treatment of mice with dexamethasone (Dex; 0.5-5 micrograms per mouse corresponding to approximately 0.015-1.5 mg kg-1) increased LC1 levels in neutrophils and monocytes. The 2-3 fold increase in LC1 levels was time-dependent with a peak at 2 h. Treatment of mice with the steroid antagonist, RU486 (two doses of 20 mg kg-1 orally) decreased LC1-like immunoreactivity in all three types of circulating leukocytes by > or = 50%. 3. Extravasation of blood neutrophils into inflamed tissue sites resulted in a consistent reduction (> or = 50%) in LC1 levels compared with circulating neutrophils. A high LC1-like immunoreactivity was also measured in resident macrophages, of which approximately one third was membrane-associated. Induction of an acute inflammatory response in the murine peritoneal cavity did not modify total LC1 levels measured in macrophages, but reduced membrane-associated LC1 to a significant extent, i.e. up to 70%. 4. In conclusion, flow cytometric analysis is a rapid and convenient method for detecting and measuring LC1 in murine leukocytes. We confirmed that LC1 protein expression is controlled by exogenous and endogenous glucocorticoids. Amongst other factor(s) influencing protein concentrations, extravasation was found to be associated with a reduced LC1 expression in the emigrated cells.

Reduction of circulating and selective limbic brain levels of (3α,5α)-3-hydroxy-pregnan-20-one (3α,5α-THP) following forced swim stress in C57BL/6J mice

PubMed Central

Maldonado-Devincci, Antoniette M.; Beattie, Matthew C.; Morrow, Danielle H.; McKinley, Raechel E.; Cook, Jason B.; O’Buckley, Todd K.

2014-01-01

Rationale Stress activates the hypothalamic-pituitary-adrenal (HPA) axis, and GABAergic neuroactive steroids contribute to homeostatic regulation of this circuitry. Acute forced swim stress (FSS) increases plasma, cortical, and hypothalamic (3α,5α)-3-hydroxy-pregnan-20-one (3α,5α-THP) levels in rats. However, there have not been systemic investigations of acute stress on changes in plasma and brain levels of 3α,5α-THP in mouse models. Objectives The present experiments aimed to assess circulating and local brain levels of 3α,5α-THP following acute FSS in C57BL/6J mice. Methods Mice were exposed to FSS (10 min), and 50 min later, blood and brains were collected. Circulating pregnenolone and 3α,5α-THP levels were assessed in serum. Free-floating brain sections (40 µm, four to five sections/region) were immunostained and analyzed in cortical and limbic brain structures. Results FSS decreased circulating 3α,5α-THP (−41.6± 10.4 %) and reduced 3α,5α-THP immunolabeling in the paraventricular nucleus of the hypothalamus (−15.2±5.7 %), lateral amygdala (LA, −31.1±13.4 %), and nucleus accumbens (NAcc) shell (−31.9±14.6). Within the LA, vesicular glutamate transporter 1 (VGLUT1) and vesicular GABA transporter were localized in 3α,5α-THP-positively stained cells, while in the NAcc shell, only VGLUT1 was localized in 3α,5α-THP-positively stained cells, suggesting that both glutamatergic and GABAergic cells within the LA are 3α,5α-THP-positive, while in the NAcc shell, 3α,5α-THP only localizes to glutamatergic cells. Conclusions The decrease in circulating and brain levels of 3α,5α-THP may be due to alterations in the biosynthesis/ metabolism or changes in the regulation of the HPA axis following FSS. Changes in GABAergic neuroactive steroids in response to stress likely mediate functional adaptations in neuronal activity. This may provide a potential targeted therapeutic avenue to address maladaptive stress responsivity. PMID:24744202

Effect of naloxone on plasma insulin, insulin-like growth factor I, and its binding protein 1 in patients with polycystic ovarian disease.

PubMed

Laatikainen, T; Anttila, L; Suikkari, A M; Ruutiainen, K; Erkkola, R; Seppälä, M

1990-09-01

Insulin and insulin-like growth factors (IGFs) stimulate ovarian steroidogenesis, and hyperinsulinemia is often accompanied by hyperandrogenemia in women with polycystic ovarian disease (PCOD). Because opioid peptides are involved in the regulation of insulin secretion, we studied the effect of naloxone-induced opiate receptor blockade on the circulating levels of insulin, IGF-I, and IGF binding protein 1 (IGFBP-1) in 13 nonobese and 7 obese PCOD patients and in 6 healthy subjects. In obese PCOD patients, the mean basal insulin concentration was significantly higher and the IGFBP-1 concentration lower than in nonobese PCOD patients. Plasma IGF-I levels were elevated both in obese and nonobese PCOD patients. After an intravenous bolus of 10 mg naloxone, no significant changes were found in the circulating insulin or IGF-I levels, whereas IGFBP-1 levels decreased in nonobese PCOD patients and remained low in obese PCOD patients. No significant decrease was found in healthy subjects. These results suggest that, in addition to insulin, endogenous opioids are involved in the regulation of serum IGFBP-1 level.

Insights Into Circulating Cytokine Dynamics during Pregnancy in HIV-Infected Beninese Exposed to Plasmodium falciparum Malaria

PubMed Central

Ibitokou, Samad A.; Denoeud-Ndam, Lise; Ezinmegnon, Sèm; Ladékpo, Rodolphe; Zannou, Djimon-Marcel; Massougbodji, Achille; Girard, Pierre-Marie; Cot, Michel; Luty, Adrian J. F.; Ndam, Nicaise Tuikue

2015-01-01

We investigated the circulating plasma levels of Th1- (Interleukin-2 [IL-2], tumor necrosis factor-α [TNF-α], interferon-gamma [IFN-γ]) and Th2-type (IL-4, IL-5, IL-10) cytokines in human immunodeficiency virus (HIV)-infected pregnant women living in a malaria-endemic area. We analyzed samples from 200 pregnant women included in the prevention of pregnancy-associated malaria in HIV-infected women: cotrimoxazole prophylaxis versus mefloquine (PACOME) clinical trial who were followed until delivery. Cytokine concentrations were measured by flow cytometry-based multiplex bead array. Significantly elevated levels of IL-10 and lower levels of TNF-α were observed at delivery compared with inclusion (P = 0.005). At inclusion, the presence of circulating IFN-γ, a higher CD4+ T cell count and having initiated intermittent preventive treatment of malaria with sulfadoxine pyrimethamine (SP-IPTp) were all associated with a lower likelihood of Plasmodium falciparum infection. At delivery, the inverse relationship between the presence of infection and circulating IFN-γ persisted, although there was a positive association between the likelihood of infection and the presence of circulating TNF-α. Initiation of antiretroviral therapy was associated with elevated IL-5 production. Consistent with our own and others' observations in HIV seronegative subjects, this study shows circulating IL-10 to be a marker of infection with P. falciparum during pregnancy even in HIV-infected women, although plasma IFN-γ may be a marker of anti-malarial protection in such women. PMID:26101276

Peptide YY kinetics and effects on blood pressure and circulating pancreatic and gastrointestinal hormones and metabolites in man.

PubMed

Adrian, T E; Sagor, G R; Savage, A P; Bacarese-Hamilton, A J; Hall, G M; Bloom, S R

1986-10-01

Peptide YY (PYY) is a 36 amino acid peptide produced by mucosal endocrine cells of the ileum and colon which inhibits acid secretion and intestinal transit in man. To assess its effects on metabolites and digestive hormones PYY was infused into 18 fasting normal subjects at three dose levels (0.06, 0.19, and 0.57 pmol kg-1 min-1), each for a period of 1 h. During the infusions mean plasma PYY levels increased by 8, 25, and 73 pmol/liter, respectively. The mean disappearance half-time on stopping the infusions was 9.2 +/- 0.4 (SEM) min. The mean MCR was 7.3 +/- 0.7 ml kg-1 min-1 and the apparent volume of distribution was calculated to be 94 +/- 9 ml kg-1. During the highest dose infusion there was a significant increase in both systolic and diastolic blood pressure, of 8.6 +/- 3.7 mmHg (P less than 0.05) and 10.9 +/- 3.0 mmHg (P less than 0.01), respectively. PYY caused a significant 50% reduction in plasma pancreatic polypeptide concentrations (P less than 0.05) and a 55% reduction in circulating motilin levels (P less than 0.05). PYY had no significant effect on circulating concentrations of insulin, glucagon, gastrin, gastric inhibitory peptide, neurotensin, enteroglucagon, or vasoactive intestinal peptide. PYY also had no significant effect on circulating concentrations of glucose, lactate, glycerol, or nonesterified fatty acids. This recently discovered human intestinal hormonal peptide thus has significant effects both on gastrointestinal hormones (motilin and pancreatic polypeptide) and blood pressure in man, but appears not to influence glucose or lipid metabolism.

Circulating FABP4 and FABP5 levels are differently linked to OSA severity and treatment.

PubMed

Català, Raquel; Cabré, Anna; Hernández-Flix, Salvador; Ferré, Raimón; Sangenís, Sandra; Plana, Núria; Texidó, Anna; Masana, Lluís

2013-12-01

To evaluate circulating adipocyte and epidermal fatty acid-binding protein (FABP4 and FABP5) concentrations in patients with obstructive sleep apnea (OSA), as well as the effects of continuous positive airway pressure (CPAP) treatment. Our cross-sectional study included 125 patients. After polysomnography, 58 participants met the criteria for CPAP treatment and were included in a closed cohort study of 8 weeks of CPAP treatment. General anthropometric and biochemical data and circulating FABP4 and FABP5 levels were determined in all patients at baseline and after CPAP treatment in those receiving this therapy. Circulating FABP4 but not FABP5 levels were higher in patients with OSA (P = 0.003). FABP4 but not FABP5 values were associated with parameters of OSA severity independently of age, gender, adiposity and insulin resistance (P < 0.05). FABP4 but not FABP5 concentrations were determinants of OSA presence (OR: 1.11, P = 0.010) and severity (OR: 1.06, P = 0.020). After CPAP treatment, FABP4 levels decreased in the more severe patients (P = 0.019), while FABP5 levels increased in all patients (P < 0.001). FABP4 is directly associated with obstructive sleep apnea severity and did not change with continuous positive airway pressure treatment, while FABP5 was not associated with obstructive sleep apnea severity and increased with continuous positive airway pressure treatment. FABP4 and FABP5 have different associations with obstructive sleep apnea. FABP4 but not FABP5 could be considered a marker of metabolic alterations in obstructive sleep apnea patients.

Circulating Zinc-α2-glycoprotein levels and Insulin Resistance in Polycystic Ovary Syndrome

PubMed Central

Lai, Yerui; Chen, Jinhua; Li, Ling; Yin, Jingxia; He, Junying; Yang, Mengliu; Jia, Yanjun; Liu, Dongfang; Liu, Hua; Liao, Yong; Yang, Gangyi

2016-01-01

The aim of study was to assess the relationship between zinc-α2-glycoprotein (ZAG) and androgen excess with insulin resistance in polycystic ovary syndrome (PCOS) women. 99 PCOS women and 100 healthy controls were recruited. Euglycemic-hyperinsulinemic clamp (EHC) was preformed to assess their insulin sensitivity. Circulating ZAG was determined with an ELISA kit. In healthy subjects, circulating ZAG levels exhibited a characteristic diurnal rhythm in humans, with a major nocturnal rise occurring between midnight and early morning. Circulating ZAG and M-value were much lower in PCOS women than in the controls. In all population, overweight/obese subjects had significantly lower circulating ZAG levels than lean individuals. Multiple linear regression analysis revealed that only M-value and the area under the curve for glucose were independently related factors to circulating ZAG in PCOS women. Multivariate logistic regression analysis showed that circulating ZAG was significantly associated with PCOS even after controlling for anthropometric variables, blood pressure, lipid profile and hormone levels. The PCOS women with high ZAG had fewer MetS, IGT and polycystic ovaries as compared with the low ZAG PCOS women. Taken together, circulating ZAG levels are reduced in women with PCOS and ZAG may be a cytokine associated with insulin resistance in PCOS women. PMID:27180914

[Dynamics of LINE-1 Retrotransposon Methylation Levels in Circulating DNA from Lung Cancer Patients Undergoing Antitumor Therapy].

PubMed

Ponomaryova, A A; Cherdyntseva, N V; Bondar, A A; Dobrodeev, A Y; Zavyalov, A A; Tuzikov, S A; Vlassov, V V; Choinzonov, E L; Laktionov, P P; Rykova, E Y

2017-01-01

Malignant cell transformation is accompanied with abnormal DNA methylation, such as the hypermethylation of certain gene promoters and hypomethylation of retrotransposons. In particular, the hypomethylation of the human-specific family of LINE-1 retrotransposons was observed in lung cancer tissues. It is also known that the circulating DNA (cirDNA) of blood plasma and cell-surface-bound circulating DNA (csb-cirDNA) of cancer patients accumulate tumor-specific aberrantly methylated DNA fragments, which are currently considered to be valuable cancer markers. This work compares LINE-1 retrotransposon methylation patterns in cirDNA of 16 lung cancer patients before and after treatment. CirDNA was isolated from blood plasma, and csb-cirDNA fractions were obtained by successive elution with EDTA-containing phosphate buffered saline and trypsin. Concentrations of methylated LINE-1 region 1 copies (LINE-1-met) were assayed by real-time methylation-specific PCR. LINE-1 methylation levels were normalized to the concentration of LINE-1 region 2, which was independent of the methylation status (LINE-1-Ind). The concentrations of LINE-1-met and LINE-1-Ind in csb-cirDNA of lung cancer patients exhibited correlations before treatment (r = 0.54), after chemotherapy (r = 0.72), and after surgery (r = 0.83) (P < 0.05, Spearman rank test). In the total group of patients, the level of LINE-1 methylation (determined as the LINE-1-met/LINE-1-Ind ratio) was shown to increase significantly during the follow-up after chemotherapy (P < 0.05, paired t test) and after surgery compared to the level of methylation before treatment (P < 0.05, paired t test). The revealed association between the level of LINE-1 methylation and the effect of antitumor therapy was more pronounced in squamous cell lung cancer than in adenocarcinoma (P < 0.05 and P > 0.05, respectively). These results suggest a need for the further investigation of dynamic changes in levels of LINE-1 methylation depending on the antitumor therapy.

Circulating levels of miR-7, miR-152 and miR-192 respond to vitamin D supplementation in adults with prediabetes and correlate with improvements in glycemic control.

PubMed

Nunez Lopez, Yury O; Pittas, Anastassios G; Pratley, Richard E; Seyhan, Attila A

2017-11-01

Vitamin D may play an important role in modifying the risk of type 2 diabetes. Supplementation with cholecalciferol has been shown to improve β cell function and to attenuate the rise in glycated hemoglobin in people at high risk of diabetes. We examined whether circulating microRNAs (miRNAs) reflect disease progression and/or respond to vitamin D supplementation. We measured plasma levels of select miRNAs implicated in diabetes in people with prediabetes treated either with placebo (n=21) or 2000 U of cholecalciferol daily (n=21) for 4 months in the Calcium and Vitamin D for Diabetes Mellitus trial and compared the baseline-adjusted changes after correcting for age, body mass index, race, time of study entry (season) and baseline disposition index. Circulating levels of miR-7 (sixfold reduction, P=.01), miR-152 (1.5-fold increase, P=.03), and miR-192 (1.7-fold reduction, P=.026) displayed significant treatment-by-time interactions between the placebo- and the vitamin-D-treated groups. Plasma levels of miR-7 were reduced in the vitamin D and increased in the placebo group. The change in miR-152 positively correlated with the change in levels of the circulating metabolite 25-hydroxyvitamin D (r=0.33, P=.046) and negatively correlated with the change in glycated hemoglobin (r=-0.37, P=.024). The change in miR-192 positively correlated with the change in fasting glucose (r=0.41, P<.011). In conclusion, reduction of circulating miR-7 and miR-192, accompanied by elevation of miR-152, reflects a beneficial metabolic response to vitamin D treatment in people with prediabetes. These miRNAs may be useful biomarkers in diabetes prevention trials and other studies of vitamin D. Copyright © 2017 Elsevier Inc. All rights reserved.

Age-dependent Impairment of HIF-1α̣Expression in Diabetic Mice: Correction with Electroporation-facilitated Gene Therapy Increases Wound Healing, Angiogenesis, and Circulating Angiogenic Cells

PubMed Central

Liu, Lixin; Marti, Guy P.; Wei, Xiaofei; Zhang, Xianjie; Zhang, Huafeng; Liu, Ye V.; Nastai, Manuel; Semenza, Gregg L.; Harmon, John W.

2009-01-01

Wound healing is impaired in elderly patients with diabetes mellitus. We hypothesized that age-dependent impairment of cutaneous wound healing in db/db diabetic mice: (a) would correlate with reduced expression of the transcription factor hypoxia-inducible factor 1α (HIF-1α) as well as its downstream target genes; and (b) could be overcome by HIF-1α replacement therapy. Wound closure, angiogenesis, and mRNA expression in excisional skin wounds were analyzed and circulating angiogenic cells were quantified in db/db mice that were untreated or received electroporation-facilitated HIF-1α gene therapy. HIF-1α mRNA levels in wound tissue were significantly reduced in older (4–6 months) as compared to younger (1.5–2 months) db/db mice. Expression of mRNAs encoding the angiogenic cytokines vascular endothelial growth factor (VEGF), angiopoietin 1 (ANGPT1), ANGPT2, platelet derived growth factor B (PDGF-B), and placental growth factor (PLGF) was also impaired in wounds of older db/db mice. Intradermal injection of plasmid gWIZ-CA5, which encodes a constitutively active form of HIF-1α, followed by electroporation, induced increased levels of HIF-1α mRNA at the injection site on day 3 and increased levels of VEGF, PLGF, PDGF-B, and ANGPT2 mRNA on day 7. Circulating angiogenic cells in peripheral blood increased 10-fold in mice treated with gWIZ-CA5. Wound closure was significantly accelerated in db/db mice treated with gWIZ-CA5 as compared to mice treated with empty vector. Thus, HIF-1α gene therapy corrects the age-dependent impairment of HIF-1α expression, angiogenic cytokine expression, and circulating angiogenic cells that contribute to the age-dependent impairment of wound healing in db/db mice. PMID:18506785

Determination of glutathione in human plasma using high-performance liquid chromatography with electrochemical detection with a carbon-epoxy resin composite electrode chemically modified with cobalt phthalocyanine.

PubMed

Wring, S A; Hart, J P; Birch, B J

1989-12-01

High-performance liquid chromatography with electrochemical detection (LCEC), incorporating a novel carbon-epoxy resin working electrode modified with cobalt phthalocyanine, has been employed for preliminary studies directed towards the determination of normal circulating levels of reduced glutathione (GSH) in human plasma. The mobile phase consisted of 0.05 M phosphate buffer (pH 3) containing 0.1% m/m ethylenediaminetetraacetic acid (EDTA); the calibration graph was linear in the range 0.24-30.7 ng of GSH injected. The mean recovery of GSH added to a control serum over the physiological concentration range (0.38-3.07 ng ml-1) was 99%; this was achieved following a simple sample pre-treatment method, prior to LCEC, involving chelation of divalent cations with EDTA and subsequent acidification with orthophosphoric acid. Using the LCEC method, the mean circulating level of GSH in plasma, found in three normal subjects, was 2.69 microM, GSH; this indicates that the method might be applicable to the determination of depressed circulating levels of GSH.

When does the lung die? Kfc, cell viability, and adenine nucleotide changes in the circulation-arrested rat lung.

PubMed

Jones, D R; Becker, R M; Hoffmann, S C; Lemasters, J J; Egan, T M

1997-07-01

Lungs harvested from cadaveric circulation-arrested donors may increase the donor pool for lung transplantation. To determine the degree and time course of ischemia-reperfusion injury, we evaluated the effect of O2 ventilation on capillary permeability [capillary filtration coefficient (Kfc)], cell viability, and total adenine nucleotide (TAN) levels in in situ circulation-arrested rat lungs. Kfc increased with increasing postmortem ischemic time (r = 0.88). Lungs ventilated with O2 1 h postmortem had similar Kfc and wet-to-dry ratios as controls. Nonventilated lungs had threefold (P < 0.05) and sevenfold (P < 0.0001) increases in Kfc at 30 and 60 min postmortem compared with controls. Cell viability decreased in all groups except for 30-min postmortem O2-ventilated lungs. TAN levels decreased with increasing ischemic time, particularly in nonventilated lungs. Loss of adenine nucleotides correlated with increasing Kfc values (r = 0.76). This study indicates that lungs retrieved 1 h postmortem may have normal Kfc with preharvest O2 ventilation. The relationship between Kfc and TAN suggests that vascular permeability may be related to lung TAN levels.

Adiposity associated changes in serum glucose and adiponectin levels modulate ovarian steroidogenesis during delayed embryonic development in the fruit bat, Cynopterus sphinx.

PubMed

Anuradha; Krishna, Amitabh

2018-06-01

The aim of the present study was to evaluate the mechanism by which embryonic development in Cynopterus sphinx is impaired during the period of increased accumulation of white adipose tissue during winter scarcity of food. The change in the mass of white adipose tissue during adipogenesis showed significant positive correlation with the circulating glucose level. But increase in circulating glucose level during the adipogenesis showed negative correlation with circulating progesterone and adiponectin levels. The in vivo study showed increased glucose uptake by the adipose tissue during adipogenesis due to increased expression of insulin receptor (IR) and glucose transporter (GLUT) 4 proteins. This study showed decline in the adiponectin level during fat accumulation. In the in vitro study, ovary treated with high doses of glucose showed impaired progesterone synthesis. This is due to decreased glucose uptake mediated decrease in the expression of luteinizing hormone-receptor, steroidogenic acute regulatory protein, IR, GLUT4 and AdipoR1 proteins. But the ovary treated with adiponectin either alone or with higher concentration of glucose showed improvement in progesterone synthesis due to increased expression of IR, GLUT4 and AdipoR1 mediated increased glucose uptake. In conclusion, increased circulating glucose level prior to winter dormancy preferably transported to white adipose tissue for fat accumulation diverting glucose away from the ovary. Consequently the decreased availability of adiponectin and glucose to the ovary and utero-embryonic unit may be responsible for impaired progesterone synthesis and delayed embryonic development. The delayed embryonic development in Cynopterus sphinx may have evolved, in part, as a mechanism to prevent pregnancy loss during the period of decreased energy availability. Copyright © 2018 Elsevier Inc. All rights reserved.

Circulating levels of cell-derived microparticles are reduced by mild hypobaric hypoxia: data from a randomised controlled trial.

PubMed

Ayers, Lisa; Stoewhas, Anne-Christin; Ferry, Berne; Latshang, Tsogyal D; Lo Cascio, Christian M; Sadler, Ross; Stadelmann, Katrin; Tesler, Noemi; Huber, Reto; Achermann, Peter; Bloch, Konrad E; Kohler, Malcolm

2014-05-01

Hypoxia is known to induce the release of microparticles in vitro. However, few publications have addressed the role of hypoxia in vivo on circulating levels of microparticles. This randomised, controlled, crossover trial aimed to determine the effect of mild hypoxia on in vivo levels of circulating microparticles in healthy individuals. Blood was obtained from 51 healthy male volunteers (mean age of 26.9 years) at baseline altitude (490 m) and after 24 and 48 h at moderate altitude (2,590 m). The order of altitude exposure was randomised. Flow cytometry was used to assess platelet-poor plasma for levels of circulating microparticles derived from platelets, endothelial cells, leucocytes, granulocytes, monocytes, red blood cells and procoagulant microparticles. Mean (standard deviation) oxygen saturation was significantly lower on the first and second day after arrival at 2,590 m, 91.0 (2.0) and 92.0 (2.0) %, respectively, compared to 490 m, 96 (1.0) %, p < 0.001 for both comparisons. A significant decrease in the levels of procoagulant microparticles (annexin V+ -221/μl 95 % CI -370.8/-119.0, lactadherin+ -202/μl 95 % CI -372.2/-93.1), platelet-derived microparticles (-114/μl 95 % CI -189.9/-51.0) and red blood cell-derived microparticles (-81.4 μl 95 % CI -109.9/-57.7) after 48 h at moderate altitude was found. Microparticles derived from endothelial cells, granulocytes, monocytes and leucocytes were not significantly altered by exposure to moderate altitude. In healthy male individuals, mild hypobaric hypoxia, induced by a short-term stay at moderate altitude, is associated with lower levels of procoagulant microparticles, platelet-derived microparticles and red blood cell-derived microparticles, suggesting a reduction in thrombotic potential.

A human APOC3 missense variant and monoclonal antibody accelerate apoC-III clearance and lower triglyceride-rich lipoprotein levels

PubMed Central

Khetarpal, Sumeet A; Zeng, Xuemei; Millar, John S; Vitali, Cecilia; Somasundara, Amritha Varshini Hanasoge; Zanoni, Paolo; Landro, James A; Barucci, Nicole; Zavadoski, William J; Sun, Zhiyuan; de Haard, Hans; Toth, Ildikó V; Peloso, Gina M; Natarajan, Pradeep; Cuchel, Marina; Lund-Katz, Sissel; Phillips, Michael C; Tall, Alan R; Kathiresan, Sekar; DaSilva-Jardine, Paul; Yates, Nathan A; Rader, Daniel J

2017-01-01

Recent large-scale genetic sequencing efforts have identified rare coding variants in genes in the triglyceride-rich lipoprotein (TRL) clearance pathway that are protective against coronary heart disease (CHD), independently of LDL cholesterol (LDL-C) levels1. Insight into the mechanisms of protection of these variants may facilitate the development of new therapies for lowering TRL levels. The gene APOC3 encodes apoC-III, a critical inhibitor of triglyceride (TG) lipolysis and remnant TRL clearance2. Here we report a detailed interrogation of the mechanism of TRL lowering by the APOC3 Ala43Thr (A43T) variant, the only missense (rather than protein-truncating) variant in APOC3 reported to be TG lowering and protective against CHD3–5. We found that both human APOC3 A43T heterozygotes and mice expressing human APOC3 A43T display markedly reduced circulating apoC-III levels. In mice, this reduction is due to impaired binding of A43T apoC-III to lipoproteins and accelerated renal catabolism of free apoC-III. Moreover, the reduced content of apoC-III in TRLs resulted in accelerated clearance of circulating TRLs. On the basis of this protective mechanism, we developed a monoclonal antibody targeting lipoprotein-bound human apoC-III that promotes circulating apoC-III clearance in mice expressing human APOC3 and enhances TRL catabolism in vivo. These data reveal the molecular mechanism by which a missense variant in APOC3 causes reduced circulating TG levels and, hence, protects from CHD. This protective mechanism has the potential to be exploited as a new therapeutic approach to reduce apoC-III levels and circulating TRL burden. PMID:28825717

IGF2R Genetic Variants, Circulating IGF2 Concentrations and Colon Cancer Risk in African Americans and Whites

PubMed Central

Hoyo, Cathrine; Murphy, Susan K.; Schildkraut, Joellen M.; Vidal, Adriana C.; Skaar, David; Millikan, Robert C.; Galanko, Joseph; Sandler, Robert S.; Jirtle, Randy; Keku, Temitope

2012-01-01

The Mannose 6 Phosphate/Insulin-like Growth Factor Receptor-2 (IGF2R) encodes a type-1 membrane protein that modulates availability of the potent mitogen, IGF2. We evaluated the associations between IGF2R non-synonymous genetic variants (c.5002G>A, Gly1619Arg(rs629849), and c.901C>G, Leu252Val(rs8191754)), circulating IGF2 levels, and colon cancer (CC) risk among African American and White participants enrolled in the North Carolina Colon Cancer Study (NCCCS). Generalized linear models were used to compare circulating levels of IGF2 among 298 African American and 518 White controls. Logistic regression models were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the association of IGF2R genetic variants and CC risk. Women homozygous for the IGF2R c.5002 G>A allele, had higher mean levels of circulating IGF2, 828 (SD=321) ng/ml compared to non-carriers, 595 (SD=217) ng/ml (p-value=0.01). This pattern was not apparent in individuals homozygous for the IGF2R c.901 C>G variant. Whites homozygous for the IGF2R c.901 C>G variant trended towards a higher risk of CC, OR=2.2 [95% CI(0.9–5.4)], whereas carrying the IGF2R c.5002 G>A variant was not associated with CC risk. Our findings support the hypothesis that being homozygous for the IGF2R c.5002 G>A modulates IGF2 circulating levels in a sex-specific manner, and while carrying the IGF2R c.901 C>G may increase cancer risk, the mechanism may not involve modulation of circulating IGF2. PMID:22377707

IGF2R genetic variants, circulating IGF2 concentrations and colon cancer risk in African Americans and Whites.

PubMed

Hoyo, Cathrine; Murphy, Susan K; Schildkraut, Joellen M; Vidal, Adriana C; Skaar, David; Millikan, Robert C; Galanko, Joseph; Sandler, Robert S; Jirtle, Randy; Keku, Temitope

2012-01-01

The Mannose 6 Phosphate/Insulin-like Growth Factor Receptor-2 (IGF2R) encodes a type-1 membrane protein that modulates availability of the potent mitogen, IGF2. We evaluated the associations between IGF2R non-synonymous genetic variants (c.5002G>A, Gly1619Arg(rs629849), and c.901C>G, Leu252Val(rs8191754)), circulating IGF2 levels, and colon cancer (CC) risk among African American and White participants enrolled in the North Carolina Colon Cancer Study (NCCCS). Generalized linear models were used to compare circulating levels of IGF2 among 298 African American and 518 White controls. Logistic regression models were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the association of IGF2R genetic variants and CC risk. Women homozygous for the IGF2R c.5002 G>A allele, had higher mean levels of circulating IGF2, 828 (SD=321) ng/ml compared to non-carriers, 595 (SD=217) ng/ml (p-value=0.01). This pattern was not apparent in individuals homozygous for the IGF2R c.901 C>G variant. Whites homozygous for the IGF2R c.901 C>G variant trended towards a higher risk of CC, OR=2.2 [95% CI(0.9-5.4)], whereas carrying the IGF2R c.5002 G>A variant was not associated with CC risk. Our findings support the hypothesis that being homozygous for the IGF2R c.5002 G>A modulates IGF2 circulating levels in a sex-specific manner, and while carrying the IGF2R c.901 C>G may increase cancer risk, the mechanism may not involve modulation of circulating IGF2.

Grazing Affects Exosomal Circulating MicroRNAs in Cattle

PubMed Central

Muroya, Susumu; Ogasawara, Hideki; Hojito, Masayuki

2015-01-01

Circulating microRNAs (c-miRNAs) are associated with physiological adaptation to acute and chronic aerobic exercise in humans. To investigate the potential effect of grazing movement on miRNA circulation in cattle, here we profiled miRNA expression in centrifugally prepared exosomes from the plasma of both grazing and housed Japanese Shorthorn cattle. Microarray analysis of the c-miRNAs resulted in detection of a total of 231 bovine exosomal miRNAs in the plasma, with a constant expression level of let-7g across the duration and cattle groups. Expression of muscle-specific miRNAs such as miR-1, miR-133a, miR-206, miR-208a/b, and miR-499 were undetectable, suggesting the mildness of grazing movement as exercise. According to validation by quantitative RT-PCR, the circulating miR-150 level in the grazing cattle normalized by the endogenous let-7g level was down-regulated after 2 and 4 months of grazing (P < 0.05), and then its levels in housed and grazing cattle equalized when the grazing cattle were returned to a housed situation. Likewise, the levels of miR-19b, miR-148a, miR-221, miR-223, miR-320a, miR-361, and miR-486 were temporarily lowered in the cattle at 1 and/or 2 month of grazing compared to those of the housed cattle (P < 0.05). In contrast, the miR-451 level was up-regulated in the grazing cattle at 2 months of grazing (P = 0.044). The elevation of miR-451 level in the plasma was coincident with that in the biceps femoris muscle of the grazing cattle (P = 0.008), which suggests the secretion or intake of miR-451 between skeletal muscle cells and circulation during grazing. These results revealed that exosomal c-miRNAs in cattle were affected by grazing, suggesting their usefulness as molecular grazing markers and functions in physiological adaptation of grazing cattle associated with endocytosis, focal adhesion, axon guidance, and a variety of intracellular signaling, as predicted by bioinformatic analysis. PMID:26308447

Circulating CD147 predicts mortality in advanced hepatocellular carcinoma.

PubMed

Lee, Aimei; Rode, Anthony; Nicoll, Amanda; Maczurek, Annette E; Lim, Lucy; Lim, Seok; Angus, Peter; Kronborg, Ian; Arachchi, Niranjan; Gorelik, Alexandra; Liew, Danny; Warner, Fiona J; McCaughan, Geoffrey W; McLennan, Susan V; Shackel, Nicholas A

2016-02-01

The glycoprotein CD147 has a role in tumor progression, is readily detectable in the circulation, and is abundantly expressed in hepatocellular carcinoma (HCC). Advanced HCC patients are a heterogeneous group with some individuals having dismal survival. The aim of this study was to examine circulating soluble CD147 levels as a prognostic marker in HCC patients. CD147 was measured in 277 patients (110 HCC, 115 chronic liver disease, and 52 non-liver disease). Clinical data included etiology, tumor progression, Barcelona Clinic Liver Cancer (BCLC) stage, and treatment response. Patients with HCC were stratified into two groups based upon the 75th percentile of CD147 levels (24 ng/mL). CD147 in HCC correlated inversely with poor survival (P = 0.031). Increased CD147 predicted poor survival in BCLC stages C and D (P = 0.045), and CD147 levels >24 ng/mL predicted a significantly diminished 90-day and 180-day survival time (hazard ratio [HR] = 6.1; 95% confidence interval [CI]: 2.1-63.2; P = 0.0045 and HR = 2.8; 95% CI: 1.2-12.6; P = 0.028, respectively). In BCLC stage C, CD147 predicted prognosis; levels >24 ng/mL were associated with a median survival of 1.5 months compared with 6.5 months with CD147 levels ≤24 ng/mL (P = 0.03). CD147 also identified patients with a poor prognosis independent from treatment frequency, modality, and tumor size. Circulating CD147 is an independent marker of survival in advanced HCC. CD147 requires further evaluation as a potential new prognostic measure in HCC to identify patients with advanced disease who have a poor prognosis. © 2015 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.

Implication of circulating irisin levels with brown adipose tissue and sarcopenia in humans.

PubMed

Choi, Hae Yoon; Kim, Sungeun; Park, Ji Woo; Lee, Nam Seok; Hwang, Soon Young; Huh, Joo Young; Hong, Ho Cheol; Yoo, Hye Jin; Baik, Sei Hyun; Youn, Byung-Soo; Mantzoros, Christos S; Choi, Kyung Mook

2014-08-01

Irisin is an exercise-induced novel myokine that drives brown-fat-like conversion of white adipose tissue and has been suggested to be a promising target for the treatment of obesity-related metabolic disorders. To assess the association of circulating irisin concentrations with brown adipose tissue (BAT) and/or sarcopenia in humans. We examined irisin levels in 40 BAT-positive and 40 BAT-negative women detected by (18)F-fluorodeoxyglucose positron emission tomography ((18)FDG-PET). In a separate study, we also examined 401 subjects with or without sarcopenia defined by skeletal muscle mass index (SMMI) and appendicular skeletal muscle (ASM)/height(2) using dual-energy x-ray absorptiometry. Among 6877 consecutive (18)FDG-PET scans in 4736 subjects, 146 subjects (3.1%) had positive BAT scans. The BAT-detectable group and the matched BAT-undetectable group did not differ in circulating irisin levels measured using two different ELISA kits (P = .747 and P = .160, respectively). Serum irisin levels were not different between individuals with sarcopenia and those without sarcopenia using either kit (P = .305 and P = .569, respectively). Also, serum irisin levels were not different between groups defined by ASM/height(2) using either kit (P = .352 and P = .134, respectively). Although visceral fat area and skeletal muscle mass showed significant difference according to tertiles of SMMI levels, irisin concentrations did not differ. Circulating irisin levels were not different in individuals with detectable BAT or those with sarcopenia compared with control subjects and were not correlated with SMMI.

Mucosal-Associated Invariant T Cell Deficiency in Chronic Obstructive Pulmonary Disease.

PubMed

Kwon, Yong Soo; Jin, Hye-Mi; Cho, Young-Nan; Kim, Moon-Ju; Kang, Jeong-Hwa; Jung, Hyun-Ju; Park, Ki-Jeong; Kee, Hae Jin; Kee, Seung-Jung; Park, Yong-Wook

2016-01-01

Mucosal-associated invariant T (MAIT) cells have been reported to play an important role in mucosal immunity. However, little is known about the roles of MAIT cells in chronic obstructive pulmonary disease (COPD). The aims of this study were to examine the levels of circulating MAIT cells and their subsets in COPD patients and to investigate the potential relationship between clinical parameters and MAIT cell levels. Forty-five COPD patients and 57 healthy control subjects were enrolled in the study. Circulating MAIT cells and their subset levels in the peripheral blood were measured by flow cytometry. Disease grades were classified according to the GOLD criteria for the assessment of severity of COPD. Circulating MAIT cell levels were found to be significantly reduced in COPD patients. In particular, this MAIT cell deficiency was more prominent in CD8+ and double-negative T cell subsets. Interestingly, elevated serum C-reactive protein level and reduced FEV1/FVC ratio were associated with MAIT cell deficiency in COPD patients. Furthermore, the circulating MAIT levels were found to be significantly lower in patients with moderate to severe COPD than in patients with mild COPD. Our data shows that MAIT cells are numerically deficient in the peripheral blood of patients with COPD. In addition, this MAIT cell deficiency was found to reflect inflammatory activity and disease severity. These findings provide important information for monitoring the changes in MAIT cell levels and for predicting the prognosis during the disease course.

A Mutation in the Dmp1 Gene Alters Phosphate Responsiveness in Mice

PubMed Central

Gerard-O'Riley, Rita L.; Acton, Dena; McQueen, Amie K.; Strobel, Isabel E.; Witcher, Phillip C.; Feng, Jian Q.; Econs, Michael J.

2017-01-01

Mutations in the dentin matrix protein 1 (DMP1) gene cause autosomal recessive hypophosphatemic rickets (ARHR). Hypophosphatemia in ARHR results from increased circulating levels of the phosphaturic hormone, fibroblast growth factor 23 (FGF23). Similarly, elevated FGF23, caused by mutations in the PHEX gene, is responsible for the hypophosphatemia in X-linked hypophosphatemic rickets (XLH). Previously, we demonstrated that a Phex mutation in mice creates a lower set point for extracellular phosphate, where an increment in phosphorus further stimulates Fgf23 production to maintain low serum phosphorus levels. To test the presence of the similar set point defect in ARHR, we generated 4- and 12-week-old Dmp1/Galnt3 double knockout mice and controls, including Dmp1 knockout mice (a murine model of ARHR), Galnt3 knockout mice (a murine model of familial tumoral calcinosis), and phenotypically normal double heterozygous mice. Galnt3 knockout mice had increased proteolytic cleavage of Fgf23, leading to low circulating intact Fgf23 levels with consequent hyperphosphatemia. In contrast, Dmp1 knockout mice had little Fgf23 cleavage and increased femoral Fgf23 expression, resulting in hypophosphatemia and low femoral bone mineral density (BMD). However, introduction of the Galnt3 null allele to Dmp1 knockout mice resulted in a significant increase in serum phosphorus and normalization of BMD. This increased serum phosphorus was accompanied by markedly elevated Fgf23 expression and circulating Fgf23 levels, an attempt to reduce serum phosphorus in the face of improving phosphorus levels. These data indicate that a Dmp1 mutation creates a lower set point for extracellular phosphate and maintains it through the regulation of Fgf23 cleavage and expression. PMID:28005411

A Mutation in the Dmp1 Gene Alters Phosphate Responsiveness in Mice.

PubMed

Ichikawa, Shoji; Gerard-O'Riley, Rita L; Acton, Dena; McQueen, Amie K; Strobel, Isabel E; Witcher, Phillip C; Feng, Jian Q; Econs, Michael J

2017-03-01

Mutations in the dentin matrix protein 1 (DMP1) gene cause autosomal recessive hypophosphatemic rickets (ARHR). Hypophosphatemia in ARHR results from increased circulating levels of the phosphaturic hormone, fibroblast growth factor 23 (FGF23). Similarly, elevated FGF23, caused by mutations in the PHEX gene, is responsible for the hypophosphatemia in X-linked hypophosphatemic rickets (XLH). Previously, we demonstrated that a Phex mutation in mice creates a lower set point for extracellular phosphate, where an increment in phosphorus further stimulates Fgf23 production to maintain low serum phosphorus levels. To test the presence of the similar set point defect in ARHR, we generated 4- and 12-week-old Dmp1/Galnt3 double knockout mice and controls, including Dmp1 knockout mice (a murine model of ARHR), Galnt3 knockout mice (a murine model of familial tumoral calcinosis), and phenotypically normal double heterozygous mice. Galnt3 knockout mice had increased proteolytic cleavage of Fgf23, leading to low circulating intact Fgf23 levels with consequent hyperphosphatemia. In contrast, Dmp1 knockout mice had little Fgf23 cleavage and increased femoral Fgf23 expression, resulting in hypophosphatemia and low femoral bone mineral density (BMD). However, introduction of the Galnt3 null allele to Dmp1 knockout mice resulted in a significant increase in serum phosphorus and normalization of BMD. This increased serum phosphorus was accompanied by markedly elevated Fgf23 expression and circulating Fgf23 levels, an attempt to reduce serum phosphorus in the face of improving phosphorus levels. These data indicate that a Dmp1 mutation creates a lower set point for extracellular phosphate and maintains it through the regulation of Fgf23 cleavage and expression. Copyright © 2017 by the Endocrine Society.

Circulating Lipocalin 2 Levels Predict Fracture-Related Hospitalizations in Elderly Women: A Prospective Cohort Study.

PubMed

Lim, Wai H; Wong, Germaine; Lim, Ee M; Byrnes, Elizabeth; Zhu, Kun; Devine, Amanda; Pavlos, Nathan J; Prince, Richard L; Lewis, Joshua R

2015-11-01

Lipocalin 2 (LCN2) or neutrophil gelatinase-associated lipocalin (NGAL) is expressed in a wide range of cells and pathological states. Mounting evidence suggests lipocalin 2 may be an important regulator of bone homeostasis. Recently it has been suggested LCN2 is a novel mechanoresponsive gene central to the pathological response to low mechanical force. We undertook a prospective study of 1009 elderly women over 70 years of age to study the association between circulating LCN2 and potential associated variables, including estimated glomerular filtration rate, physical activity, and baseline measures of hip bone density and heel bone quality. Osteoporotic fractures requiring hospitalizations were identified from the Western Australian Data Linkage System. Over 14.5 years, 272 (27%) of women sustained an osteoporotic fracture-related hospitalization; of these, 101 were hip fractures. Circulating LCN2 levels were correlated with body mass index and estimated glomerular filtration rate (r = 0.249, p < 0.001 and r = -0.481, p < 0.001, respectively) that modified the association with hip and heel bone measures. Per standard deviation increase in LCN2, there was a 30% multivariable-adjusted increase in the risk of any osteoporotic fracture (hazard ratio [HR] = 1.30, 95% confidence interval [CI] 1.13-1.50, p < 0.001). In participants with elevated LCN2 levels above the median (76.6 ng/mL), there was an 80% to 81% increase in the risk of any osteoporotic or hip fracture (HR = 1.81, 95% CI 1.38-2.36, p < 0.001 and HR = 1.80, 95% CI 1.16-2.78, p = 0.008, respectively). These associations remained significant after adjustment for total hip bone mineral density (p < 0.05). In conclusion, we have demonstrated that circulating LCN2 levels predict future risk of osteoporotic fractures requiring hospitalization. Measurement of LCN2 levels may improve fracture prediction in addition to current fracture risk factors in the elderly, particularly in those with impaired renal function. © 2015 American Society for Bone and Mineral Research.

miR-27b inhibits LDLR and ABCA1 expression but does not influence plasma and hepatic lipid levels in mice

PubMed Central

Goedeke, Leigh; Rotllan, Noemi; Ramírez, Cristina M.; Aranda, Juan F.; Canfrán-Duque, Alberto; Araldi, Elisa; Fernández-Hernando, Ana; Langhi, Cedric; de Cabo, Rafael; Baldán, Ángel; Suárez, Yajaira; Fernández-Hernando, Carlos

2015-01-01

Rationale Recently, there has been significant interest in the therapeutic administration of miRNA mimics and inhibitors to treat cardiovascular disease. In particular, miR-27b has emerged as a regulatory hub in cholesterol and lipid metabolism and potential therapeutic target for treating atherosclerosis. Despite this, the impact of miR-27b on lipid levels in vivo remains to be determined. As such, here we set out to further characterize the role of miR-27b in regulating cholesterol metabolism in vitro and to determine the effect of miR-27b overexpression and inhibition on circulating and hepatic lipids in mice. Methods and Results Our results identify miR-27b as an important regulator of LDLR activity in human and mouse hepatic cells through direct targeting of LDLR and LDLRAP1. In addition, we report that modulation of miR-27b expression affects ABCA1 protein levels and cellular cholesterol efflux to ApoA1 in human hepatic Huh7 cells. Overexpression of pre-miR-27b in the livers of wild-type mice using AAV8 vectors increased pre-miR-27b levels 50–fold and reduced hepatic ABCA1 and LDLR expression by 50% and 20%, respectively, without changing circulating and hepatic cholesterol and triglycerides. To determine the effect of endogenous miR-27b on circulating lipids, wild-type mice were fed a Western diet for one month and injected with 5 mg/kg of LNA control or LNA anti-miR-27b oligonucleotides. Following two weeks of treatment, the expression of ABCA1 and LDLR were increased by 10–20% in the liver, demonstrating effective inhibition of miR-27b function. Intriguingly, no differences in circulating and hepatic lipids were observed between treatment groups. Conclusions The results presented here provide evidence that short-term modulation of miR-27b expression in wild-type mice regulates hepatic LDLR and ABCA1 expression but does not influence plasma and hepatic lipid levels. PMID:26520906

Soluble interleukin-13rα1: a circulating regulator of glucose.

PubMed

Rachmin, Inbal; O'Meara, Caitlin C; Ricci-Blair, Elisabeth M; Feng, Yilin; Christensen, Emily M; Duffy, Jeanne F; Zitting, Kirsi M; Czeisler, Charles A; Pancoast, James R; Cannon, Christopher P; O'Donoghue, Michelle L; Morrow, David A; Lee, Richard T

2017-12-01

Soluble IL-13 receptor-α1, or sIL13rα1, is a soluble protein that binds to interleukin-13 (IL-13) that has been previously described in mice. The function of sIL13rα1 remains unclear, but it has been hypothesized to act as a decoy receptor for IL-13. Recent studies have identified a role for IL-13 in glucose metabolism, suggesting that a decoy receptor for IL-13 might increase circulating glucose levels. Here, we report that delivery of sIL13rα1 to mice by either gene transfer or recombinant protein decreases blood glucose levels. Surprisingly, the glucose-lowering effect of sIL13rα1 was preserved in mice lacking IL-13, demonstrating that IL-13 was not required for the effect. In contrast, deletion of IL-4 in mice eliminated the hypoglycemic effect of sIL13rα1. In humans, endogenous blood levels of IL13rα1 varied substantially, although there were no differences between diabetic and nondiabetic patients. There was no circadian variation of sIL13rα1 in normal human volunteers. Delivery of sIL13rα1 fused to a fragment crystallizable (Fc) domain provided sustained glucose lowering in mice on a high-fat diet, suggesting a potential therapeutic strategy. These data reveal sIL13rα1 as a circulating human protein with an unexpected role in glucose metabolism. Copyright © 2017 the American Physiological Society.

Maternal vitamin D status in pregnancy and risk of lower respiratory tract infections, wheezing, and asthma in offspring.

PubMed

Morales, Eva; Romieu, Isabelle; Guerra, Stefano; Ballester, Ferrán; Rebagliato, Marisa; Vioque, Jesús; Tardón, Adonina; Rodriguez Delhi, Cristina; Arranz, Leonor; Torrent, Maties; Espada, Mercedes; Basterrechea, Mikel; Sunyer, Jordi

2012-01-01

Adequate vitamin D status in mothers during pregnancy may influence the health status of the child later in life. We assessed whether maternal circulating 25-hydroxyvitamin D (25[OH]D) concentrations in pregnancy are associated with risk of lower respiratory tract infections, wheezing, and asthma in the offspring. Data were obtained from 1724 children of the INfancia y Medio Ambiente (INMA) Project, a population-based birth cohort study. Maternal circulating 25(OH)D concentrations were measured in pregnancy (mean gestational age = 12.6 [SD = 2.5] weeks). When the child was age 1 year, parents were asked if their child had a physician-confirmed history of lower respiratory tract infections or a history of wheezing. The questions about wheezing were repeated annually thereafter. Asthma was defined as parental report of doctor diagnosis of asthma or receiving treatment at the age of 4-6 years or wheezing since the age of 4 years. The median maternal circulating 25(OH)D concentration in pregnancy was 29.5 ng/mL (interquartile range, 22.5-37.1 ng/mL). After multivariable adjustment, there was a trend for an independent association between higher levels of maternal circulating 25(OH)D levels in pregnancy and decreased odds of lower respiratory tract infections in offspring (for cohort- and season-specific quartile Q4 vs. Q1, odds ratio = 0.67 [95% confidence interval = 0.50-0.90]; test for trend, P = 0.016). We found no association between 25(OH)D levels in pregnancy and risk of wheezing at age 1 year or 4 years, or asthma at age 4-6 years. Higher maternal circulating 25(OH)D concentrations in pregnancy were independently associated with lower risk of lower respiratory tract infections in offspring in the first year of life but not with wheezing or asthma in childhood.

Effects of Hypoglycemia on Circulating Stem and Progenitor Cells in Diabetic Patients.

PubMed

Fadini, Gian Paolo; Boscari, Federico; Cappellari, Roberta; Galasso, Silvia; Rigato, Mauro; Bonora, Benedetta Maria; D'Anna, Marianna; Bruttomesso, Daniela; Avogaro, Angelo

2018-03-01

Iatrogenic hypoglycemia is the most common acute diabetic complication, and it significantly increases morbidity. In people with diabetes, reduction in the levels of circulating stem and progenitor cells predicts adverse outcomes. To evaluate whether hypoglycemia in diabetes affects circulating stem cells and endothelial progenitor cells (EPCs). We performed an experimental hypoglycemia study (Study 1) and a case-control study (Study 2). Tertiary referral inpatient clinic. Type 1 diabetic patients (Study 1, n = 19); diabetic patients hospitalized for severe iatrogenic hypoglycemia, matched inpatient and outpatient controls (Study 2, n = 22/group). Type 1 diabetic patients underwent two in-hospital sessions of glucose monitoring during a breakfast meal with or without induction of hypoglycemia in random order. In Study 2, patients hospitalized for hypoglycemia and matched controls were compared. Circulating stem cells and EPCs were measured by flow cytometry based on the expression of CD34 and kinase insert domain receptor (KDR). In Study 1, the physiologic decline of CD34+KDR+ EPCs from 8 am to 2 pm was abolished by insulin-induced hypoglycemia in type 1 diabetic patients. In Study 2, diabetic patients hospitalized for severe iatrogenic hypoglycemia had significantly lower levels of CD34+ stem cells and CD34+KDR+ EPCs compared with diabetic inpatients or outpatient controls. In diabetic patients, a single mild hypoglycemic episode can compromise the physiologic EPC fluctuation, whereas severe hypoglycemia is associated with a marked reduction in stem cells and EPCs. These data provide a possible link between hypoglycemia and adverse outcomes of diabetes.

Endothelial and circulating C19MC microRNAs are biomarkers of infantile hemangioma

PubMed Central

Strub, Graham M.; Kirsh, Andrew L.; Whipple, Mark E.; Kuo, Winston P.; Keller, Rachel B.; Kapur, Raj P.; Majesky, Mark W.; Perkins, Jonathan A.

2016-01-01

Infantile hemangioma (IH) is the most common vascular tumor of infancy, and it uniquely regresses in response to oral propranolol. MicroRNAs (miRNAs) have emerged as key regulators of vascular development and are dysregulated in many disease processes, but the role of miRNAs in IH growth has not been investigated. We report expression of C19MC, a primate-specific megacluster of miRNAs expressed in placenta with rare expression in postnatal tissues, in glucose transporter 1–expressing (GLUT-1–expressing) IH endothelial cells and in the plasma of children with IH. Tissue or circulating C19MC miRNAs were not detectable in patients having 9 other types of vascular anomalies or unaffected children, identifying C19MC miRNAs as the first circulating biomarkers of IH. Levels of circulating C19MC miRNAs correlated with IH tumor size and propranolol treatment response, and IH tissue from children treated with propranolol or from children with partially involuted tumors contained lower levels of C19MC miRNAs than untreated, proliferative tumors, implicating C19MC miRNAs as potential drivers of IH pathogenesis. Detection of C19MC miRNAs in the circulation of infants with IH may provide a specific and noninvasive means of IH diagnosis and identification of candidates for propranolol therapy as well as a means to monitor treatment response. PMID:27660822

Stress-related alterations of acyl and desacyl ghrelin circulating levels: mechanisms and functional implications

PubMed Central

Stengel, Andreas; Wang, Lixin; Taché, Yvette

2011-01-01

Ghrelin is the only known peripherally produced and centrally acting peptide hormone that stimulates food intake and digestive functions. Ghrelin circulates as acylated and desacylated forms and recently the acylating enzyme, ghrelin-O-acyltransferase (GOAT) and the de-acylating enzyme, thioesterase 1/lysophospholipase 1 have been identified adding new layers of complexity to the regulation of ghrelin. Stress is known to alter gastrointestinal motility and food intake and was recently shown to modify circulating ghrelin and GOAT levels with differential responses related to the type of stressors including a reduction induced by physical stressors (abdominal surgery and immunological/endotoxin injection, exercise) and elevation by metabolic (cold exposure, fasting and caloric restriction) and psychological stressors. However, the pathways underlying the alterations of ghrelin under these various stress conditions are still largely to be defined and may relate to stress-associated autonomic changes. There is evidence that alterations of circulating ghrelin may contribute to the neuroendocrine and behavioral responses along with sustaining the energetic requirement needed upon repeated exposure to stressors. A better understanding of these mechanisms will allow targeting components of ghrelin signaling that may improve food intake and gastric motility alterations induced by stress. PMID:21782868

Stress-related alterations of acyl and desacyl ghrelin circulating levels: mechanisms and functional implications.

PubMed

Stengel, Andreas; Wang, Lixin; Taché, Yvette

2011-11-01

Ghrelin is the only known peripherally produced and centrally acting peptide hormone that stimulates food intake and digestive functions. Ghrelin circulates as acylated and desacylated forms and recently the acylating enzyme, ghrelin-O-acyltransferase (GOAT) and the de-acylating enzyme, thioesterase 1/lysophospholipase 1 have been identified adding new layers of complexity to the regulation of ghrelin. Stress is known to alter gastrointestinal motility and food intake and was recently shown to modify circulating ghrelin and GOAT levels with differential responses related to the type of stressors including a reduction induced by physical stressors (abdominal surgery and immunological/endotoxin injection, exercise) and elevation by metabolic (cold exposure, acute fasting and caloric restriction) and psychological stressors. However, the pathways underlying the alterations of ghrelin under these various stress conditions are still largely to be defined and may relate to stress-associated autonomic changes. There is evidence that alterations of circulating ghrelin may contribute to the neuroendocrine and behavioral responses along with sustaining the energetic requirement needed upon repeated exposure to stressors. A better understanding of these mechanisms will allow targeting components of ghrelin signaling that may improve food intake and gastric motility alterations induced by stress. Published by Elsevier Inc.

Circulating levels of miR-150 are associated with poorer outcomes of A/H1N1 infection.

PubMed

Morán, Juan; Ramírez-Martínez, Gustavo; Jiménez-Alvarez, Luis; Cruz, Alfredo; Pérez-Patrigeon, Santiago; Hidalgo, Alfredo; Orozco, Lorena; Martínez, Angélica; Padilla-Noriega, Luis; Avila-Moreno, Federico; Cabello, Carlos; Granados, Julio; Ortíz-Quintero, Blanca; Ramírez-Venegas, Alejandra; Ruíz-Palacios, Guillermo M; Zlotnik, Albert; Merino, Enrique; Zúñiga, Joaquín

2015-10-01

Overproduction of pro-inflammatory cytokines and chemokines is frequently associated with severe clinical manifestations in patients infected with influenza A/H1N1 virus. Micro-RNAs (miRNAs) are highly conserved small non-coding RNA molecules that post-transcriptionally regulate gene expression and are potential biomarkers and therapeutic targets in different inflammatory conditions. We studied the circulating and miRNA profiles in critically ill A/H1N1 patients, A/H1N1 patients with milder disease, asymptomatic housemates and healthy controls. Cytokine, chemokine and growth factors that were potential targets of differentially expressed miRNAs were assessed. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment and interactome analysis of these miRNAs were also performed. Critically ill patients exhibited a significant over-expression of circulating miR-150 (p<0.005) when compared to patients with milder disease. miR-29c, miR-145 and miR-22 were differentially expressed in patients with severe A/H1N1 disease whereas miR-210, miR-126 and miR-222 were downregulated in individuals exposed to the A/H1N1 virus. Significant correlations (p<0.05) between circulating levels of miR-150 with IL-1ra, IL-2, IL-6, CXCL8, IFN-γ, CXCL10 and G-CSF were detected, particularly in critically ill patients. The up-regulation of miR-150 is associated with poorer outcomes of A/H1N1 infection. The differential expression of miRNAs related with immune processes in severe A/H1N1 disease supports the potential role of these miRNAs as biomarkers of disease progression. Copyright © 2015 Elsevier Inc. All rights reserved.

The hypothalamic satiety peptide CART is expressed in anorectic and non-anorectic pancreatic islet tumors and in the normal islet of Langerhans.

PubMed

Jensen, P B; Kristensen, P; Clausen, J T; Judge, M E; Hastrup, S; Thim, L; Wulff, B S; Foged, C; Jensen, J; Holst, J J; Madsen, O D

1999-03-26

The hypothalamic satiety peptide CART (cocaine and amphetamine regulated transcript) is expressed at high levels in anorectic rat glucagonomas but not in hypoglycemic insulinomas. However, a non-anorectic metastasis derived from the glucagonoma retained high CART expression levels and produced circulating CART levels comparable to that of the anorectic tumors. Moreover, distinct glucagonoma lines derived by stable HES-1 transfection of the insulinoma caused severe anorexia but retained low circulating levels of CART comparable to that of insulinoma bearing or control rats. Islet tumor associated anorexia and circulating CART levels are thus not correlated, and in line with this peripheral administration of CART (5-50 mg/kg) produced no effect on feeding behavior. In the rat two alternatively spliced forms of CART mRNA exist and quantitative PCR revealed expression of both forms in the hypothalamus, in the different islet tumors, and in the islets of Langerhans. Immunocytochemistry as well as in situ hybridization localized CART expression to the somatostatin producing islet D cell. A potential endocrine/paracrine role of islet CART remains to be clarified.

Irisin in response to acute and chronic whole-body vibration exercise in humans.

PubMed

Huh, Joo Young; Mougios, Vassilis; Skraparlis, Athanasios; Kabasakalis, Athanasios; Mantzoros, Christos S

2014-07-01

Irisin is a recently identified myokine, suggested to mediate the beneficial effects of exercise by inducing browning of white adipocytes and thus increasing energy expenditure. In humans, the regulation of irisin by exercise is not completely understood. We investigated the effect of acute and chronic whole-body vibration exercise, a moderate-intensity exercise that resembles shivering, on circulating irisin levels in young healthy subjects. Healthy untrained females participated in a 6-week program of whole-body vibration exercise training. Blood was drawn before and immediately after an acute bout of exercise at baseline (week 0) and after 6 weeks of training. The resting irisin levels were not different at baseline (week 0) and after 6 weeks of training. At both 0 and 6 weeks of training, an acute bout of vibration exercise significantly elevated circulating irisin levels by 9.5% and 18.1%, respectively (p=0.05 for the percent change of irisin levels). Acute bouts of whole-body vibration exercise are effective in increasing circulating irisin levels but chronic training does not change levels of baseline irisin levels in humans. Copyright © 2014 Elsevier Inc. All rights reserved.

Sex differences in circulating and renal angiotensins of hypertensive mRen(2).Lewis but not normotensive Lewis rats

PubMed Central

Pendergrass, Karl D.; Pirro, Nancy T.; Westwood, Brian M.; Ferrario, Carlos M.; Brosnihan, K. Bridget; Chappell, Mark C.

2008-01-01

Sex differences in blood pressure are evident in experimental models and human subjects, yet the mechanisms underlying this disparity remain equivocal. The current study sought to define the extent of male-female differences in the circulating and tissue renin-angiotensin aldosterone systems (RAASs) of congenic mRen(2).Lewis and control Lewis rats. Male congenics exhibited higher systolic blood pressure than females [200 ± 4 vs. 146 ± 7 mmHg, P < 0.01] or Lewis males and females [113 ± 2 vs. 112 ± 2 mmHg, P > 0.05]. Plasma ANG II levels were twofold higher in male congenics [47 ± 3 vs. 19 ± 3 pM, P < 0.01] and fivefold higher than in male or female Lewis rats [6 ± 1 vs. 6 ± 1 pM]. ANG I levels were also highest in the males; however, plasma ANG-(1-7) was higher in female congenics. Male congenics exhibited greater circulating renin and angiotensin-converting enzyme (ACE) activities, as well as angiotensinogen, than female littermates. Renal cortical and medullary ANG II levels were also higher in the male congenics versus all the other groups; ANG I was lower in the males. Cortical ACE2 activity was higher in male congenics, yet neprilysin activity and protein were greater in the females, which may contribute to reduced renal levels of ANG II. These data reveal that sex differences in both the circulating and renal RAAS are apparent primarily in the hypertensive group. The enhanced activity of the RAAS in male congenics may contribute to the higher pressure and tissue injury evident in the strain. PMID:18456730

Circulatory shear flow alters the viability and proliferation of circulating colon cancer cells

NASA Astrophysics Data System (ADS)

Fan, Rong; Emery, Travis; Zhang, Yongguo; Xia, Yuxuan; Sun, Jun; Wan, Jiandi

2016-06-01

During cancer metastasis, circulating tumor cells constantly experience hemodynamic shear stress in the circulation. Cellular responses to shear stress including cell viability and proliferation thus play critical roles in cancer metastasis. Here, we developed a microfluidic approach to establish a circulatory microenvironment and studied circulating human colon cancer HCT116 cells in response to a variety of magnitude of shear stress and circulating time. Our results showed that cell viability decreased with the increase of circulating time, but increased with the magnitude of wall shear stress. Proliferation of cells survived from circulation could be maintained when physiologically relevant wall shear stresses were applied. High wall shear stress (60.5 dyne/cm2), however, led to decreased cell proliferation at long circulating time (1 h). We further showed that the expression levels of β-catenin and c-myc, proliferation regulators, were significantly enhanced by increasing wall shear stress. The presented study provides a new insight to the roles of circulatory shear stress in cellular responses of circulating tumor cells in a physiologically relevant model, and thus will be of interest for the study of cancer cell mechanosensing and cancer metastasis.

Association of Circulating C1q/TNF-Related Protein 1 Levels with Coronary Artery Disease in Men

PubMed Central

Yuasa, Daisuke; Ohashi, Koji; Shibata, Rei; Takeshita, Kyosuke; Kikuchi, Ryosuke; Takahashi, Ryotaro; Kataoka, Yoshiyuki; Miyabe, Megumi; Joki, Yusuke; Kambara, Takahiro; Uemura, Yusuke; Matsuo, Kazuhiro; Hayakawa, Satoko; Hiramatsu-Ito, Mizuho; Ito, Masanori; Ikeda, Nobuo; Murohara, Toyoaki; Ouchi, Noriyuki

2014-01-01

Objective Obesity is a major risk factor for cardiovascular disease. Recent evidence demonstrates that dysregulation of fat-derived hormones, also known as adipokines, is linked with the pathogenesis of obesity-related disorders including coronary artery disease (CAD). Here, we investigated whether circulating level of an adipokine C1q/TNF-related protein (CTRP) 1 is associated with the prevalence of CAD. Methods and Results Consecutive 76 male CAD patients were enrolled from inpatients that underwent coronary angiography. Sixty four healthy male subjects served as controls. Plasma CTRP1 concentration was determined by enzyme-linked immunosorbent assay. CTRP1 levels were correlated positively with systolic blood pressure (BP) and triglyceride levels, and negatively with HDL cholesterol levels in all subjects. Plasma levels of CTRP1 were significantly higher in CAD patients than in control subjects (CAD: 443.3±18.6 ng/ml, control: 307.8±21.5 ng/ml, p<0.001). Multiple logistic regression analysis with body mass index, systolic BP, glucose, total cholesterol, HDL cholesterol, triglyceride, adiponectin and CTRP1 revealed that CTRP1 levels, together with systolic BP and HDL cholesterol, correlated with CAD. Conclusions Our data indicate the close association of high CTRP1 levels with CAD prevalence, suggesting that CTRP1 represents a novel biomarker for CAD. PMID:24945145

Staphylococcus epidermidis induces complement activation, tumor necrosis factor and interleukin-1, a shock-like state and tissue injury in rabbits without endotoxemia. Comparison to Escherichia coli.

PubMed Central

Wakabayashi, G; Gelfand, J A; Jung, W K; Connolly, R J; Burke, J F; Dinarello, C A

1991-01-01

Tumor necrosis factor (TNF) and IL-1 are thought to mediate many of the pathophysiologic changes of endotoxemia and Gram-negative bacteremia. In these studies, heat-killed Staphylococcus epidermidis were infused into rabbits to determine whether an endotoxin (LPS)-free microorganism also elicits cytokinemia and the physiologic abnormalities seen in Gram-negative bacteremia. S. epidermidis induced complement activation, circulating TNF and IL-1, and hypotension to the same degree as did one-twentieth the number of heat-killed Escherichia coli. Circulating IL-1 beta levels had a greater correlation coefficient (r = 0.81, P less than 0.001) with the degree of hypotension than TNF levels (r = 0.48, P less than 0.02). Leukopenia, thrombocytopenia, diffuse pulmonary capillary aggregation of neutrophils, and hepatic necrosis with neutrophil infiltration were observed to the same extent after either S. epidermidis or E. coli infusion. However, S. epidermidis infusion did not induce significant (less than 60 pg/ml) endotoxemia, whereas E. coli infusion resulted in high (11,000 pg/ml) serum endotoxin levels. S. epidermidis, E. coli, LPS, or S. epidermidis-derived lipoteichoic acid (LTA) induced TNF and IL-1 from blood mononuclear cells in vitro. E. coli organisms and LPS were at least 100-fold more potent than S. epidermidis or LTA. Thus, a shock-like state with similar levels of complement activation as well as circulating levels of IL-1 and TNF were observed following either S. epidermidis or E. coli. These data provide further evidence that host factors such as IL-1 and TNF are common mediators of the septic shock syndrome regardless of the organism. Images PMID:2040686

Heightened circulating levels of antimicrobial peptides in tuberculosis—Diabetes co-morbidity and reversal upon treatment

PubMed Central

Kumar, Nathella Pavan; Moideen, Kadar; Viswanathan, Vijay; Sivakumar, Shanmugam; Menon, Pradeep A.; Kornfeld, Hardy

2017-01-01

Background The association of antimicrobial peptides (AMPs) with tuberculosis—diabetes comorbidity (PTB-DM) is not well understood. Methods To study the association of AMPs with PTB-DM, we examined the systemic levels of cathelicidin (LL37), human beta defensin– 2 (HBD2), human neutrophil peptides 1–3, (HNP1-3) and granulysin in individuals with either PTB-DM, PTB, latent TB (LTB) or no TB infection (NTB). Results Circulating levels of cathelicidin and HBD2 were significantly higher and granulysin levels were significantly lower in PTB-DM compared to PTB, LTB or NTB, while the levels of HNP1-3 were significantly higher in PTB-DM compared to LTB or NTB individuals. Moreover, the levels of cathelicidin and/or HBD2 were significantly higher in PTB-DM or PTB individuals with bilateral and cavitary disease and also exhibited a significant positive relationship with bacterial burden. Cathelidin, HBD2 and HNP1-3 levels exhibited a positive relationship with HbA1c and/or fasting blood glucose levels. Finally, anti-tuberculosis therapy resulted in significantly diminished levels of cathelicidin, HBD2, granulysin and significantly enhanced levels of HNP1-3 and granulysin in PTB-DM and/or PTB individuals. Conclusion Therefore, our data demonstrate that PTB-DM is associated with markedly enhanced levels of AMPs and diminished levels of granulysin. PMID:28910369

Circulating endocannabinoids in insulin sensitive vs. insulin resistant obese postmenopausal women. A MONET group study.

PubMed

Abdulnour, Joseph; Yasari, Siham; Rabasa-Lhoret, Rémi; Faraj, May; Petrosino, Stefania; Piscitelli, Fabiana; Prud' Homme, Denis; Di Marzo, Vincenzo

2014-01-01

To measure the circulating levels of endocannabinoids and related molecules at fasting, after acute hyperinsulinemia and after weight loss in insulin sensitive vs. insulin resistant obese postmenopausal women. The sample consisted of 30 obese postmenopausal women (age: 58.9 ± 5.2 yrs; BMI: 32.9 ± 3.6 kg/m(2) ). Subjects underwent a 3-hour hyperinsulinaemic-euglycaemic clamp (HEC) (glucose disposal rate (M-value): 10.7 ± 3.3 mg min(-1) kg(-1) FFM) and 6-month weight loss intervention. Participants were classified as insulin sensitive obese (ISO) or insulin resistant obese (IRO) based on a predefined cutoff. Plasma levels of the endocannabinoids, anandamide (AEA), 2-arachidonoylglycerol (2-AG), and of the AEA-related compounds, palmitoylethanolamide (PEA) and oleoylethanolamide (OEA), were measured by liquid chromatography-mass spectrometry. IRO presented higher levels of 2-AG (P < 0.05) independently of the HEC and weight loss, whereas the HEC had an independent inhibitory effect on AEA, PEA, and OEA levels (P < 0.05) in both groups. Furthermore, there was an independent stimulatory effect of weight loss only on PEA levels in both groups (P < 0.05). This study is the first to show that higher circulating levels of the endocannabinoid 2-AG are found in IRO compared to ISO postmenopausal women, and that weight loss is associated with an increase in PEA, a PPAR-α ligand. © 2013 The Obesity Society.

Dynamic Cross Talk between S1P and CXCL12 Regulates Hematopoietic Stem Cells Migration, Development and Bone Remodeling

PubMed Central

Golan, Karin; Kollet, Orit; Lapidot, Tsvee

2013-01-01

Hematopoietic stem cells (HSCs) are mostly retained in a quiescent non-motile mode in their bone marrow (BM) niches, shifting to a migratory cycling and differentiating state to replenish the blood with mature leukocytes on demand. The balance between the major chemo-attractants CXCL12, predominantly in the BM, and S1P, mainly in the blood, dynamically regulates HSC recruitment to the circulation versus their retention in the BM. During alarm situations, stress-signals induce a decrease in CXCL12 levels in the BM, while S1P levels are rapidly and transiently increased in the circulation, thus favoring mobilization of stem cells as part of host defense and repair mechanisms. Myeloid cytokines, including G-CSF, up-regulate S1P signaling in the BM via the PI3K pathway. Induced CXCL12 secretion from stromal cells via reactive oxygen species (ROS) generation and increased S1P1 expression and ROS signaling in HSCs, all facilitate mobilization. Bone turnover is also modulated by both CXCL12 and S1P, regulating the dynamic BM stromal microenvironment, osteoclasts and stem cell niches which all functionally express CXCL12 and S1P receptors. Overall, CXCL12 and S1P levels in the BM and circulation are synchronized to mutually control HSC motility, leukocyte production and osteoclast/osteoblast bone turnover during homeostasis and stress situations. PMID:24276423

Circulating Elastin Fragments Are Not Affected by Hepatic, Renal and Hemodynamic Changes, But Reflect Survival in Cirrhosis with TIPS.

PubMed

Nielsen, M J; Lehmann, J; Leeming, D J; Schierwagen, R; Klein, S; Jansen, C; Strassburg, C P; Bendtsen, F; Møller, S; Sauerbruch, T; Karsdal, M A; Krag, A; Trebicka, J

2015-11-01

Progressive fibrosis increases hepatic resistance and causes portal hypertension with complications. During progressive fibrosis remodeling and deposition of collagens and elastin occur. Elastin remodeling is crucially involved in fibrosis progression in animal models and human data. This study investigated the association of circulating elastin with the clinical outcome in cirrhotic patients with severe portal hypertension receiving transjugular intrahepatic porto-systemic shunt (TIPS). We analyzed portal and hepatic venous samples of 110 cirrhotic patients obtained at TIPS insertion and 2 weeks later. The circulating levels of elastin fragments (ELM) were determined using specific monoclonal ELISA. The relationship of ELM with clinical short-time follow-up and long-term outcome was investigated. Circulating levels of ELM showed a gradient across the liver before TIPS with higher levels in the hepatic vein. Interestingly, the circulating ELM levels remained unchanged after TIPS. The circulating levels of ELM in portal and hepatic veins correlated with platelet counts and inversely with serum sodium. Hepatic venous levels of ELM were higher in CHILD C compared to CHILD A and B and were associated with the presence of ascites. Patients with high levels of ELM in the hepatic veins before TIPS showed poorer survival. In multivariate analysis ELM levels in the hepatic veins and MELD were independent predictors of mortality in these patients. This study demonstrated that circulating levels of ELM are not associated with hemodynamic changes, but might reflect fibrosis remodeling and predict survival in patients with severe portal hypertension receiving TIPS independently of MELD.

Relationship of Circulating C5a and Complement Factor H Levels With Disease Control in Pregnant Women With Asthma.

PubMed

Bohács, Anikó; Bikov, András; Ivancsó, István; Czaller, Ibolya; Böcskei, Renáta; Müller, Veronika; Rigó, János; Losonczy, György; Tamási, Lilla

2016-04-01

Asthma often complicates pregnancy and represents a risk of serious pregnancy complications. The complement system contributes to asthma pathogenesis and is up-regulated in healthy gestation as well. The anaphylatoxin C5a has a major pro-inflammatory role, and the complement factor H is a main soluble regulator protein both in asthma and during pregnancy; however, peripheral levels of these complement factors and their relationship to disease control have not yet been evaluated in pregnant subjects with asthma. The present study aimed to investigate circulating C5a and complement factor H levels in asthma (non-pregnant subjects with asthma; n = 19) and in pregnancy with asthma (pregnant subjects with asthma; n = 22), compared with healthy non-pregnant (n = 21) and healthy pregnant women (n = 13) and to test their relationship to clinical parameters of asthma (lung function, airway inflammation, and symptoms). Circulating C5a levels were higher in the pregnant asthma subject group compared with the healthy non-pregnant, healthy pregnant, and non-pregnant asthma groups: median 2.629 (interquartile range [IQR] 2.257-3.052) ng/mL versus 1.84 (IQR 1.576-2.563), 1.783 (IQR 0.6064-2.786), and 2.024 (IQR 1.232-2.615) ng/mL, respectively (P = .02 in all cases). C5a correlated negatively with FEV1 (r = -0.44, P = .039) and FVC values (r = -0.64, P = .001) in the pregnant asthma group and positively with fraction of exhaled nitric oxide levels in the non-pregnant asthma group (n = 12, r = 0.78, P = .004). Complement factor H levels were elevated in both the healthy pregnant and pregnant asthma subject groups compared with the healthy non-pregnant group (median 1,082 [IQR 734.9-1,224] and 910.7 [IQR 614.5-1076] μg/mL vs. 559.7 [IQR 388.7-783.1] μg/mL, P = .002 and P = .004, respectively) but not in the pregnant asthma group compared with the non-pregnant asthma group (median 687.4 [IQR 441.6-947.6] μg/mL, P = .10). Asthma during pregnancy increases the circulating level of pro-inflammatory C5a, which is accompanied by impaired lung function and partly counteracted by the gestation-specific elevation of regulatory complement factor H level (detected in pregnancy both in healthy and subjects with asthma). Copyright © 2016 by Daedalus Enterprises.

Association between circulating leptin levels and multiple sclerosis: a systematic review and meta-analysis.

PubMed

Xie, Xue-Feng; Huang, Xiao-Hui; Shen, Ai-Zong; Li, Jun; Sun, Ye-Huan

2018-05-01

Leptin, synthesised by adipocytes, has been identified as a hormone that can influence inflammatory activity. Several studies have investigated leptin levels in patients with multiple sclerosis (MS), but the results are not consistent. This study aims to derive a more precise evaluation on the relationship between circulating leptin levels and MS. A comprehensive literature searched up to July 2017 was conducted to evaluate the association of circulating leptin levels and MS. The random-effect model was applied to calculate pooled standardised mean difference (SMD) and its 95% CI. Circulating leptin levels of patients with MS and healthy controls. Of 2155 studies identified, 33 met eligibility criteria and 9 studies with 645 patients with MS and 586 controls were finally included in the meta-analysis. Meta-analysis revealed that, compared with the healthy control group, the MS group had significantly higher plasma/serum leptin levels, with the SMD of 0.70% and 95% CI (0.24 to 1.15). Subgroup analyses suggested that the leptin levels of patients with MS were associated with region, age, study sample size, measurement type, gender and blood sample type. Overall, our study suggests that patients with MS have a significantly higher leptin level than in healthy controls. Further mechanism studies and longitudinal large cohort studies are still needed to further reveal the role of leptin in the pathogenesis of MS. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Serial measures of cardiac troponin T levels by a highly sensitive assay and incident atrial fibrillation in a prospective cohort of ambulatory older adults.

PubMed

Hussein, Ayman A; Bartz, Traci M; Gottdiener, John S; Sotoodehnia, Nona; Heckbert, Susan R; Lloyd-Jones, Donald; Kizer, Jorge R; Christenson, Robert; Wazni, Oussama; deFilippi, Christopher

2015-05-01

Various mechanisms in cardiac remodeling related to atrial fibrillation (AF) lead to elevated circulating cardiac troponin levels, but little is known about such elevations upstream to AF onset. The purpose of this study was to study the association between circulating troponin levels as assessed by a highly sensitive cardiac troponin T (hs-cTnT) assay and incident atrial fibrillation (AF). In a large prospective cohort of ambulatory older adults [the Cardiovascular Health Study (CHS)], hs-cTnT levels were measured in sera that were collected at enrollment from 4262 participants without AF (2871 with follow-up measurements). Incident AF was identified by electrocardiograms during CHS visits, hospital discharge diagnoses, and Medicare files, including outpatient and physician claims diagnoses. Over median follow-up of 11.2 years (interquartile range 6.1-16.5), 1363 participants (32.0%) developed AF. Higher baseline levels of hs-cTnT were associated with incident AF in covariate-adjusted analyses accounting for demographics, traditional risk factors, and incident heart failure in time-dependent analyzes (hazard ratio for 3rd tertile vs undetectable 1.75, 95% confidence interval 1.48-2.08). This association was statistically significant in analyses that additionally adjusted for biomarkers of inflammation and hemodynamic strain (hazard ratio for 3rd tertile vs undetectable 1.38, 95% confidence interval 1.16-1.65). Significant associations were also found when hs-cTnT levels were treated as a continuous variable and when examining change from baseline of hs-cTnT levels and incident AF. The findings show a significant association of circulating troponin levels in ambulatory older adults with incident AF beyond that of traditional risk factors, incident heart failure, and biomarkers of inflammation and hemodynamic strain. Copyright © 2015 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.

Satellite studies of turbidity and circulation patterns in Delaware Bay

NASA Technical Reports Server (NTRS)

Klemas, V.; Srna, R.; Treasure, W. M.; Rogers, R.

1973-01-01

Satellite imagery from four successful ERTS-1 passes over Delaware Bay during different portions of the tidal cycle are interpreted with special emphasis on visibility of suspended sediment and its use as a natural tracer for gross circulation patters. The MSS red band (band 5) appears to give the best contrast, although the sediment patterns are represented by only a few neighboring shades of grey. Color density slicing improves the differentiation of turbidity levels. However, color additive enhancements are of limited value since most of the information is in a single color band. The ability of ERTS-1 to present a synoptic view of the surface circulation over the entire bay is shown to be a valuable and unique contribution of ERTS-1 to coastal oceanography.

Ryanodine Receptor Calcium Leak in Circulating B-Lymphocytes as a Biomarker in Heart Failure.

PubMed

Kushnir, Alexander; Santulli, Gaetano; Reiken, Steven R; Coromilas, Ellie; Godfrey, Sarah J; Brunjes, Danielle L; Colombo, Paolo C; Yuzefpolskaya, Melana; Sokol, Seth I; Kitsis, Richard N; Marks, Andrew R

2018-03-28

Background -Advances in congestive heart failure (CHF) management depend on biomarkers for monitoring disease progression and therapeutic response. During systole, intracellular Ca2 + is released from the sarcoplasmic reticulum (SR) into the cytoplasm through type 2 ryanodine receptor/Ca2 + release channels (RyR2). In CHF, chronically elevated circulating catecholamine levels cause pathologic remodeling of RyR2 resulting in diastolic SR Ca2 + leak, and decreased myocardial contractility. Similarly, skeletal muscle contraction requires SR Ca2 + release through type-1 ryanodine receptors (RyR1), and chronically elevated catecholamine levels in CHF cause RyR1 mediated SR Ca2 + leak, contributing to myopathy and weakness. Circulating B-lymphocytes express RyR1 and catecholamine responsive signaling cascades, making them a potential surrogate for defects in intracellular Ca2 + handling due to leaky RyR channels in CHF. Methods -Whole blood was collected from patients with CHF, CHF status-post left-ventricular assist devices (LVAD), and controls. Blood was also collected from mice with ischemic CHF, ischemic CHF + S107 (a drug that specifically reduces RyR channel Ca2 + leak), and WT controls. Channel macromolecular complex was assessed by immunostaining RyR1 immunoprecipitated from lymphocyte enriched preparations. RyR1 Ca2 + leak was assessed using flow cytometry to measure Ca2 + fluorescence in B-lymphocytes, in the absence and presence of RyR1 agonists that empty RyR1 Ca2 + stores within the endoplasmic reticulum (ER). Results -Circulating B-lymphocytes from humans and mice with CHF exhibited remodeled RyR1 and decreased ER Ca2 + stores, consistent with chronic intracellular Ca2 + leak. This Ca2 + leak correlated with circulating catecholamine levels. The intracellular Ca2 + leak was significantly reduced in mice treated with the Rycal S107. CHF patients treated with LVAD exhibited a heterogeneous response. Conclusions -In CHF, B-lymphocytes exhibit remodeled leaky RyR1 channels and decreased ER Ca2 + stores consistent with chronic intracellular Ca2 + leak. RyR1 mediated Ca2 + leak in B-lymphocytes assessed using flow cytometry provides a surrogate measure of intracellular Ca2 + handling and systemic sympathetic burden, presenting a novel biomarker for monitoring response to pharmacologic and mechanical CHF therapy.

Lack of pro-inflammatory cytokine mobilization predicts poor prognosis in patients with acute heart failure.

PubMed

Vistnes, M; Høiseth, A D; Røsjø, H; Nygård, S; Pettersen, E; Søyseth, V; Hurlen, P; Christensen, G; Omland, T

2013-03-01

The aim of this study was to gain insight in the inflammatory response in acute heart failure (AHF) by assessing (1) plasma cytokine profiles and (2) prognostic value of circulating cytokines in AHF patients. Plasma levels of 26 cytokines were quantified by multiplex protein arrays in 36 patients with congestive AHF, characterized by echocardiographic, radiologic, and clinical examinations on admission, during hospitalization and at discharge. Recurrent AHF leading to death or readmission constituted the combined end point, and all patients were followed for 120 days after discharge. Levels of 15 of the measured cytokines were higher in AHF than in healthy subjects (n=22) on admission. Low levels of MCP-1, IL-1β and a low IL-1β/IL-1ra ratio predicted fatal and non-fatal AHF within 120 days. Patients with low circulating levels of IL-1β had lower left ventricular ejection fraction and higher levels of N-terminal pro-B-type natriuretic peptide, while patients with low levels of MCP-1 had higher E/E' and inferior caval vein diameter, than patients with high levels. Immune activation, reflected in increased cytokine levels, is present in AHF patients. Interestingly, failure to increase secretion of IL-1β and MCP-1 during AHF is associated with poor outcome. Copyright © 2013 Elsevier Ltd. All rights reserved.

Global atmospheric circulation statistics, 1000-1 mb

NASA Technical Reports Server (NTRS)

Randel, William J.

1992-01-01

The atlas presents atmospheric general circulation statistics derived from twelve years (1979-90) of daily National Meteorological Center (NMC) operational geopotential height analyses; it is an update of a prior atlas using data over 1979-1986. These global analyses are available on pressure levels covering 1000-1 mb (approximately 0-50 km). The geopotential grids are a combined product of the Climate Analysis Center (which produces analyses over 70-1 mb) and operational NMC analyses (over 1000-100 mb). Balance horizontal winds and hydrostatic temperatures are derived from the geopotential fields.

Excess Circulating Alternatively Activated Myeloid (M2) Cells Accelerate ALS Progression While Inhibiting Experimental Autoimmune Encephalomyelitis

PubMed Central

Miller, Omer; Butovsky, Oleg; Bukshpan, Shay; Beers, David R.; Henkel, Jenny S.; Yoles, Eti; Appel, Stanley H.; Schwartz, Michal

2011-01-01

Background Circulating immune cells including autoreactive T cells and monocytes have been documented as key players in maintaining, protecting and repairing the central nervous system (CNS) in health and disease. Here, we hypothesized that neurodegenerative diseases might be associated, similarly to tumors, with increased levels of circulating peripheral myeloid derived suppressor cells (MDSCs), representing a subset of suppressor cells that often expand under pathological conditions and inhibit possible recruitment of helper T cells needed for fighting off the disease. Methods and Findings We tested this working hypothesis in amyotrophic lateral sclerosis (ALS) and its mouse model, which are characterized by a rapid progression once clinical symptoms are evident. Adaptive transfer of alternatively activated myeloid (M2) cells, which homed to the spleen and exhibited immune suppressive activity in G93A mutant superoxide dismutase-1 (mSOD1) mice at a stage before emergence of disease symptoms, resulted in earlier appearance of disease symptoms and shorter life expectancy. The same protocol mitigated the inflammation-induced disease model of multiple sclerosis, experimental autoimmune encephalomyelitis (EAE), which requires circulating T cells for disease induction. Analysis of whole peripheral blood samples obtained from 28 patients suffering from sporadic ALS (sALS), revealed a two-fold increase in the percentage of circulating MDSCs (LIN−/LowHLA-DR−CD33+) compared to controls. Conclusions Taken together, these results emphasize the distinct requirements for fighting the inflammatory neurodegenerative disease, multiple sclerosis, and the neurodegenerative disease, ALS, though both share a local inflammatory component. Moreover, the increased levels of circulating MDSCs in ALS patients indicates the operation of systemic mechanisms that might lead to an impairment of T cell reactivity needed to overcome the disease conditions within the CNS. This high level of suppressive immune cells might represent a risk factor and a novel target for therapeutic intervention in ALS at least at the early stage. PMID:22073221

Associations of Circulating Gut Hormone and Adipocytokine Levels with the Spectrum of Gastroesophageal Reflux Disease

PubMed Central

Tseng, Ping-Huei; Yang, Wei-Shiung; Liou, Jyh-Ming; Lee, Yi-Chia; Wang, Hsiu-Po; Lin, Jaw-Town; Wu, Ming-Shiang

2015-01-01

Objective The pathogenesis of gastroesophageal reflux disease (GERD) is complex and poorly understood. We aim to investigate the association of various circulating peptide hormones with heterogenous manifestations of GERD. Methods One hundred and four patients that had experienced typical GERD symptoms (heartburn and/or acid regurgitation) for at least 3 episodes per week in the past 3 months were enrolled. All patients received a baseline assessment of symptom severity and frequency with the Reflux Disease Questionnaire and an upper endoscopy to classify GERD into erosive esophagitis (EE, n = 67), non-erosive esophagitis (NE, n = 37), and Barrett’s esophagus (BE, n = 8). Fifty asymptomatic subjects with an endoscopically normal esophagus were recruited as the control group. Complete anthropometric measures and blood biochemistry were obtained and fasting serum levels of adipocytokines (adiponectin and leptin) and gut hormones (ghrelin and peptide YY (PYY)) were determined by enzyme-linked immunosorbent assay in all subjects. Results All circulating peptide hormone levels were not statistically different between the GERD and control groups. However, GERD patients appeared to have lower PYY levels [median (25th-75th percentile), 80.1 (49.8–108.3) vs. 99.4 (65.8–131.9) pg/ml, p = 0.057] compared with control subjects. Among the GERD patients, ghrelin levels were inversely associated with the frequency and severity of acid regurgitation. In male GERD patients, EE was associated with significantly higher PYY levels [107.0 (55.0–120.8) vs. 32.8 (28.7–84.5) pg/ml, p = 0.026] but lower adiponectin levels [6.7 (5.6–9.3) vs. 9.9 (9.6–10.6) μg/ml, p = 0.034] than NE. Patients with BE had significantly lower adiponectin levels [6.0 (5.1–9.2) vs. 9.2 (7.1–11.2) μg/ml, p = 0.026] than those without BE. Conclusions Humoral derangement of circulating peptide hormones might participate in inflammation and symptom perception in patients suffering from GERD. Further studies to clarify the exact role of these hormones in the pathogenesis of GERD are warranted. PMID:26506614

Circulating DNA and its methylation level in inflammatory bowel disease and related colon cancer.

PubMed

Bai, Xuming; Zhu, Yaqun; Pu, Wangyang; Xiao, Li; Li, Kai; Xing, Chungen; Jin, Yong

2015-01-01

Both of chronic inflammation and abnormal immune in inflammatory bowel disease can induce colon cancer. Previous research showed that cell apoptosis and necrosis become the main source of circulating DNA in the peripheral blood during tumorigenesis that reduced along with methylation degree. However, its role in the process of colitis transforming to colon cancer is not clarified. Drinking 3% DSS was used to establish colitis model, while 3% dextran sodium sulfate (DSS) combined with azo oxidation methane (AOM) intraperitoneal injection was applied to establish colitis related colon cancer model. Circulating DNA and its methylation level in peripheral blood were tested. Morphology observation, HE staining, and p53 and β-catenin expression detection confirmed that drinking 3% DSS and 3% DSS combined with AOM intraperitoneal injection can successfully establish colitis and colitis associated colorectal cancer models. Circulating DNA level in colitis and colon cancer mice increased by gradient compared with control, while significant difference was observed between each other. Circulating DNA methylation level decreased obviously in colitis and colon cancer, and significant difference was observed between each other. Abnormal protein expression, circulating DNA and its methylation level in ulcerative colitis associated colorectal tissues change in gradient, suggesting that circulating DNA and its methylation level can be treated as new markers for colitis cancer transformation that has certain significance to explore the mechanism of human ulcerative colitis canceration.

Cardiovascular disease delay in centenarian offspring: role of heat shock proteins.

PubMed

Terry, Dellara F; McCormick, Maegan; Andersen, Stacy; Pennington, Jaemi; Schoenhofen, Emily; Palaima, Elizabeth; Bausero, Maria; Ogawa, Kishiko; Perls, Thomas T; Asea, Alexzander

2004-06-01

Cardiovascular disease is a major cause of morbidity and mortality of older Americans. We have demonstrated recently that centenarian offspring, when compared with age-matched controls, avoid and/or delay cardiovascular disease and cardiovascular risk factors. Given recent evidence suggesting that higher circulating levels of HSP70 predict the future development of cardiovascular disease in established hypertensives and a recent study demonstrating a decrease in HSP60 and HSP70 with advancing age, we hypothesized that HSP70 levels would be lower in centenarian offspring compared with controls. The circulating serum concentration of HSP70 in 20 centenarian offspring and 9 spousal controls was analyzed using a modified HSP70 ELISA method. Centenarian offspring showed approximately 10-fold lower levels of circulating serum HSP70 compared with spousal controls (P <.001). The exact biological significance of the extremely low levels of circulating serum HSP70 observed in centenarian offspring thus far is not clear. However, circulating HSP has been shown to correlate in diseases or disorders in which there is destruction or damage to target tissues or organs, including cardiovascular diseases and numerous autoimmune disorders. We hypothesize that low levels of circulating serum HSP70 may be an indicator of a healthy state and point to longevity of the host; therefore, our results suggest that levels of circulating serum HSP70 may be a marker for longevity.

Cardiovascular Disease Delay in Centenarian Offspring: Role of Heat Shock Proteins

PubMed Central

TERRY, DELLARA F.; McCORMICK, MAEGAN; ANDERSEN, STACY; PENNINGTON, JAEMI; SCHOENHOFEN, EMILY; PALAIMA, ELIZABETH; BAUSERO, MARIA; OGAWA, KISHIKO; PERLS, THOMAS T.; ASEA, ALEXZANDER

2006-01-01

Cardiovascular disease is a major cause of morbidity and mortality of older Americans. We have demonstrated recently that centenarian offspring, when compared with age-matched controls, avoid and/or delay cardiovascular disease and cardiovascular risk factors. Given recent evidence suggesting that higher circulating levels of HSP70 predict the future development of cardiovascular disease in established hypertensives and a recent study demonstrating a decrease in HSP60 and HSP70 with advancing age, we hypothesized that HSP70 levels would be lower in centenarian offspring compared with controls. The circulating serum concentration of HSP70 in 20 centenarian offspring and 9 spousal controls was analyzed using a modified HSP70 ELISA method. Centenarian offspring showed approximately 10-fold lower levels of circulating serum HSP70 compared with spousal controls (P < .001). The exact biological significance of the extremely low levels of circulating serum HSP70 observed in centenarian offspring thus far is not clear. However, circulating HSP has been shown to correlate in diseases or disorders in which there is destruction or damage to target tissues or organs, including cardiovascular diseases and numerous autoimmune disorders. We hypothesize that low levels of circulating serum HSP70 may be an indicator of a healthy state and point to longevity of the host; therefore, our results suggest that levels of circulating serum HSP70 may be a marker for longevity. PMID:15247074

Hedonic eating in Prader–Willi syndrome is associated with blunted PYY secretion

PubMed Central

Rigamonti, A. E.; Bini, S.; Piscitelli, F.; Lauritano, A.; Di Marzo, V.; Vanetti, C.; Agosti, F.; De Col, A.; Lucchetti, E.; Grugni, G.; Sartorio, A.

2017-01-01

ABSTRACT Hedonic and homeostatic hunger represent two different forms of eating: just for pleasure or following energy deprivation, respectively. Consumption of food for pleasure was reported to be associated with increased circulating levels of both the orexigenic peptide ghrelin and some specific endocannabinoids in normal-weight subjects and patients with morbid obesity. To date, the effects of palatable food on these mediators in Prader–Willi syndrome (PWS) are still unknown. To explore the role of some gastrointestinal orexigenic and anorexigenic peptides and endocannabinoids (and some related congeners) in chocolate consumption, we measured changes in circulating levels of ghrelin, cholecystokinin (CCK), peptide YY (PYY), anandamide (AEA), 2-arachidonoyl-glycerol (2-AG), palmitoylethanolamide (PEA) and oleoylethanolamide (OEA) in eight satiated adult PWS patients after consumption of chocolate and, on a separate day, of a non-palatable isocaloric food with the same macronutrient composition. Evaluation of hunger and satiety was also performed by visual analogic scale. The anticipatory phase and the consumption of food for pleasure were associated with decreased circulating levels of PYY. An increase in PEA levels was also observed. By contrast, circulating levels of ghrelin, CCK, AEA, 2-AG and OEA did not differ before and after the exposure/ingestion of either chocolate or non-palatable foods. Hunger and satiety were similar in the hedonic and non-palatable sessions. In conclusion, when motivation to eat is promoted by highly palatable foods, a depressed post-prandial PYY secretion is observed in PWS. Although preliminary, these findings seem to hypothesize a possible role of PYY agonists in the management of PWS patients. Abbreviations: AEA, Anandamide; 2-AG, 2-arachidonoyl-glycerol; CB1, cannabinoid receptor type 1; OEA, oleoylethanolamide; PEA, palmitoylethanolamide; PWS: Prader-Willi syndrome; VAS, visual analog scales PMID:28659728

Childhood Socioeconomic Status and the Occurrence of Recent Negative Life Events as Predictors of Circulating and Stimulated Levels of Interleukin-6.

PubMed

John-Henderson, Neha A; Marsland, Anna L; Kamarck, Thomas W; Muldoon, Matthew F; Manuck, Stephen B

2016-01-01

Evidence supports an inverse association of childhood socioeconomic status (SES) with systemic inflammation in adulthood. However, it remains to be determined whether this association is dependent on exposure to stressful life experiences. We predicted that the combination of a high number of recent negative life events and low childhood SES would be associated with the highest levels of both circulating interleukin (IL)-6 and lipopolysaccharide-stimulated production of IL-6. We tested this prediction among a community sample of 459 adults (47% male, mean [standard deviation] age = 42.8 [7.3] years). Inverse associations were found between childhood and adult SES indices with circulating IL-6 levels (r values between -0.07 and -0.16, p < .05) but not stimulated IL-6 levels (r values between -0.007 and 0.07, p > .05). The number of recent negative life events (mean [standard deviation] = 2.43 [2.34]) was not significantly related to subjective childhood SES and other SES indices (r values < 0.06, p > .10). Multivariate linear regression analyses revealed a significant association between the interaction of subjective childhood SES and recent negative life events and circulating IL-6 (β = -0.09, t(404) = -1.98, p = .049) and a marginally significant association with stimulated levels of IL-6 (β = -0.10, t(365) = -1.94, p = .054), whereas these covariate-adjusted models revealed no main effects for subjective SES or recent negative life events. The relationship between childhood SES and IL-6 seems to be moderated by recent life events, such that individuals with a relatively low childhood SES exhibit an inflammatory phenotype in the context of a high number of recent negative life events.

Downregulation of GPR83 in the hypothalamic preoptic area reduces core body temperature and elevates circulating levels of adiponectin.

PubMed

Dubins, Jeffrey S; Sanchez-Alavez, Manuel; Zhukov, Victor; Sanchez-Gonzalez, Alejandro; Moroncini, Gianluca; Carvajal-Gonzalez, Santos; Hadcock, John R; Bartfai, Tamas; Conti, Bruno

2012-10-01

The G protein-coupled receptor 83 (GPR83) was recently demonstrated in warm sensitive neurons (WSN) of the hypothalamic preoptic area (POA) that participate in temperature homeostasis. Thus, we investigated whether GPR83 may have a role in regulating core body temperature (CBT) by reducing its expression in the POA. Dissipation of energy in the form of heat is the primary mode of energy expenditure in mammals and can ultimately affect energy homeostasis. Thus, we also measured the level of important regulators of metabolism. Downregulation of GPR83 was obtained by lentiviral short-hairpin RNAs (shGPR83) vectors designed and selected for their ability to reduce GPR83 levels in vitro. Mice received POA injection of shGPR83 or non-silencing vectors and were monitored for CBT, motor activity, food intake body weight and circulating levels of IGF-1, insulin, leptin and adiponectin. Down-regulation of GPR83 in the POA resulted in a small (0.15°C) but significant reduction of CBT during the dark/active cycle of the day. Temperature reduction was followed by increased body weight gain independent of caloric intake. shGPR83 mice also had increased level of circulating adiponectin (31916±952 pg/mL vs. 23474±1507 pg/mL, P<.01) while no change was observed for insulin, IGF-1 or leptin. GPR83 may participate in central thermoregulation and the central control of circulating adiponectin. Further work is required to determine how GPR83 can affect POA WSN and what are the long term metabolic consequences of its down-regulation. Copyright © 2012 Elsevier Inc. All rights reserved.

An analysis of the relationship between cloud anomalies and sea surface temperature anomalies in a global circulation model

NASA Technical Reports Server (NTRS)

Peterson, Thomas C.; Barnett, Tim P.; Roeckner, Erich; Vonder Haar, Thomas H.

1992-01-01

The relationship between the sea surface temperature anomalies (SSTAs) and the anomalies of the monthly mean cloud cover (including the high-level, low-level, and total cloud cover), the outgoing longwave radiation, and the reflected solar radiation was analyzed using a least absolute deviations regression at each grid point over the open ocean for a 6-yr period. The results indicate that cloud change in association with a local 1-C increase in SSTAs cannot be used to predict clouds in a potential future world where all the oceans are 1-C warmer than at present, because much of the observed cloud changes are due to circulation changes, which in turn are related not only to changes in SSTAs but to changes in SSTA gradients. However, because SSTAs are associated with changes in the local ocean-atmosphere moisture and heat fluxes as well as significant changes in circulation (such as ENSO), SSTAs can serve as a surrogate for many aspects of global climate change.

Possible influence of atmospheric circulations on winter haze pollution in Beijing-Tianjin-Hebei region, northern China

NASA Astrophysics Data System (ADS)

Zhang, Z. Y.

2016-12-01

Using the daily records derived from the synoptic weather stations and the NCEP/NCAR and ERA-Interim reanalysis data, the variability of the winter haze pollutions (indicated by the mean visibility and number of hazy days) in Beijing-Tianjin-Hebei (BTH) region during the period 1981 to 2015 and its relationship to the atmospheric circulations in middle-high latitude were analyzed in this study. The winter haze pollution in BTH had distinct inter-annual and inter-decadal variabilities without a significant long-term trend. According to the spatial distribution of correlation coefficients, six atmospheric circulation indices (I1 to I6) were defined from the key areas in sea level pressure (SLP), zonal and meridional winds at 850 hPa (U850, V850), geopotential height field at 500 hPa (H500), zonal wind at 200 hPa (U200), and air temperature at 200 hPa (T200), respectively. All of the six indices have significant and stable correlations with the winter visibility and number of hazy days in BTH. The six circulation indices together can explain 77.7% (78.7%) and 61.7% (69.1%) variances of the winter visibility and number of hazy days in the year-to-year (inter-annual) variability, srespectively. The increase of Ic(a comprehensive index derived from the six individual circulation indices) can cause a shallowing of the East Asian trough at the middle troposphere and a weakening of the Siberian high pressure field at sea level, and then accompanied by a reduction (increase) of horizontal advection and vertical convection (relative humidity) in the lowest troposphere and a reduced boundary layer height in BTH and its neighboring areas, which are favorable for the formation of haze pollutions in BTH winter, and vice versa. The high level of the prediction statistics and the reasonable mechanism suggested that the winter haze pollutions in BTH can be forecasted or estimated credibly based on the optimized atmospheric circulation indices. Thus it is helpful for government decision-making departments to take actions in advance in dealing with probably severe haze pollutions in BTH indicated by the atmospheric circulation conditions.

A Common Variation in Deiodinase 1 Gene DIO1 Is Associated with the Relative Levels of Free Thyroxine and Triiodothyronine

PubMed Central

Panicker, Vijay; Cluett, Christie; Shields, Beverley; Murray, Anna; Parnell, Kirstie S.; Perry, John R. B.; Weedon, Michael N.; Singleton, Andrew; Hernandez, Dena; Evans, Jonathan; Durant, Claire; Ferrucci, Luigi; Melzer, David; Saravanan, Ponnusamy; Visser, Theo J.; Ceresini, Graziano; Hattersley, Andrew T.; Vaidya, Bijay; Dayan, Colin M.; Frayling, Timothy M.

2008-01-01

Introduction: Genetic factors influence circulating thyroid hormone levels, but the common gene variants involved have not been conclusively identified. The genes encoding the iodothyronine deiodinases are good candidates because they alter the balance of thyroid hormones. We aimed to thoroughly examine the role of common variation across the three deiodinase genes in relation to thyroid hormones. Methods: We used HapMap data to select single-nucleotide polymorphisms (SNPs) that captured a large proportion of the common genetic variation across the three deiodinase genes. We analyzed these initially in a cohort of 552 people on T4 replacement. Suggestive findings were taken forward into three additional studies in people not on T4 (total n = 2513) and metaanalyzed for confirmation. Results: A SNP in the DIO1 gene, rs2235544, was associated with the free T3 to free T4 ratio with genome-wide levels of significance (P = 3.6 × 10−13). The C-allele of this SNP was associated with increased deiodinase 1 (D1) function with resulting increase in free T3/T4 ratio and free T3 and decrease in free T4 and rT3. There was no effect on serum TSH levels. None of the SNPs in the genes coding for D2 or D3 had any influence on hormone levels. Conclusions: This study provides convincing evidence that common genetic variation in DIO1 alters deiodinase function, resulting in an alteration in the balance of circulating free T3 to free T4. This should prove a valuable tool to assess the relative effects of circulating free T3 vs. free T4 on a wide range of biological parameters. PMID:18492748

A common variation in deiodinase 1 gene DIO1 is associated with the relative levels of free thyroxine and triiodothyronine.

PubMed

Panicker, Vijay; Cluett, Christie; Shields, Beverley; Murray, Anna; Parnell, Kirstie S; Perry, John R B; Weedon, Michael N; Singleton, Andrew; Hernandez, Dena; Evans, Jonathan; Durant, Claire; Ferrucci, Luigi; Melzer, David; Saravanan, Ponnusamy; Visser, Theo J; Ceresini, Graziano; Hattersley, Andrew T; Vaidya, Bijay; Dayan, Colin M; Frayling, Timothy M

2008-08-01

Genetic factors influence circulating thyroid hormone levels, but the common gene variants involved have not been conclusively identified. The genes encoding the iodothyronine deiodinases are good candidates because they alter the balance of thyroid hormones. We aimed to thoroughly examine the role of common variation across the three deiodinase genes in relation to thyroid hormones. We used HapMap data to select single-nucleotide polymorphisms (SNPs) that captured a large proportion of the common genetic variation across the three deiodinase genes. We analyzed these initially in a cohort of 552 people on T(4) replacement. Suggestive findings were taken forward into three additional studies in people not on T(4) (total n = 2513) and metaanalyzed for confirmation. A SNP in the DIO1 gene, rs2235544, was associated with the free T(3) to free T(4) ratio with genome-wide levels of significance (P = 3.6 x 10(-13)). The C-allele of this SNP was associated with increased deiodinase 1 (D1) function with resulting increase in free T(3)/T(4) ratio and free T(3) and decrease in free T(4) and rT(3). There was no effect on serum TSH levels. None of the SNPs in the genes coding for D2 or D3 had any influence on hormone levels. This study provides convincing evidence that common genetic variation in DIO1 alters deiodinase function, resulting in an alteration in the balance of circulating free T(3) to free T(4). This should prove a valuable tool to assess the relative effects of circulating free T(3) vs. free T(4) on a wide range of biological parameters.

Examining the Causal Role of Leptin in Alzheimer Disease: A Mendelian Randomization Study.

PubMed

Romo, Matthew L; Schooling, C Mary

2017-01-01

Observational evidence regarding the role of leptin in Alzheimer disease (AD) is conflicting. We sought to determine the causal role of circulating leptin and soluble plasma leptin receptor (sOB-R) levels in AD using a separate-sample Mendelian randomization study. Single nucleotide polymorphisms (SNPs) independently and solely predictive of log-transformed leptin (rs10487505 [LEP], rs780093 [GCKR], rs900400 [CCNL1], rs6071166 [SLC32A1], and rs6738627 [COBLL1]) and of sOB-R (rs1137101 [LEPR], rs2767485 [LEPR], and rs1751492 [LEPR]) levels (ng/mL) were obtained from 2 previously reported genome-wide association studies. We obtained associations of leptin and sOB-R levels with AD using inverse variance weighting with fixed effects by combining Wald estimates for each SNP. Sensitivity analyses included using weighted median and MR-Egger methods and repeating the analyses using only SNPs of genome-wide significance. Using inverse variance weighting, genetically predicted circulating leptin levels were not associated with AD, albeit with wide confidence intervals (CIs): odds ratio (OR) 0.99 per log-transformed ng/mL; 95% CI 0.55-1.78. Similarly, the association of sOB-R with AD was null using inverse variance weighting (OR 1.08 per log-transformed ng/mL; 95% CI 0.83-1.41). Results from our sensitivity analyses confirmed our findings. In this first Mendelian randomization study estimating the causal effect of leptin on AD, we did not find an effect of genetically predicted circulating leptin and sOB-R levels on AD. As such, this study suggests that leptin is unlikely to be a major contributor to AD, although the wide CIs preclude a definitive assessment. © 2017 S. Karger AG, Basel.

Increased plasma levels of circulating cell-free mitochondrial DNA in suicide attempters: associations with HPA-axis hyperactivity

PubMed Central

Lindqvist, D; Fernström, J; Grudet, C; Ljunggren, L; Träskman-Bendz, L; Ohlsson, L; Westrin, Å

2016-01-01

Preclinical data suggest that chronic stress may cause cellular damage and mitochondrial dysfunction, potentially leading to the release of mitochondrial DNA (mtDNA) into the bloodstream. Major depressive disorder has been associated with an increased amount of mtDNA in leukocytes from saliva samples and blood; however, no previous studies have measured plasma levels of free-circulating mtDNA in a clinical psychiatric sample. In this study, free circulating mtDNA was quantified in plasma samples from 37 suicide attempters, who had undergone a dexamethasone suppression test (DST), and 37 healthy controls. We hypothesized that free circulating mtDNA would be elevated in the suicide attempters and would be associated with hypothalamic–pituitary–adrenal (HPA)-axis hyperactivity. Suicide attempters had significantly higher plasma levels of free-circulating mtDNA compared with healthy controls at different time points (pre- and post-DST; all P-values<2.98E−12, Cohen's d ranging from 2.55 to 4.01). Pre-DST plasma levels of mtDNA were positively correlated with post-DST cortisol levels (rho=0.49, P<0.003). Suicide attempters may have elevated plasma levels of free-circulating mtDNA, which are related to impaired HPA-axis negative feedback. This peripheral index is consistent with an increased cellular or mitochondrial damage. The specific cells and tissues contributing to plasma levels of free-circulating mtDNA are not known, as is the specificity of this finding for suicide attempters. Future studies are needed in order to better understand the relevance of increased free-circulating mtDNA in relation to the pathophysiology underlying suicidal behavior and depression. PMID:27922635

Metabolites associated with circulating interleukin-6 in older adults

USDA-ARS?s Scientific Manuscript database

Background: Circulating levels of the pro-inflammatory cytokine interleukin-6 (IL-6) levels are elevated in older adults, but mechanisms are unclear. In the current study, we used an untargeted metabolomic approach to develop an improved understanding about mechanisms related to circulating IL-6 in ...

Interdependence of skeletal sclerosis and elevated circulating levels of 1,25-dihydroxyvitamin D in osteopetrotic (op and tl) rats.

PubMed

Popoff, S N; Osier, L K; Zerwekh, J E; Marks, S C

1994-01-01

Osteopetrosis describes a heterogeneous group of inherited, metabolic bone disorders characterized by reduced bone resorption which coexists with elevated circulating levels of 1,25-dihydroxyvitamin D [1,25(OH)2D]. To determine whether or not skeletal sclerosis and high concentrations of 1,25(OH)2D are interdependent, this study used two distinct, nonallelic osteopetrotic mutations in the rat, osteopetrosis (op) and toothless (tl). The op rat is a mutation in which skeletal sclerosis can be cured (mutant) or induced (normal) following the transfer of normal or mutant osteoclast progenitors, respectively. Although these procedures are ineffective in rats of tl stock, infusions of pharmacological doses of macrophage colony-stimulating factor (CSF-1) can stimulate bone resorption and eliminate most of the excess skeletal matrix in tl mutants. This study examined the effects of cure/induction in neonatal mutant/normal rats of op stock and CSF-1 infusions in mutant rats of tl stock on skeletal (bone resorption) and serum [1,25(OH)2D] parameters as a function of time after treatment. Osteopetrotic mutants transplanted (cured) with normal spleen cells demonstrated cellular changes in osteoclast phenotype within 2-3 days followed by histologic and radiographic evidence for increased bone resorption that culminated in a normal appearance of the skeleton by 4 weeks. The markedly elevated serum levels of 1,25(OH)2D observed in untreated mutants fell significantly in transplanted mutants by the end of the first week and were similar to those in normal littermates at 3 and 4 weeks. Normal littermates transplanted (induced) with mutant spleen cells showed a progressive increase in skeletal sclerosis paralleled by significant increases in circulating levels of 1,25(OH)2D.(ABSTRACT TRUNCATED AT 250 WORDS)

Association between Circulating Vitamin D Level and Urolithiasis: A Systematic Review and Meta-Analysis.

PubMed

Hu, Henglong; Zhang, Jiaqiao; Lu, Yuchao; Zhang, Zongbiao; Qin, Baolong; Gao, Hongbin; Wang, Yufeng; Zhu, Jianning; Wang, Qing; Zhu, Yunpeng; Xun, Yang; Wang, Shaogang

2017-03-18

Many studies compared the serum/plasma 1,25 dihydroxyvitamin D₃ (1,25(OH)₂D) and 25 hydroxyvitamin D₃ (25(OH)D) between people with and without nephrolithiasis, and their results were conflicting. After systematically searching PubMed, Web of Science, The Cochrane Library, CNKI, and the Wanfang Database, we conducted a meta-analysis. Thirty-two observational studies involving 23,228 participants were included. Meta-analysis of these studies showed that of stone formers (SFs), calcium SFs had significantly higher concentrations of 1,25(OH)₂D (weighted mean difference (WMD), 10.19 pg/mL; 95% confidence interval (CI), 4.31-16.07; p = 0.0007 and WMD, 11.28 pg/mL; 95% CI, 4.07-18.50; p = 0.002, respectively) than non-stone formers, while the levels of 25(OH)D (WMD, 0.88 ng/mL; 95% CI, -1.04-2.80; p = 0.37 and WMD, -0.63 ng/mL; 95% CI, -2.72-1.47; p = 0.56, respectively) are similar. Compared with controls and normocalciuria SFs, hypercalciuria SFs had increased circulating 1,25(OH)₂D (WMD, 9.41 pg/mL; 95% CI, 0.15-18.67; p = 0.05 and WMD, 2.75 pg/mL; 95% CI, -0.20-5.69; p = 0.07, respectively) and markedly higher 25(OH)D (WMD, 5.02 ng/mL; 95% CI, 0.99-9.06; p = 0.01 and WMD, 5.02 ng/mL; 95% CI, 2.14-7.90; p = 0.0006, respectively). Normocalciuria SFs had elevated 1,25(OH)₂D level (WMD, 6.85 pg/mL; 95% CI, -5.00-18.71; p = 0.26) and comparable 25(OH)D (WMD, 0.94 ng/mL; 95% CI, -3.55-5.43; p = 0.68). Sensitivity analysis generated similar results. Current evidence suggests that increased circulating 1,25(OH)₂D is associated with urinary stones and a higher level of circulating 25(OH)D is significantly associated with hypercalciuria urolithiasis. Further studies are still needed to reconfirm and clarify the role of vitamin D in the pathogenesis of stones.

Inner Core Structure of Hurricane Alicia from Airborne Doppler Radar Observations.

NASA Astrophysics Data System (ADS)

Marks, Frank D., Jr.; Houze, Robert A., Jr.

1987-05-01

Airborne Doppler radar measurements are used to determine the horizontal winds, vertical air motions, radar reflectivity and hydrometer fallspeeds over much of the inner-core region (within 40 km of the eye) of Hurricane Alicia (1983). The reconstructed flow field is more complete and detailed than any obtained previously. The data show both the primary (azimuthal) and secondary (radial-height) circulations. The primary circulation was characterized by an outward sloping maximum of tangential wind. The secondary circulation was characterized by a deep layer of radial inflow in the lower troposphere and a layer of intense outflow above 10 km altitude. The rising branch of the secondary circulation was located in the eyewall and sloped radially outward. Discrete convective-scale bubbles of more intense upward motion were superimposed on this mean rising current, and convective-scale downdrafts were located throughout and below the core of maximum precipitation in the eyewall.Precipitation particles in the eyewall rainshaft circulated 18-20 km downwind as they fell, consistent with the typical upwind slope with increasing altitude of eyewall precipitation cores Outside the eyewall, the precipitation was predominantly stratiform. A radar bright band was evident at the melting level. Above the melting level, ice particles were advected into the stratiform region from the upper levels of the eyewall and drifted downward through a mesoscale region of ascent. Hypothetical precipitation particle trajectories showed that as these particles fell slowly through the mesoscale updraft toward the melting level, they were carried azimuthally as many as 1 1/2 times around the storm. During this spiraling descent, the particles evidently grew vigorously. The amount of water condensed by the ambient mesoscale ascent exceeded that transported into the stratiform region by the eyewall outflow by a factor of 3. As the particles fell into the lower troposphere, they entered a mesoscale region of subsidence, the top of which coincided with the radar bright band.

Reduced circulating levels of sTWEAK are associated with NAFLD and may affect hepatocyte triglyceride accumulation.

PubMed

Lozano-Bartolomé, J; Llauradó, G; Rodriguez, M M; Fernandez-Real, J M; Garcia-Fontgivell, J F; Puig, J; Maymó-Masip, E; Vendrell, J; Chacón, M R

2016-09-01

Non-alcoholic fatty liver disease (NAFLD) is the hepatic manifestation of the metabolic syndrome and is strongly associated with obesity, dyslipidaemia and altered glucose regulation. Previous data demonstrated that low circulating levels of tumour necrosis factor weak inducer of apoptosis (sTWEAK) were associated with obesity, diabetes and insulin resistance, all traits associated with an increased risk of NALFD. Circulating sTWEAK levels are expected to be reduced in the presence of NAFLD. We aimed to explore the relationship between NAFLD and circulating sTWEAK levels in obese patients, and to evaluate the effect of sTWEAK on hepatocyte triglyceride accumulation.Design setting and patients:This is an observational case-control study performed in n=112 severely obese patients evaluated for NAFLD by abdominal ultrasound and n=32 non-obese patients without steatosis. Serum sTWEAK concentrations were measured by ELISA. Multivariable analyses were performed to determine the independent predictors of NAFLD. We analysed TWEAK and Fn14 protein expression in liver biopsies by western blotting and immunohistochemistry. An immortalized primary human hepatocyte cell line (HHL) was used to evaluate the effect of sTWEAK on triglyceride accumulation. We observed a reduction in serum circulating sTWEAK concentrations with the presence of liver steatosis. On multivariable analysis, lower sTWEAK concentrations were independently associated with the presence of NAFLD (odds ratio (OR)=0.023; 95% confidence interval: 0.001-0.579; P<0.022). In human hepatocytes, sTWEAK administration reduced fat accumulation as demonstrated by the reduction in palmitic acid-induced accumulation of triglyceride and the decreased expression of cluster of differentiation 36 (CD36) and perilipin 1 and 2 (PLIN1 and PLIN2) genes. Decreased sTWEAK concentrations are independently associated with the presence of NAFLD. This is concordant with the observation that TWEAK reduces lipid accumulation in human liver cells.

The association between circulating endostatin and a disturbed circadian blood pressure pattern in patients with type 2 diabetes.

PubMed

Wuopio, Jonas; Östgren, Carl Johan; Länne, Toste; Lind, Lars; Ruge, Toralph; Carlsson, Axel C; Larsson, Anders; Nyström, Fredrik H; Ärnlöv, Johan

2018-02-28

Endostatin, cleaved from collagen XVIII in the extracellular matrix, is a promising circulating biomarker for cardiovascular damage. It possesses anti-angiogenic and anti-fibrotic functions and has even been suggested to be involved in blood pressure regulation. Less is known if endostatin levels relate to circadian blood pressure patterns. In the present paper we studied the association between circulating levels of endostatin and nocturnal dipping in blood pressure. We used the CARDIPP-study, a cohort of middle aged, type 2 diabetics (n = 593, 32% women), with data on both 24-hour and office blood pressure, serum-endostatin, cardiovascular risk factors, and incident major cardiovascular events. Nocturnal dipping was defined as a >10% difference between day- and night-time blood pressures. Two-hundred four participants (34%) were classified as non-dippers. The mean endostatin levels were significantly higher in non-dippers compared to dippers (mean ± standard deviation: 62.6 ± 1.8 µg/l vs. 58.7 ± 1.6 µg/l, respectively, p = .007). Higher serum levels of endostatin were associated with a diminished decline in nocturnal blood pressure adjusted for age, sex, HbA1c, mean systolic day blood pressure, hypertension treatment, glomerular filtration rate, and prevalent cardiovascular disease (regression coefficient per SD increase of endostatin -0.01, 95% CI, -0.02-(-0.001), p = .03). Structural equation modelling analyses suggest that endostatin mediates 7% of the association between non-dipping and major cardiovascular events. We found an independent association between higher circulating levels of endostatin and a reduced difference between day- and night-time systolic blood pressure in patients with type 2 diabetes. Yet endostatin mediated only a small portion of the association between non-dipping and cardiovascular events arguing against a clinical utility of our findings.

An Analysis of Results of a High-Resolution World Ocean Circulation Model.

DTIC Science & Technology

1988-03-01

Level Experiments ............... 16 a. Baseline (Laplacian Mixing) Integration ........ 16 b. Isopycnal Mixing Integration ................... 18 3...One-Half Degree, Twenty Level Experiments .......... 18 a. Baseline (Three Year Interior Restoring) Integration...TWENTY LEVEL EXPERIMENTS .................... 21 1. Baseline (Laplacian Mixing) Integration ............. 21 2. Isopycnal Mixing Integration

Fetus-derived DLK1 is required for maternal metabolic adaptations to pregnancy and is associated with fetal growth restriction.

PubMed

Cleaton, Mary A M; Dent, Claire L; Howard, Mark; Corish, Jennifer A; Gutteridge, Isabelle; Sovio, Ulla; Gaccioli, Francesca; Takahashi, Nozomi; Bauer, Steven R; Charnock-Jones, D Steven; Powell, Theresa L; Smith, Gordon C S; Ferguson-Smith, Anne C; Charalambous, Marika

2016-12-01

Pregnancy is a state of high metabolic demand. Fasting diverts metabolism to fatty acid oxidation, and the fasted response occurs much more rapidly in pregnant women than in non-pregnant women. The product of the imprinted DLK1 gene (delta-like homolog 1) is an endocrine signaling molecule that reaches a high concentration in the maternal circulation during late pregnancy. By using mouse models with deleted Dlk1, we show that the fetus is the source of maternal circulating DLK1. In the absence of fetally derived DLK1, the maternal fasting response is impaired. Furthermore, we found that maternal circulating DLK1 levels predict embryonic mass in mice and can differentiate healthy small-for-gestational-age (SGA) infants from pathologically small infants in a human cohort. Therefore, measurement of DLK1 concentration in maternal blood may be a valuable method for diagnosing human disorders associated with impaired DLK1 expression and to predict poor intrauterine growth and complications of pregnancy.

Metalloproteinase Inhibition Protects against Reductions in Circulating Adrenomedullin during Lead-induced Acute Hypertension.

PubMed

Nascimento, Regina A; Mendes, Gabryella; Possomato-Vieira, Jose S; Gonçalves-Rizzi, Victor Hugo; Kushima, Hélio; Delella, Flavia K; Dias-Junior, Carlos A

2015-06-01

Intoxication with lead (Pb) results in increased blood pressure by mechanisms involving matrix metalloproteinases (MMPs). Recent findings have revealed that MMP type two (MMP-2) seems to cleave vasoactive peptides. This study examined whether MMP-2 and MMP-9 levels/activities increase after acute intoxication with low lead concentrations and whether these changes were associated with increases in blood pressure and circulating endothelin-1 or with reductions in circulating adrenomedullin and calcitonin gene-related peptide (CGRP). Here, we expand previous findings and examine whether doxycycline (a MMPs inhibitor) affects these alterations. Wistar rats received intraperitoneally (i.p.) 1st dose 8 μg/100 g of lead (or sodium) acetate, a subsequent dose of 0.1 μg/100 g to cover daily loss and treatment with doxycycline (30 mg/kg/day) or water by gavage for 7 days. Similar whole-blood lead levels (9 μg/dL) were found in lead-exposed rats treated with either doxycycline or water. Lead-induced increases in systolic blood pressure (from 143 ± 2 to 167 ± 3 mmHg) and gelatin zymography of plasma samples showed that lead increased MMP-9 (but not MMP-2) levels. Both lead-induced increased MMP-9 activity and hypertension were blunted by doxycycline. Doxycycline also prevented lead-induced reductions in circulating adrenomedullin. No significant changes in plasma levels of endothelin-1 or CGRP were found. Lead-induced decreases in nitric oxide markers and antioxidant status were not prevented by doxycycline. In conclusion, acute lead exposure increases blood pressure and MMP-9 activity, which were blunted by doxycycline. These findings suggest that MMP-9 may contribute with lead-induced hypertension by cleaving the vasodilatory peptide adrenomedullin, thereby inhibiting adrenomedullin-dependent lowering of blood pressure. © 2014 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).

Association of Circulating Orexin-A Level With Metabolic Risk Factors in North Indian Pre Menopausal Women.

PubMed

Gupta, Vani; Mishra, Sameeksha; Kumar, Sandeep; Mishra, Supriya

2015-01-01

The present study was designed to investigate the association between circulating Orexin-A level with metabolic risk factors in North Indian adult women. 342 women were enrolled for the case-control study, 172 women were with metabolic syndrome (mets) and 170 healthy control women were without metabolic syndrome, (womets) according to (NCEP ATP III criteria). Circulating Orexin-A level was determined by enzyme-linked immunosorbent assay. Observations indicated low levels of orexin-A (26.06 ± 6.09 ng/ml) in women with mets and other metabolic risk factors compared to women without metabolic syndrome (36.50 ± 10.42 ng/ml). Further, in women with metabolic syndrome, circulating Orexin A was significantly associated with waist circumference, triglyceride (negative correlation) and hyperdensity lipoprotein (positive correlation). Our study shows that circulating Orexin A was found to be significantly associated with hyperlipidemia, obesity and obesity-related disorders in North Indian premenopausal women.

Vitamins and abdominal aortic aneurysm.

PubMed

Takagi, Hisato; Umemoto, Takuya

2017-02-01

To summarize the association of vitamins (B6, B12, C, D, and E) and abdominal aortic aneurysm (AAA), we reviewed clinical studies with a comprehensive literature research and meta-analytic estimates. To identify all clinical studies evaluating the association of vitamins B6/B12/C/D/E and AAA, databases including MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials were searched through April 2015, using Web-based search engines (PubMed and OVID). For each case-control study, data regarding vitamin levels in both the AAA and control groups were used to generate standardized mean differences (SMDs) and 95% confidence intervals (CIs). Pooled analyses of the 4 case-control studies demonstrated significantly lower circulating vitamin B6 levels (SMD, -0.33; 95% CI, -0.55 to -0.11; P=0.003) but non-significantly lower vitamin B12 levels (SMD, -0.42; 95% CI, -1.09 to 0.25; P=0.22) in patients with AAA than subjects without AAA. Pooled analyses of the 2 case-control studies demonstrated significantly lower levels of circulating vitamins C (SMD, -0.71; 95% CI, -1.23 to -0.19; P=0.007) and E (SMD, -1.76; 95% CI, -2.93 to 0.60; P=0.003) in patients with AAA than subjects without AAA. Another pooled analysis of the 3 case-control studies demonstrated significantly lower circulating vitamin D (25-hydroxyvitamin D) levels (SMD, -0.25; 95% CI, -0.50 to -0.01; P=0.04) in patients with AAA than subjects without AAA. In a double-blind controlled trial, 4.0-year treatment with a high-dose folic acid and vitamin B6/B12 multivitamin in kidney transplant recipients did not reduce a rate of AAA repair despite significant reduction in homocysteine level. In another randomized, double-blind, placebo-controlled trial, 5.8-year supplementation with α-tocopherol (vitamin E) had no preventive effect on large AAA among male smokers. In clinical setting, although low circulating vitamins B6/C/D/E (not B12) levels are associated with AAA presence, vitamins B6/B12/E supplementation may not reduce AAA incidence.

Circulating IL-6 concentrations and associated anthropometric and metabolic parameters in South Asian men and women in comparison to European whites.

PubMed

Peters, Mike J L; Ghouri, Nazim; McKeigue, Paul; Forouhi, Nita G; Sattar, Naveed

2013-01-01

To determine any ethnic differences in circulating interleukin (IL)-6 concentrations among SAs and Europeans, and to assess their relationship with body composition and insulin resistance measures. Body composition was assessed among 80 SA and European men and women using anthropometry, dual-energy X-ray absorptiometry and abdominal CT scan. Oral glucose tolerance tests with insulin response were performed to assess insulin resistance measures. IL-6 levels were measured by high sensitivity ELISA. Median IL-6 values were higher in SA compared with European women: 1.94 mg/l versus 1.51 mg/l, p=0.041, but not so in men (1.56 mg/l versus 1.57 mg/l). Only measures of obesity, in particular percentage fat area (r=0.6, p=0.003), were positively correlated with IL-6 in SAs. Differences in body fat percentage (visceral and total) could explain up to 30% of the IL-6 difference between Asian and European women. SA women have elevated circulating IL-6 levels, in part due to greater visceral and percent fat levels compared with European women. This observation may in part explain why Asians are at elevated cardiovascular disease risk. Future studies should address the effects of lifestyle factors (physical activity, diet) on plasma IL-6 concentrations in SA women. Copyright © 2012 Elsevier Ltd. All rights reserved.

Investigating the Relationships Between Alcohol Consumption, Cannabis Use, and Circulating Cytokines: A Preliminary Analysis.

PubMed

Karoly, Hollis C; Bidwell, L Cinnamon; Mueller, Raeghan L; Hutchison, Kent E

2018-03-01

In recent years, human and animal studies have converged to support altered inflammatory signaling as a molecular mechanism underlying the pathophysiology of alcohol use disorders (AUDs). Alcohol binds to receptors on immune cells, triggering signaling pathways that produce pro-inflammatory cytokines. Chronic inflammation is associated with tissue damage, which may contribute to negative effects of AUD. Conversely, cannabis is associated with decreased inflammatory signaling, and animal studies suggest that cannabinoids may impact alcohol-induced inflammation. Thus, the impact of cannabis on inflammation in AUDs in humans warrants examination. We explored the relationship between self-reported alcohol and cannabis use and circulating levels of the pro-inflammatory cytokines interleukin 6 (IL-6), IL-8, and IL-1β in the blood. Among 66 regular drinkers (mean age = 30.08), we examined circulating cytokines and administered questionnaires assessing alcohol consumption and days of cannabis use over the past 90 days. We examined whether alcohol consumption, cannabis use, and gender were associated with changes in circulating cytokines, and whether there was a significant interaction between alcohol and cannabis use predicting blood levels of circulating cytokines. A positive association between alcohol and IL-6 emerged. We also observed a negative association between cannabis and IL-1β. Follow-up moderation analyses indicated a cannabis by alcohol interaction predicting circulating IL-6, such that cannabis nonusers showed a stronger relationship between alcohol and IL-6 compared to cannabis users. These preliminary findings suggest that cannabinoid compounds may serve to mitigate inflammation associated with alcohol use. In addition, the present results provide data to inform future investigations, with the goal of ultimately leveraging knowledge of the role of inflammation in AUDs to develop more effective treatments focused on novel immune targets. Copyright © 2017 by the Research Society on Alcoholism.

Surviving the infarct: A profile of cardiac myosin binding protein-C pathogenicity, diagnostic utility, and proteomics in the ischemic myocardium.

PubMed

Lynch, Thomas L; Sadayappan, Sakthivel

2014-08-01

Cardiac myosin binding protein-C (cMyBP-C) is a regulatory protein of the contractile apparatus within the cardiac sarcomere. Ischemic injury to the heart during myocardial infarction (MI) results in the cleavage of cMyBP-C in a phosphorylation-dependent manner and release of an N-terminal fragment (C0C1f) into the circulation. C0C1f has been shown to be pathogenic within cardiac tissue, leading to the development of heart failure. Based on its high levels and early release into the circulation post-MI, C0C1f may serve as a novel biomarker for diagnosing MI more effectively than current clinically used biomarkers. Over time, circulating C0C1f could trigger an autoimmune response leading to myocarditis and progressive cardiac dysfunction. Given the importance of cMyBP-C phosphorylation state in the context of proteolytic cleavage and release into the circulation post-MI, understanding the posttranslational modifications (PTMs) of cMyBP-C would help in further elucidating the role of this protein in health and disease. Accordingly, recent studies have implemented the latest proteomics approaches to define the PTMs of cMyBP-C. The use of such proteomics assays may provide accurate quantitation of the levels of cMyBP-C in the circulation following MI, which could, in turn, demonstrate the efficacy of using plasma cMyBP-C as a cardiac-specific early biomarker of MI. In this review, we define the pathogenic and potential immunogenic effects of C0C1f on cardiac function in the post-MI heart. We also discuss the most advanced proteomics approaches now used to determine cMyBP-C PTMs with the aim of validating C0C1f as an early biomarker of MI. © The Authors PROTEOMICS - Clinical Applications Published by Wiley-VCH Verlag GmbH & Co. KGaA.

Circulating irisin in healthy, young individuals: day-night rhythm, effects of food intake and exercise, and associations with gender, physical activity, diet, and body composition.

PubMed

Anastasilakis, Athanasios D; Polyzos, Stergios A; Saridakis, Zacharias G; Kynigopoulos, Georgios; Skouvaklidou, Elpida C; Molyvas, Dimitrios; Vasiloglou, Maria F; Apostolou, Aggeliki; Karagiozoglou-Lampoudi, Thomai; Siopi, Aikaterina; Mougios, Vassilis; Chatzistavridis, Panagiotis; Panagiotou, Grigorios; Filippaios, Andreas; Delaroudis, Sideris; Mantzoros, Christos S

2014-09-01

The myokine irisin may increase energy expenditure and affect metabolism. The objective of the study was to elucidate predictors of irisin and study whether circulating irisin may have day-night rhythm in humans. This was an observational, cross-sectional study with an additional 24-hour prospective observational arm (day-night rhythm substudy) and two prospective interventional arms (mixed meal substudy and exercise substudy). The study was conducted at the Hellenic Military School of Medicine (Thessaloniki, Greece). One hundred twenty-two healthy, young individuals were subjected to anthropometric and body composition measurements, and their eating and exercise behavior profiles were assessed with validated questionnaires. Subgroups were subjected to day-night rhythm, standardized meal ingestion, and 30-minute aerobic exercise studies. Circulating irisin levels were measured. Ιrisin levels were lower in males than females (P = .02) after adjustment for lean body mass, which was its major determinant. Irisin levels followed a day-night rhythm (P < .001) with peak at 9:00 pm. Irisin levels were increased at the end of exercise (84.1 ± 10.0 vs 105.8 ± 14.3 ng/mL; P < .001). Irisin levels were not affected by intake of a standardized meal and were not associated with caloric intake or diet quality. In healthy, young individuals, circulating irisin displays a day-night rhythm, is correlated with lean body mass, and increases acutely after exercise.

Elevated Serum PSA is Associated With Human Herpesvirus 8 Infection and Increased Circulating Cytokine Levels in Men From Tobago.

PubMed

Henning, Jill D; Karamchandani, Jaideep M; Bonachea, Luis A; Bunker, Clareann H; Patrick, Alan L; Jenkins, Frank J

2017-05-01

Serum-prostate specific antigen (PSA) levels have been used for many years as a biomarker for prostate cancer. This usage is under scrutiny due to the fact that elevated PSA levels can be caused by other conditions such as benign prostatic hyperplasia and infections of or injury to the prostate. As a result, the identification of specific pathogens capable of increasing serum levels of PSA is important. A potential candidate responsible for elevated PSA is human herpesvirus 8 (HHV-8). We have reported previously that HHV-8 is capable of infecting and establishing a latent infection in the prostate. In this current study we test the hypothesis that HHV-8 infection is associated with elevated PSA levels. Circulating cytokine levels between men with elevated PSA and controls are also compared. HHV-8 serostatus was determined among men with elevated serum PSA (≥4 ng/ml; n = 168, no prostate cancer on biopsy) and age-matched controls (PSA <4 ng/ml; n = 234), Circulating cytokine levels were determined among a subset of each group (116 with elevated PSA and 85 controls). Men with an elevated serum PSA were significantly more likely to be HHV-8 seropositive (42.9%) than the age-matched cancer-free men (22.2%; OR 2.51; 95%CI 1.48-4.29, P = 00001). Comparison of circulating cytokine levels between men with elevated serum PSA and controls indicated that elevated serum PSA is associated with a pro-inflammatory response with a mixed Th1/Th2 response while HHV-8 infection was associated with significantly higher levels of IL12p70, IL-10, and IL-13 indicating a Th2 immune response. We found a significant association between HHV-8 infection and increased levels of serum PSA. In an age of patient-centered medicine, men with an elevated serum PSA should be considered for HHV-8 serology testing to determine if HHV-8 is responsible for the elevated PSA. Prostate 77: 617-624, 2017. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

Circulating sortilin level as a potential biomarker for coronary atherosclerosis and diabetes mellitus.

PubMed

Oh, Tae Jung; Ahn, Chang Ho; Kim, Bo-Rahm; Kim, Kyoung Min; Moon, Jae Hoon; Lim, Soo; Park, Kyong Soo; Lim, Cheong; Jang, HakChul; Choi, Sung Hee

2017-07-20

A previous genome-wide association study showed that a genetic variant of sortilin was associated with the risk of coronary artery disease (CAD). However, the role of circulating sortilin is still unknown. We investigated the potential role of plasma sortilin as a biomarker for CAD and diabetes mellitus. We enrolled statin-naïve subjects with CAD (n = 31) who underwent coronary artery bypass surgery and control subjects (n = 116) who were free from CAD as evaluated by coronary CT angiography. The presence of diabetes mellitus was evaluated and plasma sortilin levels were measured with a commercial ELISA kit. Plasma sortilin levels were higher in subjects with CAD and subjects with diabetes mellitus than in those without CAD or diabetes mellitus. Subjects in the highest sortilin tertile group were older and had higher glucose and HbA1c levels, but lipid profiles in the three tertile groups were comparable. Multivariable logistic regression analysis revealed that sortilin levels were independently associated with CAD. In addition, the receiver operating characteristic curve analysis showed that plasma sortilin levels could identify the presence of CAD or diabetes mellitus. Elevated circulating sortilin levels are associated with CAD and diabetes mellitus and can be used as a biomarker of both diseases in statin-naïve subjects.

FABP4 dynamics in obesity: discrepancies in adipose tissue and liver expression regarding circulating plasma levels.

PubMed

Queipo-Ortuño, María Isabel; Escoté, Xavier; Ceperuelo-Mallafré, Victoria; Garrido-Sanchez, Lourdes; Miranda, Merce; Clemente-Postigo, Mercedes; Pérez-Pérez, Rafael; Peral, Belen; Cardona, Fernando; Fernández-Real, Jose Manuel; Tinahones, Francisco J; Vendrell, Joan

2012-01-01

FABP4 is predominantly expressed in adipose tissue, and its circulating levels are linked with obesity and a poor atherogenic profile. In patients with a wide BMI range, we analyze FABP4 expression in adipose and hepatic tissues in the settings of obesity and insulin resistance. Associations between FABP4 expression in adipose tissue and the FABP4 plasma level as well as the main adipogenic and lipolytic genes expressed in adipose tissue were also analyzed. The expression of several lipogenic, lipolytic, PPAR family and FABP family genes was analyzed by real time PCR. FABP4 protein expression in total adipose tissues and its fractions were determined by western blot. In obesity FABP4 expression was down-regulated (at both mRNA and protein levels), with its levels mainly predicted by ATGL and inversely by the HOMA-IR index. The BMI appeared as the only determinant of the FABP4 variation in both adipose tissue depots. FABP4 plasma levels showed a significant progressive increase according to BMI but no association was detected between FABP4 circulating levels and SAT or VAT FABP4 gene expression. The gene expression of FABP1, FABP4 and FABP5 in hepatic tissue was significantly higher in tissue from the obese IR patients compared to the non-IR group. The inverse pattern in FABP4 expression between adipose and hepatic tissue observed in morbid obese patients, regarding the IR context, suggests that both tissues may act in a balanced manner. These differences may help us to understand the discrepancies between circulating plasma levels and adipose tissue expression in obesity.

FABP4 Dynamics in Obesity: Discrepancies in Adipose Tissue and Liver Expression Regarding Circulating Plasma Levels

PubMed Central

Ceperuelo-Mallafré, Victoria; Garrido-Sanchez, Lourdes; Miranda, Merce; Clemente-Postigo, Mercedes; Pérez-Pérez, Rafael; Peral, Belen; Cardona, Fernando; Fernández-Real, Jose Manuel; Tinahones, Francisco J.; Vendrell, Joan

2012-01-01

Background FABP4 is predominantly expressed in adipose tissue, and its circulating levels are linked with obesity and a poor atherogenic profile. Objective In patients with a wide BMI range, we analyze FABP4 expression in adipose and hepatic tissues in the settings of obesity and insulin resistance. Associations between FABP4 expression in adipose tissue and the FABP4 plasma level as well as the main adipogenic and lipolytic genes expressed in adipose tissue were also analyzed. Methods The expression of several lipogenic, lipolytic, PPAR family and FABP family genes was analyzed by real time PCR. FABP4 protein expression in total adipose tissues and its fractions were determined by western blot. Results In obesity FABP4 expression was down-regulated (at both mRNA and protein levels), with its levels mainly predicted by ATGL and inversely by the HOMA-IR index. The BMI appeared as the only determinant of the FABP4 variation in both adipose tissue depots. FABP4 plasma levels showed a significant progressive increase according to BMI but no association was detected between FABP4 circulating levels and SAT or VAT FABP4 gene expression. The gene expression of FABP1, FABP4 and FABP5 in hepatic tissue was significantly higher in tissue from the obese IR patients compared to the non-IR group. Conclusion The inverse pattern in FABP4 expression between adipose and hepatic tissue observed in morbid obese patients, regarding the IR context, suggests that both tissues may act in a balanced manner. These differences may help us to understand the discrepancies between circulating plasma levels and adipose tissue expression in obesity. PMID:23139800

The effect of circulating nitric oxide level on axial bone mineral density in postmenopausal Turkish women with rheumatoid arthritis: A preliminary report.

PubMed

Sahin, Gunsah; Guler, Hayal; Sezgin, Melek; Incel, Nurgul Arinci; Polat, Gurbuz

2006-07-01

The aim is to investigate the differences in the circulating nitric oxide (NO) levels of rheumatoid arthritis (RA) patients, healthy controls and osteoporotic (OP) patients. We also examined whether the circulating NO levels may be correlated with bone mineral density (BMD) in RA patients. Forty-five patients with RA, 30 healthy women and 30 osteoporotic patients were recruited from the outpatient clinic. All the subjects were female and postmenopausal. Serum NO levels were measured (Nitrite/Nitrate, calorimetric method 1746081, Roche diagnostics, Mannheim, Germany) and BMD was measured at the spine and hip using dual energy X-Ray absorbtiometry (DEXA, Norland XR-46). Height and weight were measured and body mass index was calculated. Circulating NO levels were significantly higher in RA patients than other groups. Moreover, the RA group showed significantly higher BMD at lumbar spine and femoral neck regions compared to osteoporotic patients. However, the RA group showed significantly lower BMD at all sites than the controls. There was no correlation between circulating NO levels and BMD in all groups. We suggest that, unlike postmenopausal osteoporosis, inflammation induced osteoporosis is associated with RA is characterised by relatively preserved bone mass at the axial bone regions, and circulating NO levels as a parameter or determinant of inflammation are not correlated with axial BMD in RA patients.

Different effects of fenofibrate on metabolic and cardiovascular risk factors in mixed dyslipidemic women with normal thyroid function and subclinical hypothyroidism.

PubMed

Krysiak, Robert; Gilowski, Wojciech; Szkrobka, Witold; Okopien, Bogusław

2014-12-01

Subclinical hypothyroidism is suggested to increase cardiovascular risk. No previous study compared the effect of any fibrate on plasma levels of lipids and other cardiovascular risk factors in patients with different thyroid function status. The study included three age-, weight- and lipid-matched groups of women with mixed dyslipidemia in different thyroid function status: patients with untreated subclinical hypothyroidism (group 1, n = 18), women with treated hypothyroidism (group 2, n = 15), and subjects without thyroid disorders (group 3, n = 19). Plasma lipids, glucose homeostasis markers, as well as plasma levels of uric acid, high-sensitivity C-reactive protein (hsCRP), homocysteine, and fibrinogen were determined before and after 12 weeks of fenofibrate therapy. Despite similar plasma lipid levels, mixed dyslipidemic patients with untreated hypothyroidism had decreased insulin sensitivity, as well as higher circulating levels of uric acid, hsCRP, homocysteine, and fibrinogen in comparison with the other groups. The effect of fenofibrate on plasma lipids and, with the exception of homocysteine, on circulating levels of all investigated risk factors was stronger in patients from groups 2 and 3 than in patients from group 1. The obtained results indicate that the effect of fenofibrate on plasma lipids and circulating levels of cardiovascular risk factors is partially related to thyroid function. They also suggest that to improve the strength of fibrate action in dyslipidemic patients with subclinical hypothyroidism, they should be administered together with L-thyroxine. © 2014 John Wiley & Sons Ltd.

Does soy protein affect circulating levels of unbound IGF-1?

PubMed

Messina, Mark; Magee, Pamela

2018-03-01

Despite the enormous amount of research that has been conducted on the role of soyfoods in the prevention and treatment of chronic disease, the mechanisms by which soy exerts its physiological effects are not fully understood. The clinical data show that neither soyfoods nor soy protein nor isoflavones affect circulating levels of reproductive hormones in men or women. However, some research suggests that soy protein, but not isoflavones, affects insulin-like growth factor I (IGF-1). Since IGF-1 may have wide-ranging physiological effects, we sought to determine the effect of soy protein on IGF-1 and its major binding protein insulin-like growth factor-binding protein (IGFBP-3). Six clinical studies were identified that compared soy protein with a control protein, albeit only two studies measured IGFBP-3 in addition to IGF-1. Although the data are difficult to interpret because of the different experimental designs employed, there is some evidence that large amounts of soy protein (>25 g/day) modestly increase IGF-1 levels above levels observed with the control protein. The clinical data suggest that a decision to incorporate soy into the diet should not be based on its possible effects on IGF-1.

Early Detection of Junctional Adhesion Molecule-1 (JAM-1) in the Circulation after Experimental and Clinical Polytrauma

PubMed Central

Denk, Stephanie; Wiegner, Rebecca; Hönes, Felix M.; Messerer, David A. C.; Radermacher, Peter; Kalbitz, Miriam; Braumüller, Sonja; McCook, Oscar; Gebhard, Florian; Weckbach, Sebastian; Huber-Lang, Markus

2015-01-01

Severe tissue trauma-induced systemic inflammation is often accompanied by evident or occult blood-organ barrier dysfunctions, frequently leading to multiple organ dysfunction. However, it is unknown whether specific barrier molecules are shed into the circulation early after trauma as potential indicators of an initial barrier dysfunction. The release of the barrier molecule junctional adhesion molecule-1 (JAM-1) was investigated in plasma of C57BL/6 mice 2 h after experimental mono- and polytrauma as well as in polytrauma patients (ISS ≥ 18) during a 10-day period. Correlation analyses were performed to indicate a linkage between JAM-1 plasma concentrations and organ failure. JAM-1 was systemically detected after experimental trauma in mice with blunt chest trauma as a driving force. Accordingly, JAM-1 was reduced in lung tissue after pulmonary contusion and JAM-1 plasma levels significantly correlated with increased protein levels in the bronchoalveolar lavage as a sign for alveolocapillary barrier dysfunction. Furthermore, JAM-1 was markedly released into the plasma of polytrauma patients as early as 4 h after the trauma insult and significantly correlated with severity of disease and organ dysfunction (APACHE II and SOFA score). The data support an early injury- and time-dependent appearance of the barrier molecule JAM-1 in the circulation indicative of a commencing trauma-induced barrier dysfunction. PMID:26556956

ELABELA/APELA levels are not decreased in the maternal circulation or placenta among women with preeclampsia.

PubMed

Pritchard, Natasha; Kaitu'u-Lino, Tu'uhevaha J; Gong, Sungsam; Dopierala, Justyna; Smith, Gordon C S; Charnock-Jones, D Stephen; Tong, Stephen

2018-05-24

The genetic deletion of Elabela (official name APELA, encoding the peptide hormone apelin receptor early endogenous ligand) produces a preeclampsia-like phenotype in mice. However, evidence linking ELABELA with human disease is lacking. Therefore, we measured placental mRNA and circulating ELABELA in human samples. ELABELA mRNA (measured by RNA-Seq) was unchanged in 82 preeclamptic placentas compared to 82 matched controls (mean difference 0.53 %; 95% CI, -25.9 to 27.0, P = 0.78). We measured circulating ELABELA in 32 women with preterm preeclampsia (delivered <34 weeks' gestation) and 32 matched controls sampled at the same gestational age. There was no difference in circulating ELABELA concentration (median (95% CI) in the preeclamptic cohort 28.5 pg/mL (5.3 to 63.2) vs 20.5 pg/mL (9.2 to 58.0) controls; median difference (95% CI) was 8.0 pg/mL (CI -17.7 to 12.1), P = 0.43). In contrast, soluble FLT1 (sFLT1, a protein with an established association with preeclampsia) mRNA was elevated in placental tissue (mean difference 34.9%; 95% CI, 16.6 to 53.1, P = 0.001), and circulating concentrations were 16.8-fold higher among the preeclamptic cohort (P < 0.0001). In conclusion, we were able to recapitulate the well-recognized association between circulating sFLT1 and preeclampsia but there was no such association with ELABELA. Hence, the speculated clinical relevance of observations in the murine model linking ELABELA to preeclampsia are likely incorrect. Copyright © 2018. Published by Elsevier Inc.

Inhibition of aberrant circulating Tfh cell proportions by corticosteroids in patients with systemic lupus erythematosus.

PubMed

Feng, Xuebing; Wang, Dandan; Chen, Jingjing; Lu, Lin; Hua, Bingzhu; Li, Xia; Tsao, Betty P; Sun, Lingyun

2012-01-01

To observe the proportion of peripheral T follicular helper (Tfh) cells in patients with systemic lupus erythematosus (SLE) and to assess the role of steroids on Tfh cells from SLE patients. Peripheral blood mononuclear cells (PBMCs) from 42 SLE patients and 22 matched healthy subjects were collected to assess proportions of circulating CXCR5(+)PD1(+)/CD4(+) T cells (Tfh), CD4(+)CCR6(+) T cells (Th17-like) and CD19(+)CD138(+) plasma cells by flow cytometry. 8 of the patients had their blood redrawn within one week after receiving methylprednisolone pulse treatment. Disease activity was evaluated by SLE disease activity index. To test the effect of IL-21 and corticosteroids on Tfh cells in vitro, PBMCs harvested from another 15 SLE patients were cultured with medium, IL-21, or IL-21+ dexamethasone for 24 hours and 72 hours. PBMCs from an independent 23 SLE patients were cultured with different concentrations of dexamethasone for 24 hours. Compared to normal controls, percentages of circulating Tfh cells, but not Th17 cells, were elevated in SLE patients and correlated with disease activity. Proportions of Tfh cells in SLE patients were positively correlated with those of plasma cells and serum levels of antinuclear antibodies. After methylprednisolone pulse treatment, both percentages and absolute numbers of circulating Tfh cells were significantly decreased. In vitro cultures showed an increase of Tfh cell proportion after IL-21 stimulation that was totally abolished by the addition of dexamethasone. Both 0.5 and 1 µM dexamethasone decreased Tfh cells dose dependently (overall p = 0.013). We demonstrated that elevated circulating Tfh cell proportions in SLE patients correlated with their disease activities, and circulating levels of plasma cells and ANA. Corticosteroids treatment down-regulated aberrant circulating Tfh cell proportions both in vivo and in vitro, making Tfh cells a new treatment target for SLE patients.

Accuracy of circulating histones in predicting persistent organ failure and mortality in patients with acute pancreatitis.

PubMed

Liu, T; Huang, W; Szatmary, P; Abrams, S T; Alhamdi, Y; Lin, Z; Greenhalf, W; Wang, G; Sutton, R; Toh, C H

2017-08-01

Early prediction of acute pancreatitis severity remains a challenge. Circulating levels of histones are raised early in mouse models and correlate with disease severity. It was hypothesized that circulating histones predict persistent organ failure in patients with acute pancreatitis. Consecutive patients with acute pancreatitis fulfilling inclusion criteria admitted to Royal Liverpool University Hospital were enrolled prospectively between June 2010 and March 2014. Blood samples were obtained within 48 h of abdominal pain onset and relevant clinical data during the hospital stay were collected. Healthy volunteers were enrolled as controls. The primary endpoint was occurrence of persistent organ failure. The predictive values of circulating histones, clinical scores and other biomarkers were determined. Among 236 patients with acute pancreatitis, there were 156 (66·1 per cent), 57 (24·2 per cent) and 23 (9·7 per cent) with mild, moderate and severe disease respectively, according to the revised Atlanta classification. Forty-seven healthy volunteers were included. The area under the receiver operating characteristic (ROC) curve (AUC) for circulating histones in predicting persistent organ failure and mortality was 0·92 (95 per cent c.i. 0·85 to 0·99) and 0·96 (0·92 to 1·00) respectively; histones were at least as accurate as clinical scores or biochemical markers. For infected pancreatic necrosis and/or sepsis, the AUC was 0·78 (0·62 to 0·94). Histones did not predict or correlate with local pancreatic complications, but correlated negatively with leucocyte cell viability (r = -0·511, P = 0·001). Quantitative assessment of circulating histones in plasma within 48 h of abdominal pain onset can predict persistent organ failure and mortality in patients with acute pancreatitis. Early death of immune cells may contribute to raised circulating histone levels in acute pancreatitis. © 2017 The Authors. BJS published by John Wiley & Sons Ltd on behalf of BJS Society Ltd.

Serum Progranulin Concentrations May Be Associated With Macrophage Infiltration Into Omental Adipose Tissue

PubMed Central

Youn, Byung-Soo; Bang, Sa-Ik; Klöting, Nora; Park, Ji Woo; Lee, Namseok; Oh, Ji-Eun; Pi, Kyung-Bae; Lee, Tae Hee; Ruschke, Karen; Fasshauer, Mathias; Stumvoll, Michael; Blüher, Matthias

2009-01-01

OBJECTIVE—Progranulin is an important molecule in inflammatory response. Chronic inflammation is frequently associated with central obesity and associated disturbances; however, the role of circulating progranulin in human obesity, type 2 diabetes, and dyslipidemia is unknown. RESEARCH DESIGN AND METHODS—For the measurement of progranulin serum concentrations, we developed an enzyme-linked immunosorbent assay (ELISA). Using this ELISA, we assessed circulating progranulin in a cross-sectional study of 209 subjects with a wide range of obesity, body fat distribution, insulin sensitivity, and glucose tolerance and in 60 individuals with normal (NGT) or impaired (IGT) glucose tolerance or type 2 diabetes before and after a 4-week physical training program. Progranulin mRNA and protein expression was measured in paired samples of omental and subcutaneous adipose tissue (adipocytes and cells of the stromal vascular fraction) from 55 lean or obese individuals. Measurement of Erk activation and chemotactic activity induced by progranulin in vitro was performed using THP-1–based cell migration assays. RESULTS—Progranulin serum concentrations were significantly higher in individuals with type 2 diabetes compared with NGT and in obese subjects with predominant visceral fat accumulation. Circulating progranulin significantly correlates with BMI, macrophage infiltration in omental adipose tissue, C-reactive protein (CRP) serum concentrations, A1C values, and total cholesterol. Multivariable linear regression analyses revealed CRP levels as the strongest independent predictor of circulating progranulin. The extent of in vitro progranulin-mediated chemotaxis is similar to that of monocyte chemoattractant protein-1 but independent of Gα. Moreover, in type 2 diabetes, but not in IGT and NGT individuals, physical training for 4 weeks resulted in significantly decreased circulating progranulin levels. CONCLUSIONS—Elevated progranulin serum concentrations are associated with visceral obesity, elevated plasma glucose, and dyslipidemia. We identified progranulin as a novel marker of chronic inflammation in obesity and type 2 diabetes that closely reflects omental adipose tissue macrophage infiltration. Physical training significantly reduces elevated circulating progranulin in patients with type 2 diabetes. PMID:19056610

The effects of conventional extracorporeal circulation versus miniaturized extracorporeal circulation on microcirculation during cardiopulmonary bypass-assisted coronary artery bypass graft surgery.

PubMed

Yuruk, Koray; Bezemer, Rick; Euser, Mariska; Milstein, Dan M J; de Geus, Hilde H R; Scholten, Evert W; de Mol, Bas A J M; Ince, Can

2012-09-01

OBJECTIVES To reduce the complications associated with cardiopulmonary bypass (CPB) during cardiac surgery, many modifications have been made to conventional extracorporeal circulation systems. This trend has led to the development of miniaturized extracorporeal circulation systems. Cardiac surgery using conventional extracorporeal circulation systems has been associated with significantly reduced microcirculatory perfusion, but it remains unknown whether this could be prevented by an mECC system. Here, we aimed to test the hypothesis that microcirculatory perfusion decreases with the use of a conventional extracorporeal circulation system and would be preserved with the use of an miniaturized extracorporeal circulation system. METHODS Microcirculatory density and perfusion were assessed using sublingual side stream dark-field imaging in patients undergoing on-pump coronary artery bypass graft (CABG) surgery before, during and after the use of either a conventional extracorporeal circulation system (n = 10) or a miniaturized extracorporeal circulation system (n = 10). In addition, plasma neutrophil gelatinase-associated lipocalin and creatinine levels and creatinine clearance were assessed up to 5 days post-surgery to monitor renal function. RESULTS At the end of the CPB, one patient in the miniaturized extracorporeal circulation-treated group and five patients in the conventional extracorporeal circulation-treated group received one bag of packed red blood cells (300 ml). During the CPB, the haematocrit and haemoglobin levels were slightly higher in the miniaturized extracorporeal circulation-treated patients compared with the conventional extracorporeal circulation-treated patients (27.7 ± 3.3 vs 24.7 ± 2.0%; P = 0.03; and 6.42 ± 0.75 vs 5.41 ± 0.64 mmol/l; P < 0.01). The density of perfused vessels with a diameter <25 µm (i.e. perfused vessel density) decreased slightly in the conventional extracorporeal circulation-treated group from 16.4 ± 3.8 to 12.8 ± 3.3 mm/mm(2) (P < 0.01) and remained stable in the miniaturized extracorporeal circulation-treated group (16.3 ± 2.7 and 15.2 ± 2.9 mm/mm(2) before and during the pump, respectively). Plasma neutrophil gelatinase-associated lipocalin levels were increased following the use of extracorporeal circulation in both groups, and no differences were observed between the groups. Plasma creatinine levels and creatinine clearance were not affected by CABG surgery or CPB. CONCLUSIONS The results from this relatively small study suggest that the use of the miniaturized extracorporeal circulation system is associated with a statistically significant (but clinically insignificant) reduction in haemodilution and microcirculatory hypoperfusion compared with the use of the conventional extracorporeal circulation system.

Physiological levels of blood coagulation factors IX and X control coagulation kinetics in an in vitro model of circulating tissue factor

NASA Astrophysics Data System (ADS)

Tormoen, Garth W.; Khader, Ayesha; Gruber, András; McCarty, Owen J. T.

2013-06-01

Thrombosis significantly contributes to cancer morbidity and mortality. The mechanism behind thrombosis in cancer may be circulating tissue factor (TF), as levels of circulating TF are associated with thrombosis. However, circulating TF antigen level alone has failed to predict thrombosis in patients with cancer. We hypothesize that coagulation factor levels regulate the kinetics of circulating TF-induced thrombosis. Coagulation kinetics were measured as a function of individual coagulation factor levels and TF particle concentration. Clotting times increased when pooled plasma was mixed at or above a ratio of 4:6 with PBS. Clotting times increased when pooled plasma was mixed at or above a ratio of 8:2 with factor VII-depleted plasma, 7:3 with factor IX- or factor X-depleted plasmas, or 2:8 with factor II-, V- or VIII-depleted plasmas. Addition of coagulation factors VII, X, IX, V and II to depleted plasmas shortened clotting and enzyme initiation times, and increased enzyme generation rates in a concentration-dependent manner. Only additions of factors IX and X from low-normal to high-normal levels shortened clotting times and increased enzyme generation rates. Our results demonstrate that coagulation kinetics for TF particles are controlled by factor IX and X levels within the normal physiological range. We hypothesize that individual patient factor IX and X levels may be prognostic for susceptibility to circulating TF-induced thrombosis.

Inhalational botulism in rhesus macaques exposed to botulinum neurotoxin complex serotypes A1 and B1.

PubMed

Sanford, Daniel C; Barnewall, Roy E; Vassar, Michelle L; Niemuth, Nancy; Metcalfe, Karen; House, Robert V; Henderson, Ian; Shearer, Jeffry D

2010-09-01

A recombinant botulinum vaccine (rBV A/B) is being developed for protection against inhalational intoxication with botulinum neurotoxin (BoNT) complex serotype A, subtype A1 (BoNT/A1), and BoNT serotype B, subtype B1 (BoNT/B1). A critical component for evaluating rBV A/B efficacy will be the use of animal models in which the pathophysiology and dose-response relationships following aerosol exposure to well-characterized BoNT are thoroughly understood and documented. This study was designed to estimate inhaled 50% lethal doses (LD(50)) and to estimate 50% lethal exposure concentrations relative to time (LCt(50)) in rhesus macaques exposed to well-characterized BoNT/A1 and BoNT/B1. During the course of this study, clinical observations, body weights, clinical hematology results, clinical chemistry results, circulating neurotoxin levels, and telemetric parameters were documented to aid in the understanding of disease progression. The inhaled LD(50) and LCt(50) for BoNT/A1 and BoNT/B1 in rhesus macaques were determined using well-characterized challenge material. Clinical observations were consistent with the recognized pattern of botulism disease progression. A dose response was demonstrated with regard to the onset of these clinical signs for both BoNT/A1 and BoNT/B1. Dose-related changes in physiologic parameters measured by telemetry were also observed. In contrast, notable changes in body weight, hematology, and clinical chemistry parameters were not observed. Circulating levels of BoNT/B1 were detected in animals exposed to the highest levels of BoNT/B1; however, BoNT/A1 was not detected in the circulation at any aerosol exposure level. The rhesus macaque aerosol challenge model will be used for future evaluations of rBV A/B efficacy against inhalational BoNT/A1 and BoNT/B1 intoxication.

Inhalational Botulism in Rhesus Macaques Exposed to Botulinum Neurotoxin Complex Serotypes A1 and B1▿ †

PubMed Central

Sanford, Daniel C.; Barnewall, Roy E.; Vassar, Michelle L.; Niemuth, Nancy; Metcalfe, Karen; House, Robert V.; Henderson, Ian; Shearer, Jeffry D.

2010-01-01

A recombinant botulinum vaccine (rBV A/B) is being developed for protection against inhalational intoxication with botulinum neurotoxin (BoNT) complex serotype A, subtype A1 (BoNT/A1), and BoNT serotype B, subtype B1 (BoNT/B1). A critical component for evaluating rBV A/B efficacy will be the use of animal models in which the pathophysiology and dose-response relationships following aerosol exposure to well-characterized BoNT are thoroughly understood and documented. This study was designed to estimate inhaled 50% lethal doses (LD50) and to estimate 50% lethal exposure concentrations relative to time (LCt50) in rhesus macaques exposed to well-characterized BoNT/A1 and BoNT/B1. During the course of this study, clinical observations, body weights, clinical hematology results, clinical chemistry results, circulating neurotoxin levels, and telemetric parameters were documented to aid in the understanding of disease progression. The inhaled LD50 and LCt50 for BoNT/A1 and BoNT/B1 in rhesus macaques were determined using well-characterized challenge material. Clinical observations were consistent with the recognized pattern of botulism disease progression. A dose response was demonstrated with regard to the onset of these clinical signs for both BoNT/A1 and BoNT/B1. Dose-related changes in physiologic parameters measured by telemetry were also observed. In contrast, notable changes in body weight, hematology, and clinical chemistry parameters were not observed. Circulating levels of BoNT/B1 were detected in animals exposed to the highest levels of BoNT/B1; however, BoNT/A1 was not detected in the circulation at any aerosol exposure level. The rhesus macaque aerosol challenge model will be used for future evaluations of rBV A/B efficacy against inhalational BoNT/A1 and BoNT/B1 intoxication. PMID:20660138

The Association of Subclinical Hypothyroidism and Pattern of Circulating Endothelial-Derived Microparticles Among Chronic Heart Failure Patients

PubMed Central

Berezin, Alexander E.; Kremzer, Alexander A.; Martovitskaya, Yulia V.; Samura, Tatyana A.; Berezina, Tatyana A.

2015-01-01

Background: Subclinical hypothyroidism (SH) is diagnosed biochemically by the presence of normal serum free thyroxine concentration, in conjunction with an elevated serum thyroid-stimulating hormone level. Recent studies have demonstrated the frequent association between SH and cardiovascular diseases and risk factors. Objectives: To evaluate the impact of SH on patterns of circulating endothelial-derived microparticles, (EMPs) among chronic heart failure (CHF) patients Patients and Methods: This is a retrospective study involving a cohort of 388 patients with CHF. Fifty-three CHF subjects had SH and 335 patients were free from thyroid dysfunction. Circulating levels of N-terminal-pro brain natriuretic peptide (NT-proBNP), high-sensitivity C-reactive protein (hs-CRP), thyroid-stimulating hormone (TSH), total and free thyroxine (T4), and triiodothyronine (T3), and endothelial apoptotic microparticles (EMPs), were measured at baseline. SH was defined, according to contemporary clinical guidelines, as a biochemical state associated with an elevated serum TSH level of greater 10 μU/L and normal basal free T3 and T4 concentrations. Results: Circulating CD31+/annexin V+ EMPs were higher in patients with SH compared to those without SH. In contrast, activated CD62E+ EMP numbers were not significantly different between both patient cohorts. Using uni (bi) variate and multivariate age- and gender-adjusted regression analysis, we found several predictors that affected the increase of the CD31+/annexin V+ to CD62E+ ratio in the patient study population. The independent impact of TSH per 6.5 μU/L (odds ratio [OR] = 1.23, P = 0.001), SH (OR = 1.22, P = 0.001), NT-proBNP (OR = 1.19, P = 0.001), NYHA class (OR = 1.09, P = 0.001), hs-CRP per 4.50 mg/L (OR = 1.05, P = 0.001), dyslipidemia (OR = 1.06, P = 0.001), serum uric acid per 9.5 mmol/L (OR = 1.04, P = 0.022) on the increase in the CD31+/annexin V+ to CD62E+ ratio, was determined. Conclusions: We believe that the SH state in CHF patients may be associated with the impaired pattern of circulating EMPs, with the predominantly increased number of apoptotic-derived microparticles. PMID:26528453

Endocrine Society of Australia position statement on male hypogonadism (part 1): assessment and indications for testosterone therapy.

PubMed

Yeap, Bu B; Grossmann, Mathis; McLachlan, Robert I; Handelsman, David J; Wittert, Gary A; Conway, Ann J; Stuckey, Bronwyn Ga; Lording, Douglas W; Allan, Carolyn A; Zajac, Jeffrey D; Burger, Henry G

2016-08-15

This article, Part 1 of the Endocrine Society of Australia's position statement on male hypogonadism, focuses on assessment of male hypogonadism, including the indications for testosterone therapy. (Part 2 will deal with treatment and therapeutic considerations.) Key points and recommendations are:Pathological hypogonadism arises due to diseases of the hypothalamus or pituitary gland (hypogonadotropic hypogonadism) or testes (hypergonadotropic hypogonadism). It is a clinical diagnosis with a pathological basis, confirmed by hormone assays.Hormonal assessment is based on measurement of circulating testosterone, luteinising hormone (LH) and follicle-stimulating hormone (FSH) concentrations. Measurement of sex hormone-binding globulin levels can be informative, but use of calculated free testosterone is not recommended for clinical decision making.Testosterone replacement therapy is warranted in men with pathological hypogonadism, regardless of age.Currently, there are limited data from high-quality randomised controlled trials with clinically meaningful outcomes to justify testosterone treatment in older men, usually with chronic disease, who have low circulating testosterone levels but without hypothalamic, pituitary or testicular disease.Obesity, metabolic syndrome and type 2 diabetes are associated with lowering of circulating testosterone level, but without elevation of LH and FSH levels. Whether these are non-specific consequences of non-reproductive disorders or a correctable deficiency state is unknown, but clear evidence for efficacy and safety of testosterone therapy in this setting is lacking.Glucocorticoid and opioid use is associated with possibly reversible reductions in circulating testosterone level, without elevation of LH and FSH levels. Where continuation of glucocorticoid or opioid therapy is necessary, review by an endocrinologist may be warranted.Changes in management as result of the position statement: Men with pathological hypogonadism should be identified and considered for testosterone therapy, while further research is needed to clarify whether there is a role for testosterone in these other settings.

Metabolomic markers of fatigue: Association between circulating metabolome and fatigue in women with chronic widespread pain.

PubMed

Freidin, Maxim B; Wells, Helena R R; Potter, Tilly; Livshits, Gregory; Menni, Cristina; Williams, Frances M K

2018-02-01

Fatigue is a sensation of unbearable tiredness that frequently accompanies chronic widespread musculoskeletal pain (CWP) and inflammatory joint disease. Its mechanisms are poorly understood and there is a lack of effective biomarkers for diagnosis and onset prediction. We studied the circulating metabolome in a population sample characterised for CWP to identify biomarkers showing specificity for fatigue. Untargeted metabolomic profiling was conducted on fasting plasma and serum samples of 1106 females with and without CWP from the TwinsUK cohort. Linear mixed-effects models accounting for covariates were used to determine relationships between fatigue and metabolites. Receiver operating curve (ROC)-analysis was used to determine predictive value of metabolites for fatigue. While no association between fatigue and metabolites was identified in twins without CWP (n=711), in participants with CWP (n=395), levels of eicosapentaenoate (EPA) ω-3 fatty acid were significantly reduced in those with fatigue (β=-0.452±0.116; p=1.2×10 -4 ). A significant association between fatigue and two other metabolites also emerged when BMI was excluded from the model: 3-carboxy-4-methyl-5-propyl-2-furanpropanoate (CMPF), and C-glycosyltryptophan (p=1.5×10 -4 and p=3.1×10 -4 , respectively). ROC analysis has identified a combination of 15 circulating metabolites with good predictive potential for fatigue in CWP (AUC=75%; 95% CI 69-80%). The results of this agnostic metabolomics screening show that fatigue is metabolically distinct from CWP, and is associated with a decrease in circulating levels of EPA. Our panel of circulating metabolites provides the starting point for a diagnostic test for fatigue in CWP. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

High Levels of Peripheral Blood Circulating Plasma Cells as a Specific Risk Factor for Progression of Smoldering Multiple Myeloma

PubMed Central

Bianchi, Giada; Kyle, Robert A.; Larson, Dirk R.; Witzig, Thomas E.; Kumar, Shaji; Dispenzieri, Angela; Morice, William G.; Rajkumar, S. Vincent

2012-01-01

Smoldering multiple myeloma (SMM) carries a 50% risk of progression to multiple myeloma (MM) or related malignancy within the first 5 years following diagnosis. The goal of this study was to determine if high levels of circulating plasma cells (PCs) are predictive of SMM transformation within the first 2–3 years from diagnosis. Ninety-one patients diagnosed with SMM at Mayo Clinic from January 1994 through January 2007 who had testing for circulating PCs using an immunofluorescent assay and adequate follow up to ascertain disease progression, were studied. High level of circulating PCs was defined as absolute peripheral blood PCs >5000 ×106/L and/or > 5% cytoplasmic immunoglobulin (Ig) positive PCs per 100 peripheral blood mononuclear cells. Patients with high circulating PCs (14 of 91 patients, 15%) were significantly more likely to progress to active disease within 2 years compared with patients without high circulating PCs, 71% versus 25%, respectively, P=0.001. Corresponding rates for progression within 3 years were 86% versus 35%, respectively, P<0.001. Overall survival (OS) after both SMM diagnosis and MM diagnosis was also significantly different. High levels of circulating PCs identify SMM patients with an elevated risk of progression within the first 2 to 3 years following diagnosis. PMID:22902364

Association of circulating insulin-like growth factor 1 and insulin-like growth factor binding protein 3 with the risk of ovarian cancer: A systematic review and meta-analysis.

PubMed

Wang, Qiao; Bian, C E; Peng, Hongling; He, Lei; Zhao, Xia

2015-05-01

Insulin-like growth factor 1 (IGF-1) and its main binding protein (IGFBP-3) in blood have been associated with the risk of several types of cancer. However, epidemiological studies have inconsistent results regarding the association of circulating IGF-1/IGFBP-3 levels with ovarian cancer risk. A systematic review of the prospective studies was conducted using meta-analysis to evaluate the existing evidence. Pubmed and Embase databases were searched to identify the relevant studies published before May 1, 2014. Four highly qualified studies with a total of 627 cases and 1,358 controls were finally included in the meta-analysis. Random effects meta-analysis was conducted by combining study-specific odds ratios (ORs) of ovarian cancer for the highest verses lowest exposure levels. A dose-response association was further assessed by relating the log of ORs for different exposure levels. As a result, the pooled ORs for the highest verses lowest categories of IGF-1/IGFBP-3 were 0.85 [95% confidence interval (CI), 0.51-1.40]/0.78 (95% CI, 0.43-1.40). In the subgroup analyses, the pooled ORs of IGF-1/IGFBP-3 were 1.89 (95% CI, 0.64-5.59)/1.08 (95% CI, 0.50-2.32) for the subgroup with cases diagnosed at <55 years, and 0.74 (95% CI, 0.50-1.08)/0.98 (95% CI, 0.73-1.33) for the subgroup with cases diagnosed at ≥55 years. No linear association between circulating IGF-1/IGFBP-3 levels and ovarian cancer risk was identified. As no significant association of IGF-1/IGFBP-3 with ovarian cancer risk was identified in the present meta-analysis of existing studies, more studies with greater quality are required in the future.

Genetic regulation of the variation of circulating insulin-like growth factors and leptin in human pedigrees.

PubMed

Pantsulaia, Ia; Pantsulaia, I; Trofimov, Svetlana; Kobyliansky, Eugene; Livshits, Gregory

2005-07-01

Recent literature has shown that circulating levels of insulin-like growth factor I (IGF-I) and/or IGF binding proteins (IGF-BPs) may be of importance in the risk assessment of several chronic diseases including cancer, cardiovascular disease, diabetes mellitus and so on. The present study examined the extent of genetic and environmental influences on the populational variation of circulating IGF-I and IGF-BP-1 in apparently healthy and ethnically homogeneous white families. The plasma levels of each of the studied biochemical indices were determined by enzyme-linked immunoassay in 563 individuals aged 18 to 80 years. Quantitative genetic analysis showed that the IGF-I variation was appreciably attributable to genetic effects (47.1% +/- 9.0%), whereas for IGF-BP-1, only 23.3% +/- 7.8% of the interindividual variation was explained by genetic determinants. Common familial environment factors contributed significantly only to IGF-BP-1 variation (23.3% +/- 7.8%). In addition, we examined the covariations between these molecules and between them and IGF-BP-3 and leptin that were previously studied in the same sample. The analysis revealed that the pleiotropic genetic effects were significant for 2 pairs of traits, namely for IGF-I and IGF-BP-3, and for IGF-BP-1 and leptin. The bivariate heritability estimates were 0.21 +/- 0.04 and 0.15 +/- 0.05. The common environmental factors were consistently a significant source of correlation between all pairs (barring IGF-I and leptin) of the studied molecules; they were the sole predictors of correlation between IGF-I and IGF-BP-1, and between IGF-BP-1 and IGF-BP-3. Our results affirm the existence of specific and common genetic pathways that in combination determine a substantial proportion of the circulating variation of these molecules.

Association between the level of circulating adiponectin and prediabetes: A meta-analysis

PubMed Central

Lai, Huasheng; Lin, Nie; Xing, Zhenzhen; Weng, Huanhuan; Zhang, Hua

2015-01-01

Aims/Introduction Adiponectin has been proposed to have an essential role in the regulation of insulin sensitivity and metabolism, but previous studies on levels of adiponectin in prediabetes remain inconsistent. The present study aimed to assess the differences of adiponectin levels between prediabetes patients and healthy controls by carrying out a meta-analysis. Materials and Methods We carried out a systematic literature search of PubMed, EMBASE, and other databases for case–control studies and cohort studies measuring adiponectin levels in serum or plasma from prediabetes patients and healthy controls. The pooled weighted mean difference (WMD) and 95% confidence interval (CI) were used to estimate the association between adiponectin levels and prediabetes. Results Three cohort studies and 15 case–control studies with a total of 41,841 participants were included in the meta-analysis. The results showed that circulating adiponectin levels in prediabetes patients were significantly lower than that of healthy controls (WMD –1.694 μg/mL; 95% CI –2.151, –1.237; P < 0.001). Subgroup analysis showed more significant differences between prediabetes patients and healthy controls when the ratio of the homeostatic model assessment of insulin resistance was >2.12 (WMD −2.95 μg/mL; 95% CI –4.103, –1.806; P < 0.001) and average age was >60 years (WMD −2.20 μg/mL; 95% CI –3.207, –1.201; P < 0.001). Additionally, WMD in adiponectin showed a trend of direct correlation in subgroups of homeostatic model assessment of insulin resistance ratio, body mass index and age. Conclusions The present meta-analysis supports adiponectin levels in prediabetes patients being lower than that of healthy controls,indicating that the level of circulating adiponectin decreases before the onset of diabetes. PMID:26221520

Circulating Sex Hormones and Terminal Duct Lobular Unit Involution of the Normal Breast

PubMed Central

Khodr, Zeina G.; Sherman, Mark E.; Pfeiffer, Ruth M.; Gierach, Gretchen L.; Brinton, Louise A.; Falk, Roni T.; Patel, Deesha A.; Linville, Laura M.; Papathomas, Daphne; Clare, Susan E.; Visscher, Daniel W.; Mies, Carolyn; Hewitt, Stephen M.; Storniolo, Anna Maria V.; Rosebrock, Adrian; Caban, Jesus J.; Figueroa, Jonine D.

2014-01-01

Background Terminal duct lobular units (TDLUs) are the predominant source of breast cancers. Lesser degrees of age-related TDLU involution have been associated with increased breast cancer risk, but factors that influence involution are largely unknown. We assessed whether circulating hormones, implicated in breast cancer risk, are associated with levels of TDLU involution using data from the Susan G. Komen Tissue Bank (KTB) at the Indiana University Simon Cancer Center (2009-2011). Methods We evaluated three highly reproducible measures of TDLU involution, using normal breast tissue samples from the KTB (n=390): TDLU counts, median TDLU span, and median acini counts per TDLU. Relative risks (RRs, for continuous measures), odds ratios (ORs, for categorical measures), 95% confidence intervals (CIs), and p-trends were calculated to assess the association between tertiles of estradiol, testosterone, sex hormone-binding globulin (SHBG), progesterone, and prolactin with TDLU measures. All models were stratified by menopausal status and adjusted for confounders. Results Among premenopausal women, higher prolactin levels were associated with higher TDLU counts (RRT3vsT1:1.18, 95% CI: 1.07-1.31; p-trend=0.0005), but higher progesterone was associated with lower TDLU counts (RRT3vsT1: 0.80, 95% CI: 0.72-0.89; p-trend<0.0001). Among postmenopausal women, higher levels of estradiol (RRT3vsT1:1.61, 95% CI: 1.32-1.97; p-trend<0.0001) and testosterone (RRT3vsT1: 1.32, 95% CI: 1.09-1.59; p-trend=0.0043) were associated with higher TDLU counts. Conclusions These data suggest that select hormones may influence breast cancer risk potentially through delaying TDLU involution. Impact Increased understanding of the relationship between circulating markers and TDLU involution may offer new insights into breast carcinogenesis. PMID:25472681

IL-6-driven STAT signalling in circulating CD4+ lymphocytes is a marker for early anticitrullinated peptide antibody-negative rheumatoid arthritis.

PubMed

Anderson, Amy E; Pratt, Arthur G; Sedhom, Mamdouh A K; Doran, John Paul; Routledge, Christine; Hargreaves, Ben; Brown, Philip M; Lê Cao, Kim-Anh; Isaacs, John D; Thomas, Ranjeny

2016-02-01

A previously identified signal transduction and activator of transcription-3 (STAT3) target-enriched gene signature in circulating CD4+ T cells of patients with early rheumatoid arthritis (RA) was prominent in autoantibody-negative individuals. Here, interleukin (IL)-6-mediated STAT signalling was investigated in circulating lymphocytes of an independent early arthritis patient cohort, seeking further insight into RA pathogenesis and biomarkers of potential clinical utility. Constitutive and IL-6-induced expression of phosphorylated STAT1 (pSTAT1) and pSTAT3 was determined in T and B cells using Phosflow cytometric analysis in patients with RA and controls. Contemporaneous levels of serum cytokines were measured by immunoassay. Induced gene expression was measured in cultured CD4+T cells by quantitative real-time PCR. Among circulating lymphocytes of 187 patients with early arthritis, constitutive pSTAT3 correlated with serum IL-6 levels maximally in CD4+ T cells. Increased constitutive pSTAT3, but not pSTAT1, was observed in circulating CD4+ T cells of patients with early anticitrullinated peptide autoantibody (ACPA)-negative RA compared with disease controls, and these levels decreased alongside markers of disease activity with IL-6R-targeted treatment. Among patients presenting with seronegative undifferentiated arthritis (UA) the ratio of constitutive pSTAT3:pSTAT1 in CD4+ T cells contributed substantially to an algorithm for predicting progression to classifiable RA during a median of 20 months follow-up (area under receiver operator characteristic curve=0.84; p<0.001). Our findings support a particular role for IL-6-driven CD4+ T cell activation via STAT3 during the induction of RA, particularly as a feature of ACPA-negative disease. CD4+ T cell pSTAT measurements show promise as biomarkers of UA-RA progression and now require independent validation. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

Differential Regulation of PAI-1 in Hantavirus Cardiopulmonary Syndrome and Hemorrhagic Fever With Renal Syndrome.

PubMed

Bellomo, Carla; Korva, Miša; Papa, Anna; Mäkelä, Satu; Mustonen, Jukka; Avšič-Županc, Tatjana; Vaheri, Antti; Martinez, Valeria P; Strandin, Tomas

2018-02-01

We analyzed the levels of circulating tissue plasminogen activator (tPA) and plasminogen activator inhibitor (PAI)-1 in acute hantavirus cardiopulmonary syndrome (HCPS) and hemorrhagic fever with renal syndrome (HFRS). The levels of tPA commonly increased in both diseases, whereas PAI-1 correlated with disease severity in HCPS but not in HFRS.

Lower placental growth factor and higher free β-hCG and PAPP-A levels in the fetal circulation of near-term pregnancies complicated with severe preeclampsia.

PubMed

Paredes, Verónica; Espinoza-Caicedo, Jasson A; Salazar-Pousada, Danny; Escobar, Gustavo S; Pérez-López, Faustino R; Chedraui, Peter

2017-01-01

An imbalance between anti- and angiogenic factors during early placentation is key for the development of preeclampsia. Nevertheless, the majority of studies addressing this issue relate to maternal blood and not the fetal circulation. To measure placental growth factor (PlGF), free beta human chorionic gonadotropin (β-hCG), and pregnancy-associated plasma protein-A (PAPP-A) levels in the fetal circulation of near-term pregnancies complicated with severe preeclampsia (n = 20), and their controls matched for parity, and maternal and gestational age. Upon delivery, a blood sample was withdrawn from the umbilical artery and vein of each case and its control in order to measure the proposed analytes using direct fluoroimmunoassay. Preeclampsia cases showed significantly lower median PlGF levels in fetal circulation as compared to controls (25.2 versus 36.9 and 23.6 versus 33.9 pg/mL, artery and vein, respectively, p < 0.05). Contrarily, cases displayed higher concentrations of PAPP-A (1024.0 versus 720.9 [median] and 1027.0 ± 298.4 versus 690.3 ± 401.9 mIU/L, artery and vein, respectively, p < 0.05), and free β-hCG (mean: 33.9 ± 4.3 versus 17.2 ± 4.0 and 30.1 ± 5.2 versus 13.7 ± 3.3 ng/mL, artery, and vein respectively, p < 0.05). Lower PlGF and higher PAPP-A and free β-hCG levels were found in the fetal circulation of near-term severe preeclamptic pregnancies. There is a need for more research in this regard.

Genetic diminution of circulating prothrombin ameliorates multiorgan pathologies in sickle cell disease mice.

PubMed

Arumugam, Paritha I; Mullins, Eric S; Shanmukhappa, Shiva Kumar; Monia, Brett P; Loberg, Anastacia; Shaw, Maureen A; Rizvi, Tilat; Wansapura, Janaka; Degen, Jay L; Malik, Punam

2015-10-08

Sickle cell disease (SCD) results in vascular occlusions, chronic hemolytic anemia, and cumulative organ damage. A conspicuous feature of SCD is chronic inflammation and coagulation system activation. Thrombin (factor IIa [FIIa]) is both a central protease in hemostasis and a key modifier of inflammatory processes. To explore the hypothesis that reduced prothrombin (factor II [FII]) levels in SCD will limit vaso-occlusion, vasculopathy, and inflammation, we used 2 strategies to suppress FII in SCD mice. Weekly administration of FII antisense oligonucleotide "gapmer" to Berkeley SCD mice to selectively reduce circulating FII levels to ∼10% of normal for 15 weeks significantly diminished early mortality. More comprehensive, long-term comparative studies were done using mice with genetic diminution of circulating FII. Here, cohorts of FII(lox/-) mice (constitutively carrying ∼10% normal FII) and FII(WT) mice were tracked in parallel for a year following the imposition of SCD via hematopoietic stem cell transplantation. This genetically imposed suppression of FII levels resulted in an impressive reduction in inflammation (reduction in leukocytosis, thrombocytosis, and circulating interleukin-6 levels), reduced endothelial cell dysfunction (reduced endothelial activation and circulating soluble vascular cell adhesion molecule), and a significant improvement in SCD-associated end-organ damage (nephropathy, pulmonary hypertension, pulmonary inflammation, liver function, inflammatory infiltration, and microinfarctions). Notably, all of these benefits were achieved with a relatively modest 1.25-fold increase in prothrombin times, and in the absence of hemorrhagic complications. Taken together, these data establish that prothrombin is a powerful modifier of SCD-induced end-organ damage, and present a novel therapeutic target to ameliorate SCD pathologies. © 2015 by The American Society of Hematology.

Circulating follistatin displays a day-night rhythm and is associated with muscle mass and circulating leptin levels in healthy, young humans

PubMed Central

Anastasilakis, Athanasios D.; Polyzos, Stergios A.; Skouvaklidou, Elpida C.; Kynigopoulos, Georgios; Saridakis, Zacharias G.; Apostolou, Aggeliki; Triantafyllou, Georgios A.; Karagiozoglou-Lampoudi, Thomai; Mantzoros, Christos S.

2016-01-01

Purpose Follistatin may affect lean and fat mass and be implicated in metabolic diseases. We aimed to elucidate physiological predictors of circulating follistatin variation in healthy young humans. Procedures This was an observational, cross-sectional study with two additional prospective observational arms (circadian, seasonal sub-studies) and one prospective interventional arm (mixed meal sub-study). Healthy, young individuals of both sexes (n=122) were subjected to anthropometric and body composition measurements and their eating and exercise behavior profiles were assessed by validated questionnaires. Sub-groups were subjected to standardized meal ingestion (n=36), day-night rhythm (n=20) and seasonal variation (n=20) studies. Main outcome of the study were circulating follistatin levels. Results At baseline follistatin levels were correlated with creatinine (r=0.24; p=0.01), creatine phosphokinase (rs=0.22; p=0.02), and with lean body mass (rs=0.19; p=0.04) and were higher in males than females (p=0.004) after adjustment for leptin, which was its major predictor. Follistatin levels showed a circadian (p<0.001), but not a seasonal, variation, and were also affected by the phase of menstrual cycle in females (p=0.004). Follistatin levels were not affected by dietary or exercise habits but levels increased after a standardized meal ingestion (250 kcal) (p=0.002). Conclusions In healthy young individuals circulating follistatin levels are correlated with muscle mass. Follistatin levels are associated with circulating leptin levels and display a day-night rhythm and a menstrual cycle, but not a seasonal, variation. PMID:27621181

Circulating follistatin displays a day-night rhythm and is associated with muscle mass and circulating leptin levels in healthy, young humans.

PubMed

Anastasilakis, Athanasios D; Polyzos, Stergios A; Skouvaklidou, Elpida C; Kynigopoulos, Georgios; Saridakis, Zacharias G; Apostolou, Aggeliki; Triantafyllou, Georgios A; Karagiozoglou-Lampoudi, Thomai; Mantzoros, Christos S

2016-10-01

Follistatin may affect lean and fat mass and be implicated in metabolic diseases. We aimed to elucidate physiological predictors of circulating follistatin variation in healthy young humans. This was an observational, cross-sectional study with two additional prospective observational arms (circadian, seasonal sub-studies) and one prospective interventional arm (mixed meal sub-study). Healthy, young individuals of both sexes (n=122) were subjected to anthropometric and body composition measurements and their eating and exercise behavior profiles were assessed by validated questionnaires. Sub-groups were subjected to standardized meal ingestion (n=36), day-night rhythm (n=20) and seasonal variation (n=20) studies. Main outcome of the study were circulating follistatin levels. At baseline follistatin levels were correlated with creatinine (r=0.24; p=0.01), creatine phosphokinase (rs=0.22; p=0.02), and with lean body mass (rs=0.19; p=0.04) and were higher in males than females (p=0.004) after adjustment for leptin, which was its major predictor. Follistatin levels showed a circadian (p<0.001), but not a seasonal, variation, and were also affected by the phase of menstrual cycle in females (p=0.034). Follistatin levels were not affected by dietary or exercise habits but levels increased after a standardized meal ingestion (250kcal) (p=0.002). In healthy young individuals circulating follistatin levels are correlated with muscle mass. Follistatin levels are associated with circulating leptin levels and display a day-night rhythm and a menstrual cycle, but not a seasonal, variation. Copyright © 2016 Elsevier Inc. All rights reserved.

Benzene exposure is associated with cardiovascular disease risk.

PubMed

Abplanalp, Wesley; DeJarnett, Natasha; Riggs, Daniel W; Conklin, Daniel J; McCracken, James P; Srivastava, Sanjay; Xie, Zhengzhi; Rai, Shesh; Bhatnagar, Aruni; O'Toole, Timothy E

2017-01-01

Benzene is a ubiquitous, volatile pollutant present at high concentrations in toxins (e.g. tobacco smoke) known to increase cardiovascular disease (CVD) risk. Despite its prevalence, the cardiovascular effects of benzene have rarely been studied. Hence, we examined whether exposure to benzene is associated with increased CVD risk. The effects of benzene exposure in mice were assessed by direct inhalation, while the effects of benzene exposure in humans was assessed in 210 individuals with mild to high CVD risk by measuring urinary levels of the benzene metabolite trans,trans-muconic acid (t,t-MA). Generalized linear models were used to assess the association between benzene exposure and CVD risk. Mice inhaling volatile benzene had significantly reduced levels of circulating angiogenic cells (Flk-1+/Sca-1+) as well as an increased levels of plasma low-density lipoprotein (LDL) compared with control mice breathing filtered air. In the human cohort, urinary levels of t,t-MA were inversely associated several populations of circulating angiogenic cells (CD31+/34+/45+, CD31+/34+/45+/AC133-, CD34+/45+/AC133+). Although t,t-MA was not associated with plasma markers of inflammation or thrombosis, t,t-MA levels were higher in smokers and in individuals with dyslipidemia. In smokers, t,t-MA levels were positively associated with urinary metabolites of nicotine (cotinine) and acrolein (3-hydroxymercapturic acid). Levels of t,t-MA were also associated with CVD risk as assessed using the Framingham Risk Score and this association was independent of smoking. Thus, benzene exposure is associated with increased CVD risk and deficits in circulating angiogenic cells in both smokers and non-smokers.

Circulating interleukin-10 levels and human papilloma virus and Epstein-Barr virus-associated cancers: evidence from a Mendelian randomization meta-analysis based on 11,170 subjects.

PubMed

Qu, Kai; Pang, Qing; Lin, Ting; Zhang, Li; Gu, Mingliang; Niu, Wenquan; Liu, Chang; Zhang, Ming

2016-01-01

Recent studies have showed interleukin 10 (IL-10) is a critical cytokine that determines antiviral immune response and is related to virus-associated cancers. However, whether genetically elevated circulating IL-10 levels are associated with the risk of human papilloma virus and Epstein-Barr virus-associated cancers (HEACs) is still unclear. Mendelian randomization method was implemented to meta-analyze available observational studies by employing IL-10 three variants (-592C>A, -819C>T, and -1082A>G) as instruments. A total of 24 articles encompassing 11,170 subjects were ultimately eligible for the meta-analysis. Overall, there was a significant association between IL-10 promoter variant -1082A>G and HEACs under allelic and dominant models (both P<0.01). Subgroup analysis by cancer type indicated that the risk estimate of -1082A>G was significant for nasopharyngeal cancer under allelic, homozygous genotypic and dominant models (all P<0.001). Moreover by ethnicity, carriers of -1082G allele had a 74% increased risk for nasopharyngeal cancer in Asians under dominant model (odds ratio [OR] =1.737; 95% confidence interval [CI]: 1.280-2.358; P<0.001). In further Mendelian randomization analysis, the predicted OR for 10 pg/mL increment in IL-10 levels was 1.14 (95% CI: 1.01-16.99) in HEACs. Our findings provided strong evidence for a critical role of genetically elevated circulating IL-10 levels in the development of HEACs, especially in Asian population and for nasopharyngeal cancer.

Ovarian Cancer, Stem Cells, and Bioreactors

DTIC Science & Technology

2009-10-01

also indirectly assessed by measuring CEA and CA125 levels in the circulating medium. CEA and CA125, belonging to the CEA antigen family, are...with OVC#6 could not be detected. The low level of CA125 may be due to a dilution of the protein in the circulating medium as protein concentrations...lower than 8.7U/ml are below the assay sensitivity. Unfortunately, we have been unable to obtain the CA125 circulating level for either patient so

Genome-wide and gene-centric analyses of circulating myeloperoxidase levels in the charge and care consortia.

PubMed

Reiner, Alexander P; Hartiala, Jaana; Zeller, Tanja; Bis, Joshua C; Dupuis, Josée; Fornage, Myriam; Baumert, Jens; Kleber, Marcus E; Wild, Philipp S; Baldus, Stephan; Bielinski, Suzette J; Fontes, João D; Illig, Thomas; Keating, Brendan J; Lange, Leslie A; Ojeda, Francisco; Müller-Nurasyid, Martina; Munzel, Thomas F; Psaty, Bruce M; Rice, Kenneth; Rotter, Jerome I; Schnabel, Renate B; Tang, W H Wilson; Thorand, Barbara; Erdmann, Jeanette; Jacobs, David R; Wilson, James G; Koenig, Wolfgang; Tracy, Russell P; Blankenberg, Stefan; März, Winfried; Gross, Myron D; Benjamin, Emelia J; Hazen, Stanley L; Allayee, Hooman

2013-08-15

Increased systemic levels of myeloperoxidase (MPO) are associated with the risk of coronary artery disease (CAD). To identify the genetic factors that are associated with circulating MPO levels, we carried out a genome-wide association study (GWAS) and a gene-centric analysis in subjects of European ancestry and African Americans (AAs). A locus on chromosome 1q31.1 containing the complement factor H (CFH) gene was strongly associated with serum MPO levels in 9305 subjects of European ancestry (lead SNP rs800292; P = 4.89 × 10(-41)) and in 1690 AA subjects (rs505102; P = 1.05 × 10(-8)). Gene-centric analyses in 8335 subjects of European ancestry additionally identified two rare MPO coding sequence variants that were associated with serum MPO levels (rs28730837, P = 5.21 × 10(-12); rs35897051, P = 3.32 × 10(-8)). A GWAS for plasma MPO levels in 9260 European ancestry subjects identified a chromosome 17q22 region near MPO that was significantly associated (lead SNP rs6503905; P = 2.94 × 10(-12)), but the CFH locus did not exhibit evidence of association with plasma MPO levels. Functional analyses revealed that rs800292 was associated with levels of complement proteins in serum. Variants at chromosome 17q22 also had pleiotropic cis effects on gene expression. In a case-control analysis of ∼80 000 subjects from CARDIoGRAM, none of the identified single-nucleotide polymorphisms (SNPs) were associated with CAD. These results suggest that distinct genetic factors regulate serum and plasma MPO levels, which may have relevance for various acute and chronic inflammatory disorders. The clinical implications for CAD and a better understanding of the functional basis for the association of CFH and MPO variants with circulating MPO levels require further study.

[Circulating levels of MCP-1, VEGF-A, sICAM-1, sVCAM-1, sE-selectin and sVE-cadherin: Relationship with components of metabolic syndrome in young population].

PubMed

Guzmán-Guzmán, Iris Paola; Zaragoza-García, Oscar; Vences-Velázquez, Amalia; Castro-Alarcón, Natividad; Muñoz-Valle, José Francisco; Parra-Rojas, Isela

2016-11-18

Inflammation and endothelial dysfunction are considered the primary manifestations of the cardiovascular disease. Studies have established a relationship among components of metabolic syndrome (MetS) with inflammatory markers and the loss of permeability, vasoconstriction and vasodilatation endothelial. To determine the relationship among the concentrations of soluble endothelial dysfunction molecules and inflammation cytokines and components of the metabolic syndrome in young population. A study was performed in 240 young adult students ages 18-28 years. To define the presence of clinical and metabolic alterations and MetS the modified ATP-III criteria was considered. In all subjects were determined sociodemographic characteristics, anthropometric measures and the metabolic profile. Circulating levels of MCP-1, VEGF-A, sICAM-1, sVCAM-1, sE-selectin and sVE-cadherin were determined by ELISA immunoassay (Bioscience). Statistical analysis was performed using STATA statistical software v. 9.2. From all the participants, 44.6% had obesity, 59.9% had abdominal obesity, 49.6% low HDL-c and 16.7% high levels triglycerids. The 16.25% of the population showed 3 or more components of the MetS. Elevated MCP-1, sICAM-1 and sE-selectin levels were linked to the presence of obesity. In a model adjusted by age-gender, high soluble levels of MCP-1 and VEGF-A were linked with abdominal obesity (OR=1.83; 1.02-3.28 and OR=2.03; 1.15-3.56, respectively), as well as to the presence of the 2 components of MetS. sVCAM-1 levels were associated with impaired glucose (OR=4.74; 1.32-17.0); sE-selectin with low HDL-c (OR=1.99; 1.05-3.75), although sICAM-1 and sVE-cadherin were associated with impaired systolic blood pressure (OR=4.04; 1.24-13.1 and OR=6.28; 1.90-20.7, respectively). Levels of circulating MCP-1 and VEGF-A were associated with adiposity, levels of sVCAM-1 with the presence of impaired glucose, sE-selectin with low HDL-c, while the levels of sICAM-1 and sVE-cadherin were associated with impaired systolic blood pressure in young adults independently of other traditional risk factors. Copyright © 2016 Elsevier España, S.L.U. All rights reserved.

Differential Serum Cytokine Levels and Risk of Lung Cancer between African and European Americans

PubMed Central

Pine, Sharon R.; Mechanic, Leah E.; Enewold, Lindsey; Bowman, Elise D.; Ryan, Bríd M.; Cote, Michele L.; Wenzlaff, Angela S.; Loffredo, Christopher A.; Olivo-Marston, Susan; Chaturvedi, Anil; Caporaso, Neil E.; Schwartz, Ann G.; Harris, Curtis C.

2015-01-01

Background African Americans have a higher risk of developing lung cancer than European Americans. Previous studies suggested that certain circulating cytokines were associated with lung cancer. We hypothesized that variations in serum cytokine levels exist between African Americans and European Americans, and increased circulating cytokine levels contribute to lung cancer differently in the two races. Methods Differences in ten serum cytokine levels, interleukin (IL)-1β, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12, granulocyte macrophage colony-stimulating factor (GMCSF), interferon (IFN)-γ and tumor necrosis factor (TNF)-α between 170 African-American and 296 European-American controls from the National Cancer Institute-Maryland (NCI-MD) case-control study were assessed. Associations of the serum cytokine levels with lung cancer were analyzed. Statistically significant results were replicated in the prospective Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial and the Wayne State University (WSU) Karmanos Cancer Institute case-control study. Results Six cytokines: IL-4, IL-5, IL-8, IL-10, IFNγ, and TNFα, were significantly higher among European-American as compared to African-American controls. Elevated IL-6 and IL-8 levels were associated with lung cancer among both races in all three studies. Elevated IL-1β, IL-10 and TNFα levels were associated with lung cancer only among African Americans. The association between elevated TNFα levels and lung cancer among European Americans was significant after adjustment for additional factors. Conclusions Serum cytokine levels vary by race and might contribute to lung cancer differently between African Americans and European Americans. Impact Future work examining risk prediction models of lung cancer can measure circulating cytokines to accurately characterize risk within racial groups. PMID:26711330

Circulating miR-200c is up-regulated in paediatric patients with familial hypercholesterolaemia and correlates with miR-33a/b levels: implication of a ZEB1-dependent mechanism.

PubMed

D'Agostino, Marco; Martino, Francesco; Sileno, Sara; Barillà, Francesco; Beji, Sara; Marchetti, Lorenza; Gangi, Fabio Maria; Persico, Luca; Picozza, Mario; Montali, Anna; Martino, Eliana; Zanoni, Cristina; Avitabile, Daniele; Parrotto, Sandro; Capogrossi, Maurizio Colognesi; Magenta, Alessandra

2017-09-15

Hypercholesterolaemia provokes reactive oxygen species (ROS) increase and is a major risk factor for cardiovascular disease (CVD) development. We previously showed that circulating miR-33a/b expression levels were up-regulated in children with familial hypercholesterolaemia (FH). miR-33a/b control cholesterol homoeostasis and recently miR-33b has been demonstrated to directly target the transcription factor zinc finger E-box-binding homeobox 1 (ZEB1). The latter acts in a negative feedback loop with the miR-200 family. Our previous studies showed that the ROS-dependent miR-200c up-regulation induces endothelial dysfunction and provokes a ZEB1-dependent apoptosis and senescence. In the present study, we aimed to verify whether circulating miR-200c was induced in FH children, and whether a correlation existed with miR-33a/b Total RNA was extracted from plasma of 28 FH children and 25 age-matched healthy subjects (HS) and miR-200c levels were measured. We found that miR-200c was up-regulated in FH compared with HS (4.00 ± 0.48-fold increase, P <0.05) and exhibited a positive correlation with miR-33a/b. miR-200c did not correlate with plasma lipids, but correlated with C-reactive protein (CRP) plasma levels and glycaemia (GLI). Ordinary least squares (OLS) regression analysis revealed that miR-200c was significantly affected by GLI and by miR-33a ( P <0.01; P <0.001 respectively). Moreover, we found that miR-33 overexpression, in different cell lines, decreased ZEB1 expression and up-regulated both the intracellular and the extracellular miR-200c expression levels. In conclusion, circulating miR-200c is up-regulated in FH, probably due to oxidative stress and inflammation and via a miR-33a/b -ZEB1-dependent mechanism. The present study could provide the first evidence to point to the use of miR-33a/b and miR-200c , as early biomarkers of CVD, in paediatric FH. © 2017 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.

Effect of circulation on wastewater treatment by Lemna gibba and Lemna minor (floating aquatic macrophytes).

PubMed

Demirezen Yilmaz, Dilek; Akbulut, Hatice

2011-01-01

In this study, laboratory tests were performed in order to examine growth characteristics of floating aquatic macrophytes (Lemna gibba and Lemna minor) in the presence of wastewater with circulation. The results showed that circulation of the waste water enhanced the kinetics of the process, as compared to the control systems. However, prolonged application of high circulation level had a different effect. In the presence of circulation with aquatic plants, there was additional 85.3-88.2% for BODs and 59.6-66.8% for COD decreases in the water quality indicators. In this study, the effectiveness of L. gibba and L. minor with circulation addition for the removal of four heavy metals (Pb, Ni, Mn, and Cu) from waste water was also investigated. Results from analysis confirmed the accumulation of different metals within the plant and a corresponding decrease of metals in the waste water. At the end of the study of circulation, L. gibba provided the metal removal for Cu, Pb, Ni, and Mn in the waste water as the ratio of 57%, 60%, 60%, and 62%, respectively. In this context, the best results were obtained when the action of L. gibba and L. minor plants, was combined with that of circulation. It is shown that in the presence of L. gibba and L. minor plants that are supplemented with circulation, the national standards of biochemical oxygen demand (BOD5) 27-33 mgL(-1) and chemical oxygen demand (COD) 62-78 mgL(-1) for L. minor and L. gibba, respectively, were reached after treatment. The new results can be used for design calculations regarding expected removal of pollutants by aquatic floating plants.

Non-extracorporeal circulation for coronary artery bypass graft surgery is more beneficial than extracorporeal circulation.

PubMed

Yang, F-Y; Bao, Y-Z; Liu, F-S; Zhu, Y-C; Zheng, J; Zhang, J-H; Zheng, X-F; Wei, G-C

2015-04-01

The objective of this study was to compare coronary artery bypass graft (CABG) surgery with non-extracorporeal vs. extracorporeal circulation. The study outcomes included operative time, number of graft vessels, pulmonary infection rates, and systemic inflammatory markers. 96 patients received selective CABG, either with non-extracorporeal (study group; n = 48) or extracorporeal circulation (control group; n = 48). Operative time, pulmonary infection rates, and blood levels of inflammatory markers TNF-α, IL-6, and IL-8 before and 4, 24, and 48 hours after the surgery were quantified. Graft vessels were quantified using computed tomography. Operative time was significantly shorter in study group (4.58 ± 0.91 vs. 5.36 ± 1.12 hours in control group; p < 0.05). The number of graft vessels and pulmonary infection rates were comparable between both techniques. However, systemic inflammatory markers were significantly (p < 0.05) lower in study group at 4 and, partly, 24 hours after the surgery. Extracorporeal circulation prolongs operation and can aggravate systemic inflammatory response. Therefore, CABG with non-extracorporeal circulation offers more beneficial outcomes.

Genetic variation in the CYP1A1 gene is related to circulating PCB118 levels in a population-based sample

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lind, Lars; Penell, Johanna; Syvänen, Anne-Christine

2014-08-15

Several of the polychlorinated biphenyls (PCBs), i.e. the dioxin-like PCBs, are known to induce the P450 enzymes CYP1A1, CYP1A2 and CYP1B1 by activating the aryl hydrocarbon receptor (Ah)-receptor. We evaluated if circulating levels of PCBs in a population sample were related to genetic variation in the genes encoding these CYPs. In the population-based Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study (1016 subjects all aged 70), 21 SNPs in the CYP1A1, CYP1A2 and CYP1B1 genes were genotyped. Sixteen PCB congeners were analysed by high-resolution chromatography coupled to high-resolution mass spectrometry (HRGC/ HRMS). Of the investigated relationships between SNPsmore » in the CYP1A1, CYP1A2 and CYP1B1 and six PCBs (congeners 118, 126, 156, 169, 170 and 206) that captures >80% of the variation of all PCBs measured, only the relationship between CYP1A1 rs2470893 was significantly related to PCB118 levels following strict adjustment for multiple testing (p=0.00011). However, there were several additional SNPs in the CYP1A2 and CYP1B1 that showed nominally significant associations with PCB118 levels (p-values in the 0.003–0.05 range). Further, several SNPs in the CYP1B1 gene were related to both PCB156 and PCB206 with p-values in the 0.005–0.05 range. Very few associations with p<0.05 were seen for PCB126, PCB169 or PCB170. Genetic variation in the CYP1A1 was related to circulating PCB118 levels in the general elderly population. Genetic variation in CYP1A2 and CYP1B1 might also be associated with other PCBs. - Highlights: • We studied the relationship between PCBs and the genetic variation in the CYP genes. • Cross sectional data from a cohort of elderly were analysed. • The PCB levels were evaluated versus 21 SNPs in three CYP genes. • PCB 118 was related to variation in the CYP1A1 gene.« less

Circulating gonadotropins and ovarian adiponectin system are modulated by acupuncture independently of sex steroid or β-adrenergic action in a female hyperandrogenic rat model of polycystic ovary syndrome.

PubMed

Maliqueo, Manuel; Benrick, Anna; Alvi, Asif; Johansson, Julia; Sun, Miao; Labrie, Fernand; Ohlsson, Claes; Stener-Victorin, Elisabet

2015-09-05

Acupuncture with combined manual and low-frequency electrical stimulation, or electroacupuncture (EA), reduces endocrine and reproductive dysfunction in women with polycystic ovary syndrome (PCOS), likely by modulating sympathetic nerve activity or sex steroid synthesis. To test this hypothesis, we induced PCOS in rats by prepubertal implantation of continuous-release letrozole pellets (200 µg/day) or vehicle. Six weeks later, rats were treated for 5-6 weeks with low-frequency EA 5 days/week, subcutaneous injection of 17β-estradiol (2.0 µg) every fourth day, or a β-adrenergic blocker (propranolol hydrochloride, 0.1 mg/kg) 5 days/week. Letrozole controls were handled without needle insertion or injected with sesame oil every fourth day. Estrous cyclicity, ovarian morphology, sex steroids, gonadotropins, insulin-like growth factor I, bone mineral density, and gene and protein expression in ovarian tissue were measured. Low-frequency EA induced estrous-cycle changes, decreased high levels of circulating luteinizing hormone (LH) and the LH/follicle-stimulating hormone (FSH) ratio, decreased high ovarian gene expression of adiponectin receptor 2, and increased expression of adiponectin receptor 2 protein and phosphorylation of ERK1/2. EA also increased cortical bone mineral density. Propranolol decreased ovarian expression of Foxo3, Srd5a1, and Hif1a. Estradiol decreased circulating LH, induced estrous cycle changes, and decreased ovarian expression of Adipor1, Foxo3, and Pik3r1. Further, total bone mineral density was higher in the letrozole-estradiol group. Thus, EA modulates the circulating gonadotropin levels independently of sex steroids or β-adrenergic action and affects the expression of ovarian adiponectin system. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Circulating long non-coding RNAs NRON and MHRT as novel predictive biomarkers of heart failure.

PubMed

Xuan, Lina; Sun, Lihua; Zhang, Ying; Huang, Yuechao; Hou, Yan; Li, Qingqi; Guo, Ying; Feng, Bingbing; Cui, Lina; Wang, Xiaoxue; Wang, Zhiguo; Tian, Ye; Yu, Bo; Wang, Shu; Xu, Chaoqian; Zhang, Mingyu; Du, Zhimin; Lu, Yanjie; Yang, Bao Feng

2017-09-01

This study sought to evaluate the potential of circulating long non-coding RNAs (lncRNAs) as biomarkers for heart failure (HF). We measured the circulating levels of 13 individual lncRNAs which are known to be relevant to cardiovascular disease in the plasma samples from 72 HF patients and 60 non-HF control participants using real-time reverse transcription-polymerase chain reaction (real-time RT-PCR) methods. We found that out of the 13 lncRNAs tested, non-coding repressor of NFAT (NRON) and myosin heavy-chain-associated RNA transcripts (MHRT) had significantly higher plasma levels in HF than in non-HF subjects: 3.17 ± 0.30 versus 1.0 ± 0.07 for NRON (P < 0.0001) and 1.66 ± 0.14 versus 1.0 ± 0.12 for MHRT (P < 0.0001). The area under the ROC curve was 0.865 for NRON and 0.702 for MHRT. Univariate and multivariate analyses identified NRON and MHRT as independent predictors for HF. Spearman's rank correlation analysis showed that NRON was negatively correlated with HDL and positively correlated with LDH, whereas MHRT was positively correlated with AST and LDH. Hence, elevation of circulating NRON and MHRT predicts HF and may be considered as novel biomarkers of HF. © 2017 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

Functional Consequences of Mannose and Asialoglycoprotein Receptor Ablation*

PubMed Central

Mi, Yiling; Coonce, Marcy; Fiete, Dorothy; Steirer, Lindsay; Dveksler, Gabriela; Townsend, R. Reid; Baenziger, Jacques U.

2016-01-01

The mannose receptor (ManR, Mrc1) and asialoglycoprotein receptor (ASGR, Asgr1 and Asgr2) are highly abundant endocytic receptors expressed by sinusoidal endothelial cells and parenchymal cells in the liver, respectively. We genetically manipulated either receptor individually or in combination, revealing phenotypic changes in female and male mice associated with changes in circulating levels of many glycoproteins. Both receptors rise and fall in response to progesterone during pregnancy. Thirty percent of Asgr2−/− and 65% of Mrc1−/−Asgr2−/− mice are unable to initiate parturition at the end of pregnancy, whereas Mrc1−/− mice initiate normally. Twenty five percent of Mrc1−/−Asgr2−/− male mice develop priapism when mating due to thrombosis of the penile vein, but neither Mrc1−/− nor Asgr2−/− mice do so. The half-life for luteinizing hormone (LH) clearance increases in Mrc1−/− and Mrc1−/−Asgr2−/− mice but not in Asgr2−/− mice; however, LH and testosterone are elevated in all three knockouts. The ManR clears LH thus regulating testosterone production, whereas the ASGR appears to mediate clearance of an unidentified glycoprotein that increases LH levels. More than 40 circulating glycoproteins are elevated >3.0-fold in pregnant Mrc1−/−Asgr2−/− mice. Pregnancy-specific glycoprotein 23, undetectable in WT mice (<50 ng/ml plasma), reaches levels of 1–10 mg/ml in the plasma of Mrc1−/−Asgr2−/− and Asgr2−/− mice, indicating it is cleared by the ASGR. Elevation of multiple coagulation factors in Mrc1−/−Asgr2−/− mice may account for priapism seen in males. These male and female phenotypic changes underscore the key roles of the ManR and ASGR in controlling circulating levels of numerous glycoproteins critical for regulating reproductive hormones and blood coagulation. PMID:27405760

Angiotensin II type 1 receptor autoantibody as a novel regulator of aldosterone independent of preeclampsia.

PubMed

Yang, Jie; Li, Li; Shang, Jian-Yu; Cai, Lin; Song, Li; Zhang, Su-Li; Li, Hao; Li, Xiao; Lau, Wayne Bond; Ma, Xin-Liang; Liu, Hui-Rong

2015-05-01

Preeclamptic women and their infants have significant morbidity and mortality worldwide. Abnormal aldosterone signaling is involved in the pathogenesis of preeclampsia, and the presence of agonistic autoantibodies against the angiotensin II type 1 receptor (AT1-AA) during disease has been observed. The role of AT1-AA in aldosterone generation with or without disease and the long-term impact of AT1-AA circulation in blood remain unclear. We therefore assessed circulating AT1-AA and aldosterone levels in 76 patients with preeclampsia (35 severe and 41 mild), 26 patients with gestational hypertension, and 50 normotensive healthy pregnant women. First, the correlation of AT1-AA levels was confirmed for preeclamptic patients. We report here that all AT1-AA-positive hypertensive pregnant women exhibited decreased aldosterone levels, and early-onset preeclampsia patients with high proteinuria showed an inverse correlation of aldosterone levels with AT1-AA. To study this effect in more detail, we confirmed that AT1-AA decreased aldosterone levels in pregnant rats and then demonstrated that aldosterone levels decreased in response to the chronic administration of AT1-AA into nonpregnant rats. These results suggested that AT1-AA regulates levels of aldosterone, which was tested with cell culture studies, revealing that activation of AT1 receptors by AT1-AA directly led to abnormal aldosterone generation in a time and dose-dependent manner. We present here a mechanism for regulation of aldosterone production: AT1-AA activates AT1 receptors on adrenocortical cells independent of pregnancy, in a time and dose-dependent manner.

Parity-induced decrease in systemic growth hormone alters mammary gland signaling: A potential role in pregnancy protection from breast cancer

PubMed Central

Dearth, Robert K.; Delgado, David A.; Hiney, Jill K; Pathiraja, Thushangi; Oesterreich, Steffi; Medina, Dan; Dees, W. Les; Lee, Adrian V.

2009-01-01

Early full-term pregnancy is an effective natural protection against breast cancer in both humans and experimental rodents. The protective effect of an early pregnancy is in part linked to changes in circulating hormones that are involved in both normal breast development and breast cancer. For example, a reduction in circulating growth hormone (GH) has been shown to protect rats from carcinogen-induced mammary tumors. We examined the ability of a full-term pregnancy to alter the endocrine GH/IGF-I axis and how this change affected normal mammary gland function in two commonly used rat models (Sprague-Dawley and Wistar-Furth). Circulating GH and IGF-I were measured in blood drawn every 30 minutes from parous and aged-matched virgin (AMV) female rats. Mean serum GH levels were significantly decreased (p<0.01) in parous compared to AMV in both rat strains. Changes in GH levels were independent of estrous cycle, indicated by a significant (p<0.05) reduction in circulating levels of GH during estrus and diestrus in both parous strains. Despite the decrease in circulating GH, pituitary GH mRNA levels were unaltered in parous rats. Circulating IGF-I and hepatic IGF-I mRNA were also unaltered by parity in either rat strain. Immunoblot analysis of mammary glands showed decreases in phosphorylation of Stat5A and Jak2, suggesting reduced action of GH in the mammary gland. Therefore, while the parity reduction in circulating GH doesn’t impact upon circulating IGF-I levels, it is possible that reduced GH action directly at the mammary gland and may play a role in pregnancy protection from breast cancer. PMID:20145191

Thrombin generation during cardiopulmonary bypass: the possible role of retransfusion of blood aspirated from the surgical field

PubMed Central

Weerwind, Patrick W; Lindhout, Theo; Caberg, Nicole EH; de Jong, Dick S

2003-01-01

Background In spite of using heparin-coated extracorporeal circuits, cardiopulmonary bypass (CPB) is still associated with an extensive thrombin generation, which is only partially suppressed by the use of high dosages of heparin. Recent studies have focused on the origins of this thrombotic stimulus and the possible role of retransfused suctioned blood from the thoracic cavities on the activation of the extrinsic coagulation pathway. The present study was designed to find during CPB an association between retransfusion of suctioned blood from the pericardium and pleural space, containing activated factor VIIa and systemic thrombin generation. Methods Blood samples taken from 12 consenting patients who had elective cardiac surgery were assayed for plasma factor VIIa, prothrombin fragment 1+2 (F1+2), and thrombin-antithrombin (TAT) concentrations. Blood aspirated from the pericardium and pleural space was collected separately, assayed for F1+2, TAT, and factor VIIa and retransfused to the patient after the aorta occlusion. Results After systemic heparinization and during CPB thrombin generation was minimal, as indicated by the lower than base line plasma levels of F1+2, and TAT after correction for hemodilution. In contrast, blood aspirated from the thoracic cavities had significantly higher levels of factor VIIa, F1+2, and TAT compared to the simultaneous samples from the blood circulation (P < 0.05). Furthermore, after retransfusion of the suctioned blood (range, 200–1600 mL) circulating levels of F1+2, and TAT rose significantly from 1.6 to 2.9 nmol/L (P = 0.002) and from 5.1 to 37.5 μg/L (P = 0.01), respectively. The increase in both F1+2, and TAT levels correlated significantly with the amount of retransfused suctioned blood (r = 0.68, P = 0.021 and r = 0.90, P = 0.001, respectively). However, the circulating factor VIIa levels did not correlate with TAT and F1+2 levels. Conclusions These data suggest that blood aspirated from the thoracic cavities during CPB is highly thrombogenic. Retransfusion of this blood may, therefore, promote further systemic thrombin generation during CPB. PMID:12904260

Plasma processing conditions substantially influence circulating microRNA biomarker levels.

PubMed

Cheng, Heather H; Yi, Hye Son; Kim, Yeonju; Kroh, Evan M; Chien, Jason W; Eaton, Keith D; Goodman, Marc T; Tait, Jonathan F; Tewari, Muneesh; Pritchard, Colin C

2013-01-01

Circulating, cell-free microRNAs (miRNAs) are promising candidate biomarkers, but optimal conditions for processing blood specimens for miRNA measurement remain to be established. Our previous work showed that the majority of plasma miRNAs are likely blood cell-derived. In the course of profiling lung cancer cases versus healthy controls, we observed a broad increase in circulating miRNA levels in cases compared to controls and that higher miRNA expression correlated with higher platelet and particle counts. We therefore hypothesized that the quantity of residual platelets and microparticles remaining after plasma processing might impact miRNA measurements. To systematically investigate this, we subjected matched plasma from healthy individuals to stepwise processing with differential centrifugation and 0.22 µm filtration and performed miRNA profiling. We found a major effect on circulating miRNAs, with the majority (72%) of detectable miRNAs substantially affected by processing alone. Specifically, 10% of miRNAs showed 4-30x variation, 46% showed 30-1,000x variation, and 15% showed >1,000x variation in expression solely from processing. This was predominantly due to platelet contamination, which persisted despite using standard laboratory protocols. Importantly, we show that platelet contamination in archived samples could largely be eliminated by additional centrifugation, even in frozen samples stored for six years. To minimize confounding effects in microRNA biomarker studies, additional steps to limit platelet contamination for circulating miRNA biomarker studies are necessary. We provide specific practical recommendations to help minimize confounding variation attributable to plasma processing and platelet contamination.

The Curves Exercise Suppresses Endotoxemia in Korean Women with Obesity.

PubMed

Jin, Seon Ah; Kim, Sun Kyeong; Seo, Hee Jung; Kim, Mijoo; Ahn, Kye Taek; Kim, Jun Hyung; Park, Jae Hyeong; Lee, Jae Hwan; Choi, Si Wan; Jeong, Jin Ok

2017-02-01

Obesity and metabolic syndrome is a worldwide pandemic and associated with high cardiovascular risk. Metabolic endotoxemia (ME) is thought to be an underlying molecular mechanism. It triggers toll-like receptor 4-mediated inflammatory adipokines and causes a chronic low grade inflammatory status, which results in cardiovascular risk increase. Exercise is the best nonpharmacological treatment to improve prognosis. In this study, we examined the circulating endotoxin level in Korean obese women and investigated effects of exercise on it. Women over body mass index (BMI) 25 kg/m² participated in a resistance training exercise, Curves. At baseline and after 12 weeks exercise, tests including blood samples were taken. In Korean obese women, the fasting endotoxin was 1.45 ± 0.11 EU/mL. Ingestion of a high calorie meal led to a peak level after 2 hours (postprandial 2 hours [PP2]) and a significant rise over the 4 hours (postprandial 4 hours [PP4]) in it (1.78 ± 0.15 and 1.75 ± 0.14 EU/mL for PP2 and PP4, P < 0.05 vs. fasting). After exercise, BMI and hip circumference were reduced significantly. The total cholesterol (TC) at fasting, PP2 and PP4 were decreased significantly. All levels of circulating endotoxin at fasting, PP2 and PP4 showed reduction. But, the peak change was only significant (baseline vs. 12 weeks for PP2; 1.78 ± 0.15 vs. 1.48 ± 0.06 EU/mL, P < 0.05). We report the circulating endotoxin level in Korean obese women for the first time. Also, we establish that energy intake leads to endotoxemia and exercise suppresses the peak endotoxemia after meal. It suggests an impact for a better prognosis in obese women who follow regular exercise.

Euglycemic Hyperinsulinemia Increases Blood Pressure in Pregnant Rats Independent of Placental Antiangiogenic and Inflammatory Factors

PubMed Central

2013-01-01

BACKGROUND Although pregnancies associated with hyperinsulinemia and altered placental angiogenic and inflammatory factors are at increased risk for developing preeclampsia, the effects of euglycemic hyperinsulinemia on placental factors and blood pressure regulation during pregnancy are unclear. We hypothesized that chronic hyperinsulinemia results in increased placental soluble fms-like tyrosine kinase 1(sFlt-1) and tumor necrosis factor α (TNF- α) levels and hypertension in pregnant rats. METHODS On gestational day (GD) 14, Sprague-Dawley rats were assigned as normal pregnant or pregnant + insulin. Insulin was infused subcutaneously by osmotic minipump for 5 days at a dose of 1.5 mU/kg/min. Those rats receiving insulin were supplemented with 20% glucose in drinking water to maintain euglycemia. On GD 19, mean arterial pressure (MAP) and heart rate (HR) were assessed in conscious rats by indwelling carotid catheters, followed by collections of blood, placentas, and fetuses. In addition to pl acental sFlt-1 and TNF-α levels, circulating insulin, glucose, leptin, cholesterol, triglyceride, and free fatty acid concentrations were measured. RESULTS MAP was higher in pregnant + insulin vs. normal pregnant rats; however, HR was similar between groups. Although litter size and placental weight were comparable, fetuses from pregnant + insulin rats were heavier. Importantly, circulating insulin concentration was elevated in the pregnant + insulin group, with no change in glucose level. Moreover, circulating leptin, cholesterol, triglyceride, and free fatty acid concentrations were increased in the pregnant + insulin group. There were no differences in placental sFlt-1 and TNF-α concentrations between groups. CONCLUSIONS In summary, sustained euglycemic hyperinsulinemia, comparable with insulin levels in preeclamptic women, can raise blood pressure in pregnancy independent of recognized placental factors associated with preeclampsia. PMID:23955606

The effects of conventional extracorporeal circulation versus miniaturized extracorporeal circulation on microcirculation during cardiopulmonary bypass-assisted coronary artery bypass graft surgery

PubMed Central

Yuruk, Koray; Bezemer, Rick; Euser, Mariska; Milstein, Dan M.J.; de Geus, Hilde H.R.; Scholten, Evert W.; de Mol, Bas A.J.M.; Ince, Can

2012-01-01

OBJECTIVES To reduce the complications associated with cardiopulmonary bypass (CPB) during cardiac surgery, many modifications have been made to conventional extracorporeal circulation systems. This trend has led to the development of miniaturized extracorporeal circulation systems. Cardiac surgery using conventional extracorporeal circulation systems has been associated with significantly reduced microcirculatory perfusion, but it remains unknown whether this could be prevented by an mECC system. Here, we aimed to test the hypothesis that microcirculatory perfusion decreases with the use of a conventional extracorporeal circulation system and would be preserved with the use of an miniaturized extracorporeal circulation system. METHODS Microcirculatory density and perfusion were assessed using sublingual side stream dark-field imaging in patients undergoing on-pump coronary artery bypass graft (CABG) surgery before, during and after the use of either a conventional extracorporeal circulation system (n = 10) or a miniaturized extracorporeal circulation system (n = 10). In addition, plasma neutrophil gelatinase-associated lipocalin and creatinine levels and creatinine clearance were assessed up to 5 days post-surgery to monitor renal function. RESULTS At the end of the CPB, one patient in the miniaturized extracorporeal circulation-treated group and five patients in the conventional extracorporeal circulation-treated group received one bag of packed red blood cells (300 ml). During the CPB, the haematocrit and haemoglobin levels were slightly higher in the miniaturized extracorporeal circulation-treated patients compared with the conventional extracorporeal circulation-treated patients (27.7 ± 3.3 vs 24.7 ± 2.0%; P = 0.03; and 6.42 ± 0.75 vs 5.41 ± 0.64 mmol/l; P < 0.01). The density of perfused vessels with a diameter <25 µm (i.e. perfused vessel density) decreased slightly in the conventional extracorporeal circulation-treated group from 16.4 ± 3.8 to 12.8 ± 3.3 mm/mm2 (P < 0.01) and remained stable in the miniaturized extracorporeal circulation-treated group (16.3 ± 2.7 and 15.2 ± 2.9 mm/mm2 before and during the pump, respectively). Plasma neutrophil gelatinase-associated lipocalin levels were increased following the use of extracorporeal circulation in both groups, and no differences were observed between the groups. Plasma creatinine levels and creatinine clearance were not affected by CABG surgery or CPB. CONCLUSIONS The results from this relatively small study suggest that the use of the miniaturized extracorporeal circulation system is associated with a statistically significant (but clinically insignificant) reduction in haemodilution and microcirculatory hypoperfusion compared with the use of the conventional extracorporeal circulation system. PMID:22700685

High-Mobility Group Box 1 From Hypoxic Trophoblasts Promotes Endothelial Microparticle Production and Thrombophilia in Preeclampsia.

PubMed

Hu, Yae; Yan, Ruhong; Zhang, Ce; Zhou, Zhichao; Liu, Meng; Wang, Can; Zhang, Hong; Dong, Liang; Zhou, Tiantian; Wu, Yi; Dong, Ningzheng; Wu, Qingyu

2018-04-12

Thrombophilia is a major complication in preeclampsia, a disease associated with placental hypoxia and trophoblast inflammation. Preeclampsia women are known to have increased circulating microparticles that are procoagulant, but the underlying mechanisms remain unclear. In this study, we sought to understand the mechanism connecting placental hypoxia, circulating microparticles, and thrombophilia. We analyzed protein markers on plasma microparticles from preeclampsia women and found that the increased circulating microparticles were mostly from endothelial cells. In proteomic studies, we identified HMGB1 (high-mobility group box 1), a proinflammatory protein, as a key factor from hypoxic trophoblasts in stimulating microparticle production in human umbilical vein endothelial cells. Immunodepletion or inhibition of HMGB1 in the conditioned medium from hypoxic human trophoblasts abolished the endothelial microparticle-stimulating activity. Conversely, recombinant HMGB1 stimulated microparticle production in cultured human umbilical vein endothelial cells. The microparticles from recombinant HMGB1-stimulated human umbilical vein endothelial cells promoted blood coagulation and neutrophil activation in vitro. Injection of recombinant HMGB1 in pregnant mice increased plasma endothelial microparticles and promoted blood coagulation. In preeclampsia women, elevated placental HMGB1 expression was detected and high levels of plasma HMGB1 correlated with increased plasma endothelial microparticles. Our results indicate that placental hypoxia-induced HMGB1 expression and release from trophoblasts are important mechanism underlying increased circulating endothelial microparticles and thrombophilia in preeclampsia. © 2018 American Heart Association, Inc.

Combination of plasma HA and circulating M2-like monocytes may serve as a diagnostic marker for breast cancer.

PubMed

Zhang, Boke; Cao, Manlin; He, Yiqing; Liu, Yiwen; Zhang, Guoliang; Yang, Cuixia; Du, Yan; Xu, Jing; Hu, Jiajie; Gao, Feng

2017-01-01

Background: Breast cancer (BC)-derived hyaluronan (HA) can induce the formation of M2-like tumor-associated macrophages (TAMs) in tumor context. However, little is known about the correlation between circulating M2-like monocytes and plasma HA in BC patients. This study focused on evaluating the relationship between circulating M2-like monocytes and plasma HA, and further appraised the diagnostic value of them in BC. Methods: The expression of M2-like TAMs and HA was determined in pathological tissues by immunohistochemistry. Flow cytometry was used to detect the levels of circulating CD14 + CD204 + M2-like monocytes in 81 BC patients, 45 patients with breast benign diseases, and 46 healthy subjects. The levels of HA, CEA, and CA15-3 were measured in plasma samples using chemiluminescence method. Results: M2-like TAMs and HA expressions were elevated in BC tissues compared with benign tissues. In correspondence, the frequency of circulating CD14 + CD204 + M2-like monocytes and the plasma HA levels were significantly higher in patients with BC than those in control groups. Importantly, there was a positive correlation between circulating M2-like monocytes and the plasma HA (Spearman r = 0.404, p < 0.001). Area under receiver operating characteristic curve (ROC) for the combination of circulating M2-like monocytes and HA was 0.899 (95% CI: 0.853-0.946), which was higher than the panel of CEA and CA15-3. Conclusions: The frequency of circulating CD14 + CD204 + M2-like monocytes was positively correlated to plasma HA levels. The combination of circulating CD14 + CD204 + M2-like monocytes and plasma HA could provide considerable diagnostic value in BC.

Circulating MOTS-c levels are decreased in obese male children and adolescents and associated with insulin resistance.

PubMed

Du, Caiqi; Zhang, Cai; Wu, Wei; Liang, Yan; Wang, Anru; Wu, Shimin; Zhao, Yue; Hou, Ling; Ning, Qin; Luo, Xiaoping

2018-04-25

A novel bioactive peptide, mitochondrial-derived peptide (MOTS-c), has recently attracted attention as a potential prevention or therapeutic option for obesity and type 2 diabetes mellitus (T2DM). MOTS-c profiles have not yet been reported in human obesity and T2DM. We aimed to determine circulating MOTS-c levels in obesity and explore the association between MOTS-c levels and various metabolic parameters. In this case-control study, 40 obese children and adolescents (27 males) and 57 controls (40 males) were recruited in the Hubei Province of China in 2017. Circulating MOTS-c levels were measured, clinical data (e.g., glucose, insulin and lipid profile) were recorded, and anthropometric measurements were performed. Finally, we investigated correlations between MOTS-c levels and related variables. MOTS-c levels were significantly decreased in the obese group compared with the control group (472.61 ± 22.83 ng/mL vs. 561.64 ± 19.19 ng/mL, p < 0.01). After classification by sex, MOTS-c levels were significantly decreased in obese male children and adolescents compared to their counterparts (465.26 ± 24.53 ng/mL vs. 584.07 ± 21.18 ng/mL, p < 0.001), while they were comparable between the obese and healthy female subjects (487.89 ± 49.77 ng/mL vs. 508.85 ± 38.76 ng/mL, p > 0.05). Further, MOTS-c levels were negatively correlated with body mass index (BMI), BMI standard deviation score, waist circumference, waist-to-hip ratio, fasting insulin level, HOMA-IR, and HbA1c in the male cohort. Circulating MOTS-c levels were decreased in obese male children and adolescents and correlated with markers of insulin resistance and obesity. This article is protected by copyright. All rights reserved.

FOXO1 orchestrates the bone-suppressing function of gut-derived serotonin

PubMed Central

Kode, Aruna; Mosialou, Ioanna; Silva, Barbara C.; Rached, Marie-Therese; Zhou, Bin; Wang, Ji; Townes, Tim M.; Hen, Rene; DePinho, Ronald A.; Guo, X. Edward; Kousteni, Stavroula

2012-01-01

Serotonin is a critical regulator of bone mass, fulfilling different functions depending on its site of synthesis. Brain-derived serotonin promotes osteoblast proliferation, whereas duodenal-derived serotonin suppresses it. To understand the molecular mechanisms of duodenal-derived serotonin action on osteoblasts, we explored its transcriptional mediation in mice. We found that the transcription factor FOXO1 is a crucial determinant of the effects of duodenum-derived serotonin on bone formation We identified two key FOXO1 complexes in osteoblasts, one with the transcription factor cAMP-responsive element–binding protein 1 (CREB) and another with activating transcription factor 4 (ATF4). Under normal levels of circulating serotonin, the proliferative activity of FOXO1 was promoted by a balance between its interaction with CREB and ATF4. However, high circulating serotonin levels prevented the association of FOXO1 with CREB, resulting in suppressed osteoblast proliferation. These observations identify FOXO1 as the molecular node of an intricate transcriptional machinery that confers the signal of duodenal-derived serotonin to inhibit bone formation. PMID:22945629

PCSK1 Mutations and Human Endocrinopathies: From Obesity to Gastrointestinal Disorders.

PubMed

Stijnen, Pieter; Ramos-Molina, Bruno; O'Rahilly, Stephen; Creemers, John W M

2016-08-01

Prohormone convertase 1/3, encoded by the PCSK1 gene, is a serine endoprotease that is involved in the processing of a variety of proneuropeptides and prohormones. Humans who are homozygous or compound heterozygous for loss-of-function mutations in PCSK1 exhibit a variable and pleiotropic syndrome consisting of some or all of the following: obesity, malabsorptive diarrhea, hypogonadotropic hypogonadism, altered thyroid and adrenal function, and impaired regulation of plasma glucose levels in association with elevated circulating proinsulin-to-insulin ratio. Recently, more common variants in the PCSK1 gene have been found to be associated with alterations in body mass index, increased circulating proinsulin levels, and defects in glucose homeostasis. This review provides an overview of the endocrinopathies and other disorders observed in prohormone convertase 1/3-deficient patients, discusses the possible biochemical basis for these manifestations of the disease, and proposes a model whereby certain missense mutations in PCSK1 may result in proteins with a dominant negative action.

Circulating Hepcidin-25 Is Reduced by Endogenous Estrogen in Humans.

PubMed

Lehtihet, Mikael; Bonde, Ylva; Beckman, Lena; Berinder, Katarina; Hoybye, Charlotte; Rudling, Mats; Sloan, John H; Konrad, Robert J; Angelin, Bo

2016-01-01

Hepcidin reduces iron absorption by binding to the intestinal iron transporter ferroportin, thereby causing its degradation. Although short-term administration of testosterone or growth hormone (GH) has been reported to decrease circulating hepcidin levels, little is known about how hepcidin is influenced in human endocrine conditions associated with anemia. We used a sensitive and specific dual-monoclonal antibody sandwich immunoassay to measure hepcidin-25 in patients (a) during initiation of in vitro fertilization when endogenous estrogens were elevated vs. suppressed, (b) with GH deficiency before and after 12 months substitution treatment, (c) with hyperthyroidism before and after normalization, and (d) with hyperprolactinemia before and after six months of treatment with a dopamine agonist. In response to a marked stimulation of endogenous estrogen production, median hepcidin levels decreased from 4.85 to 1.43 ng/mL (p < 0.01). Hyperthyroidism, hyperprolactinemia, or GH substitution to GH-deficient patients did not influence serum hepcidin-25 levels. In humans, gonadotropin-stimulated endogenous estrogen markedly decreases circulating hepcidin-25 levels. No clear and stable correlation between iron biomarkers and hepcidin-25 was seen before or after treatment of hyperthyroidism, hyperprolactinemia or growth hormone deficiency.

Circulating Hepcidin-25 Is Reduced by Endogenous Estrogen in Humans

PubMed Central

Lehtihet, Mikael; Bonde, Ylva; Beckman, Lena; Berinder, Katarina; Hoybye, Charlotte; Rudling, Mats; Sloan, John H.; Konrad, Robert J.; Angelin, Bo

2016-01-01

Objective Hepcidin reduces iron absorption by binding to the intestinal iron transporter ferroportin, thereby causing its degradation. Although short-term administration of testosterone or growth hormone (GH) has been reported to decrease circulating hepcidin levels, little is known about how hepcidin is influenced in human endocrine conditions associated with anemia. Research design and methods We used a sensitive and specific dual–monoclonal antibody sandwich immunoassay to measure hepcidin-25 in patients (a) during initiation of in vitro fertilization when endogenous estrogens were elevated vs. suppressed, (b) with GH deficiency before and after 12 months substitution treatment, (c) with hyperthyroidism before and after normalization, and (d) with hyperprolactinemia before and after six months of treatment with a dopamine agonist. Results In response to a marked stimulation of endogenous estrogen production, median hepcidin levels decreased from 4.85 to 1.43 ng/mL (p < 0.01). Hyperthyroidism, hyperprolactinemia, or GH substitution to GH-deficient patients did not influence serum hepcidin-25 levels. Conclusions In humans, gonadotropin-stimulated endogenous estrogen markedly decreases circulating hepcidin-25 levels. No clear and stable correlation between iron biomarkers and hepcidin-25 was seen before or after treatment of hyperthyroidism, hyperprolactinemia or growth hormone deficiency. PMID:26866603

Circulating free soluble fms-like tyrosine kinase-1 during late first trimester in relation with placental volume as a surrogate for trophoblastic production: a physiology study in low-risk cohort.

PubMed

Manthati, Sudtawin; Pratumvinit, Busadee; Hanyongyuth, Ratchaneekorn; Udompunthurak, Suthipol; Phaophan, Amprapha; Wataganara, Tuangsit

2017-08-01

Data on first-trimester circulating soluble fms-like tyrosine kinase-1 (sFlt-1) and ischemic placental disease is limited and conflicting. This study aimed to study its physiology in relation to trophoblastic mass as the source of production. Low-risk (representing normal placentation) women from 11 0/7 to 13 6/7 weeks' gestation were prospectively enrolled. Selective measurement of serum free sFlt-1 using a new automated assay from 100 eligible subjects was analyzed with gestational age, maternal weight, fetal crown-rump length (CRL), and mean uterine artery Doppler pulsatility index (PI). Placental volume (surrogate for trophoblastic mass) was estimated using 3-dimensional ultrasound and was assessed for its association with serum free sFlt-1. There was no significant association between serum free sFlt-1 and placental volume in either arithmetic (r = 0.053, p = 0.600), logarithmic (r = 0.005, p = 0.963), or quartile (p = 0.703) scale. There was a significant negative correlation between free sFlt-1 level and maternal weight (r=-0.213, p = 0.033). No significant correlation was found between free sFlt-1 level and gestational age (r = 0.007, p = 0.947), CRL (r = 0.027, p = 0.788), and uterine artery Doppler mean PI (r = 0.020, p = 0.828). Lack of correlation between circulating free sFlt-1 level and placental volume suggests that trophoblasts are not its major source during first trimester with presumably physiologic placentation.

Circulating levels of endothelin-1 in a homogenous Gulf Arab population with untreated essential hypertension.

PubMed

Obineche, Enyioma; Abdulle, Abdishakur M; Bokhari, Awais M; Yasin, Javed Y; Gillett, Michael P T

2006-01-01

Racial variations are reported in the natural history of hypertension. For example, hypertension is significantly more prevalent in blacks than whites. Endothelial cells are important regulators of vascular tone and homeostasis, in part through secretions of vasoactive substances including endothelin-1 (ET-1), a small peptide with potent vasopressor actions. In black hypertensives, ET-1 levels are higher than in normotensive blacks and in both hypertensive and normotensive whites. Since ET-1 might play a significant role in the development and severity of hypertension in the indigenous Arab population of the United Arab Emirates, we investigated the circulating levels of ET-1 in this homogenous population. ET-1 levels were measured in plasma samples from 60 untreated hypertensive Arabs and compared with 60 age- and sex-matched normotensive controls. ET-1 levels were significantly higher in hypertensives (mean 10.1 +/- 1 pmol/L) than normotensives (mean 2.2 +/- 0.5 pmol/L). Body mass index (BMI) was slightly higher among the hypertensives. For all subjects these levels significantly (P < 0.001) correlated with systolic blood pressure and less significantly (P < 0.05) with diastolic blood pressure and body weight. The correlation between ET-1 and both systolic and diastolic blood pressure was persistently significant after adjusting for BMI. Plasma concentrations of ET-1 are significantly higher in hypertensive Gulf Arabs as compared with reported levels in white hypertensives and ET-1 could be a risk factor for cardiovascular diseases in this population. The endothelial system might be particularly important with respect to hypertension in this racial group and merits further study.

Longitudinal development of hormone levels and grey matter density in 9 and 12-year-old twins.

PubMed

Brouwer, Rachel M; Koenis, M M G; Schnack, Hugo G; van Baal, G Caroline; van Soelen, Inge L C; Boomsma, Dorret I; Hulshoff Pol, Hilleke E

2015-05-01

Puberty is characterized by major changes in hormone levels and structural changes in the brain. To what extent these changes are associated and to what extent genes or environmental influences drive such an association is not clear. We acquired circulating levels of luteinizing hormone, follicle stimulating hormone (FSH), estradiol and testosterone and magnetic resonance images of the brain from 190 twins at age 9 [9.2 (0.11) years; 99 females/91 males]. This protocol was repeated at age 12 [12.1 (0.26) years] in 125 of these children (59 females/66 males). Using voxel-based morphometry, we tested whether circulating hormone levels are associated with grey matter density in boys and girls in a longitudinal, genetically informative design. In girls, changes in FSH level between the age of 9 and 12 positively associated with changes in grey matter density in areas covering the left hippocampus, left (pre)frontal areas, right cerebellum, and left anterior cingulate and precuneus. This association was mainly driven by environmental factors unique to the individual (i.e. the non-shared environment). In 12-year-old girls, a higher level of circulating estradiol levels was associated with lower grey matter density in frontal and parietal areas. This association was driven by environmental factors shared among the members of a twin pair. These findings show a pattern of physical and brain development going hand in hand.

The reduction in circulating levels of melatonin may be associated with the development of preeclampsia.

PubMed

Zeng, K; Gao, Y; Wan, J; Tong, M; Lee, A C; Zhao, M; Chen, Q

2016-11-01

Placental dysfunction and oxidative stress contribute to the pathogenesis of preeclampsia, which is a pregnancy-specific disorder. It has been suggested that the incidence of preeclampsia has a seasonal variation. Melatonin, as a seasonal factor, has been suggested to be involved in a successful pregnancy. In this study, we investigated the association of circulating levels of melatonin with preeclampsia. Serum was collected from women with preeclampsia (n=113) and gestation-matched healthy pregnant women, and the levels of melatonin were measured. In addition, the expression of melatonin receptors was examined in preeclamptic placentae (n=27). The association of the incidence of preeclampsia and seasonal variation was also analysed from 1491 women with preeclampsia within 77 745 healthy pregnancies. The serum levels of melatonin were significantly reduced in women with preeclampsia at presentation and these reduced serum levels of melatonin were not associated with the severity or time onset of preeclampsia nor with seasonal variation. The expression of melatonin receptor, MT1 was reduced in preeclamptic placentae. The incidence of preeclampsia was did exhibit seasonal variation, but this was largely due to the increase in the incidence of mild or late-onset preeclampsia. Our results demonstrate that reduced melatonin levels are associated with the development of preeclampsia but that the circulating levels of melatonin do not appear to be subject to seasonal variation during pregnancy.

Increased levels of circulating CD34+ cells in neovascular age-related macular degeneration: relation with clinical and OCT features.

PubMed

Kara, Caner; Özdal, Pınar Ç; Beyazyıldız, Emrullah; Özcan, Nurgül E; Teke, Mehmet Y; Vural, Gülden; Öztürk, Faruk

2018-01-01

To investigate the levels of circulating CD34+ stem cells in patients with neovascular type age-related macular degeneration (AMD) and its relation with clinical and optical coherence tomography (OCT) findings. The study consisted of 55 patients: 28 patients (18 male and 10 female) with neovascular type AMD as a study group and 27 patients (12 male and 15 female) scheduled for cataract surgery as a control group. The level of CD34+ stem cells was measured by flow cytometry. Demographic and clinical data were recorded. The mean ages of patients in the study and control groups were 71 ± 8 and 68 ± 6 years, respectively. There was no statistically significant difference in terms of age, sex, or systemic disease association between study and control groups. However, smoking status was significantly higher in the study group (67.9% vs 37.0%; p = 0.02). Stem cell levels were significantly higher in the study group (1.5 ± 0.9 vs 0.5 ± 0.3; p<0.001), but there was no relation between stem cell levels and clinical and OCT findings. Increased circulating CD34+ stem cell levels were observed in patients with choroidal neovascular membrane associated with AMD, but no significant relation was found between cell levels and clinical and OCT findings.

Tracking Normalization of Brain Tumor Vasculature by Magnetic Imaging and Proangiogenic Biomarkers

PubMed Central

Hormigo, Adília; Gutin, Philip H.; Rafii, Shahin

2010-01-01

Clinical assessment of the response to antiangiogenic therapy has been cumbersome. A study in this issue of Cancer Cell demonstrates that a combination of magnetic resonance imaging (MRI) for quantification of normalized vessels with measurements of circulating levels of proangiogenic factors, including FGF2, SDF1, and viable circulating endothelial cells, provides an effective means to evaluate the response of recurrent glioblastoma to a prototypical pan-VEGF receptor tyrosine kinase inhibitor, AZD2171. PMID:17222788

Acute Ozone-Induced Pulmonary and Systemic Metabolic ...

EPA Pesticide Factsheets

Acute ozone exposure increases circulating stress hormones and induces metabolic alterations in animals and humans. We hypothesized that the increase of adrenal-derived stress hormones is necessary for both ozone-induced metabolic effects and lung injury. Male Wistar-Kyoto rats underwent adrenal demedullation (DEMED), total bilateral adrenalectomy (ADREX), or sham surgery (SHAM). After a 4 day recovery, rats were exposed to air or ozone (1ppm), 4h/day for 1 or 2 days. Circulating adrenaline levels dropped to nearly zero in DEMED and ADREX rats relative to air-exposed SHAM. Corticosterone levels tended to be low in DEMED rats and dropped to nearly zero in ADREX rats. Adrenalectomy in air-exposed rats caused modest changes in metabolites and lung toxicity parameters. Ozone-induced hyperglycemia and glucose intolerance were markedly attenuated in DEMED rats with nearly complete reversal in ADREX rats. Ozone increased circulating epinephrine and corticosterone in SHAM but not in DEMED or ADREX rats. Free fatty acids (p=0.15) and branched-chain amino acids increased after ozone exposure in SHAM but not in DEMED or ADREX rats. Lung minute volume was not affected by surgery or ozone but ozone-induced labored breathing was less pronounced in ADREX rats. Ozone-induced increases in lung protein leakage and neutrophilic inflammation were markedly reduced in DEMED and ADREX rats (ADREX>DMED). Ozone-mediated decreases in circulating white blood cells in SHAM were not obser

Acute Ozone-Induced Pulmonary and Systemic Metabolic ...

EPA Pesticide Factsheets

Acute ozone exposure increases circulating stress hormones and induces peripheral metabolic alterations in animals and humans. We hypothesized that the increase of adrenal-derived stress hormones is necessary for ozone-induced systemic metabolic effects and lung injury. Male Wistar-Kyoto rats (12 week-old) underwent total bilateral adrenalectomy (ADREX), adrenal demedullation (DEMED) or sham surgery (SHEM). After 4 day recovery, rats were exposed to air or ozone (1ppm), 4h/day for 1 or 2 days. Circulating adrenaline levels dropped to nearly zero in DEMED and ADREX rats relative to air-exposed SHAM. Corticosterone levels tended to be low in DEMED rats and dropped to nearly zero in ADREX rats. Adrenalectomy in air-exposed rats caused modest changes in metabolites and lung toxicity parameters. Ozone-induced hyperglycemia and glucose intolerance were markedly attenuated in DEMED with nearly complete reversal in ADREX rats. Ozone increased circulating epinephrine and corticosterone in SHAM but not in DEMED or ADREX rats. Free fatty acids and branched-chain amino acids tended to increase after ozone exposure in SHAM but not in DEMED or ADREX rats. Lung minute volume was not affected by surgery or ozone but ozone-induced labored breathing was less pronounced in ADREX rats. Ozone-induced increases in lung protein leakage and neutrophilic inflammation were markedly reduced in DEMED and ADREX rats (ADREX>DMED). Ozone-mediated decrease in circulating WBC in SHAM was not

Depression in type 1 diabetes was associated with high levels of circulating galectin-3

PubMed Central

Melin, Eva Olga; Dereke, Jonatan; Thunander, Maria; Hillman, Magnus

2018-01-01

Objective Neuroinflammatory responses are implicated in depression. The aim was to explore whether depression in patients with type 1 diabetes (T1D) was associated with high circulating galectin-3, controlling for metabolic variables, s-creatinine, life style factors, medication and cardiovascular complications. Design Cross-sectional. Methods Participants were T1D patients (n = 283, 56% men, age 18–59 years, diabetes duration ≥1 year). Depression was assessed by Hospital Anxiety and Depression Scale-depression subscale. Blood samples, anthropometrics and blood pressure were collected, and supplemented with data from medical records and the Swedish National Diabetes Registry. Galectin-3 ≥2.562 µg/l, corresponding to the 85th percentile, was defined as high galectin-3. Results Median (quartile1, quartile3) galectin-3 (µg/l) was 1.3 (0.8, 2.9) for the 30 depressed patients, and 0.9 (0.5, 1.6) for the 253 non-depressed, P = 0.009. Depression was associated with high galectin-3 in all the 283 patients (adjusted odds ratio (AOR) 3.5), in the 161 men (AOR 3.4), and in the 122 women (AOR 3.9). HbA1c, s-lipids, s-creatinine, blood pressure, obesity, smoking, physical inactivity, cardiovascular complications and drugs (antihypertensive, lipid lowering, oral antidiabetic drugs and antidepressants) were not associated with high galectin-3. Conclusions This is the first study to show an association between depression and galectin-3. Depression was the only explored parameter associated with high circulating galectin-3 levels in 283 T1D patients. High galectin-3 levels might contribute to the increased risk for Alzheimer’s disease, cardiovascular and all-cause mortality observed in persons with depression. Potentially, in the future, treatment targeting galactin-3 might improve the prognosis for patients with high galectin-3 levels. PMID:29760188

Association between circulating microRNA-208a and severity of coronary heart disease.

PubMed

Zhang, Yao; Li, Hai-Hong; Yang, Rui; Yang, Bai-Jing; Gao, Zhao-Yu

2017-09-01

Circulating microRNA (miR)-208a is specifically expressed in the heart muscle, which is involved in the regulation of myosin during cardiac development. Previous studies reported that cardiac-specific miR-208a level is significantly higher in plasma of coronary heart disease (CHD) patients. However, whether it correlates with severity of CHD, has never been elucidated before. The aim of this study was to explore the association between miR-208a and the presence and severity of CHD. Samples were collected from 290 CHD patients and 110 subjects with angiographic exclusion of CHD. Circulating miRNA-208a expression was detected using quantitative real-time PCR. The Gensini score was used to evaluate the severity of coronary stenotic lesions. Expression of miRNA-208a was identified on the basis of the quartiles of the Gensini score, and association between the miRNA-208a levels and CHD was analyzed. Diagnostic potential of miR-208a of CHD was performed by ROC analysis. CHD patients had higher miRNA-208a expression (1.61, 0.45-3.86 vs. 0.66, 0.11-1.42, p < .001), and the biomarker level significantly increased following an increasing the Gensini score (p < .001). Gensini score was significantly associated with miRNA-208a expression (r = 0.8525, p < .001). The optimal cut-off value of the relative level of miR-208a was with a specificity of 93.6% and a sensitivity of 75.5%. The AUC of miR-208a was 0.919 (95% CI, 0.893-0.945; p < .001). These preliminary results suggest that the expression of miR-208a may be associated with atherogenesis. The level of circulating miR-208a in predicting the severity of coronary atherosclerosis may have a relatively certain value.

Circulating Anti-Müllerian Hormone Levels in Daughters of Women with and without Polycystic Ovary Syndrome.

PubMed

Olszanecka-Glinianowicz, Magdalena; Zachurzok, Agnieszka; Drosdzol-Cop, Agnieszka; Bożętowicz-Wikarek, Maria; Owczarek, Aleksander; Gawlik, Aneta; Chudek, Jerzy; Skrzypulec-Plinta, Violetta; Małecka-Tendera, Ewa

2016-01-01

The aim of this study was to assess whether circulating anti-Müllerian hormone (AMH) levels in daughters of women with polycystic ovary syndrome (PCOSd) correspond with clinical and biochemical features of hyperandrogenism, polycystic ovary morphology and menstrual cycle disturbances. Menstrual cycle disturbances, hirsutism, acne and ultrasonographic ovarian morphology were assessed in 75 girls aged 13-18 years (35 PCOSd and 40 daughters of healthy women). Serum gonadotropins, androgens, sex hormone-binding globulin and plasma AMH were measured in a fasting state, and the free androgen index was calculated. A significant correlation between the AMH level and mean ovary volume was found (r = 0.36; p < 0.01). AMH levels were not related to hirsutism, acne and polycystic ovary morphology. Significantly higher AMH levels were found only in PCOSd with irregular menstruation or secondary amenorrhea. The results of logistic regression analysis showed that in that group for each 1-ng/ml increase in the AMH level, the odds ratio of the PCOS occurrence in the future was increased 1.27 times (95% CI: 1.09-1.47; p < 0.01). A higher AMH level in PCOSd is associated with menstrual cycle disturbances and larger ovarian volume but not with clinical and biochemical features of hyperandrogenism. Thus, the risk for PCOS development among genetically predisposed girls may be related to increased AMH levels. © 2016 S. Karger AG, Basel.

Patients with high serum substance P levels previously to liver transplantation for hepatocellular carcinoma have higher risk of one-year liver transplantation mortality.

PubMed

Lorente, Leonardo; Rodriguez, Sergio T; Sanz, Pablo; Pérez-Cejas, Antonia; Padilla, Javier; Díaz, Dácil; González, Antonio; Martín, María M; Jiménez, Alejandro; Cerro, Purificación; Barrera, Manuel A

2018-04-20

Substance P is a tachykinins family member with inflammatory effects. Higher circulating levels of substance P have been found in patients with liver diseases and in patients with higher severity of liver diseases. The objective of this study was to determine whether serum levels of substance P levels, prior to liver transplantation (LT) for hepatocellular carcinoma (HCC) are associated with one-year LT mortality. In this observational retrospective unicenter study were included patients with LT for HCC. Serum levels of substance P were measured before LT. The end-point of the study was one-year mortality after LT. We found that one-year survivor patients ( n = 127) showed a lower age in liver donors ( p = 0.03) and lower levels of serum substance P levels ( p = 0.003) than non-survivor patients ( n = 15). Logistic regression analysis showed that serum levels of substance P (levels) were associated with one-year mortality (Odds Ratio = 1.011; 95% CI = 1.004-1.018; p = 0.002) controlling for the age of the LT donor. We believe that our study is the first study reporting data on circulating levels of substance P previously to LT for HCC, and an association between elevated levels of serum substance P before LT and mortality during the first year of LT.

Patients with high serum substance P levels previously to liver transplantation for hepatocellular carcinoma have higher risk of one-year liver transplantation mortality

PubMed Central

Lorente, Leonardo; Rodriguez, Sergio T.; Sanz, Pablo; Pérez-Cejas, Antonia; Padilla, Javier; Díaz, Dácil; González, Antonio; Martín, María M.; Jiménez, Alejandro; Cerro, Purificación; Barrera, Manuel A.

2018-01-01

Purpose Substance P is a tachykinins family member with inflammatory effects. Higher circulating levels of substance P have been found in patients with liver diseases and in patients with higher severity of liver diseases. The objective of this study was to determine whether serum levels of substance P levels, prior to liver transplantation (LT) for hepatocellular carcinoma (HCC) are associated with one-year LT mortality. Material and Methods In this observational retrospective unicenter study were included patients with LT for HCC. Serum levels of substance P were measured before LT. The end-point of the study was one-year mortality after LT. Results We found that one-year survivor patients (n = 127) showed a lower age in liver donors (p = 0.03) and lower levels of serum substance P levels (p = 0.003) than non-survivor patients (n = 15). Logistic regression analysis showed that serum levels of substance P (levels) were associated with one-year mortality (Odds Ratio = 1.011; 95% CI = 1.004–1.018; p = 0.002) controlling for the age of the LT donor. Conclusions We believe that our study is the first study reporting data on circulating levels of substance P previously to LT for HCC, and an association between elevated levels of serum substance P before LT and mortality during the first year of LT. PMID:29765559

Exposure to low levels of hydrogen sulfide elevates circulating glucose in maternal rats

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hayden, L.J.; Goeden, H.; Roth, S.H.

1990-09-01

Although the lethal effect of hydrogen sulfide (H{sub 2}S) has long been known, the results of exposure to low levels of H{sub 2}S have not been well documented. Rat dams and pups were exposed to low levels of H{sub 2}S (less than or equal to 75 ppm) from d 1 of gestation until d 21 postpartum and analyzed for changes in circulating enzymatic activity and metabolites. Blood glucose was significantly elevated in maternal blood on d 21 postpartum at all exposure levels. This increase in glucose was accompanied by a possible decrease in serum triglyceride in the pups and inmore » the dams on d 21 postpartum. There was no evidence of alterations in serum alkaline phosphatase, lactate dehydrogenase, or serum glutamate oxaloacetate transaminase.« less

Effects of wetland management on carrying capacity of diving ducks and shorebirds in a coastal estuary

USGS Publications Warehouse

Brand, L. Arriana; Takekawa, John Y.; Shinn, Joel; Graham, Tanya; Buffington, Kevin; Gustafson, K. Benjamin; Smith, Lacy M.; Spring, Sarah E.; Miles, A. Keith

2014-01-01

With global loss of natural wetlands, managed wetlands increasingly support energy requirements for wintering shorebirds and waterfowl. Despite numerous studies of avian bioenergetics in freshwater systems, less is known of the energetic capacity of estuarine systems. In San Francisco Bay, managed saline ponds converted from former commercial salt evaporation ponds form part of the largest wetland restoration project on the Pacific coast of North America. A daily-ration model was applied to assess carrying capacity for diving ducks and shorebirds during four winter seasons (2007–2010) in seasonal and circulation ponds, each in two salinity classes. Diving ducks comprised an estimated 35,450 ± 1,559 (x ± SE) in average years and 45,458 ± 1,653 in peak years with > 95% in circulation ponds. Shorebirds comprised 64,253 ± 14,838 (x ± SE) in average years and 108,171 ± 4,854 in peak years with > 64% in seasonal ponds. Macroinvertebrate energy density was highest in mesohaline (5–30 ppt) circulation ponds and lowest in seasonal ponds for both guilds. Energy requirements for diving ducks in mesohaline followed by low-hyperhaline (30–80 ppt) circulation ponds were mostly met by available prey energy. Available energy for shorebirds was substantially less than they required in seasonal ponds but exceeded their needs in mesohaline circulation ponds. Mesohaline circulation ponds supported 9,443 ± 1,649 (x ± SE) shorebird use-days·ha-1 of accessible habitat and 2,297 ± 402 diving duck use-days·ha-1 of accessible habitat, twice the capacity of low-hyperhaline circulation ponds and greater than five times that of seasonal ponds for both guilds. Our results indicated that reducing salinity to mesohaline levels and altering water depth to increase accessibility substantially increased energy available for these species in estuarine managed ponds.

Effects of wetland management on carrying capacity of diving ducks and shorebirds in a coastal estuary

USGS Publications Warehouse

Brand, Arianna L.; Takekawa, John Y.; Shinn, Joel; Graham, Tanya R.; Buffington, Kevin J.; Gustafson, K. Ben; Smith, Lacy M.; Spring, Sarah E.; Miles, A. Keith

2014-01-01

With global loss of natural wetlands, managed wetlands increasingly support energy requirements for wintering shorebirds and waterfowl. Despite numerous studies of avian bioenergetics in freshwater systems, less is known of the energetic capacity of estuarine systems. In San Francisco Bay, managed saline ponds converted from former commercial salt evaporation ponds form part of the largest wetland restoration project on the Pacific coast of North America. A daily-ration model was applied to assess carrying capacity for diving ducks and shorebirds during four winter seasons (2007–2010) in seasonal and circulation ponds, each in two salinity classes. Diving ducks comprised an estimated 35,450 ± 1,559 ( ± SE) in average years and 45,458 ± 1,653 in peak years with > 95% in circulation ponds. Shorebirds comprised 64,253 ± 14,838 ( ± SE) in average years and 108,171 ± 4,854 in peak years with > 64% in seasonal ponds. Macroinvertebrate energy density was highest in mesohaline (5–30 ppt) circulation ponds and lowest in seasonal ponds for both guilds. Energy requirements for diving ducks in mesohaline followed by low-hyperhaline (30–80 ppt) circulation ponds were mostly met by available prey energy. Available energy for shorebirds was substantially less than they required in seasonal ponds but exceeded their needs in mesohaline circulation ponds. Mesohaline circulation ponds supported 9,443 ± 1,649 ( ± SE) shorebird use-days·ha-1 of accessible habitat and 2,297 ± 402 diving duck use-days·ha-1 of accessible habitat, twice the capacity of low-hyperhaline circulation ponds and greater than five times that of seasonal ponds for both guilds. Our results indicated that reducing salinity to mesohaline levels and altering water depth to increase accessibility substantially increased energy available for these species in estuarine managed ponds.

Real-time measurement of free thrombin: evaluation of the usability of a new thrombin assay for coagulation monitoring during extracorporeal circulation.

PubMed

Krajewski, Stefanie; Krauss, Sabrina; Kurz, Julia; Neumann, Bernd; Schlensak, Christian; Wendel, Hans P

2014-03-01

In patients undergoing cardiac surgery with heart-lung machine support, adequate anticoagulation to mitigate blood clotting caused by the artificial surfaces of the extracorporeal circulation (ECC) system is essential. These patients routinely receive heparin, whose effectiveness is monitored by measurements of the activated clotting time (ACT). However, ACT values only poorly correlate with the actual hemostatic status. The aim of our study was to evaluate the detection of free thrombin in heparinized human blood as a monitor of anticoagulation during ECC. Human whole blood was anticoagulated with different concentrations of heparin (0.75, 1, 2 or 3 IU/ml) and circulated in the Chandler-loop model for up to 240 min at 37 °C. Next to ACT, ECC-mediated changes in free active thrombin, prothrombin fragment 1+2 (F1+2) and thrombin-antithrombin-III (TAT) levels were measured before and during circulation. Platelet activation and cell count parameters were further investigated. Our study shows that detection of ECC-mediated changes in free thrombin is possible in blood anticoagulated with 0.75 or 1 IU/ml heparin, whereas no thrombin was detectable at higher heparin concentrations. Thrombin generation during 240 min of ECC is comparable to F 1+2 and TAT plasma levels during ECC. Thrombin is the key enzyme in the coagulation cascade and hence represents a promising marker for monitoring the coagulation status of patients. Although detection of free thrombin was not feasible at high heparin concentrations, the employed test represents an additional test to current laboratory methods investigating blood coagulation at low heparin concentrations. Copyright © 2013 Elsevier Ltd. All rights reserved.

Synoptic and climatological analysis of atmospheric circulation impacts on particulate matter pollution in Shanghai, China

NASA Astrophysics Data System (ADS)

Liao, Z.; Fan, S.

2016-12-01

This study investigated the particulate matter characteristics within different circulation types (CTs) in the megacity of Shanghai during the period 2001-2015, and provided a quantitative evaluation of atmospheric circulation influences on PM10 pollution across a wide range of spatial and temporal scales, from local to region and daily to interannual. Ten CTs were identified over the Asian-Pacific region by objective Lamb Weather Type approach and each resulting CT was characterized with distinct local meteorology and air mass source. The PM10 loadings in the CTs associated with continental westerly flow were significant higher than that in the CTs linked to marine easterly air masses. Regional backgrounds that transported by the synoptic flows were more responsible for the distinct PM10 levels in different CTs. The locally-produced PM10 generally stabilized in range of 20-25 μg m-3, but enhanced to 41.2 μg m-3 in case of anticyclone type. There were distinct PM10 trends in different CTs (ranged from -3.74 to -0.28 μg m-3 yr-1), indicating the different background trends. Overall, the PM10 concentrations have decreased (-2.33 μg m-3 yr-1) in the studied period and the estimated locally-produced trend (-0.79 μg m-3 yr-1) accounted for 33.9% of overall downward trend. The occurrence frequency presented an increase (0.15 % yr-1) for anticyclone type, but a decrease (-0.10 % yr-1) for the type N associated with invasion of cold air. The 15-yr frequency change of atmospheric circulation induced an increase in PM­10 level (0.17 μg m-3) in Shanghai. On the contrary, controls on the pollutant emission had always positive effects and hence should be always encouraged.

Exploiting serological data to understand the epidemiology of foot-and-mouth disease virus serotypes circulating in Libya

PubMed Central

Eldaghayes, Ibrahim; Dayhum, Abdunaser; Kammon, Abdulwahab; Sharif, Monier; Ferrari, Giancarlo; Bartels, Christianus; Sumption, Keith; King, Donald P.; Grazioli, Santina; Brocchi, Emiliana

2017-01-01

Sporadic outbreaks of foot-and-mouth disease (FMD) have occurred in Libya for almost fifty years. During the spring of 2013, a countrywide serosurvey was undertaken to assess the level of FMD virus circulation and identify FMD virus serotypes in the country. A total of 4221 sera were collected, comprising samples from large ruminants (LR; n=1428 samples from 357 farms) and small ruminants (SR; n=2793 samples from 141 farms). FMD sero-prevalence of NSP antibodies determined by ELISA were 19.0% (271/1428) with 95% CI (16.9 – 21.0) and 13.5% (378/2793) with 95% CI (12.3 – 14.8) for LR and SR samples, respectively. The sero-prevalence of NSP antibodies in LR was 12.3% and 19.8% for age group < 1 year and ≥ 1 year, respectively (X2= 4.95, P= 0.026), while in SR was 3.7%, 13.6% and 21.3% for age group < 1 year, 1-2 year and > 2 year, respectively (X2= 118.1, P= 0.000). These observed NSP serologic profiles support the hypothesis of an endemic level of FMD circulation in Libya. All positive sera were tested for SP antibodies for O, A and SAT-2 FMD virus serotypes. Serotype O was the dominant circulating serotype followed by serotype A, while evidence of SAT-2 was not found. These data provide an insight into the wider epidemiology of FMD in Libya, and contribute to field and laboratory investigations that during 2013 serotype O (O/ME-SA/Ind-2001 lineage) was isolated from clinical samples collected from the country. PMID:28180094

Effect of propranolol on the splanchnic and peripheral renin angiotensin system in cirrhotic patients

PubMed Central

Vilas-Boas, Walkíria Wingester; Jr, Antônio Ribeiro-Oliveira; da Cunha Ribeiro, Renata; Vieira, Renata Lúcia Pereira; Almeida, Jerusa; Nadu, Ana Paula; Silva, Ana Cristina Simões e; Santos, Robson Augusto Souza

2008-01-01

AIM: To evaluate the effect of β-blockade on angiotensins in the splanchnic and peripheral circulation of cirrhotic patients and also to compare hemodynamic parameters during liver transplantation according to propranolol pre-treatment or not. METHODS: Patients were allocated into two groups: outpatients with advanced liver disease(LD) and during liver transplantation(LT). Both groups were subdivided according to treatment with propranolol or not. Plasma was collected through peripheral venipuncture to determine plasma renin activity(PRA), Angiotensin(Ang) I, Ang II, and Ang-(1-7) levels by radioimmunoassay in LD group. During liver transplantation, hemodynamic parameters were determined and blood samples were obtained from the portal vein to measure renin angiotensin system(RAS) components. RESULTS: PRA, Ang I, Ang II and Ang-(1-7) were significantly lower in the portal vein and periphery in all subgroups treated with propranolol as compared to non-treated. The relationships between Ang-(1-7) and Ang I levels and between Ang II and Ang I were significantly increased in LD group receiving propranolol. The ratio between Ang-(1-7) and Ang II remained unchanged in splanchnic and peripheral circulation in patients under β-blockade, whereas the relationship between Ang II and Ang I was significantly increased in splanchnic circulation of LT patients treated with propranolol. During liver transplantation, cardiac output and index as well systemic vascular resistance and index were reduced in propranolol-treated subgroup. CONCLUSION: In LD group, propranolol treatment reduced RAS mediators, but did not change the ratio between Ang-(1-7) and Ang II in splanchnic and peripheral circulation. Furthermore, the modification of hemodynamic parameters in propranolol treated patients was not associated with changes in the angiotensin ratio. PMID:19058308

Multidecadal Weakening of Indian Summer Monsoon Circulation Induces an Increasing Northern Indian Ocean Sea Level

NASA Astrophysics Data System (ADS)

Swapna, P.; Jyoti, J.; Krishnan, R.; Sandeep, N.; Griffies, S. M.

2017-10-01

North Indian Ocean sea level has shown significant increase during last three to four decades. Analyses of long-term climate data sets and ocean model sensitivity experiments identify a mechanism for multidecadal sea level variability relative to global mean. Our results indicate that North Indian Ocean sea level rise is accompanied by a weakening summer monsoon circulation. Given that Indian Ocean meridional heat transport is primarily regulated by the annual cycle of monsoon winds, weakening of summer monsoon circulation has resulted in reduced upwelling off Arabia and Somalia and decreased southward heat transport, and corresponding increase of heat storage in the North Indian Ocean. These changes in turn lead to increased retention of heat and increased thermosteric sea level rise in the North Indian Ocean, especially in the Arabian Sea. These findings imply that rising North Indian Ocean sea level due to weakening of monsoon circulation demands adaptive strategies to enable a resilient South Asian population.

Circulating Angiogenic Factors and the Risk of Preeclampsia in Systemic Lupus Erythematosus Pregnancies.

PubMed

Leaños-Miranda, Alfredo; Campos-Galicia, Inova; Berumen-Lechuga, María Guadalupe; Molina-Pérez, Carlos José; García-Paleta, Yolanda; Isordia-Salas, Irma; Ramírez-Valenzuela, Karla Leticia

2015-07-01

To investigate whether angiogenic factors are associated with risk of developing preeclampsia in pregnant women with systemic lupus erythematosus (SLE). We performed a nested case-control study within a cohort of SLE women with singleton pregnancies. The study included 42 patients with SLE who eventually developed preeclampsia and 75 normal SLE pregnancies. Serum samples were collected at 4-week intervals (from weeks 12 to 36). Serum samples were analyzed for soluble fms-like tyrosine kinase-1 (sFlt-1), placental growth factor (PlGF), and soluble endoglin (sEng). Women destined to develop preeclampsia had lower PlGF levels and higher sFlt-1 and sEng levels, and a higher sFlt-1/PlGF ratio than normal pregnancies. These changes became significant at 12 weeks in patients destined to develop either early onset (< 34 weeks, p ≤ 0.003) or late-onset preeclampsia (≥ 34 weeks, p ≤ 0.02). The risk to develop preeclampsia was higher among patients with PlGF concentration values in the lowest quartile or with sFlt-1 and sEng levels, and sFlt-1/PlGF ratio, in the highest quartile of the normal SLE pregnancies distribution. The OR were higher and appeared earlier in patients destined to develop early onset preeclampsia (OR ≥ 16.2, from Week 12 onward) than in patients who presented preeclampsia later (OR ≥ 8.9, from Week 24 onward). Changes in circulating concentrations of sFlt-1, PlGF, sEng, and the sFlt-1/PlGF ratio precede the onset of preeclampsia in SLE pregnancies. The risk profile of circulating angiogenic factors for developing preeclampsia distinctly evolves depending on whether this condition is manifested earlier or later.

Risk mapping of West Nile virus circulation in Spain, 2015.

PubMed

Sánchez-Gómez, Amaya; Amela, Carmen; Fernández-Carrión, Eduardo; Martínez-Avilés, Marta; Sánchez-Vizcaíno, José Manuel; Sierra-Moros, María José

2017-05-01

West Nile fever is an emergent disease in Europe. The objective of this study was to conduct a predictive risk mapping of West Nile Virus (WNV) circulation in Spain based on historical data of WNV circulation. Areas of Spain with evidence of WNV circulation were mapped based on data from notifications to the surveillance systems and a literature review. A logistic regression-based spatial model was used to assess the probability of WNV circulation. Data were analyzed at municipality level. Mean temperatures of the period from June to October, presence of wetlands and presence of Special Protection Areas for birds were considered as potential predictors. Two predictors of WNV circulation were identified: higher temperature [adjusted odds ratio (AOR) 2.07, 95% CI 1.82-2.35, p<0.01] and presence of wetlands (3.37, 95% CI 1.89-5.99, p<0.01). Model validations indicated good predictions: area under the ROC curve was 0.895 (95% CI 0.870-0.919) for internal validation and 0.895 (95% CI 0.840-0.951) for external validation. This model could support improvements of WNV risk- based surveillance in Spain. The importance of a comprehensive surveillance for WNF, including human, animal and potential vectors is highlighted, which could additionally result in model refinements. Copyright © 2017 Elsevier B.V. All rights reserved.

Associations between blood persistent organic pollutants and 25-hydroxyvitamin D3 in pregnancy.

PubMed

Morales, Eva; Gascon, Mireia; Martinez, David; Casas, Maribel; Ballester, Ferran; Rodríguez-Bernal, Clara L; Ibarluzea, Jesus; Marina, Loreto Santa; Espada, Mercedes; Goñi, Fernando; Vizcaino, Esther; Grimalt, Joan O; Sunyer, Jordi

2013-07-01

Persistent organic pollutants (POPs) are suggested to contribute to lower vitamin D levels; however, studies in humans are scarce and have never focused on pregnancy, a susceptibility period for vitamin D deficiency. We investigated whether serum levels of POPs were associated with circulating 25-hydroxyvitamin D3 [25(OH)D3] concentration in pregnancy. Cross-sectional associations of serum concentrations of eight POPs with plasma 25(OH)D3 concentration were analyzed in 2031 pregnant women participating in the Spanish population-based cohort INfancia y Medio Ambiente (INMA) Project. Serum concentrations of POPs were measured by gas chromatography and plasma 25(OH)D3 concentration was measured by high-performance liquid chromatography in pregnancy (mean 13.3±1.5weeks of gestation). Multivariable regression models were performed to assess the relationship between blood concentrations of POPs and 25(OH)D3. An inverse linear relationship was found between serum concentration of PCB180 and circulating 25(OH)D3. Multivariate linear regression models showed higher PCB180 levels to be associated with lower 25(OH)D3 concentration: quartile Q4 vs. quartile Q1, coefficient=-1.59, 95% CI -3.27, 0.08, p trend=0.060. A non-monotonic inverse relationship was found between the sum of predominant PCB congeners (PCB 180, 153 and 138) and 25(OH)D3 concentration: coefficient (95% CI) for quartile Q2 vs. Q1 [-0.50 (-1.94, 0.94)], quartile Q3 vs. Q1 [-1.56 (-3.11, -0.02)] and quartile Q4 vs. Q1 [-1.21 (-2.80, 0.38)], p trend=0.081. No significant associations were found between circulating 25(OH)D3 and serum levels of p,p'-DDE, p,p'-DDT, HCB, and ß-HCH. Our results suggest that the background exposure to PCBs may result in lower 25(OH)D3 concentration in pregnant women. Copyright © 2013 Elsevier Ltd. All rights reserved.

Arsenic abrogates the estrogen-signaling pathway in the rat uterus

PubMed Central

2010-01-01

Background Arsenic, a major pollutant of water as well as soil, is a known endocrine disruptor, and shows adverse effects on the female reproductive physiology. However, the exact molecular events leading to reproductive dysfunctions as a result of arsenic exposure are yet to be ascertained. This report evaluates the effect and mode of action of chronic oral arsenic exposure on the uterine physiology of mature female albino rats. Methods The effect of chronic oral exposure to arsenic at the dose of 4 microg/ml for 28 days was evaluated on adult female albino rats. Hematoxylin-eosin double staining method evaluated the changes in the histological architecture of the uterus. Circulating levels of gonadotropins and estradiol were assayed by enzyme-linked immunosorbent assay. Expression of the estrogen receptor and estrogen-induced genes was studied at the mRNA level by RT-PCR and at the protein level by immunohistochemistry and western blot analysis. Results Sodium arsenite treatment decreased circulating levels of estradiol in a dose and time-dependent manner, along with decrease in the levels of both LH and FSH. Histological evaluation revealed degeneration of luminal epithelial cells and endometrial glands in response to arsenic treatment, along with reduction in thickness of the longitudinal muscle layer. Concomitantly, downregulation of estrogen receptor (ER alpha), the estrogen-responsive gene - vascular endothelial growth factor (VEGF), and G1 cell cycle proteins, cyclin D1 and CDK4, was also observed. Conclusion Together, the results indicate that arsenic disrupted the circulating levels of gonadotropins and estradiol, led to degeneration of luminal epithelial, stromal and myometrial cells of the rat uterus and downregulated the downstream components of the estrogen signaling pathway. Since development and functional maintenance of the uterus is under the influence of estradiol, arsenic-induced structural degeneration may be attributed to the reduction in circulating estradiol levels. Downregulation of the estrogen receptor and estrogen-responsive genes in response to arsenic indicates a mechanism of suppression of female reproductive functions by an environmental toxicant that is contra-mechanistic to that of estrogen. PMID:20598115

Sustained apnea induces endothelial activation.

PubMed

Eichhorn, Lars; Dolscheid-Pommerich, Ramona; Erdfelder, Felix; Ayub, Muhammad Ajmal; Schmitz, Theresa; Werner, Nikos; Jansen, Felix

2017-09-01

Apnea diving has gained worldwide popularity, even though the pathophysiological consequences of this challenging sport on the human body are poorly investigated and understood. This study aims to assess the influence of sustained apnea in healthy volunteers on circulating microparticles (MPs) and microRNAs (miRs), which are established biomarkers reflecting vascular function. Short intermittent hypoxia due to voluntary breath-holding affects circulating levels of endothelial cell-derived MPs (EMPs) and endothelial cell-derived miRs. Under dry laboratory conditions, 10 trained apneic divers performed maximal breath-hold. Venous blood samples were taken, once before and at 4 defined points in time after apnea. Samples were analyzed for circulating EMPs and endothelial miRs. Average apnea time was 329 seconds (±103), and SpO 2 at the end of apnea was 79% (±12). Apnea was associated with a time-dependent increase of circulating endothelial cell-derived EMPs and endothelial miRs. Levels of circulating EMPs in the bloodstream reached a peak 4 hours after the apnea period and returned to baseline levels after 24 hours. Circulating miR-126 levels were elevated at all time points after a single voluntary maximal apnea, whereas miR-26 levels were elevated significantly only after 30 minutes and 4 hours. Also miR-21 and miR-92 levels increased, but did not reach the level of significance. Even a single maximal breath-hold induces acute endothelial activation and should be performed with great caution by subjects with preexisting vascular diseases. Voluntary apnea might be used as a model to simulate changes in endothelial function caused by hypoxia in humans. © 2017 Wiley Periodicals, Inc.

Increased levels of nitrite in the sera of children infected with human immunodeficiency virus type 1.

PubMed

Torre, D; Ferrario, G; Speranza, F; Martegani, R; Zeroli, C

1996-04-01

Nitric oxide (NO) is a newly discovered gas that plays an important role in cell communication and host resistance to infection. The production of NO was examined in the sera of seven children infected with human immunodeficiency virus type 1 (HIV-1) and in the sera of 14 children who became seronegative for HIV-1 during the first year of life. In addition, we determined serum levels of various cytokines, such as interleukin (IL)-1 beta, tumor necrosis factor (TNF)-alpha, and gamma interferon (IFN-gamma), inasmuch as these cytokines are potent inducers of NO production. Production of NO, detected as circulating serum levels of nitrite, was measured with use of the Griess reagent. Serum levels of cytokines were determined by enzyme immunoassay. Increased serum levels of nitrite were observed in children with HIV-1 infection (0.4 +/- 0.2 mumol/L; P = .013), and in those who became seronegative for HIV-1 during the first year of life (0.5 +/- 0.3 mumol/L; P = .04). Furthermore, serum levels of IL-1 beta and TNF-alpha were significantly elevated in children with HIV-1 infection (37.5 +/- 23.6 pg/mL and 91.2 +/- 45.1 pg/mL, respectively). Prophylactic administration of intravenous immune globulin provoked a significant decrease of circulating levels of nitrite in children with HIV-1 infection. In conclusion, NO may play a role as a cytostatic or cytotoxic factor for invading microorganisms, and thus it is probably involved in limiting and/or eradicating infection.

Industrial water supply for the Kursk TETs-1 heating and electric power plant with the ecological safety of the River Seim taken into account

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kyakk, V. A.

2009-09-15

The Kursk TETs-1 heating and electric power plant is discussed as an illustration of preventing thermal contamination of its water supply (River Seim) by circulating water. An effective water supply system is taken to be one for which the overheating of the water at a monitoring site (near the outlet location) does not exceed an approved level for the water use conditions. The required cooling capacity of a spray pond for circulating and flow-through water supplies is determined.

Immunoglobulins against Tyrosine Nitrated Epitopes in Coronary Artery Disease

PubMed Central

Thomson, Leonor; Tenopoulou, Margarita; Lightfoot, Richard; Tsika, Epida; Parastatidis, Ioannis; Martinez, Marissa; Greco, Todd M.; Doulias, Paschalis-Thomas; Wu, Yuping; Tang, W. H. Wilson; Hazen, Stanley L.; Ischiropoulos, Harry

2012-01-01

Background Several lines of evidence support a pathophysiological role of immunity in atherosclerosis. Tyrosine nitrated proteins, a footprint of oxygen and nitrogen derived oxidants generated by cells of the immune system, are enriched in atheromatous lesions and in circulation of coronary artery disease (CAD) subjects. However, the consequences of possible immune reactions triggered by the presence of nitrated proteins in subjects with clinically documented atherosclerosis have not been explored. Methods and Results Specific immunoglobulins that recognize 3-nitrotyrosine epitopes were identified in human lesions, as well as in circulation of CAD subjects. The levels of circulating immunoglobulins against 3-nitrotyrosine epitopes were quantified in CAD patients (n=374) and subjects without CAD (non CAD controls, n=313). A ten-fold increase in the mean level of circulating immunoglobulins against protein-bound 3-nitrotyrosine was documented in the CAD subjects (3.75 ± 1.8 μg antibody Eq/mL plasma vs. 0.36 ± 0.8 μg antibody Eq/mL plasma), and was strongly associated with angiographic evidence of significant CAD. Conclusions The results of this cross sectional study suggest that post-translational modification of proteins via nitration within atherosclerotic plaque-laden arteries and in circulation serve as neoepitopes for elaboration of immunoglobulins, thereby providing an association between oxidant production and the activation of the immune system in CAD. PMID:23081989

Comprehensive analysis of circulating adipokines and hsCRP association with cardiovascular disease risk factors and metabolic syndrome in Arabs.

PubMed

Abu-Farha, Mohamed; Behbehani, Kazem; Elkum, Naser

2014-04-09

Cardiovascular diseases (CVD) are a leading cause of death worldwide including the Middle East. This is caused in part by the dysregulation of adipose tissue leading to increased production of pro-inflammatory adipokines and reduction in cardio-protective adipokines such as adiponectin. Ethnicity has been recognized as a major factor in the association between CVD risk factors and the different circulating adipokines. In this study, for the first time, the relationship between traditional cardiovascular risk factors, Metabolic Syndrome (MetS) and circulating level of adipokines in Arab ethnicity was investigated. We conducted a population-based cross-sectional survey on 379 adult Arab participants living in Kuwait. Traditional cardiovascular risk factors such as blood pressure (BP), low density lipoprotein (LDL) and triglyceride (TG) were measured. Plasma levels of circulating Leptin, Plasminogen Activator Inhibitor (PAI-1) visfatin, adiponectin, resistin and adipsin were assessed using the multiplexing immunobead-based assay. Circulating levels of High sensitivity C-Reactive Protein (hsCRP), Leptin, PAI-1 and adiponectin were significantly higher in Arab women than men (p < 0.0001). In multi-variate analysis, the homeostasis model assessment-insulin resistance (HOMA-IR) and body mass index (BMI) showed strong association with most of the biomarkers (p < 0.05). HsCRP showed significant association with all risk factors (p < 0.05). Leptin, PAI-1 and adipsin showed significant positive correlation with BMI, unlike adiponectin which showed inverse correlation (p < 0.05). Subjects in the highest tertile of leptin, PAI-1 and hsCRP had higher odds of having Metabolic Syndrome (MetS) (odd ratio [OR] = 3.02, 95% confidence interval [CI] = 1.47-6.19) and (OR = 2.52, 95% CI = 1.45-4.35), (OR = 4.26, 95% CI = 2.39-7.59) respectively. On the other hand subjects with highest tertile of adiponectin had lower odds of having MetS (OR = 0.22, 95% CI = 0.12-0.40). Leptin, PAI-1 and hsCRP showed significant positive association with increased MetS components (P-trend <0.05), while adiponectin was negatively associated with increased MetS components (P-trend <0.0001). Our results show positive association between hsCRP, leptin, PAI-1 with increased MetS components and increase the odds of having MetS. Adiponectin on the other hand showed inverse correlation with MetS components and associated with reduction in MetS. Overall, our data highlights the significant clinical value these markers have in MetS especially hsCRP which can be used as good marker of low grade inflammation in Arabs.

Increased Circulating Level of the Survival Factor GP88 (Progranulin) in the Serum of Breast Cancer Patients When Compared to Healthy Subjects

PubMed Central

Tkaczuk, Katherine Rak; Yue, Binbin; Zhan, Min; Tait, Nancy; Yarlagadda, Lavanya; Dai, Huifang; Serrero, Ginette

2011-01-01

Introduction: GP88 (PC-Cell Derived Growth Factor, progranulin) is a glycoprotein overexpressed in breast tumors and involved in their proliferation and survival. Since GP88 is secreted, an exploratory study was established to compare serum GP88 level between breast cancer patients (BC) and healthy volunteers (HV). Methods: An IRB approved prospective study enrolled 189 stage 1–4 BC patients and 18 HV. GP88 serum concentration was determined by immunoassay. Results: Serum GP88 level was 28.7 + 5.8 ng/ml in HV and increased to 40.7 + 16.0 ng/ml (P = 0.007) for stage 1–3 and 45.3 + 23.3 ng/ml (P = 0.0007) for stage 4 BC patients. There was no correlation between the GP88 level and BC characteristics such as age, race, tumor grade, ER, PR and HER-2 expression. Conclusion: These data suggest that serial testing of serum GP88 levels may have value as a circulating biomarker for detection, monitoring and follow up of BC. PMID:21792312

Angiogenin: a novel inhibitor of neutrophil lactoferrin release during extracorporeal circulation.

PubMed

Schmaldienst, Sabine; Oberpichler, André; Tschesche, Harald; Hörl, Walter H

2003-01-01

Degranulation of polymorphonuclear leukocytes (PMNL) occurs during extracorporeal circulation. A degranulation-inhibiting protein identical to angiogenin was recently isolated from high-flux dialyzer ultrafiltrate. This protein inhibits the release of lactoferrin and metalloproteinases from PMNL in vitro. In the present study, we investigated end-stage renal disease patients undergoing regular hemodialysis treatment with either high-flux dialyzers (n = 51) or low-flux dialyzers (n = 44), and chronically uremic patients undergoing hemodiafiltration (n = 30). Hemodialysis therapy with low-flux polysulfone or cellulose triacetate membranes caused no or only minimal reduction (

Niemann-Pick C1 modulates hepatic triglyceride metabolism and its genetic variation contributes to serum triglyceride levels.

PubMed

Uronen, Riikka-Liisa; Lundmark, Per; Orho-Melander, Marju; Jauhiainen, Matti; Larsson, Kristina; Siegbahn, Agneta; Wallentin, Lars; Zethelius, Björn; Melander, Olle; Syvänen, Ann-Christine; Ikonen, Elina

2010-08-01

To study how Niemann-Pick disease type C1 (NPC1) influences hepatic triacylglycerol (TG) metabolism and to determine whether this is reflected in circulating lipid levels. In Npc1(-/-) mice, the hepatic cholesterol content is increased but the TG content is decreased. We investigated lipid metabolism in Npc1(-/-) mouse hepatocytes and the association of NPC1 single-nucleotide polymorphisms with circulating TGs in humans. TGs were reduced in Npc1(-/-) mouse serum and hepatocytes. In Npc1(-/-) hepatocytes, the incorporation of [3H]oleic acid and [3H]acetate into TG was decreased, but shunting of oleic acid- or acetate-derived [3H]carbons into cholesterol was increased. Inhibition of cholesterol synthesis normalized TG synthesis, content, and secretion in Npc1(-/-) hepatocytes, suggesting increased hepatic cholesterol neogenesis as a cause for the reduced TG content and secretion. We found a significant association between serum TG levels and 5 common NPC1 single-nucleotide polymorphisms in a cohort of 1053 men, with the lowest P=8.7 x 10(-4) for the single-nucleotide polymorphism rs1429934. The association between the rs1429934 A allele and higher TG levels was replicated in 2 additional cohorts, which included 8041 individuals. This study provides evidence of the following: (1) in mice, loss of NPC1 function reduces hepatocyte TG content and secretion by increasing the metabolic flux of carbons into cholesterol synthesis; and (2) common variation in NPC1 contributes to serum TG levels in humans.

The granin VGF promotes genesis of secretory vesicles, and regulates circulating catecholamine levels and blood pressure

PubMed Central

Fargali, Samira; Garcia, Angelo L.; Sadahiro, Masato; Jiang, Cheng; Janssen, William G.; Lin, Wei-Jye; Cogliani, Valeria; Elste, Alice; Mortillo, Steven; Cero, Cheryl; Veitenheimer, Britta; Graiani, Gallia; Pasinetti, Giulio M.; Mahata, Sushil K.; Osborn, John W.; Huntley, George W.; Phillips, Greg R.; Benson, Deanna L.; Bartolomucci, Alessandro; Salton, Stephen R.

2014-01-01

Secretion of proteins and neurotransmitters from large dense core vesicles (LDCVs) is a highly regulated process. Adrenal LDCV formation involves the granin proteins chromogranin A (CgA) and chromogranin B (CgB); CgA- and CgB-derived peptides regulate catecholamine levels and blood pressure. We investigated function of the granin VGF (nonacronymic) in LDCV formation and the regulation of catecholamine levels and blood pressure. Expression of exogenous VGF in nonendocrine NIH 3T3 fibroblasts resulted in the formation of LDCV-like structures and depolarization-induced VGF secretion. Analysis of germline VGF-knockout mouse adrenal medulla revealed decreased LDCV size in noradrenergic chromaffin cells, increased adrenal norepinephrine and epinephrine content and circulating plasma epinephrine, and decreased adrenal CgB. These neurochemical changes in VGF-knockout mice were associated with hypertension. Germline knock-in of human VGF1–615 into the mouse Vgf locus rescued the hypertensive knockout phenotype, while knock-in of a truncated human VGF1–524 that lacks several C-terminal peptides, including TLQP-21, resulted in a small but significant increase in systolic blood pressure compared to hVGF1–615 mice. Finally, acute and chronic administration of the VGF-derived peptide TLQP-21 to rodents decreased blood pressure. Our studies establish a role for VGF in adrenal LDCV formation and the regulation of catecholamine levels and blood pressure.—Fargali, S., Garcia, A. L., Sadahiro, M., Jiang, C., Janssen, W. G., Lin, W.-J., Cogliani, V., Elste, A., Mortillo, S., Cero, C., Veitenheimer, B., Graiani, G., Pasinetti, G. M., Mahata, S. K., Osborn, J. W., Huntley, G. W., Phillips, G. R., Benson, D. L., Bartolomucci, A., Salton, S. R. The granin VGF promotes genesis of secretory vesicles, and regulates circulating catecholamine levels and blood pressure. PMID:24497580

The effect of low and high plasma levels of insulin-like growth factor-1 (IGF-1) on the morphology of major organs: studies of Laron dwarf and bovine growth hormone transgenic (bGHTg) mice

PubMed Central

Piotrowska, Katarzyna; Borkowska, Sylwia J.; Wiszniewska, Barbara; Laszczyńska, Maria; Słuczanowska-Głąbowska, Sylwia; Havens, Aaron M.; Kopchick, John J.; Bartke, Andrzej; Taichman, Russel S.; Kucia, Magda; Ratajczak, Mariusz Z.

2014-01-01

Summary It is well known that somatotrophic/insulin signaling affects lifespan in experimental animals. To study the effects of insulin-like growth factor-1 (IGF-1) plasma level on the morphology of major organs, we analyzed lung, heart, liver, kidney, bone marrow, and spleen isolated from 2-year-old growth hormone receptor knockout (GHR-KO) Laron dwarf mice (with low circulating plasma levels of IGF-1) and 6-month-old bovine growth hormone transgenic (bGHTg) mice (with high circulating plasma levels of IGF-1). The ages of the two mutant strains employed in our studies were selected based on their overall ~50% survival (Laron dwarf mice live up to ~4 years and bGHTg mice up to ~1 year). Morphological analysis of the organs of long-living 2-year-old Laron dwarf mice revealed a lower biological age for their organs compared with normal littermates, with more brown adipose tissue (BAT) surrounding the main body organs, lower levels of steatosis in liver, and a lower incidence of leukocyte infiltration in different organs. By contrast, the organs of 6-month-old, short-living bGHTg mice displayed several abnormalities in liver and kidney and a reduced content of BAT around vital organs. PMID:23613169

Circulating microRNA-1a is a biomarker of Graves' disease patients with atrial fibrillation.

PubMed

Wang, Fang; Zhang, Sheng-Jie; Yao, Xuan; Tian, Dong-Mei; Zhang, Ke-Qin; She, Dun-Min; Guo, Fei-Fan; Zhai, Qi-Wei; Ying, Hao; Xue, Ying

2017-07-01

It has been increasingly suggested that specific microRNAs expression profiles in the circulation and atrial tissue are associated with the susceptibility to atrial fibrillation. Nonetheless, the role of circulating microRNAs in Graves' disease patients with atrial fibrillation has not yet been well described. The objective of the study was to identify the role of circulating microRNAs as specific biomarkers for the diagnosis of Graves' disease with atrial fibrillation. The expression profiles of eight serum microRNAs, which are found to be critical in the pathogenesis of atrial fibrillation, were determined in patients with Graves' disease with or without atrial fibrillation. MicroRNA expression analysis was performed by real-time PCR in normal control subjects (NC; n = 17), patients with Graves' disease without atrial fibrillation (GD; n = 29), patients with Graves' disease with atrial fibrillation (GD + AF; n = 14), and euthyroid patients with atrial fibrillation (AF; n = 22). Three of the eight serum microRNAs,i.e., miR-1a, miR-26a, and miR-133, had significantly different expression profiles among the four groups. Spearman's correlation analysis showed that the relative expression level of miR-1a was positively correlated with free triiodothyronine (FT3) and free thyroxine (FT4), and negatively related to thyroid stimulating hormone. Spearman's correlations analysis also revealed that the level of miR-1a was negatively correlated with a critical echocardiographic parameter (left atrial diameter), which was dramatically increased in GD + AF group compared to GD group. Furthermore, the receiver-operating characteristic curve analysis indicated that, among the eight microRNAs, miR-1a had the largest area under the receiver-operating characteristic curves not only for discriminating between individuals with and without Graves' disease, but also for predicting the presence of atrial fibrillation in patients with Graves' disease. Our findings showed that the levels of serum miR-1a were significantly decreased in GD + AF group compared with GD group, suggesting that serum miR-1a might serve as a novel biomarker for diagnosis of atrial fibrillation in patients with Graves' disease.

Exercise training with dietary restriction enhances circulating irisin level associated with increasing endothelial progenitor cell number in obese adults: an intervention study.

PubMed

Huang, Junhao; Wang, Shen; Xu, Fengpeng; Wang, Dan; Yin, Honggang; Lai, Qinhao; Liao, Jingwen; Hou, Xiaohui; Hu, Min

2017-01-01

Circulating endothelial progenitor cells (EPCs) correlate negatively with obesity. Previous studies have shown that exercise significantly restores circulating EPC levels in obese people; however, the underlying mechanisms have not been elucidated. Recently, irisin has been reported to have a critical role in the regulation of EPCs. This exercise-induced myokine has been demonstrated to play a therapeutic role in obesity. In this study, we hypothesized that the increase in circulating irisin may form a link with increasing EPC levels in obese people after exercise. Seventeen obese adults completed an 8-week program of combined exercise and dietary intervention. Clinical characteristics, blood biochemistry, and circulating irisin levels of subjects were measured before and after eight weeks of training. EPC levels were evaluated via flow cytometry, and EPC migratory and adhesive functions were also determined. Circulating irisin levels significantly increased following the 8-week training program ( P  < 0.05). We furthermore observed an improvement in EPC numbers ( P  < 0.05), and EPC migratory and adhesive functions ( P  < 0.001 and P  < 0.05, respectively) after the intervention. Additionally, we detected a positive correlation between changes in irisin and changes in EPC number ( r  = 0.52, P  < 0.05). For the first time, a positive correlation between increasing irisin levels and increasing EPC levels has been reported after an 8-week program, consisting of exercise and dietary intervention. This result suggests a novel effect of irisin on the regulation of EPC mobilization, which might contribute to improvement of endothelial function in obese people.

Plasma matrix metalloproteinase 1, 3, and 7 levels and breast cancer risk in the Nurses' Health study.

PubMed

Aroner, Sarah A; Rosner, Bernard A; Tamimi, Rulla M; Tworoger, Shelley S; Baur, Nadja; Joos, Thomas O; Hankinson, Susan E

2014-12-01

Matrix metalloproteinases (MMPs), in particular MMP1, 3, and 7, are believed to be critical to breast cancer invasion and metastasis and also may have important functions earlier in breast carcinogenesis. However, the relationship between circulating levels of MMP1, 3, and 7 and breast cancer risk is uncertain. We examined associations between plasma MMP1, 3, and 7 and breast cancer risk in a prospective case-control study nested within the Nurses' Health Study. Blood samples were collected from 801 cases who developed breast cancer between 1992 and 2000 and 801 matched controls, and MMP levels were measured via immunofluorescence assay. No overall association was observed between any of these MMPs and breast cancer risk [top vs. bottom quintile; MMP1: odds ratio (OR) 0.9; 95 % confidence interval (CI) 0.7, 1.3; p-trend = 0.51; MMP3: OR 1.1; 95 % CI 0.8, 1.5; p-trend = 0.88; MMP7: OR = 1.2; 95 % CI 0.8, 1.7; p-trend = 0.18]. Further, findings did not significantly vary by time since blood draw, body mass index, or postmenopausal hormone use, or by breast cancer subtypes. Circulating MMP1, 3, and 7 levels do not appear to be predictive of overall breast cancer risk.

Adipokines and the cardiovascular system: mechanisms mediating health and disease.

PubMed

Northcott, Josette M; Yeganeh, Azadeh; Taylor, Carla G; Zahradka, Peter; Wigle, Jeffrey T

2012-08-01

This review focuses on the role of adipokines in the maintenance of a healthy cardiovascular system, and the mechanisms by which these factors mediate the development of cardiovascular disease in obesity. Adipocytes are the major cell type comprising the adipose tissue. These cells secrete numerous factors, termed adipokines, into the blood, including adiponectin, leptin, resistin, chemerin, omentin, vaspin, and visfatin. Adipose tissue is a highly vascularised endocrine organ, and different adipose depots have distinct adipokine secretion profiles, which are altered with obesity. The ability of many adipokines to stimulate angiogenesis is crucial for adipose tissue expansion; however, excessive blood vessel growth is deleterious. As well, some adipokines induce inflammation, which promotes cardiovascular disease progression. We discuss how these 7 aforementioned adipokines act upon the various cardiovascular cell types (endothelial progenitor cells, endothelial cells, vascular smooth muscle cells, pericytes, cardiomyocytes, and cardiac fibroblasts), the direct effects of these actions, and their overall impact on the cardiovascular system. These were chosen, as these adipokines are secreted predominantly from adipocytes and have known effects on cardiovascular cells.

Benzene exposure is associated with cardiovascular disease risk

PubMed Central

Riggs, Daniel W.; Conklin, Daniel J.; McCracken, James P.; Srivastava, Sanjay; Xie, Zhengzhi; Rai, Shesh; Bhatnagar, Aruni; O’Toole, Timothy E.

2017-01-01

Benzene is a ubiquitous, volatile pollutant present at high concentrations in toxins (e.g. tobacco smoke) known to increase cardiovascular disease (CVD) risk. Despite its prevalence, the cardiovascular effects of benzene have rarely been studied. Hence, we examined whether exposure to benzene is associated with increased CVD risk. The effects of benzene exposure in mice were assessed by direct inhalation, while the effects of benzene exposure in humans was assessed in 210 individuals with mild to high CVD risk by measuring urinary levels of the benzene metabolite trans,trans-muconic acid (t,t-MA). Generalized linear models were used to assess the association between benzene exposure and CVD risk. Mice inhaling volatile benzene had significantly reduced levels of circulating angiogenic cells (Flk-1+/Sca-1+) as well as an increased levels of plasma low-density lipoprotein (LDL) compared with control mice breathing filtered air. In the human cohort, urinary levels of t,t-MA were inversely associated several populations of circulating angiogenic cells (CD31+/34+/45+, CD31+/34+/45+/AC133–, CD34+/45+/AC133+). Although t,t-MA was not associated with plasma markers of inflammation or thrombosis, t,t-MA levels were higher in smokers and in individuals with dyslipidemia. In smokers, t,t-MA levels were positively associated with urinary metabolites of nicotine (cotinine) and acrolein (3-hydroxymercapturic acid). Levels of t,t-MA were also associated with CVD risk as assessed using the Framingham Risk Score and this association was independent of smoking. Thus, benzene exposure is associated with increased CVD risk and deficits in circulating angiogenic cells in both smokers and non-smokers. PMID:28886060

Getting too sweet: galectin-1 dysregulation in gestational diabetes mellitus.

PubMed

Blois, Sandra M; Gueuvoghlanian-Silva, Barbara Y; Tirado-González, Irene; Torloni, Maria R; Freitag, Nancy; Mattar, Rosiane; Conrad, Melanie L; Unverdorben, Laura; Barrientos, Gabriela; Knabl, Julia; Toldi, Gergely; Molvarec, Attila; Rose, Matthias; Markert, Udo R; Jeschke, Udo; Daher, Silvia

2014-07-01

Galectin-1 (gal-1) is a prototype carbohydrate-binding protein, whose dysregulation is associated with adverse pregnancy outcomes such as spontaneous abortion and pre-eclampsia. Furthermore, it is known that faulty gal-1 protein production or gene regulation can be caused by single-nucleotide polymorphisms in the LGALS1 gene. Gestational diabetes mellitus (GDM) is also an adverse pregnancy outcome and the most common metabolic disorder during gestation. However, gal-1 expression patterns during GDM remain largely unknown. Our aims were to define local and peripheral gal-1 expression patterns during pregnancy, and to investigate LGALS1 gene polymorphisms in GDM patients. Circulating gal-1 levels were determined by ELISA in GDM patients and normal pregnant controls, and LGALS1 gene polymorphisms were assessed for association with GDM. Placental tissues were collected from control and GDM term pregnancies to evaluate local gal-1 expression by immunofluorescence. Our results show that GDM is associated with a failure to increase circulating gal-1 levels during the second and third trimester, as well as overexpression of gal-1 in placental tissue. Additionally, the LGALS1 polymorphism rs4820294 was associated with the development of GDM. In pregnancies complicated by GDM, we observed gal-1 dysregulation both locally in the placenta and peripherally in the circulation. Furthermore, the association between the LGALS1 polymorphism and GDM may indicate a genetic contribution to this adverse pregnancy outcome. © The Author 2014. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

A moderate elevation of circulating levels of IGF-I does not alter ErbB2 induced mammary tumorigenesis

PubMed Central

2011-01-01

Background Epidemiological evidence suggests that moderately elevated levels of circulating insulin-like growth factor-I (IGF-I) are associated with increased risk of breast cancer in women. How circulating IGF-I may promote breast cancer incidence is unknown, however, increased IGF-I signaling is linked to trastuzumab resistance in ErbB2 positive breast cancer. Few models have directly examined the effect of moderately high levels of circulating IGF-I on breast cancer initiation and progression. The purpose of this study was to assess the ability of circulating IGF-I to independently initiate mammary tumorigenesis and/or accelerate the progression of ErbB2 mediated mammary tumor growth. Methods We crossed heterozygous TTR-IGF-I mice with heterozygous MMTV-ErbB2 mice to generate 4 different genotypes: TTR-IGF-I/MMTV-ErbB2 (bigenic), TTR-IGF-I only, MMTV-ErbB2 only, and wild type (wt). Virgin females were palpated twice a week and harvested when tumors reached 1000 mm3. For study of normal development, blood and tissue were harvested at 4, 6 and 9 weeks of age in TTR-IGF-I and wt mice. Results TTR-IGF-I and TTR-IGF-I/ErbB2 bigenic mice showed a moderate 35% increase in circulating total IGF-I compared to ErbB2 and wt control mice. Elevation of circulating IGF-I had no effect upon pubertal mammary gland development. The transgenic increase in IGF-I alone wasn't sufficient to initiate mammary tumorigenesis. Elevated circulating IGF-I had no effect upon ErbB2-induced mammary tumorigenesis or metastasis, with median time to tumor formation being 30 wks and 33 wks in TTR-IGF-I/ErbB2 bigenic and ErbB2 mice respectively (p = 0.65). Levels of IGF-I in lysates from ErbB2/TTR-IGF-I tumors compared to ErbB2 was elevated in a similar manner to the circulating IGF-I, however, there was no effect on the rate of tumor growth (p = 0.23). There were no morphological differences in tumor type (solid adenocarcinomas) between bigenic and ErbB2 mammary glands. Conclusion Using the first transgenic animal model to elevate circulating levels of IGF-I to those comparable to women at increased risk of breast cancer, we showed that moderately high levels of systemic IGF-I have no effect on pubertal mammary gland development, initiating mammary tumorigenesis or promoting ErbB2 driven mammary carcinogenesis. Our work suggests that ErbB2-induced mammary tumorigenesis is independent of the normal variation in circulating levels of IGF-I. PMID:21867536

Circulating leptin levels are associated with increased craving to smoke in abstinent smokers

PubMed Central

al’Absi, Mustafa; Hooker, Stephanie; Fujiwara, Koji; Kiefer, Falk; von der Goltz, Christoph; Cragin, Tiffany; Wittmers, Lorentz E.

2018-01-01

The adipocyte hormone leptin regulates satiety and energy expenditure. Recent evidence suggests that leptin is associated with increased craving for alcohol and with shorter length of abstinence during alcohol treatment. This study examined leptin’s associations with craving for cigarettes and smoking relapse among smokers interested in cessation. Participants (32 smokers; 14 women) attended a laboratory session 24 h following their designated quit day where circulating leptin levels and craving for smoking were assessed. Other measures of withdrawal symptoms, affect, physical symptoms, as well as neuroendocrine and cardiovascular measures were collected before and after performing two stress tasks (public speaking and cognitive tasks). High circulating leptin levels were associated with increased craving, withdrawal symptoms, negative affect, physical symptoms, and reduced positive affect. Circulating leptin levels were not related to cardiovascular and neuroendocrine measures, responses to acute stressors, or to smoking relapse. These results indicate that circulating leptin is a promising biological marker of craving for smoking and warrant further investigation of the links between appetite regulation and nicotine dependence. PMID:20951159

The Pattern and Dynamics of the Meridional Overturning Circulation in the Upper Ocean

DTIC Science & Technology

2008-09-01

Atlantic . Figure 4a shows that the center of meridional overturning circulation occurs at a level of about one kilometer. Circulation is weak at...maintenance of the meridional overturning circulation in the Atlantic Ocean. 5. Global Simulation The most exciting experiment would be to fully model the...mechanisms responsible for the strength and maintenance of the meridional overturning circulation in the Atlantic Ocean are not

Circulating betatrophin concentrations are decreased in human obesity and type 2 diabetes.

PubMed

Gómez-Ambrosi, Javier; Pascual, Eider; Catalán, Victoria; Rodríguez, Amaia; Ramírez, Beatriz; Silva, Camilo; Gil, María J; Salvador, Javier; Frühbeck, Gema

2014-10-01

Betatrophin is a secreted protein recently involved in β-cell replication with a potential role in type 2 diabetes mellitus (T2D). The aim of the present study was to compare the circulating concentrations of betatrophin in human obesity and T2D. Serum concentrations of betatrophin were measured by ELISA in 153 subjects: 75 obese normoglycemic subjects (OB-NG), 30 obese subjects with impaired glucose tolerance (OB-IGT), and 15 obese subjects with T2D (OB-T2D) matched by sex, age, and body adiposity, in comparison with 33 lean normoglycemic individuals (LN-NG). Circulating levels of betatrophin were significantly decreased in obese individuals and further diminished in IGT and T2D participants (LN-NG, 45.1 ± 24.4 ng/mL; OB-NG, 26.9 ± 15.4 ng/mL; OB-IGT, 18.3 ± 10.7 ng/mL; OB-T2D, 13.5 ± 8.8 ng/mL; P < .001). A marked sexual dimorphism was found, with betatrophin levels being significantly higher in women than in men (males, 21.1 ± 16.0 ng/mL; females, 34.1 ± 20.1 ng/mL; P < .001). Interestingly, betatrophin levels were positively correlated with the quantitative insulin sensitivity check index (r = 0.46; P < .001) and with high-density lipoprotein-cholesterol concentrations (r = 0.51; P < .001). We conclude that serum betatrophin is decreased in human obesity, being further reduced in obesity-associated insulin resistance. Betatrophin levels are closely related to obesity-associated cardiometabolic risk factors, emerging as a potential biomarker of insulin resistance and T2D.

Assessing the role of insulin-like growth factors and binding proteins in prostate cancer using Mendelian randomization: Genetic variants as instruments for circulating levels.

PubMed

Bonilla, Carolina; Lewis, Sarah J; Rowlands, Mari-Anne; Gaunt, Tom R; Davey Smith, George; Gunnell, David; Palmer, Tom; Donovan, Jenny L; Hamdy, Freddie C; Neal, David E; Eeles, Rosalind; Easton, Doug; Kote-Jarai, Zsofia; Al Olama, Ali Amin; Benlloch, Sara; Muir, Kenneth; Giles, Graham G; Wiklund, Fredrik; Grönberg, Henrik; Haiman, Christopher A; Schleutker, Johanna; Nordestgaard, Børge G; Travis, Ruth C; Pashayan, Nora; Khaw, Kay-Tee; Stanford, Janet L; Blot, William J; Thibodeau, Stephen; Maier, Christiane; Kibel, Adam S; Cybulski, Cezary; Cannon-Albright, Lisa; Brenner, Hermann; Park, Jong; Kaneva, Radka; Batra, Jyotsna; Teixeira, Manuel R; Pandha, Hardev; Lathrop, Mark; Martin, Richard M; Holly, Jeff M P

2016-10-01

Circulating insulin-like growth factors (IGFs) and their binding proteins (IGFBPs) are associated with prostate cancer. Using genetic variants as instruments for IGF peptides, we investigated whether these associations are likely to be causal. We identified from the literature 56 single nucleotide polymorphisms (SNPs) in the IGF axis previously associated with biomarker levels (8 from a genome-wide association study [GWAS] and 48 in reported candidate genes). In ∼700 men without prostate cancer and two replication cohorts (N ∼ 900 and ∼9,000), we examined the properties of these SNPS as instrumental variables (IVs) for IGF-I, IGF-II, IGFBP-2 and IGFBP-3. Those confirmed as strong IVs were tested for association with prostate cancer risk, low (< 7) vs. high (≥ 7) Gleason grade, localised vs. advanced stage, and mortality, in 22,936 controls and 22,992 cases. IV analysis was used in an attempt to estimate the causal effect of circulating IGF peptides on prostate cancer. Published SNPs in the IGFBP1/IGFBP3 gene region, particularly rs11977526, were strong instruments for IGF-II and IGFBP-3, less so for IGF-I. Rs11977526 was associated with high (vs. low) Gleason grade (OR per IGF-II/IGFBP-3 level-raising allele 1.05; 95% CI: 1.00, 1.10). Using rs11977526 as an IV we estimated the causal effect of a one SD increase in IGF-II (∼265 ng/mL) on risk of high vs. low grade disease as 1.14 (95% CI: 1.00, 1.31). Because of the potential for pleiotropy of the genetic instruments, these findings can only causally implicate the IGF pathway in general, not any one specific biomarker. © 2016 UICC.

Increased circulating procoagulant and anticoagulant factors as TF and TFPI according to severity or infecting serotypes in human dengue infection.

PubMed

Leal de Azeredo, Elzinandes; Solórzano, Victor Edgar Fiestas; de Oliveira, Débora Batista; Marinho, Cintia Ferreira; de Souza, Luiz José; da Cunha, Rivaldo Venâncio; Damasco, Paulo Vieira; Kubelka, Claire Fernandes; de-Oliveira-Pinto, Luzia Maria

2017-01-01

Tissue Factor (TF) is the initiator of coagulation and Tissue Factor Inhibitor (TFPI) is the physiological inhibitor of the TF/FVIIa complex. Circulating levels of TF and TFPI were quantified in dengue patients and the relationships with disease severity and infecting serotype analysed. A significant decrease in TF and TPFI plasma levels was observed in mild DF patients compared with severe dengue. Furthermore, both factors were associated with haemorrhagic manifestations. Finally, TF levels were significantly increased in DENV-1/2 infected patients as compared with DENV-4. These findings suggest that activation of TF-pathway is an important component of DENV -related coagulation disorders. Copyright © 2016 Institut Pasteur. Published by Elsevier Masson SAS. All rights reserved.

Relationship between Circulating and Tissue microRNAs in a Murine Model of Breast Cancer

PubMed Central

Waters, Peadar S.; McDermott, Ailbhe M.; Wall, Deirdre; Heneghan, Helen M.; Miller, Nicola; Newell, John; Kerin, Michael J.; Dwyer, Roisin M.

2012-01-01

MiRNAs are key regulators of tumorigenesis that are aberrantly expressed in the circulation and tissue of patients with cancer. The aim of this study was to determine whether miRNA dysregulation in the circulation reflected similar changes in tumour tissue. Athymic nude mice (n = 20) received either a mammary fat pad (n = 8, MFP), or subcutaneous (n = 7, SC) injection of MDA-MB-231 cells. Controls received no tumour cells (n = 5). Tumour volume was monitored weekly and blood sampling performed at weeks 1, 3 and 6 following tumour induction (total n = 60). Animals were sacrificed at week 6 and tumour tissue (n = 15), lungs (n = 20) and enlarged lymph nodes (n = 3) harvested. MicroRNAs were extracted from all samples (n = 98) and relative expression quantified using RQ-PCR. MiR-221 expression was significantly increased in tumour compared to healthy tissue (p<0.001). MiR-10b expression was significantly higher in MFP compared to SC tumours (p<0.05), with the highest levels detected in diseased lymph nodes (p<0.05). MiR-10b was undetectable in the circulation, with no significant change in circulating miR-221 expression detected during disease progression. MiR-195 and miR-497 were significantly decreased in tumour tissue (p<0.05), and also in the circulation of animals 3 weeks following tumour induction (p<0.05). At both tissue and circulating level, a positive correlation was observed between miR-497 and miR-195 (r = 0.61, p<0.001; r = 0.41, p<0.01 respectively). This study highlights the distinct roles of miRNAs in circulation and tissue. It also implicates miRNAs in disease dissemination and progression, which may be important in systemic therapy and biomarker development. PMID:23226290

Diagnostic calculations of the circulation in the Martian atmosphere

NASA Technical Reports Server (NTRS)

Santee, Michelle L.; Crisp, David

1995-01-01

The circulation of the Martian atmosphere during late southern summer is derived from atmospheric temperature and dust distributions retrieved from a subset of the Mariner 9 infrared interferometer spectrometer (IRIS) thermal emission spectra (L(sub s) = 343-348 deg). Zonal-mean zonal winds are calculated by assuming gradient wind balance and zero surface zonal wind. Both hemispheres have intense midlatitude westerly jets with velocities of 80-90 m/s near 50 km; in the southern tropics the winds are easterly with velocities of 40 m/s near 50 km. The net effect of the zonal mean meridional circulation and large-scale waves can be approximated by the diabatic circulation, which is defined from the atmospheric thermal structure and net radiative heating rates. The radiative transfer model described by Crisp (1990) and Santee (1993) is used to compute solar heating and thermal cooling rates from diurnal averages of the retrieved IRIS temperature and dust distributions. At pressures below 4 mbar, there are large net radiative heating rates (up to 5 K/d) in the equatorial region and large net radiative cooling rates (up to 12 K/d) in the polar regions. These net radiative heating rates are used in a diagnostic stream function model which solves for the meridional and vertical components of the diabatic circulation simultaneously. We find a two-cell circulation, with rising motion over the equator, poleward flow in both hemispheres, sinking motion over both polar regions, and return flow in the lowest atmospheric levels. The maximum poleward velocity is 3 m/s in the tropics at approx. 55 km altitude, and the maximum vertical velocity is 2.5 cm/s downward over the north pole at approx. 60 km altitude. If these large transport rates are sustained for an entire season, the Martian atmosphere above the 1-mbar level is overturned in about 38 days. This diabatic circulation is qualitatively similar to the terrestrial diabatic circulation at the comparable season, but is more vigorous.

Rising Poverty, Declining Health: The Nutritional Status of the Rural Poor.

ERIC Educational Resources Information Center

Public Voice for Food and Health Policy, Washington, DC.

Using five key indicators of nutritional status (dietary intake, biochemical tests for circulating levels of nutrients or their metabolites, anthropometric measures, low birth weight and infant mortality rates, and food, health, and income assistance program participation rates and benefit levels), this 1-year research project identified national,…

Effects of 2-year calorie restriction on circulating levels of IGF-1, IGF-binding proteins and cortisol in non-obese men and women: a randomized clinical trial

USDA-ARS?s Scientific Manuscript database

Young-onset calorie restriction (CR) in rodents decreases serum IGF-1 concentration and increases serum corticosterone levels, which have been hypothesized to play major roles in mediating its anti-cancer and anti-aging effects. However, little is known on the effects of CR on the IGF-1 system and c...

Circulating autoantibodies to recombinant lipocortin-1 in asthma.

PubMed

Chung, K F; Podgorski, M R; Goulding, N J; Godolphin, J L; Sharland, P R; O'Connor, B; Flower, R J; Barnes, P J

1991-03-01

One of the postulated mechanisms of corticosteroid action is through the de novo synthesis and release of lipocortins. We assayed circulating antibodies to lipocortin-1 in sera obtained from normal (n = 67) and asthmatic (n = 57) subjects using an ELISA technique. Asthmatic subjects with a wide range of severity, with the mildest needing only occasional inhaled beta-agonist therapy to the most severe needing maintenance oral corticosteroid treatment, were recruited from our Asthma Clinic and classified into five categories according to the need of therapy. Median values of IgM and IgG lipocortin-1 antibody for normal subjects were 19.3 (interquartile range (r) = 11.0-30.4) and 16.9 (r = 10.54-29.4) ELISA units (EU) ml-1 respectively. These levels were significantly elevated in asthmatic subjects: IgM = 43.9 EU ml-1 (r = 31.7-64.5) and IgG = 29.0 EU ml-1 (r = 21.2-44.7) (P less than 0.001). There was no significant relationship between the levels of lipocortin antibody and the clinical severity of asthma. Asthmatics with significantly raised levels of antibody were found within all five categories of severity. We conclude that the level of this antibody is not related to severity of asthma, to previous or current corticosteroid therapy or to the development of corticosteroid resistance.

Lipoprotein(a) Levels in Patients With Abdominal Aortic Aneurysm.

PubMed

Kotani, Kazuhiko; Sahebkar, Amirhossein; Serban, Maria-Corina; Ursoniu, Sorin; Mikhailidis, Dimitri P; Mariscalco, Giovanni; Jones, Steven R; Martin, Seth; Blaha, Michael J; Toth, Peter P; Rizzo, Manfredi; Kostner, Karam; Rysz, Jacek; Banach, Maciej

2017-02-01

Circulating markers relevant to the development of abdominal aortic aneurysm (AAA) are currently required. Lipoprotein(a), Lp(a), is considered a candidate marker associated with the presence of AAA. The present meta-analysis aimed to evaluate the association between circulating Lp(a) levels and the presence of AAA. The PubMed-based search was conducted up to April 30, 2015, to identify the studies focusing on Lp(a) levels in patients with AAA and controls. Quantitative data synthesis was performed using a random effects model, with standardized mean difference (SMD) and 95% confidence interval (CI) as summary statistics. Overall, 9 studies were identified. After a combined analysis, patients with AAA were found to have a significantly higher level of Lp(a) compared to the controls (SMD: 0.87, 95% CI: 0.41-1.33, P < .001). This result remained robust in the sensitivity analysis, and its significance was not influenced after omitting each of the included studies from the meta-analysis. The present meta-analysis confirmed a higher level of circulating Lp(a) in patients with AAA compared to controls. High Lp(a) levels can be associated with the presence of AAA, and Lp(a) may be a marker in screening for AAA. Further studies are needed to establish the clinical utility of measuring Lp(a) in the prevention and management of AAA.

Noninvasive Measurement of Steroid Hormones in Zebrafish Holding-Water

PubMed Central

Félix, Ana S.; Faustino, Ana I.; Cabral, Eduarda M.

2013-01-01

Abstract Zebrafish (Danio rerio) has recently emerged as a new animal model in neuroendocrinology and behavior (e.g., stress physiology and ecotoxicology studies). In these areas, the concentrations of steroid hormones in the blood are often used to study the endocrinological status of individuals. However, due to the small body size of zebrafish, blood sampling is difficult to perform and the amount of plasma obtained per sample for assaying hormones is very small (ca. 1–5 μL), and therefore most studies have been using whole-body hormone concentrations, which implies sacrificing the individuals and hampers sequential sampling of the same individual. Here a noninvasive method to assay steroid hormones from zebrafish holding-water, based on the fact that steroids are released into the fish holding-water through the gills by passive diffusion, is validated. Cortisol and the androgen 11-ketotestosterone (KT) were measured in water samples and compared to plasma levels in the same individuals. Cortisol released to holding-water correlates positively with plasma concentrations, but there was a lack of correlation between KT water and circulating levels. However, KT levels showed a highly significant sex difference that can be used to noninvasively sex individuals. An ACTH challenge test demonstrated that an induced increase in circulating cortisol concentration can be reliably detected in holding-water levels, hence attesting the responsiveness of holding-water levels to fluctuations in circulating levels. PMID:23445429

Reversal of diabetic vasculopathy in a rat model of type 1 diabetes by opiorphin-related peptides

PubMed Central

Calenda, Giulia; Tong, Yuehong; Kanika, Nirmala D.; Tar, Moses T.; Suadicani, Sylvia O.; Zhang, Xinhua; Melman, Arnold; Rougeot, Catherine

2011-01-01

Diabetes results in a myriad of vascular complications, often referred to as diabetic vasculopathy, which encompasses both microvascular [erectile dysfunction (ED), retinopathy, neuropathy, and nephropathy] and macrovascular complications (hypertension, coronary heart disease, and myocardial infarction). In diabetic animals and patients with ED, there is decreased opiorphin or opiorphin-related gene expression in corporal tissue. Both opiorphin and the rat homologous peptide sialorphin are found circulating in the plasma. In the present study, we investigated if diabetes induced changes in plasma sialorphin levels and if changes in these levels could modulate the biochemistry and physiology of vascular smooth muscle. We show that circulating sialorphin levels are reduced in a rat model of type I diabetes. Intracorporal injection of plasmids expressing sialorphin into diabetic rats restores sialorphin levels to those seen in the blood of nondiabetic animals and results in both improved erectile function and blood pressure. Sialorphin modulated the ability of C-type natriuretic peptide to relax both corporal and aortic smooth muscle strips and of bradykinin to regulate intracellular calcium levels in both corporal and aortic smooth muscle cells. We have previously shown that expression of genes encoding opiorphins is increased when erectile function is improved. Our findings thus suggest that by affecting circulating levels of opiorphin-related peptides, proper erectile function is not only an indicator but also a modulator of overall vascular health of a man. PMID:21784987

Reversal of diabetic vasculopathy in a rat model of type 1 diabetes by opiorphin-related peptides.

PubMed

Calenda, Giulia; Tong, Yuehong; Kanika, Nirmala D; Tar, Moses T; Suadicani, Sylvia O; Zhang, Xinhua; Melman, Arnold; Rougeot, Catherine; Davies, Kelvin P

2011-10-01

Diabetes results in a myriad of vascular complications, often referred to as diabetic vasculopathy, which encompasses both microvascular [erectile dysfunction (ED), retinopathy, neuropathy, and nephropathy] and macrovascular complications (hypertension, coronary heart disease, and myocardial infarction). In diabetic animals and patients with ED, there is decreased opiorphin or opiorphin-related gene expression in corporal tissue. Both opiorphin and the rat homologous peptide sialorphin are found circulating in the plasma. In the present study, we investigated if diabetes induced changes in plasma sialorphin levels and if changes in these levels could modulate the biochemistry and physiology of vascular smooth muscle. We show that circulating sialorphin levels are reduced in a rat model of type I diabetes. Intracorporal injection of plasmids expressing sialorphin into diabetic rats restores sialorphin levels to those seen in the blood of nondiabetic animals and results in both improved erectile function and blood pressure. Sialorphin modulated the ability of C-type natriuretic peptide to relax both corporal and aortic smooth muscle strips and of bradykinin to regulate intracellular calcium levels in both corporal and aortic smooth muscle cells. We have previously shown that expression of genes encoding opiorphins is increased when erectile function is improved. Our findings thus suggest that by affecting circulating levels of opiorphin-related peptides, proper erectile function is not only an indicator but also a modulator of overall vascular health of a man.

Importance of circulating IGF-1 for normal cardiac morphology, function and post infarction remodeling.

PubMed

Scharin Täng, M; Redfors, B; Lindbom, M; Svensson, J; Ramunddal, T; Ohlsson, C; Shao, Y; Omerovic, E

2012-12-01

IGF-1 plays an important role in cardiovascular homeostasis, and plasma levels of IGF-1 correlate inversely with systolic function in heart failure. It is not known to what extent circulating IGF-1 secreted by the liver and local autocrine/paracrine IGF-1 expressed in the myocardium contribute to these beneficial effects on cardiac function and morphology. In the present study, we used a mouse model of liver-specific inducible deletion of the IGF-1 gene (LI-IGF-1 -/- mouse) in an attempt to evaluate the importance of circulating IGF-I on cardiac morphology and function under normal and pathological conditions, with an emphasis on its regulatory role in myocardial phosphocreatine metabolism. Echocardiography was performed in LI-IGF-1 -/- and control mice at rest and during dobutamine stress, both at baseline and post myocardial infarction (MI). High-energy phosphate metabolites were compared between LI-IGF-1 -/- and control mice at 4 weeks post MI. We found that LI-IGF-1 -/- mice had significantly greater left ventricular dimensions at baseline and showed a greater relative increase in cardiac dimensions, as well as deterioration of cardiac function, post MI. Myocardial creatine content was 17.9% lower in LI-IGF-1 -/- mice, whereas there was no detectable difference in high-energy nucleotides. These findings indicate an important role of circulating IGF-1 in preserving cardiac structure and function both in physiological settings and post MI. Copyright © 2012 Elsevier Ltd. All rights reserved.

Ramadan fasting in Saudi Arabia is associated with altered expression of CLOCK, DUSP and IL-1alpha genes, as well as changes in cardiometabolic risk factors.

PubMed

Ajabnoor, Ghada M A; Bahijri, Suhad; Shaik, Noor Ahmad; Borai, Anwar; Alamoudi, Aliaa A; Al-Aama, Jumana Y; Chrousos, George P

2017-01-01

During the fasting month of Ramadan, practicing Saudis develop severe disturbances in sleeping and feeding patterns. Concomitantly, cortisol circadian rhythm is abolished, diurnal cortisol levels are elevated and circulating levels of several adipokines are altered favouring insulin resistance. To examine changes in the expression of CLOCK and glucocorticoid-controlled genes, such as DUSP1 and IL-1α in Saudi adults before and during Ramadan, and to investigate possible associations with selected cardiometabolic risk factors. Healthy young volunteers (5 females, 18 males; mean age +SEM = 23.2 +1.2 years) were evaluated before Ramadan and two weeks into it. Blood samples were collected at 9 am (±1 hour) and twelve hours later for determination of serum lipid profile, high sensitivity CRP (hsCRP), and adiponectin. The expression of CLOCK, DUSP1 and IL-1α was evaluated in circulating leukocytes. Mean levels of GGT and morning adiponectin decreased, while those of LDL-c/ HDL-c and atherogenic index (AI) increased significantly in Ramadan compared to Shabaan. There was no significant difference between morning and evening adiponectin during Ramadan, while the diurnal rhythm of hsCRP was lost. CLOCK gene expression mean was significantly higher in morning than in evening during Shabaan. Mean morning and evening DUSP1 mRNA levels showed significant increase during Ramadan compared to Shabaan, however, its diurnal rhythm was maintained. Morning IL-1α mRNA expression remained significantly higher than in the evening during Ramadan, but was markedly decreased compared to Shabaan. Ramadan fasting in Saudi Arabia is associated with improvements in some cardiometabolic risk factors, such as circulating GGT and hsCRP and leukocyte expression of IL-1α mRNA, suggesting that intermittent fasting might have a beneficial component. These benefits may be offset by the previously reported dysregulation in the circadian rhythm, excess glucocorticoid levels and action, and insulin resistance, explaining increased prevalence of cardiometabolic disorders and type 2 diabetes mellitus.

Role of circulating soluble chemokines in septic shock.

PubMed

de Pablo, R; Monserrat, J; Prieto, A; Alvarez-Mon, M

2013-11-01

Chemokines are a large superfamily of small proteins that function not only in leukocyte trafficking, but are also necessary for linkage between innate and adaptive immunity. Little is known about their role in septic shock. We hypothesized that serum levels of the most important chemokines are related to organ failure, disease severity and outcome. A prospective observational study was carried out. Surgical-clinical Intensive Care Unit. Ninety-two patients diagnosed with septic shock using international criteria. Forty patients were excluded due to acquired immunity disturbances. Samples from 36 healthy controls were also analyzed. None. In 46% of the patients who suffered acute respiratory distress syndrome (ARDS), IL-8 levels were higher than in patients without ARDS (499.9±194.1 vs. 190.8±91.7 pg/ml; P=.039). This molecule was also higher in 36% of the patients with sepsis-induced acute renal failure (ARF) (453.3±181.6 vs. 201.3±95.9 pg/ml; P=.049). Coagulopathy was found in 19% of the septic shock patients with elevated serum IL-8 levels (635.8±292.3 vs. 218.7±87.0 pg/ml; P=.010), elevated MIP-1α (91.4±27.3 vs. 58.8±11.1 pg/ml; P=.044), and low circulating RANTES levels (8162.2±6321.0 vs. 18781.8±11.1 pg/ml; P=.027). No significant differences were found between survivors and non-survivors at any time of follow-up. Upon admission to the ICU, IL-8 is a reliable biomarker of sepsis-induced AFR, ARDS and coagulopathy. Altered circulating MIP-1α and RANTES levels are also found in patients with septic shock and coagulopathy. However, chemokines do not appear to be good biomarkers of mortality in septic shock. Copyright © 2012 Elsevier España, S.L. and SEMICYUC. All rights reserved.

Levels of circulating soluble receptor activator of NF-κB and interleukins-1 predicting outcome of locally advanced basal cell carcinoma.

PubMed

Lin, Quan; Li, Yan; Zhang, Duo; Jin, Hongjuan

2016-12-01

Decreasing levels of cytokines are associated with better responses to therapies, while increasing levels are related to progression or recurrence and decreased survival. NF-κB's role in the cell cycle and its ubiquity are only stressed out by the evidence for the importance of activation (aberrant activation in the majority of cancers) of both canonical and non-canonical pathways in advanced basal cell carcinomas (aBCCs), a subset of basal cell carcinoma (BCC). NF-κB acts through its canonical, or classical, form activated by interleukin-1 (IL-1), regulates cytoprotective, innate, and adaptive immune responses. However, NF-κB2 often acts through its non-canonical or alternate pathway. During the two-year study period, we selected 21 patients presenting with aBCCs due to delay in accessing medical attention with an advanced form of BCCs (n = 19) and infiltrative BCCs (n = 2). Initial diagnosis of BCCs of head and neck was made clinically and verified by skin biopsy. Venous blood was drawn and serum was obtained. Samples were collected at baseline and every three days thereafter (days 3, 6, 9, etc. until surgery). Antigenes' quantities (cytokines) were determined by ELISA kits. Initially, the mean value of all cytokine subjects was significantly different related to the control group (P <0.05). Changes in serum levels of circulating soluble receptor activator of NF-κB and interleukins-1 (α and β) were observed following the surgery. Changes in serum levels of circulating soluble receptor activator of NF-κB and interleukins-1 (α and β) are evident throughout our study period and a certain regularity in its dynamics is evident as the follow-up period moves away. It was therefore concluded that measurement of these factors might be useful in predicting the overall outcome of patients with aBCCs. This study highlights the systemic effects of aBCCs, but further studies are required on this topic. © The Author(s) 2016.

Levels of circulating soluble receptor activator of NF-κB and interleukins-1 predicting outcome of locally advanced basal cell carcinoma

PubMed Central

Lin, Quan; Li, Yan; Zhang, Duo; Jin, Hongjuan

2016-01-01

Decreasing levels of cytokines are associated with better responses to therapies, while increasing levels are related to progression or recurrence and decreased survival. NF-κB’s role in the cell cycle and its ubiquity are only stressed out by the evidence for the importance of activation (aberrant activation in the majority of cancers) of both canonical and non-canonical pathways in advanced basal cell carcinomas (aBCCs), a subset of basal cell carcinoma (BCC). NF-κB acts through its canonical, or classical, form activated by interleukin-1 (IL-1), regulates cytoprotective, innate, and adaptive immune responses. However, NF-κB2 often acts through its non-canonical or alternate pathway. During the two-year study period, we selected 21 patients presenting with aBCCs due to delay in accessing medical attention with an advanced form of BCCs (n = 19) and infiltrative BCCs (n = 2). Initial diagnosis of BCCs of head and neck was made clinically and verified by skin biopsy. Venous blood was drawn and serum was obtained. Samples were collected at baseline and every three days thereafter (days 3, 6, 9, etc. until surgery). Antigenes’ quantities (cytokines) were determined by ELISA kits. Initially, the mean value of all cytokine subjects was significantly different related to the control group (P <0.05). Changes in serum levels of circulating soluble receptor activator of NF-κB and interleukins-1 (α and β) were observed following the surgery. Changes in serum levels of circulating soluble receptor activator of NF-κB and interleukins-1 (α and β) are evident throughout our study period and a certain regularity in its dynamics is evident as the follow-up period moves away. It was therefore concluded that measurement of these factors might be useful in predicting the overall outcome of patients with aBCCs. This study highlights the systemic effects of aBCCs, but further studies are required on this topic. PMID:27760847

Circulating periostin level in asthmatic pregnancy.

PubMed

Ivancsó, István; Bohács, Anikó; Szalay, Balázs; Toldi, Gergely; Szilasi, Magdolna E; Müller, Veronika; Losonczy, György; Rigó, János; Vásárhelyi, Barna; Tamási, Lilla

2016-11-01

Asthma often complicates pregnancy and represents a risk for complications. Periostin is considered as a biomarker of asthma; however, as it also plays a role in normal gestation, pregnancy may influence circulating periostin levels. This is the first study assessing periostin in asthmatic pregnancy. Plasma periostin levels were investigated in asthma (asthmatic non-pregnant, ANP; N = 19) and asthmatic pregnancy (AP; N = 14), compared to healthy non-pregnant controls (HNP; N = 12) and healthy pregnant women (HP; N = 17). The relationship between periostin levels and asthma control determinants was also evaluated. The diagnostic efficacy of periostin to detect uncontrolled asthma was analyzed using ROC analysis. Plasma periostin levels were similar in the HNP and ANP (55.68 [37.21-67.20] vs. 45.25 [32.67-64.55], p > 0.05), and elevated in the HP (68.81 [57.34-98.84] ng/mL, p = 0.02 vs. HNP) and AP groups (54.02 [44.30-74.94] ng/mL, p = 0.0346 vs. ANP). Periostin levels of the two pregnant groups were similar (p > 0.05). In AP women periostin correlated negatively with FEV1 (r = -0.5516) and positively with Raw (r = 0.5535; both p < 0.05). Pregnancy itself increases circulating periostin levels and this elevation is detectable in asthmatic pregnancy as well. Although periostin correlates with lung function in asthmatic pregnancy, periostin as a biomarker has to be handled with caution in pregnant patients due to the influence of pregnancy on its plasma level.

Phosphate homeostasis in Bartter syndrome: a case-control study.

PubMed

Bettinelli, Alberto; Viganò, Cristina; Provero, Maria Cristina; Barretta, Francesco; Albisetti, Alessandra; Tedeschi, Silvana; Scicchitano, Barbara; Bianchetti, Mario G

2014-11-01

Bartter patients may be hypercalciuric. Additional abnormalities in the metabolism of calcium, phosphate, and calciotropic hormones have occasionally been reported. The metabolism of calcium, phosphate, and calciotropic hormones was investigated in 15 patients with Bartter syndrome and 15 healthy subjects. Compared to the controls, Bartter patients had significantly reduced plasma phosphate {mean [interquartile range]:1.29 [1.16-1.46] vs. 1.61 [1.54-1.67] mmol/L} and maximal tubular phosphate reabsorption (1.16 [1.00-1.35] vs. 1.41 [1.37-1.47] mmol/L) and significantly increased parathyroid hormone (PTH) level (6.1 [4.5-7.7] vs. 2.8 [2.2-4.4] pmol/L). However, patients and controls did not differ in blood calcium, 25-hydroxyvitamin D, alkaline phosphatase, and osteocalcin levels. In patients, an inverse correlation (P < 0.05) was noted between total plasma calcium or glomerular filtration rate and PTH concentration. A positive correlation was also noted between PTH and osteocalcin concentrations (P < 0.005), as well as between chloriduria or natriuria and phosphaturia (P < 0.001). No correlation was noted between calciuria and PTH concentration or between urinary or circulating phosphate and PTH. The results of this study demonstrate a tendency towards renal phosphate wasting and elevated circulating PTH levels in Bartter patients.

Effects of diabatic heating on the ageostrophic circulation of an upper tropospheric jet streak

NASA Technical Reports Server (NTRS)

Keyser, D. A.; Johnson, D. R.

1982-01-01

Interaction between the mass circulation within a mesoscale convective complex (MCC) and a direct mass circulation in the entrance region of an upper tropospheric polar jet streak was examined within the isentropic structure to investigate mechanisms responsible for linking these two scales of motion. The results establish that latent heating in the MCC modifies the direct mass circulation in the jet streak entrance region through the diabatically induced components of ageostrophic motion analyzed within isentropic coordinates. Within the strong mesoscale mass circulation of each MCC, strong horizontal mass flux convergence into the MCC at low levels is balanced by strong horizontal mass flux divergence away from the convergence at upper levels. Locations of large diabatic heating rates correspond well to the MCC position for each case; diabatic heating forces the upward vertical branch for the mesoscale mass circulation.

Low levels of circulating platelet factor 4 (PF4, CXCL4) in subclinically hypothyroid autoimmune thyroiditis.

PubMed

Görar, S; Ademoğlu, E; Çarlıoğlu, A; Alioğlu, B; Bekdemir, H; Sağlam, B; Candan, Z; Üçler, R; Culha, C; Aral, Y

2016-02-01

Chemokines play an important role in the pathogenesis of autoimmune thyroid diseases. Platelet factor 4 (PF4, CXCL4) released from activated platelets is a chemokine. However, its clinical importance in autoimmune thyroiditis remains unknown. This study is intended to determine circulating levels of PF4 levels in patients with autoimmune thyroiditis (AIT). Circulating levels of PF4 were measured in 34 consecutive patients with newly diagnosed AIT and 18 euthyroid controls. Among AIT group, 16 patients were euthyroid and 18 had subclinic hypothyroidism. Controls and individuals with AIT were similar in terms of age. Serum levels of PF4 were comparable in patients with AIT and in controls. Among patients with AIT, PF4 was significantly lower in those with subclinical hypothyroidism than in euthyroid individuals (p = 0.001). In correlation analysis, PF4 was negatively correlated with TSH (r = -0.663, p = 0.000) and positively correlated with free T4 (r = 0.428, p = 0.012). There was not any significant correlation between PF4 and AbTPO, AbTg. The present study demonstrated for the first time that circulating PF4 levels are decreased in subclinically hypothyroid AIT. This result draws attention to the circulating PF4 levels in subclinically hypothyroid AIT and may shed light on further researches at this topic.

Impact of fibrates on circulating cystatin C levels: a systematic review and meta-analysis of clinical trials.

PubMed

Sahebkar, Amirhossein; Simental-Mendía, Luis E; Pirro, Matteo; Montecucco, Fabrizio; Carbone, Federico; Banach, Maciej; Barreto, George E; Butler, Alexandra E

2018-06-29

To assess the effect of fibrates on circulating cystatin C levels. Clinical studies evaluating the effect of a fibrate on circulating cystatin C levels were searched in PubMed-Medline, SCOPUS, Web of Science and Google Scholar databases. A random-effect model and generic inverse variance method were used for quantitative data synthesis, sensitivity analysis conducted using the leave-one-out method, and weighted random-effects meta-regression performed to evaluate potential confounders on cystatin C levels. This meta-analysis of data from 9 published studies (16 treatment arms) involved a total of 2195 subjects. In a single-arm analysis of clinical trials (without control group; 8 studies comprising 14 treatment arms), fibrate therapy increased circulating cystatin C concentrations (WMD: 0.07 mg/dL, 95% CI: 0.04, 0.10, p <0.001; I 2 = 82.66%). When the analysis was restricted to randomized controlled trials (4 studies comprising 6 treatment arms), again elevation of circulating cystatin C levels was observed (WMD: 0.06 mg/L, 95% CI: 0.03, 0.09, p <0.001; I 2 = 42.98%). Elevated cystatin C levels were only seen with fenofibrate, not other fibrates. The results suggest that fenofibrate treatment adversely affects cystatin C levels and might partially explain the limited efficacy of fenofibrate in reducing cardiovascular events.

Application of classical thermodynamic principles to the study of oceanic overturning circulation

NASA Astrophysics Data System (ADS)

Gade, Herman G.; Gustafsson, Karin E.

2004-08-01

Stationary deep-reaching overturning circulation in the ocean is studied by means of classical thermodynamic methods employing closed cycles in pV-space (p, pressure; V, volume). From observed (or computed) density fields, the pV-method may be used to infer the power required for driving a circulation with a given mass flux, or, if the available power is known, the resulting mass flux of the circulation may be assessed. Here, the circulation is assumed to be driven by diapycnal mixing caused by internal disturbances of meteorological and tidal origin and from transfer of geothermal heat through the ocean bottom. The analysis is developed on the basis that potential energy produced by any of these mechanisms is available for driving a circulation of the water masses above its level of generation. The method also takes into account secondary generated potential energy resulting from turbulence developed by the ensuing circulation.Models for different types of circulation are developed and applied to four types of hemispheric circulation with deep-water formation, convection and sinking in an idealized North Atlantic. Our calculations show that the energy input must exceed 15 J kg1 for a cycle to the bottom to exist. An energy supply of 2 TW would in that case support a constant vertical mass flux of 3.2 G kg s1 (3.1 Sv). Computed mass fluxes reaching the surface in the subtropics, corresponding to the same energy input, range between 2.3 5.2 G kg s1, depending on the type of convection/sinking involved. Much higher flux values ensue with ascending water masses reaching the surface at higher geographical latitudes.The study reveals also that compressibility of sea water does not enhance the circulation. An incompressible system, operating within the same mass flux and temperature range, would require about 25% less energy supply, provided that the circulation comprises the same water masses. It is furthermore shown that the meridional distribution of surface salinity, with higher values in the tropics and lower values in regions of deep-water formation, actually enhances the circulation in comparison with one of a more uniform surface salinity. With a homohaline North Atlantic, operating within the same temperature range as presently observed, an increase of 66% of power supply would be required in order that the mass flux of the overturning circulation should remain the same.

Relationship between High Red Cell Distribution Width and Systemic Inflammatory Response Syndrome after Extracorporeal Circulation.

PubMed

Seth, Harsh Sateesh; Mishra, Prashant; Khandekar, Jayant V; Raut, Chaitanya; Mohapatra, Chandan Kumar Ray; Ammannaya, Ganesh Kumar K; Saini, Jaskaran Singh; Shah, Vaibhav

2017-01-01

Cardiac surgical operations involving extracorporeal circulation may develop severe inflammatory response. This severe inflammatory response syndrome (SIRS) is usually associated with poor outcome with no predictive marker. Red cell distribution width (RDW) is a routine hematological marker with a role in inflammation. We aim to determine the relationship between RDW and SIRS through our study. A total of 1250 patients who underwent cardiac surgery with extracorporeal circulation were retrospectively analyzed out of which 26 fell into the SIRS criteria and 26 consecutive control patients were taken. RDW, preoperative clinical data, operative time and postoperative data were compared between SIRS and control groups. The demographic profile of the patients was similar. RDW was significantly higher in the SIRS versus control group (15.5±2.0 vs. 13.03±1.90), respectively with P value <0.0001. There was significant mortality in the SIRS group, 20 (76.92%) as compared to 2 (7.6%) in control group with a P value of <0.005. Multiple logistic regression analysis revealed that there was significant association with high RDW and development of SIRS after extracorporeal circulation (OR for RDW levels exceeding 13.5%; 95% CI 1.0-1.2; P<0.05). Increased RDW was significantly associated with increased risk of SIRS after extracorporeal circulation. Thus, RDW can act as a useful tool to predict SIRS in patients undergoing cardiac surgery with extracorporeal circulation. Hence, more aggressive measures can be taken in patients with high RDW to prevent postoperative morbidity and mortality.

Plants and Photosynthesis: Level III, Unit 3, Lesson 1; The Human Digestive System: Lesson 2; Functions of the Blood: Lesson 3; Human Circulation and Respiration: Lesson 4; Reproduction of a Single Cell: Lesson 5; Reproduction by Male and Female Cells: Lesson 6; The Human Reproductive System: Lesson 7; Genetics and Heredity: Lesson 8; The Nervous System: Lesson 9; The Glandular System: Lesson 10. Advanced General Education Program. A High School Self-Study Program.

ERIC Educational Resources Information Center

Manpower Administration (DOL), Washington, DC. Job Corps.

This self-study program for the high-school level contains lessons in the following subjects: Plants and Photosynthesis; The Human Digestive System; Functions of the Blood; Human Circulation and Respiration; Reproduction of a Single Cell; Reproduction by Male and Female Cells; The Human Reproductive System; Genetics and Heredity; The Nervous…

Splenic release of platelets contributes to increased circulating platelet size and inflammation after myocardial infarction.

PubMed

Gao, Xiao-Ming; Moore, Xiao-Lei; Liu, Yang; Wang, Xin-Yu; Han, Li-Ping; Su, Yidan; Tsai, Alan; Xu, Qi; Zhang, Ming; Lambert, Gavin W; Kiriazis, Helen; Gao, Wei; Dart, Anthony M; Du, Xiao-Jun

2016-07-01

Acute myocardial infarction (AMI) is characterized by a rapid increase in circulating platelet size but the mechanism for this is unclear. Large platelets are hyperactive and associated with adverse clinical outcomes. We determined mean platelet volume (MPV) and platelet-monocyte conjugation (PMC) using blood samples from patients, and blood and the spleen from mice with AMI. We further measured changes in platelet size, PMC, cardiac and splenic contents of platelets and leucocyte infiltration into the mouse heart. In AMI patients, circulating MPV and PMC increased at 1-3 h post-MI and MPV returned to reference levels within 24 h after admission. In mice with MI, increases in platelet size and PMC became evident within 12 h and were sustained up to 72 h. Splenic platelets are bigger than circulating platelets in normal or infarct mice. At 24 h post-MI, splenic platelet storage was halved whereas cardiac platelets increased by 4-fold. Splenectomy attenuated all changes observed in the blood, reduced leucocyte and platelet accumulation in the infarct myocardium, limited infarct size and alleviated cardiac dilatation and dysfunction. AMI-induced elevated circulating levels of adenosine diphosphate and catecholamines in both human and the mouse, which may trigger splenic platelet release. Pharmacological inhibition of angiotensin-converting enzyme, β1-adrenergic receptor or platelet P2Y12 receptor reduced platelet abundance in the murine infarct myocardium albeit having diverse effects on platelet size and PMC. In conclusion, AMI evokes release of splenic platelets, which contributes to the increase in platelet size and PMC and facilitates myocardial accumulation of platelets and leucocytes, thereby promoting post-infarct inflammation. © 2016 The Author(s). published by Portland Press Limited on behalf of the Biochemical Society.

Biomarker of Long-Chain n-3 Fatty Acid Intake and Breast Cancer: Accumulative Evidence from an Updated Meta-Analysis of Epidemiological Studies.

PubMed

Yang, Bo; Ren, Xiao L; Wang, Zhi Y; Wang, Liang; Zhao, Feng; Guo, Xiao J; Li, Duo

2018-06-14

We aimed to summarize the up-to-date epidemiology evidence on biomarkers of long-chain (LC) n-3 fatty acid (FA) intake in relation to breast cancer (BC). Epidemiology studies determining FA levels in biospecimen (circulating blood or adipose tissue (AT)) were identified from PubMed, EMBASE, and Cochrane Library databases until March 2018. Multivariate-adjusted risk ratios (RRs) with 95% confidence intervals (CIs) were pooled using a random-effect model. Difference in biospecimen proportions of LC n-3 FA between BC cases and non-cases were analyzed as a standardized mean difference (SMD). Thirteen cohort and eleven case-control studies were eligible for the present meta-analysis. The estimated SMD was -0.14 (95% CI: -0.27, -0.11) for LC n-3 FA and -0.27 (95% CI: -0.42, -0.11) for LC n-3/n-6 FA ratio. When comparing the top tertiles with the bottom baseline levels, circulating LC n-3 FA was significantly associated with a lower risk of BC (RR: 0.84, 95% CI: 0.74, 0.96), but not AT (RR: 1.02, 95% CI: 0.70, 1.48). Significant inverse dose-response associations were observed for each 1% increment of circulating 20:5n-3 and 22:6n-3. This meta-analysis highlights that circulating LC n-3 FA as a biomarker of intake may be an independent predictive factor for BC, especially 20:5n-3 and 22:6n-3.

Regional climate change predictions from the Goddard Institute for Space Studies high resolution GCM

NASA Technical Reports Server (NTRS)

Crane, Robert G.; Hewitson, B. C.

1991-01-01

A new diagnostic tool is developed for examining relationships between the synoptic scale circulation and regional temperature distributions in GCMs. The 4 x 5 deg GISS GCM is shown to produce accurate simulations of the variance in the synoptic scale sea level pressure distribution over the U.S. An analysis of the observational data set from the National Meteorological Center (NMC) also shows a strong relationship between the synoptic circulation and grid point temperatures. This relationship is demonstrated by deriving transfer functions between a time-series of circulation parameters and temperatures at individual grid points. The circulation parameters are derived using rotated principal components analysis, and the temperature transfer functions are based on multivariate polynomial regression models. The application of these transfer functions to the GCM circulation indicates that there is considerable spatial bias present in the GCM temperature distributions. The transfer functions are also used to indicate the possible changes in U.S. regional temperatures that could result from differences in synoptic scale circulation between a 1XCO2 and a 2xCO2 climate, using a doubled CO2 version of the same GISS GCM.

The role of zonally asymmetric heating in the vertical and temporal structure of the global scale flow fields during FGGE SOP-1. [First Global Atmospheric Research Program Global Experiment (FGGE); Special Observing Period (SOP)

NASA Technical Reports Server (NTRS)

Paegle, J.; Kalnay-Rivas, E.; Baker, W. E.

1981-01-01

By examining the vertical structure of the low order spherical harmonics of the divergence and vorticity fields, the relative contribution of tropical and monsoonal circulations upon the global wind fields was estimated. This indicates that the overall flow over North America and the Pacific between January and February is quite distinct both in the lower and upper troposphere. In these longitudes there is a stronger tropical overturning and subtropical jet stream in January than February. The divergent flow reversed between 850 and 200 mb. Poleward rotational flow at upper levels is associated with an equatorward rotational flow at low levels. This suggests that the monsoon and other tropical circulations project more amplitude upon low order (global scale) representations of the flow than do the typical midlatitude circulations and that their structures show conspicuous changes on a time scale of a week or less.

The Sharav Cyclone: Observations and some theoretical considerations

NASA Astrophysics Data System (ADS)

Alpert, P.; Ziv, B.

1989-12-01

A special study of the Sharav Cyclones indicates that they are the result of large-scale weak baroclinicity, enhanced by vigorous boundary-layer baroclinicity between the North African coast and the Mediterranean. It is illustrated how the jet stream plays a major role in the vertical circulation in producing a complex cyclonic circulation dominated by at least three mechanisms: large-scale interior baroclinicity, boundary-layer baroclinicity, and jet stream related circulations. The main characteristics of the Sharav Cyclone (also called the Saharan Depression or Khamsin Depression) in the Mediterranean are reviewed. Unlike the cold winter cyclone, the Sharav Cyclone is a spring cyclone. Its tracks lie mainly along the North African coast and turn to the north near the southeastern Mediterranean. Its warm front is active and is sometimes associated with extremely high surface temperatures. Its cold front is shallow. The Sharav Cyclone moves eastward relatively fast, typically faster than 10 m s-1, and with a small speed variability. In general, there is an upper level trough to the west of the surface low and the surface horizontal scale is of the order of 500-1000 km. Finally, it is frequently associated with heavy dust/sand storms and low visibilities. Some of these features are illustrated in a case study of the April 28-30, 1986, cyclone. Vertical cross sections indicate a deep circulation associated with the exit region of an upper level jet. In addition to presenting evidence that the Sharav Cyclone is a deep tropospheric circulation, it is shown that the transverse indirect circulation at the exit region of the jet is a major component of its circulation. The classic two-level baroclinic model (Phillips, 1954) is applied. The effects of the major diabatic heating due to the sensible heat flux above the North African desert and the large north to south temperature gradients are incorporated through the thermal wind of the basic state. The model predicts the fast eastward motion, the relatively smaller horizontal scale and the fast growth rate. Furthermore, the model predicts an annual maximum growth rate in April and a secondary peak in October, which agrees with the frequency of occurrences of the Sharav Cyclones.

Adrenal hormones and circulating leukocyte subtypes in stroke patients treated with reperfusion therapy.

PubMed

Miró-Mur, Francesc; Laredo, Carlos; Renú, Arturo; Rudilosso, Salvatore; Zhao, Yashu; Amaro, Sergio; Llull, Laura; Urra, Xabier; Planas, Anna M; Chamorro, Ángel

2018-03-13

Ischemic stroke sets in motion a dialogue between the central nervous and the immune systems that includes the sympathetic/adrenal system. We investigated the course of immune cells and adrenocortical and adrenomedullary effectors in a cohort of 51 patients with acute stroke receiving reperfusion therapy (intravenous alteplase or mechanical thrombectomy) and its correlation with stroke outcomes and infarct growth. Cortisol increased rapidly and fleetingly after stroke, but 39% of patients who had larger infarctions on admission showed a positive delta cortisol at day 1. It was associated with enhanced infarct growth (p = 0.002) and poor outcome [OR (95% CI) 5.30 (1.30-21.69)], and correlated with less lymphocytes and T cells at follow up. Likewise, fewer circulating lymphocytes, T cells, and Tregs were associated with infarct growth. By contrast, metanephrines did not increase at clinical onset, and decreased over time. Higher levels of NMN correlated with more Treg and B cells. Eventually, complete reperfusion at the end of therapy headed the identification of more circulating Tregs at day 1. Then activation of cortical or medullar compartments of the adrenal gland result in specific signatures on leukocyte subpopulations. Manipulation of the adrenal gland hormone levels warrants further investigation. Copyright © 2018. Published by Elsevier Inc.

Kinetics of plasma heat shock protein HSP-70 release in coronary artery surgery: on-pump versus off-pump.

PubMed

Pizon, M T; Gburek, T; Pizon, M; Sztefko, K

2006-12-01

Heat shock protein HSP-70 is known as protective chaperone molecule synthetized in response following ischemia and stress agents. It is detected in the myocardium and endothelium as well as in the circulation. Damaged as well as viable but exposed to stress cells contribute to the release of HSP-70 into the circulation. The aim of the study was to investigate if cardiopulmonary bypss (CPB) leads to more circulating HSP-70, on the basis of comparison dynamics of plasma concentration HSP-70 in 8 men undergoing procedures with the use of CPB (coronary artery bypass grafting, CABG group) and 8 men undergoing off-pump surgery (OPCAB group). Blood samples were taken preoperatively, twice intraoperatively, immediately after surgical procedure (1 h) and 24-hours thereafter. The concentration of plasma HSP-70 was measured by means of immunoassay. The derived results were compared statistically with the frequency of incidence postoperative atrial fibrillation (AF). In CABG group was observed continuous gradual increase of plasma HSP-70 concentration during the operation with the peak 1 h after surgery (P<0.01), in striking contrast to OPCAB group, in which was detected small, but non statistically significant increase of HSP-70 1 h after operation. Significantly more of circulating HSP-70 it was detected in CABG group during the operation and 1 h after surgery (CABG vs OPCAB, respectively P<0.015 and P<0.028). In both groups among patients witch AF it was found higher postoperative values of circulating HSP-70 compared with the non-AF group (P=0.0415). The use of CPB leads to significant more release of HSP-70 into the circulation. According to our findings high plasma concentration of HSP-70 may be the measure of operative cellular stress, ischemia or injury and may be related with greater onset of postoperative AF. High circulating HSP-70 levels is connected with higher incidence of postoperative AF after open heart surgery.

Measurement of Circulating Cytokines and Immune-Activation Markers by Multiplex Technology in the Clinical Setting: What Are We Really Measuring?

PubMed

Aziz, Najib

2015-01-01

Measurement of circulating cytokine levels can provide important information in the study of the pathogenesis of disease. John L. Fahey was a pioneer in the measurement of circulating cytokines and immune-activation markers and a leader in the quality assessment/control of assays for measurement of circulating cytokines. Insights into the measurement of circulating cytokines, including consideration of multiplex assays, are presented here.

Testosterone and acute stress are associated with fibrinogen and von Willebrand factor in African men: the SABPA study.

PubMed

Malan, Nicolaas T; von Känel, Roland; Schutte, Alta E; Huisman, Hugo W; Schutte, Rudolph; Smith, Wayne; Mels, Carina M; Kruger, Ruan; Meiring, Muriel; van Rooyen, Johannes M; Malan, Leoné

2013-10-12

Low testosterone, acute and chronic stress and hypercoagulation are all associated with hypertension and hypertension-related diseases. The interaction between these factors and future risk for coronary artery disease in Africans has not been fully elucidated. In this study, associations of testosterone, acute cardiovascular and coagulation stress responses with fibrinogen and von Willebrand factor in African and Caucasian men in a South African cohort were investigated. Cardiovascular variables were studied by means of beat-to-beat and ambulatory blood pressure monitoring. Fasting serum-, salivary testosterone and citrate coagulation markers were obtained from venous blood samples. Acute mental stress responses were evoked with the Stroop test. The African group demonstrated a higher cardiovascular risk compared to Caucasian men with elevated blood pressure, low-grade inflammation, chronic hyperglycemia (HbA1c), lower testosterone levels, and elevated von Willebrand factor (VWF) and fibrinogen levels. Blunted testosterone acute mental stress responses were demonstrated in African males. In multiple regression analyses, higher circulating levels of fibrinogen and VWF in Africans were associated with a low T environment (R(2) 0.24-0.28; p≤0.01), but only circulating fibrinogen in Caucasians. Regarding endothelial function, a low testosterone environment and a profile of augmented α-adrenergic acute mental stress responses (diastolic BP, D-dimer and testosterone) were associated with circulating VWF levels in Africans (Adj R(2) 0.24; p<0.05). An interdependence between acute mental stress, salivary testosterone, D-dimer and vascular responses existed in African males in their association with circulating VWF but no interdependence of the independent variables occurred with fibrinogen levels. © 2013.

The Variability of the Horizontal Circulation in the Troposphere and Stratosphere: A Comparison

NASA Technical Reports Server (NTRS)

Perlwitz, Judith; Graf, Hans-F.; Hansem, James E. (Technical Monitor)

2001-01-01

The variability of the horizontal circulation in the stratosphere and troposphere of the Northern Hemisphere (NH) is compared by using various approaches. Spatial degrees of freedom (dof) on different time scales were derived. Modes of variability were computed in geopotential height fields at the tropospheric and stratospheric pressure levels by applying multivariate statistical approaches. Features of the spatial and temporal variability of the winterly zonal wind were studied with the help of recurrence and persistence analyses. The geopotential height and zonally-averaged zonal wind at the 50-, 500- and 1000-hPa level are used to investigate the behavior of the horizontal circulation in the lower stratosphere, mid-troposphere and at the near surface level, respectively. It is illustrated that the features of the variability of the horizontal circulation are very similar in the mid-troposphere and at the near surface level. Due to the filtering of tropospheric disturbances by the stratospheric and upper tropospheric zonal mean flow, the variability of the stratospheric circulation exhibits less spatial complexity than the circulation at tropospheric pressure levels. There exist enormous differences in the number of degrees of freedom (or free variability modes) between both atmospheric layers. Results of the analyses clearly show that the concept of a zonally symmetric AO with a simple structure in the troposphere similar to the one in the stratosphere is not valid. It is concluded that the spatially filtered climate change signal can be detected earlier in the stratosphere than in the mid-troposphere or at the near surface level.

Study of lubricant circulation in HVAC systems. Volume 1: Description of technical effort and results; Final technical report, March 1995--April 1996

DOE Office of Scientific and Technical Information (OSTI.GOV)

Biancardi, F.R.; Michels, H.H.; Sienel, T.H.

1996-10-01

The purpose of this program was to conduct experimental and analytical efforts to determine lubricant circulation characteristics of new HFC/POE pairs and HFC/mineral oil pairs in a representative central residential HVAC system and to compare their behavior with the traditional HCFC-22/mineral oil (refrigerant/lubricant) pair. A dynamic test facility was designed and built to conduct the experimental efforts. This facility provided a unique capability to visually and physically measure oil circulation rates, on-line, in operating systems. A unique on-line ultraviolet-based measurement device was used to obtain detailed data on the rate and level of lubricant oil circulated within the operating heatmore » pump system. The experimental and analytical data developed during the program are presented as a function of vapor velocity, refrigerant/lubricant viscosity, system features and equipment. Both visual observations and instrumentation were used to understand ``worst case`` oil circulation situations. This report is presented in two volumes. Volume 1 contains a complete description of the program scope, objective, test results summary, conclusions, description of test facility and recommendations for future effort. Volume 2 contains all of the program test data essentially as taken from the laboratory dynamic test facility during the sequence of runs.« less

The investigation of circulating microRNAs associated with lipid metabolism in childhood obesity.

PubMed

Can, U; Buyukinan, M; Yerlikaya, F H

2016-06-01

Childhood obesity is an increasing health challenge related to increased risk of chronic diseases. microRNAs (miRNAs) are noncoding short RNA molecules regulating multiple biological processes linked to obesity. We aimed at evaluating the association between circulating miRNA levels and lipid metabolism in obese and non-obese children and adolescents. By constituting study group, 45 obese children and adolescents were recruited. To perform comparisons with study group, 41 lean controls were matched for age and sex. Using real-time quantitative PCR analysis, circulating miRNAs were evaluated in both groups. Circulating miR-335 (P < 0.001), miR-143 (P = 0.001) and miR-758 (P = 0.006) in obese children were significantly lower than those of controls. However, circulating miR-27 (P = 0.032), miR-378 (P < 0.001) and miR-370 (P = 0.045) in obese children were significantly higher, compared with those of controls. In addition, circulating miR-33 in obese children was higher than those of controls, but no significant difference was present (P = 0.687). Our findings showed that a significant association is present between circulating miR-370, miR-33, miR-378, miR-27, miR-335, miR-143 and miR-758 values, and childhood obesity. Low levels of miR-335, miR-143 and miR-758, and high levels of miR-27, miR-378, miR-33 and miR-370 may have been responsible for elevated triglycerides and low-density lipoprotein (LDL-C) levels, and low level of high-density lipoprotein (HDL-C) in obese subjects. Therefore, miRNAs may be a good novel biomarker for childhood obesity. © 2015 World Obesity.

The effect of sudden ice sheet melt on ocean circulation and surface climate

NASA Astrophysics Data System (ADS)

Ivanovic, R. F.; Gregoire, L. J.; Wickert, A. D.; Valdes, P. J.; Burke, A.

2017-12-01

Collapse of ice sheets can cause significant sea-level rise and widespread climate change. Around 14.6 thousand years ago, global mean sea level rose by 15 m in less than 350 years during an event known as Meltwater Pulse 1a. Ice sheet modelling and sea-level fingerprinting has suggested that approximately half of this 50 mm yr-1 sea level rise may have come from a North American ice Saddle Collapse that drained into the Arctic and Atlantic Oceans. However, dating uncertainties make it difficult to determine the sequence of events and their drivers, leaving many fundamental questions. For example, was melting from the northern ice sheets responsible for the Older-Dryas or other global-scale cooling events, or did a contribution from Antarctica counteract the climatic effects? What was the role of the abrupt Bølling Warming? And how were all these signals linked to changes in Atlantic Ocean overturning circulation?To address these questions, we examined the effect of the North American ice Saddle Collapse using a high resolution network drainage model coupled to an atmosphere-ocean-vegetation General Circulation Model. Here, we present the quantitative routing estimates of the consequent meltwater discharge and its impact on climate. We also tested a suite of more idealised meltwater forcing scenarios to examine the global influence of Arctic versus Antarctic ice melt. The results show that 50% of the Saddle Collapse meltwater pulse was routed via the Mackenzie River into the Arctic Ocean, and 50% was discharged directly into the Atlantic/Gulf of Mexico. This meltwater flux, equivalent to a total of 7.3 m of sea-level rise, caused a strong (6 Sv) weakening of Atlantic Meridional Overturning Circulation (AMOC) and widespread Northern Hemisphere cooling of 1-5 °C. The greatest cooling is in the Arctic (5-10 °C in the winter), but there is also significant winter warming over eastern North America (1-3 °C). We propose that this robust submillennial mechanism was triggered by the Bølling Warming, ending the warm event and/or causing the Older Dryas cooling. Furthermore, we find that AMOC is most sensitive to meltwater discharged to the Arctic Ocean and that high-latitude northern melt overwhelms any opposing influence of Antarctic melt, which would otherwise cause northern warming.

1,25 Dihydroxyvitamin D circulating levels, calcitriol administration, and incidence of acute rejection, CMV infection, and polyoma virus infection in renal transplant recipients.

PubMed

Moscarelli, Luciano; Antognoli, Giulia; Buti, Elisa; Dervishi, Egrina; Fani, Filippo; Caroti, Leonardo; Tsalouchos, Aris; Romoli, Elena; Ghiandai, Giulia; Minetti, Enrico

2016-10-01

Observation that 1,25-Dihydroxyvitamin-D3 has an immunomodulatory effect on innate and adaptive immunity raises the possible effect on clinical graft outcome. Aim of this study was to evaluate the correlation of biopsy-proven acute rejection, CMV infection, BKV infection, with 1,25-Dihydroxyvitamin-D3 deficiency and the benefit of calcitriol supplementation before and during the transplantation. Risk factors and kidney graft function were also evaluated. All RTRs received induction therapy with basiliximab, cyclosporine, mycophenolic acid, and steroids. During the first year, the incidence of BPAR (4% vs 11%, P=.04), CMV infection (3% vs 9%, P=.04), and BKV infection (6% vs 19%, P=.04) was significantly lower in users compared to controls. By multivariate Cox regression analysis, 1,25-Dihydroxyvitamin-D3 deficiency and no calcitriol exposure were independent risk factors for BPAR (HR=4.30, P<.005 and HR=3.25, P<.05), for CMV infection (HR=2.33, P<.05 and HR=2.31, P=.001), and for BKV infection (HR=2.41, P<.05 and HR=2.45, P=.001). After one year, users had a better renal function: eGFR was 62.5±6.7 mL/min vs 51.4±7.6 mL/min (P<.05). Only one user developed polyomavirus-associated nephropathy vs 15 controls. Two users lost their graft vs 11 controls. 1,25(OH)2-D3 deficiency circulating levels increased the risk of BPAR, CMV infection, BKV infection after kidney transplantation. Administration of calcitriol is a way to obtain adequate 1,25(OH)2-D3 circulating levels. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Upregulation of circulating components of the alternative renin-angiotensin system in inflammatory bowel disease: A pilot study.

PubMed

Garg, Mayur; Burrell, Louise M; Velkoska, Elena; Griggs, Karen; Angus, Peter W; Gibson, Peter R; Lubel, John S

2015-09-01

The relationship between intestinal inflammation and circulating components of the renin-angiotensin system (RAS) is poorly understood. Demographic and clinical data were obtained from healthy controls and patients with inflammatory bowel disease (IBD). Plasma concentrations of the classical RAS components (angiotensin-converting enzyme (ACE) and angiotensin II (Ang II)) and alternative RAS components (ACE2 and angiotensin (1-7) (Ang (1-7))) were analysed by radioimmuno- and enzymatic assays. Systemic inflammation was assessed using serum C-reactive protein (CRP), white cell count, platelet count and albumin, and intestinal inflammation by faecal calprotectin. Nineteen healthy controls (11 female; mean age 38 years, range 23-68), 19 patients with Crohn's disease (11 female; aged 45 years, range 23-76) and 15 patients with ulcerative colitis (6 female; aged 42 years, 26-64) were studied. Circulating classical RAS component levels were similar across the three groups, whereas ACE2 activity and Ang (1-7) concentrations were higher in patients with IBD compared to controls (ACE2: 21.5 vs 13.3 pmol/ml/min, p<0.05; Ang (1-7): 22.8 vs 14.1 pg/ml, p<0.001). Ang (1-7) correlated weakly with platelet and white cell counts, but not calprotectin or CRP, in patients with IBD. Circulating components of the alternative RAS are increased in patients with IBD. © The Author(s) 2014.

Genome-Wide Association Study for Circulating Tissue Plasminogen Activator (tPA) Levels and Functional Follow-up Implicates Endothelial STXBP5 and STX2

PubMed Central

Huang, Jie; Huffman, Jennifer E.; Yamkauchi, Munekazu; Trompet, Stella; Asselbergs, Folkert W.; Sabater-Lleal, Maria; Trégouët, David-Alexandre; Chen, Wei-Min; Smith, Nicholas L.; Kleber, Marcus E.; Shin, So-Youn; Becker, Diane M.; Tang, Weihong; Dehghan, Abbas; Johnson, Andrew D.; Truong, Vinh; Folkersen, Lasse; Yang, Qiong; Oudot-Mellakh, Tiphaine; Buckley, Brendan M.; Moore, Jason H.; Williams, Frances M.K.; Campbell, Harry; Silbernagel, Günther; Vitart, Veronique; Rudan, Igor; Tofler, Geoffrey H.; Navis, Gerjan J.; DeStefano, Anita; Wright, Alan F.; Chen, Ming-Huei; de Craen, Anton J.M.; Worrall, Bradford B.; Rudnicka, Alicja R.; Rumley, Ann; Bookman, Ebony B.; Psaty, Bruce M.; Chen, Fang; Keene, Keith L.; Franco, Oscar H.; Böhm, Bernhard O.; Uitterlinden, Andre G.; Carter, Angela M.; Jukema, J. Wouter; Sattar, Naveed; Bis, Joshua C.; Ikram, Mohammad A.; Sale, Michèle M.; McKnight, Barbara; Fornage, Myriam; Ford, Ian; Taylor, Kent; Slagboom, P. Eline; McArdle, Wendy L.; Hsu, Fang-Chi; Franco-Cereceda, Anders; Goodall, Alison H.; Yanek, Lisa R.; Furie, Karen L.; Cushman, Mary; Hofman, Albert; Witteman, Jacqueline CM.; Folsom, Aaron R.; Basu, Saonli; Matijevic, Nena; van Gilst, Wiek H.; Wilson, James F.; Westendorp, Rudi G.J.; Kathiresan, Sekar; Reilly, Muredach P.; Tracy, Russell P.; Polasek, Ozren; Winkelmann, Bernhard R.; Grant, Peter J.; Hillege, Hans L.; Cambien, Francois; Stott, David J.; Lowe, Gordon D.; Spector, Timothy D.; Meigs, James B.; Marz, Winfried; Eriksson, Per; Becker, Lewis C.; Morange, Pierre-Emmanuel; Soranzo, Nicole; Williams, Scott M.; Hayward, Caroline; van der Harst, Pim; Hamsten, Anders; Lowenstein, Charles J.; Strachan, David P.; O'Donnell, Christopher J.

2014-01-01

Objective Tissue plasminogen activator (tPA), a serine protease, catalyzes the conversion of plasminogen to plasmin, the major enzyme responsible for endogenous fibrinolysis. In some populations, elevated plasma levels of tPA have been associated with myocardial infarction and other cardiovascular diseases (CVD). We conducted a meta-analysis of genome-wide association studies (GWAS) to identify novel correlates of circulating levels of tPA. Approach and Results Fourteen cohort studies with tPA measures (N=26,929) contributed to the meta-analysis. Three loci were significantly associated with circulating tPA levels (P <5.0×10−8). The first locus is on 6q24.3, with the lead SNP (rs9399599, P=2.9×10−14) within STXBP5. The second locus is on 8p11.21. The lead SNP (rs3136739, P=1.3×10−9) is intronic to POLB and less than 200kb away from the tPA encoding gene PLAT. We identified a non-synonymous SNP (rs2020921) in modest LD with rs3136739 (r2 = 0.50) within exon 5 of PLAT (P=2.0×10−8). The third locus is on 12q24.33, with the lead SNP (rs7301826, P=1.0×10−9) within intron 7 of STX2. We further found evidence for association of lead SNPs in STXBP5 and STX2 with expression levels of the respective transcripts. In in vitro cell studies, silencing STXBP5 decreased release of tPA from vascular endothelial cells, while silencing of STX2 increased tPA release. Through an in-silico lookup, we found no associations of the three lead SNPs with coronary artery disease or stroke. Conclusions We identified three loci associated with circulating tPA levels, the PLAT region, STXBP5 and STX2. Our functional studies implicate a novel role for STXBP5 and STX2 in regulating tPA release. PMID:24578379

Body mass index and circulating oestrone sulphate in women treated with adjuvant letrozole★

PubMed Central

Sini, V; Lunardi, G; Cirillo, M; Turazza, M; Bighin, C; Giraudi, S; Levaggi, A; Piccioli, P; Bisagni, G; Gnoni, R; Stridi, G; Porpiglia, M; Picardo, E; Ponzone, R; Marenco, D; Mansutti, M; Puglisi, F; Del Mastro, L

2014-01-01

Background: Obesity is an independent adverse prognostic factor in early breast cancer patients, but it is still controversial whether obesity may affect adjuvant endocrine therapy efficacy. The aim of our study (ancillary to the two clinical trials Gruppo Italiano Mammella (GIM)4 and GIM5) was to investigate whether the circulating oestrogen levels during treatment with the aromatase inhibitor letrozole are related to body mass index (BMI) in postmenopausal women with breast cancer. Methods: Plasma concentration of oestrone sulphate (ES) was evaluated by radioimmunoassay in 370 patients. Plasma samples were obtained after at least 6 weeks of letrozole therapy (steady-state time). Patients were divided into four groups according to BMI. Differences among the geometric means (by ANOVA and ANCOVA) and correlation (by Spearman's rho) between the ES levels and BMI were assessed. Results: Picomolar geometric mean values (95% confidence interval, n=patients) of circulating ES during letrozole were 58.6 (51.0–67.2, n=150) when BMI was <25.0 kg m−2; 65.6 (57.8–74.6, n=154) when 25.0–29.9 kg m−2; 59.3 (47.1–74.6, n=50) when 30.0–34.9 kg m−2; and 43.3 (23.0–81.7, n=16) when ⩾35.0 kg m−2. No statistically significant difference in terms of ES levels among groups and no correlation with BMI were observed. Conclusions: Body mass index does not seem to affect circulating oestrogen levels in letrozole-treated patients. PMID:24448359

Avian Influenza Virus Infection of Immortalized Human Respiratory Epithelial Cells Depends upon a Delicate Balance between Hemagglutinin Acid Stability and Endosomal pH*

PubMed Central

Daidoji, Tomo; Watanabe, Yohei; Ibrahim, Madiha S.; Yasugi, Mayo; Maruyama, Hisataka; Masuda, Taisuke; Arai, Fumihito; Ohba, Tomoyuki; Honda, Ayae; Ikuta, Kazuyoshi; Nakaya, Takaaki

2015-01-01

The highly pathogenic avian influenza (AI) virus, H5N1, is a serious threat to public health worldwide. Both the currently circulating H5N1 and previously circulating AI viruses recognize avian-type receptors; however, only the H5N1 is highly infectious and virulent in humans. The mechanism(s) underlying this difference in infectivity remains unclear. The aim of this study was to clarify the mechanisms responsible for the difference in infectivity between the current and previously circulating strains. Primary human small airway epithelial cells (SAECs) were transformed with the SV40 large T-antigen to establish a series of clones (SAEC-Ts). These clones were then used to test the infectivity of AI strains. Human SAEC-Ts could be broadly categorized into two different types based on their susceptibility (high or low) to the viruses. SAEC-T clones were poorly susceptible to previously circulating AI but were completely susceptible to the currently circulating H5N1. The hemagglutinin (HA) of the current H5N1 virus showed greater membrane fusion activity at higher pH levels than that of previous AI viruses, resulting in broader cell tropism. Moreover, the endosomal pH was lower in high susceptibility SAEC-T clones than that in low susceptibility SAEC-T clones. Taken together, the results of this study suggest that the infectivity of AI viruses, including H5N1, depends upon a delicate balance between the acid sensitivity of the viral HA and the pH within the endosomes of the target cell. Thus, one of the mechanisms underlying H5N1 pathogenesis in humans relies on its ability to fuse efficiently with the endosomes in human airway epithelial cells. PMID:25673693

Circulating CXCR5+CXCR3+PD-1lo Tfh-like cells in HIV-1 controllers with neutralizing antibody breadth

PubMed Central

Martin-Gayo, Enrique; Cronin, Jacqueline; Hickman, Taylor; Ouyang, Zhengyu; Lindqvist, Madelene; Kolb, Kellie E.; Schulze zur Wiesch, Julian; Cubas, Rafael; Porichis, Filippos; Shalek, Alex K.; van Lunzen, Jan; Haddad, Elias K.; Walker, Bruce D.; Kaufmann, Daniel E.; Lichterfeld, Mathias; Yu, Xu G.

2017-01-01

HIV-1–specific broadly neutralizing antibodies (bnAbs) typically develop in individuals with continuous high-level viral replication and increased immune activation, conditions that cannot be reproduced during prophylactic immunization. Understanding mechanisms supporting bnAb development in the absence of high-level viremia may be important for designing bnAb-inducing immunogens. Here, we show that the breadth of neutralizing antibody responses in HIV-1 controllers was associated with a relative enrichment of circulating CXCR5+CXCR3+PD-1lo CD4+ T cells. These CXCR3+PD-1lo Tfh-like cells were preferentially induced in vitro by functionally superior dendritic cells from controller neutralizers, and able to secrete IL-21 and support B cells. In addition, these CXCR3+PD-1lo Tfh-like cells contained higher proportions of stem cell–like memory T cells, and upon antigenic stimulation differentiated into PD-1hi Tfh-like cells in a Notch-dependent manner. Together, these data suggest that CXCR5+CXCR3+PD-1lo cells represent a dendritic cell–primed precursor cell population for PD-1hi Tfh-like cells that may contribute to the generation of bnAbs in the absence of high-level viremia. PMID:28138558

Frequencies and expression levels of programmed death ligand 1 (PD-L1) in circulating tumor RNA (ctRNA) in various cancer types.

PubMed

Ishiba, Toshiyuki; Hoffmann, Andreas-Claudius; Usher, Joshua; Elshimali, Yahya; Sturdevant, Todd; Dang, Mai; Jaimes, Yolanda; Tyagi, Rama; Gonzales, Ronald; Grino, Mary; Pinski, Jacek K; Barzi, Afsaneh; Raez, Luis E; Eberhardt, Wilfried E; Theegarten, Dirk; Lenz, Heinz-Josef; Uetake, Hiroyuki; Danenberg, Peter V; Danenberg, Kathleen

2018-06-07

Precision medicine and prediction of therapeutic response requires monitoring potential biomarkers before and after treatment. Liquid biopsies provide noninvasive prognostic markers such as circulating tumor DNA and RNA. Circulating tumor RNA (ctRNA) in blood is also used to identify mutations in genes of interest, but additionally, provides information about relative expression levels of important genes. In this study, we analyzed PD-L1 expression in ctRNA isolated from various cancer types. Tumors inhibit antitumor response by modulating the immune checkpoint proteins programmed death ligand 1 (PD-L1) and its cognate receptor PD1. The expression of these genes has been implicated in evasion of immune response and resistance to targeted therapies. Blood samples were collected from gastric (GC), colorectal (CRC), lung (NSCLC), breast (BC), prostate cancer (PC) patients, and a healthy control group. ctRNA was purified from fractionated plasma, and following reverse transcription, levels of PD-L1 expression were analyzed using qPCR. PD-L1 expression was detected in the plasma ctRNA of all cancer types at varying frequencies but no PD-L1 mRNA was detected in cancer-free individuals. The frequencies of PD-L1 expression were significantly different among the various cancer types but the median relative PD-L1 expression values were not significantly different. In 12 cases where plasma and tumor tissue were available from the same patients, there was a high degree of concordance between expression of PD-L1 protein in tumor tissues and PD-L1 gene expression in plasma, and both methods were equally predictive of response to nivolumab. PD-L1 mRNA can be detected and quantitated in ctRNA of cancer patients. These results pave the way for further studies aimed at determining whether monitoring the levels of PD-L1 mRNA in blood can identify patients who are most likely to benefit from the conventional treatment. Copyright © 2018 Elsevier Inc. All rights reserved.

Androgen Supplementation During Aging: Development of a Physiologically Appropriate Protocol

PubMed Central

Sorwell, Krystina G.; Garyfallou, Vasilios T.; Garten, Jamie; Weiss, Alison; Renner, Laurie; Neuringer, Martha; Kohama, Steven G.

2014-01-01

Abstract Men show an age-related decline in the circulating levels of testosterone (T) and dehydroepiandrosterone sulfate (DHEAS). Consequently, there is interest in developing androgen supplementation paradigms for old men that replicate the hormone profiles of young adults. In the present study, we used old (21–26 years old) male rhesus monkeys as a model to examine the efficacy of an androgen supplementation paradigm that comprised oral T administration (12 mg/kg body weight, dissolved in sesame oil/chocolate) in the evening, and two oral DHEA administrations, 3 hr apart (0.04 mg/kg body weight, dissolved in sesame oil/chocolate) in the morning. After 5 days of repeated hormone supplementation, serial blood samples were remotely collected from each animal hourly across the 24-hr day, and assayed for cortisol, DHEAS, T, 5α-dihydrotestosterone (DHT), estrone (E1), and 17β-estradiol (E2). Following androgen supplementation, T levels were significantly elevated and this was associated with a more sustained nocturnal elevation of T's primary bioactive metabolites, DHT and E1 and E2. Plasma DHEAS levels were also significantly elevated after androgen supplementation; DHEAS levels rose in the early morning and gradually declined during the course of the day, closely mimicking the profiles observed in young adults (7–12 years old); in contrast, cortisol levels were unaltered by the supplementation. Together the data demonstrate a non-invasive androgen supplementation paradigm that restores youthful circulating androgen levels in old male primates. Because this paradigm preserves the natural circulating circadian hormone patterns, we predict that it will produce fewer adverse side effects, such as perturbed sleep or cognitive impairment. PMID:24134213

Overexpression of porcine lipoprotein-associated phospholipase A2 in swine.

PubMed

Tang, Xiaochun; Wang, Gangqi; Liu, Xingxing; Han, Xiaolei; Li, Zhuang; Ran, Guangyao; Li, Zhanjun; Song, Qi; Ji, Yuan; Wang, Haijun; Wang, Yuhui; Ouyang, Hongsheng; Pang, Daxin

2015-09-25

Lipoprotein-associated phospholipase A 2 (Lp-PLA2) is associated with the risk of vascular disease. It circulates in human blood predominantly in association with low-density lipoprotein cholesterol (LDL-C) and hydrolyses oxidized phospholipids into pro-inflammatory products. However, in the mouse circulation, it predominantly binds to high-density lipoprotein cholesterol (HDL-C) and exhibits anti-inflammatory properties. To further investigate the effects of Lp-PLA2 in the circulation, we generated over-expressed Lp-PLA2 transgenic swine. The eukaryotic expression plasmid of porcine Lp-PLA2 which driven by EF1α promoter was constructed and generate transgenic swine via SCNT. The expression and activity of Lp-PLA2 in transgenic swine were evaluated, and the total cholesterol (TC), HDL-C, LDL-C and triglyceride (TG) levels in the fasting and fed states were also assessed. Compared with wild-type swine controls, the transgenic swine exhibited elevated Lp-PLA2 mRNA levels and activities, and the activity did not depend on the feeding state. The TC, HDL-C and LDL-C levels were not significantly increased. There was no change in the TG levels in the fasting state between transgenic and control pigs. However, in the fed state, the TG levels of transgenic swine were slightly increased compared with the control pigs and were significantly elevated compared with the fasting state. In addition, inflammatory gene (interleukin [IL]-6, monocyte chemotactic protein [MCP]-1 and tumor necrosis factor [TNF]-α) mRNA levels in peripheral blood mononuclear cells (PBMCs) were significantly increased. The results demonstrated that Lp-PLA2 is associated with triglycerides which may be helpful for understanding the relationship of this protein with cardiovascular disease. Copyright © 2015 Elsevier Inc. All rights reserved.

Sirtuin-1 regulation of mammalian metabolism

PubMed Central

Gillum, Matthew P.; Erion, Derek M.; Shulman, Gerald I.

2011-01-01

Sirtuin-1 (SirT1) is a nutrient-sensing deacetylase whose levels and activity increase with caloric restriction to preserve euglycemia and promote efficient energy utilization. Focusing on data obtained in vivo, we review how SirT1 orchestrates the adaptive response to fasting by stimulating hepatic gluconeogenesis and fatty acid oxidation, increasing circulating adiponectin levels, and limiting immune activation. Finally, we consider its viability as a therapeutic target for the treatment of type 2 diabetes. PMID:20971038

Stationary waves and slowly moving features in the night upper clouds of Venus

NASA Astrophysics Data System (ADS)

Peralta, J.; Hueso, R.; Sánchez-Lavega, A.; Lee, Y. J.; Muñoz, A. García; Kouyama, T.; Sagawa, H.; Sato, T. M.; Piccioni, G.; Tellmann, S.; Imamura, T.; Satoh, T.

2017-08-01

At the cloud top level of Venus (65-70 km altitude) the atmosphere rotates 60 times faster than the underlying surface—a phenomenon known as superrotation1,2. Whereas on Venus's dayside the cloud top motions are well determined3,4,5,6 and Venus general circulation models predict the mean zonal flow at the upper clouds to be similar on both the day and nightside2, the nightside circulation remains poorly studied except for the polar region7,8. Here, we report global measurements of the nightside circulation at the upper cloud level. We tracked individual features in thermal emission images at 3.8 and 5.0 μm obtained between 2006 and 2008 by the Visible and Infrared Thermal Imaging Spectrometer-Mapper onboard Venus Express and in 2015 by ground-based measurements with the Medium-Resolution 0.8-5.5 Micron Spectrograph and Imager at the National Aeronautics and Space Administration Infrared Telescope Facility. The zonal motions range from -110 to -60 m s-1, which is consistent with those found for the dayside but with larger dispersion6. Slow motions (-50 to -20 m s-1) were also found and remain unexplained. In addition, abundant stationary wave patterns with zonal speeds from -10 to +10 m s-1 dominate the night upper clouds and concentrate over the regions of higher surface elevation.

Effect of heterogeneity of carcinoembryonic antigen on liver cell membrane binding and its kinetics of removal from circulation.

PubMed

Byrn, R A; Medrek, P; Thomas, P; Jeanloz, R W; Zamcheck, N

1985-07-01

Carcinoembryonic antigen (CEA) is a glycoprotein metabolized primarily by the liver. Subcellular fractions of rat liver were examined for CEA binding activity. Hepatocyte plasma membrane and microsome fractions bound CEA, and this binding shared the calcium requirement, neuraminidase sensitivity, and carbohydrate specificity of the hepatocyte asialoglycoprotein receptor. CEA had previously been shown to react with this galactose-specific receptor, in vivo, only following neuraminidase treatment. Galactose receptor binding of CEA was measured in three different purified CEA preparations. The fraction of CEA capable of binding to excess levels of galactose receptor on membranes varied (46.5%, 40.2%, and 4.7% for CEA-1, -2, and -3, respectively). These CEAs were shown to be 2.3%, 7.9%, and 0.7% as effective, respectively, as asialo-alpha 1-acid glycoprotein in inhibiting the binding of radiolabeled asialo-alpha 1-acid glycoprotein to liver cell membranes. Each of the three CEA preparations showed different clearance kinetics from the circulation of mice. Coinjection of asialo-alpha 1-acid glycoprotein with the CEAs revealed differing inhibition of the clearances. These results show that differences in the carbohydrate components of purified CEA preparations affect their rate of removal from circulation and thus possibly the relationship between CEA production and observed plasma levels in patients. The possible origin of these CEA differences is discussed with their clinical implications.

Nutrient pumping by submesoscale circulations in the mauritanian upwelling system

NASA Astrophysics Data System (ADS)

Hosegood, P. J.; Nightingale, P. D.; Rees, A. P.; Widdicombe, C. E.; Woodward, E. M. S.; Clark, D. R.; Torres, R. J.

2017-12-01

Observations made within a cold filament in the Mauritanian upwelling system demonstrate that intense submesoscale circulations at the peripheral edges of the filament are likely responsible for anomalously high levels of observed primary productivity by resupplying nutrients to the euphotic zone. Measurements made on the shelf within the recently upwelled water reveal that primary production (PP) of 8.2 gC/m-2 day-1 was supported by nitrate concentrations (NC) of 8 mmol m-3. Towards the front that defined the edge of the filament containing the upwelled water as it was transported offshore, PP dropped to 1.6 gC m-2 day-1 whilst NC dropped to 5.5 mmol m-3. Thus, whilst the observed nutrients on the shelf accounted for 90% of new production, this value dropped to ∼60% near the filament's front after accounting for vertical turbulent fluxes and Ekman pumping. We demonstrate that the N15 was likely to have been supplied at the front by submesoscale circulations that were directly measured as intense vertical velocities ⩾100 m day-1 by a drifting acoustic Doppler current profiler that crossed a submesoscale surface temperature front. At the same time, a recently released tracer was subducted out of the mixed layer within 24 h of release, providing direct evidence that the frontal circulations were capable of accessing the reservoir of nutrients beneath the pycnocline. The susceptibility of the filament edge to submesoscale instabilities was demonstrated by O(1) Rossby numbers at horizontal scales of 1-10 km. The frontal circulations are consistent with instabilities arising from a wind-driven nonlinear Ekman buoyancy flux generated by the persistent northerly wind stress that has a down-front component at the northern edge of the inshore section of the filament. The prevalence of submesoscale instabilities and their associated vertical circulations are proposed to be a key mechanism operating at sub-grid scales and sustaining new production throughout the upwelling system.

Communist China. Section 23. Weather and Climate. Part 3 - North China

DTIC Science & Technology

1964-06-01

Introduction 1 2. Climatic controls 2 a. General circulation and air masses 2 b. Migratory pressure systems and fronts 3 (1) Extratropical ...Sea-level pressure and surface airflow, January (map) 2 Fig. 2 Sea-level pressure and surface airflow, July (mop) 2 Fig. 3 Tracks of extratropical ...become weaker and less frequent as those of the invading monsoon become more prevalent. b. MIGRATORY PRESSURE SYSTEMS AND FRONTS (1) Extratropical

Endurance capacity is not correlated with endothelial function in male university students.

PubMed

Wang, Yan; Zeng, Xian-bo; Yao, Feng-juan; Wu, Fang; Su, Chen; Fan, Zhen-guo; Zhu, Zhu; Tao, Jun; Huang, Yi-jun

2014-01-01

Endurance capacity, assessed by 1000-meter (1000 m) run of male university students, is an indicator of cardiovascular fitness in Chinese students physical fitness surveillance. Although cardiovascular fitness is related to endothelial function closely in patients with cardiovascular diseases, it remains unclear whether endurance capacity correlates with endothelial function, especially with circulating endothelial microparticles (EMPs), a new sensitive marker of endothelial dysfunction in young students. The present study aimed to investigate the relationship between endurance capacity and endothelial function in male university students. Forty-seven healthy male university students (mean age, 20.1 ± 0.6 years; mean height, 172.4 ± 6.3 cm; and mean weight, 60.0 ± 8.2 kg) were recruited in this study. The measurement procedure of 1000 m run time was followed to Chinese national students Constitutional Health Criterion. Endothelium function was assessed by flow-mediated vasodilation (FMD) in the brachial artery measured by ultrasonic imaging, and the level of circulating EMPs was measured by flow cytometry. Cardiovascular fitness indicator--maximal oxygen uptake (VO2max)--was also measured on a cycle ergometer using a portable gas analyzer. 1000 m run time was correlated with VO2max (r  =  -0.399, p<0.05). However, there were no correlations between VO2max and FMD or levels of circulating CD31+/CD42- microparticles. Similarly, no correlations were found between 1000 m run time and FMD, and levels of circulating CD31+/CD42- microparticles in these male university students (p>0.05). The correlations between endurance capacity or cardiovascular fitness and endothelial function were not found in healthy Chinese male university students. These results suggest that endurance capacity may not reflect endothelial function in healthy young adults with well preserved FMD and low level of circulating CD31+/CD42-EMPs.

Endurance Capacity Is Not Correlated with Endothelial Function in Male University Students

PubMed Central

Wu, Fang; Su, Chen; Fan, Zhen-guo; Zhu, Zhu; Tao, Jun; Huang, Yi-jun

2014-01-01

Background Endurance capacity, assessed by 1000-meter (1000 m) run of male university students, is an indicator of cardiovascular fitness in Chinese students physical fitness surveillance. Although cardiovascular fitness is related to endothelial function closely in patients with cardiovascular diseases, it remains unclear whether endurance capacity correlates with endothelial function, especially with circulating endothelial microparticles (EMPs), a new sensitive marker of endothelial dysfunction in young students. The present study aimed to investigate the relationship between endurance capacity and endothelial function in male university students. Methods Forty-seven healthy male university students (mean age, 20.1±0.6 years; mean height, 172.4±6.3 cm; and mean weight, 60.0±8.2 kg) were recruited in this study. The measurement procedure of 1000 m run time was followed to Chinese national students Constitutional Health Criterion. Endothelium function was assessed by flow-mediated vasodilation (FMD) in the brachial artery measured by ultrasonic imaging, and the level of circulating EMPs was measured by flow cytometry. Cardiovascular fitness indicator - maximal oxygen uptake (VO2 max) - was also measured on a cycle ergometer using a portable gas analyzer. Results 1000 m run time was correlated with VO2max (r = −0.399, p<0.05). However, there were no correlations between VO2max and FMD or levels of circulating CD31+/CD42- microparticles. Similarly, no correlations were found between 1000 m run time and FMD, and levels of circulating CD31+/CD42- microparticles in these male university students (p>0.05). Conclusion The correlations between endurance capacity or cardiovascular fitness and endothelial function were not found in healthy Chinese male university students. These results suggest that endurance capacity may not reflect endothelial function in healthy young adults with well preserved FMD and low level of circulating CD31+/CD42-EMPs. PMID:25101975

Steroid profiling reveals widespread local regulation of glucocorticoid levels during mouse development.

PubMed

Taves, Matthew D; Plumb, Adam W; Sandkam, Benjamin A; Ma, Chunqi; Van Der Gugten, Jessica Grace; Holmes, Daniel T; Close, David A; Abraham, Ninan; Soma, Kiran K

2015-02-01

Glucocorticoids (GCs) are produced by the adrenal glands and circulate in the blood to coordinate organismal physiology. In addition, different tissues may independently regulate their local GC levels via local GC synthesis. Here, we find that in the mouse, endogenous GCs show tissue-specific developmental patterns, rather than mirroring GCs in the blood. Using solid-phase extraction, HPLC, and specific immunoassays, we quantified endogenous steroids and found that in tissues of female and male mice, (1) local GC levels can be much higher than systemic GC levels, (2) local GCs follow age-related patterns different from those of systemic GCs, and (3) local GCs have identities different from those of systemic GCs. For example, whereas corticosterone is the predominant circulating adrenal GC in mice, high concentrations of cortisol were measured in neonatal thymus, bone marrow, and heart. The presence of cortisol was confirmed with liquid chromatography-tandem mass spectrometry. In addition, gene expression of steroidogenic enzymes was detected across multiple tissues, consistent with local GC production. Our results demonstrate that local GCs can differ from GCs in circulating blood. This finding suggests that steroids are widely used as local (paracrine or autocrine) signals, in addition to their classic role as systemic (endocrine) signals. Local GC regulation may even be the norm, rather than the exception, especially during development.

Angiogenic T cell expansion correlates with severity of peripheral vascular damage in systemic sclerosis.

PubMed

Manetti, Mirko; Pratesi, Sara; Romano, Eloisa; Bellando-Randone, Silvia; Rosa, Irene; Guiducci, Serena; Fioretto, Bianca Saveria; Ibba-Manneschi, Lidia; Maggi, Enrico; Matucci-Cerinic, Marco

2017-01-01

The mechanisms underlying endothelial cell injury and defective vascular repair in systemic sclerosis (SSc) remain unclear. Since the recently discovered angiogenic T cells (Tang) may have an important role in the repair of damaged endothelium, this study aimed to analyze the Tang population in relation to disease-related peripheral vascular features in SSc patients. Tang (CD3+CD31+CXCR4+) were quantified by flow cytometry in peripheral blood samples from 39 SSc patients and 18 healthy controls (HC). Circulating levels of the CXCR4 ligand stromal cell-derived factor (SDF)-1α and proangiogenic factors were assessed in paired serum samples by immunoassay. Serial skin sections from SSc patients and HC were subjected to CD3/CD31 and CD3/CXCR4 double immunofluorescence. Circulating Tang were significantly increased in SSc patients with digital ulcers (DU) compared either with SSc patients without DU or with HC. Tang levels were significantly higher in SSc patients with late nailfold videocapillaroscopy (NVC) pattern than in those with early/active NVC patterns and in HC. No difference in circulating Tang was found when comparing either SSc patients without DU or patients with early/active NVC patterns and HC. In SSc peripheral blood, Tang percentage was inversely correlated to levels of SDF-1α and CD34+CD133+VEGFR-2+ endothelial progenitor cells (EPC), and positively correlated to levels of vascular endothelial growth factor and matrix metalloproteinase-9. Tang were frequently detected in SSc dermal perivascular inflammatory infiltrates. In summary, our findings demonstrate for the first time that Tang cells are selectively expanded in the circulation of SSc patients displaying severe peripheral vascular complications like DU. In SSc, Tang may represent a potentially useful biomarker reflecting peripheral vascular damage severity. Tang expansion may be an ineffective attempt to compensate the need for increased angiogenesis and EPC function. Further studies are required to clarify the function of Tang cells and investigate the mechanisms responsible for their change in SSc.

Circulating autoantibodies against neuroblastoma suppressor of tumorigenicity 1 (NBL1): A potential biomarker for coronary artery disease in patients with obstructive sleep apnea

PubMed Central

Matsumura, Takuma; Kinoshita, Taku; Sakurai, Yoriko; Yahaba, Misuzu; Tsushima, Kenji; Sakao, Seiichiro; Nagashima, Kengo; Ozaki, Toshinori; Kobayashi, Yoshio; Hiwasa, Takaki; Tatsumi, Koichiro

2018-01-01

Objective Although severe obstructive sleep apnea (OSA) is an important risk factor for atherosclerosis-related diseases including coronary artery disease (CAD), there is no reliable biomarker of CAD risks in patients with OSA. This study aimed to test our hypothesis that circulating autoantibodies against neuroblastoma suppressor of tumorigenicity 1 (NBL1-Abs) are associated with the prevalence of CAD in patients with OSA. Methods Eighty-two adults diagnosed with OSA by polysomnography, 96 patients with a diagnosis of acute coronary syndrome (ACS) and 64 healthy volunteers (HVs) were consecutively enrolled. Serum samples were collected from patients with OSA at diagnostic polysomnography and from patients with ACS at disease onset. Serum NBL1-Ab level was measured by amplified luminescence proximity homogeneous assay and its association with clinical variables related to atherosclerosis was evaluated. Results NBL1-Ab level was significantly elevated in patients with both OSA and ACS compared with HVs. Subgroup analyses showed that NBL1-Ab level was markedly higher in patients with severe OSA and OSA patients with a history of CAD. Weak associations were observed between NBL1-Ab level and apnea-hypopnea index, age, mean SpO2 and arousal index, whereas significantly higher NBL1-Ab levels were observed in OSA patients with a history of CAD than in those without a history of CAD. Sensitivity analysis using a logistic regression model also demonstrated that increased NBL1-Ab levels were associated with the previous history of CAD in patients with OSA. Conclusions Elevated NBL1-Ab levels may be associated with the prevalence of CAD in patients with OSA, which needs to be confirmed further. PMID:29596467

Subtidal circulation in a deep-silled fjord: Douglas Channel, British Columbia

NASA Astrophysics Data System (ADS)

Wan, Di; Hannah, Charles G.; Foreman, Michael G. G.; Dosso, Stan

2017-05-01

Douglas Channel, a deep fjord on the west coast of British Columbia, Canada, is the main waterway in the fjord system that connects the town of Kitimat to Queen Charlotte Sound and Hecate Strait. A 200 m depth sill divides Douglas Channel into an outer and an inner basin. This study examines the low-frequency (from seasonal to meteorological bands) circulation in Douglas Channel from data collected at three moorings deployed during 2013-2015. The deep flows are dominated by a yearly renewal that takes place from May/June to early September. A dense bottom layer with a thickness of 100 m that cascades through the system at the speed of 0.1-0.2 m s-1, which is consistent with gravity currents. Estuarine flow dominates the circulation above the sill depth, and the observed landward net volume flux suggests that it is necessary to include the entire complex channel network to fully understand the estuarine circulation in the system. The influence of the wind forcing on the subtidal circulation is not only at the surface, but also at middepth. The along-channel wind dominates the surface current velocity fluctuations and the sea level response to the wind produces a velocity signal at 100-120 m in the counter-wind direction. Overall, the circulation in the seasonal and the meteorological bands is a mix of estuarine flow, direct wind-driven flow, and the barotropic and baroclinic responses to changes to the surface pressure gradient caused by the wind stress.

Effect of intensive glycaemic control on endothelial progenitor cells in patients with long-standing uncontrolled type 2 diabetes.

PubMed

Lev, Eli I; Singer, Joel; Leshem-Lev, Dorit; Rigler, Merav; Dadush, Oshrat; Vaduganathan, Muthiah; Battler, Alexander; Kornowski, Ran

2014-09-01

Endothelial progenitor cells (EPCs) have an important role in repair following vascular injury. However, in patients with diabetes, EPC number and function are markedly reduced. It is unclear whether intensive glycaemic control can modify EPC properties in diabetic patients. We aimed to examine whether glycaemic control can improve EPC number and function in patients with long-standing uncontrolled type 2 diabetes. Thirty-five patients with treated type 2 diabetes and HgA1c ≥ 8.5% were included. Patients were tested at baseline and after 3-4 months of an intensive glycaemic control programme, with the aim of achieving HgA1c of 7%. The diabetes group was compared to 20 patients without diabetes (control). Circulating EPC levels were assessed by flow cytometry for expression of VEGFR2, CD133, and CD34. The capacity of the cells to form colony-forming units (CFUs), and their migration and viability were quantified after 1 week of culture. Patients with diabetes (mean age 61.1 ± 7 years, 28.6% women, disease duration of 19.2 ± 8 years) had a baseline HgA1c of 9.4 ± 0.8%. After the glycaemic control period, HgA1c decreased to 8 ± 0.8%. Circulating EPC levels increased significantly after the intensive control period and reached a level similar to the control group. The number of EPC CFUs also increased significantly after glycaemic control but remained lower than the control group. All EPC functional assays improved following the glycaemic control. In patients with uncontrolled long-standing type 2 diabetes, intensive glycaemic control was associated with an increase in the levels of circulating EPCs, and improvement in their functional properties. © The European Society of Cardiology 2013 Reprints and permissions:sagepub.co.uk/journalsPermissions.nav.

Effect of aerobic training and resistance training on circulating irisin level and their association with change of body composition in overweight/obese adults: a pilot study.

PubMed

Kim, H-J; Lee, H-J; So, B; Son, J S; Yoon, D; Song, W

2016-06-20

The novel myokine irisin has been reported as a therapeutic target for metabolic disease. The objective of this study is to reveal the effects of aerobic training (AT) and resistance training (RT) on circulating irisin levels and their associations with change of body composition in overweight/obese adults. Twenty eight overweight/obese adults (BMI>23 kg/m(2)) were included in this study and compared before and after 8 weeks of exercise program (60 min/day, 5 times in a week). The subjects, in both aerobic and resistance training, showed significant improvement in anthropometric parameters and exercise capacities including maximal oxygen uptake and muscle strength. Interestingly, the circulating irisin was significantly increased in resistance training group (p=0.002) but not in aerobic training (p=0.426) compared to control group. In addition, we found the positive correlation between change of the circulating irisin and muscle mass (r=0.432, p=0.022) and the negative correlation between change of the circulating irisin and fat mass (r=-0.407, p=0.031). In the present pilot study, we found that circulating irisin level was increased by 8 weeks of resistance training in overweight/obese adults, suggesting that resistance training could be the efficient exercise type in overweight/obese considering positive change of body composition concomitant with increase of irisin levels.

Elevated circulating levels of succinate in human obesity are linked to specific gut microbiota.

PubMed

Serena, Carolina; Ceperuelo-Mallafré, Victoria; Keiran, Noelia; Queipo-Ortuño, Maria Isabel; Bernal, Rosa; Gomez-Huelgas, Ricardo; Urpi-Sarda, Mireia; Sabater, Mónica; Pérez-Brocal, Vicente; Andrés-Lacueva, Cristina; Moya, Andres; Tinahones, Francisco J; Fernández-Real, Jose Manuel; Vendrell, Joan; Fernández-Veledo, Sonia

2018-02-12

Gut microbiota-related metabolites are potential clinical biomarkers for cardiovascular disease (CVD). Circulating succinate, a metabolite produced by both microbiota and the host, is increased in hypertension, ischemic heart disease, and type 2 diabetes. We aimed to analyze systemic levels of succinate in obesity, a major risk factor for CVD, and its relationship with gut microbiome. We explored the association of circulating succinate with specific metagenomic signatures in cross-sectional and prospective cohorts of Caucasian Spanish subjects. Obesity was associated with elevated levels of circulating succinate concomitant with impaired glucose metabolism. This increase was associated with specific changes in gut microbiota related to succinate metabolism: a higher relative abundance of succinate-producing Prevotellaceae (P) and Veillonellaceae (V), and a lower relative abundance of succinate-consuming Odoribacteraceae (O) and Clostridaceae (C) in obese individuals, with the (P + V/O + C) ratio being a main determinant of plasma succinate. Weight loss intervention decreased (P + V/O + C) ratio coincident with the reduction in circulating succinate. In the spontaneous evolution after good dietary advice, alterations in circulating succinate levels were linked to specific metagenomic signatures associated with carbohydrate metabolism and energy production with independence of body weight change. Our data support the importance of microbe-microbe interactions for the metabolite signature of gut microbiome and uncover succinate as a potential microbiota-derived metabolite related to CVD risk.

Examining the transplacental passage of apixaban using the dually perfused human placenta.

PubMed

Bapat, P; Pinto, L S R; Lubetsky, A; Aleksa, K; Berger, H; Koren, G; Ito, S

2016-07-01

Essentials Apixaban is a novel oral anticoagulant that has not been studied in pregnant patients. Our objective was to determine the rate and extent of the placental transfer of apixaban. Apixaban rapidly crosses the ex vivo term human placenta from maternal to fetal circulation. Fetal apixaban levels in vivo are estimated to be 35-90% of the corresponding maternal levels. Background Apixaban is a novel oral anticoagulant that is increasingly being prescribed to women of reproductive age. However, information regarding its placental transfer is non-existent. Objective To determine the rate and extent of placental transfer of apixaban, using the human placenta ex vivo. Methods Placentae collected after Caesarean or vaginal delivery of healthy term infants were perfused in the respective maternal and fetal circulation. At the start of the experiment, apixaban was added to the maternal circulation at a concentration of 150 ng mL(-1) , and samples from maternal and fetal reservoirs were collected over 3 h. Results There was a rapid decline of apixaban in the maternal compartment, followed by emergence in the fetal compartment with a median fetal-to-maternal drug concentration ratio of 0.77 (interquartile range [IQR], 0.76-0.81) and fetal concentration of 39.0 ng mL(-1) (IQR, 36.8-40.6) after 3 h (n = 5). The perfusion results were subsequently adjusted to account for differences in the concentration of plasma proteins in maternal and fetal blood, as apixaban remains highly bound to albumin and alpha-1 acid glycoprotein. After the adjustment, the predicted fetal-to-maternal ratio of total (bound plus unbound) apixaban concentrations in vivo ranged from 0.35 to 0.90. Conclusions We conclude that unbound apixaban rapidly crosses from the maternal to fetal circulation. We further predict that total apixaban concentrations in cord blood in vivo are 35-90% of the corresponding maternal levels, suggesting that apixaban could have a possible adverse effect on fetal and neonatal coagulation. © 2016 International Society on Thrombosis and Haemostasis.

Circulating microparticles and the risk of thromboembolic events in Egyptian beta thalassemia patients.

PubMed

Youssry, Ilham; Soliman, Nohair; Ghamrawy, Mona; Samy, Rania Mohamed; Nasr, Amal; Abdel Mohsen, Mohamed; ElShahaat, Mohamed; Bou Fakhredin, Rayan; Taher, Ali

2017-04-01

The presence of elevated numbers of circulating microparticles (MPs) has been hypothesized to be responsible for the occurrence of thromboembolic events (TEEs) in thalassemic patients. Our aim is to evaluate the presence and the thrombotic risk of circulating MPs in thalassemia patients and to determine the difference in MPs between β-thalassemia major (β-TM) and thalassemia intermedia (TI). The percentage of the annexin-labeled MPs, platelet-derived MPs (PMPs), erythrocyte-derived MPs (RMPs), and endothelial-derived MPs (EMPs) was measured by flow cytometry, in 87 thalassemia patients (39 β-TM and 48 TI). By multiple regression analysis, we then assessed the various independent risk factors for the occurrence of TEE. The thalassemic patients who experienced TEE had a significantly higher platelet count, higher percentage of annexin-labeled MPs, and higher percentage of PMPs (p value = 0.014, 0.003, and 0.014, respectively). There was no significant difference between β-TM and TI patients at the level of any of the studied MPs. The predictive risk factors for TEE in thalassemic patients were splenectomy, total and direct bilirubin, the RMPs, and the EMPs (OR = 10.07 (CI = 3.7-27.1), 4.3 (CI = 2.1-8.7), 1.4 (CI = 1.5-6.2), 1.6 (CI = 1.1-2.2), 3.0 (CI = 1.9-4.9), respectively). In conclusion, the elevated numbers of circulating MPs is a risk factor for the TEE in thalassemia patients.

Circulating interleukin-10 and risk of cardiovascular events: a prospective study in the elderly at risk.

PubMed

Welsh, Paul; Murray, Heather M; Ford, Ian; Trompet, Stella; de Craen, Anton J M; Jukema, J Wouter; Stott, David J; McInnes, Iain B; Packard, Chris J; Westendorp, Rudi G J; Sattar, Naveed

2011-10-01

The goal of this study was to examine the association of the antiinflammatory interleukin-10 (IL-10) with risk of cardiovascular disease (CVD). In the PROSPER (PROspective Study of Pravastatin in the Elderly at Risk) cohort, we related baseline concentrations of circulating IL-10 to risk of CVD events in a nested case (n=819)-control (n=1618) study of 3.2 years of follow-up. Circulating IL-10 showed few strong associations with classical risk factors but was positively correlated with IL-6 and C-reactive protein. IL-10 was positively associated with risk of CVD events (odds ratio [OR] 1.17, 95% CI 1.05 to 1.31 per unit increase in log IL-10) after adjusting for classical risk factors and C-reactive protein. Furthermore, IL-10 was associated more strongly with CVD risk among those with no previous history of CVD (OR 1.42, 95% CI 1.18 to 1.70), compared with those with previous CVD (OR 1.04, 95% CI 0.90 to 1.19; P=0.018). Overall, IL-10 showed a modest ability to add discrimination to classical risk factors (C-statistic +0.005, P=0.002). Baseline circulating levels of the antiinflammatory IL-10 are positively associated with risk of CVD among the elderly without prior CVD events, although the association is less evident in those with a history of CVD. Additional epidemiological and mechanistic studies investigating the role of IL-10 in CVD are warranted.

Circulation weather types and their influence on precipitation in Serbia

NASA Astrophysics Data System (ADS)

Putniković, Suzana; Tošić, Ivana; Đurđević, Vladimir

2016-10-01

An objective classification scheme of atmospheric circulation, in which daily circulation is determined by the strength, direction, and vorticity of geostrophic flow, has been applied to the atmosphere over Serbia for the time period 1961-2010. The results for the sea level and isobaric level of 500 hPa for winter and summer are presented. The 26 circulation types (eight pure direction, 16 hybrid, cyclonic, and anticyclonic types) are determined and described. Each of the circulation types has a distinct underlying synoptic pattern that produces the expected type and direction of flow over the study area. The relative frequencies of the circulation types, and the relationship between the precipitation and circulation types at three stations on a seasonal time scale are analyzed. The anticyclonic weather type dominates in winter (18.93 %) and summer (18.70 %), followed by the northeasterly type (16.65 %) in summer, and the cyclonic type (12.83 %) in winter. The cyclonic types (C and hybrid) have a higher than average probability of rain at all stations. Conversely, the anticyclonic types are associated with a lower than average probability and intensity of rainfall.

Sex differences and the impact of steroid hormones on the developing human brain.

PubMed

Neufang, Susanne; Specht, Karsten; Hausmann, Markus; Güntürkün, Onur; Herpertz-Dahlmann, Beate; Fink, Gereon R; Konrad, Kerstin

2009-02-01

Little is known about the hormonal effects of puberty on the anatomy of the developing human brain. In a voxel-based morphometry study, sex-related differences in gray matter (GM) volume were examined in 46 subjects aged 8-15 years. Males had larger GM volumes in the left amygdala, whereas females had larger right striatal and bilateral hippocampal GM volumes than males. Sexually dimorphic areas were related to Tanner stages (TS) of pubertal development and to circulating level of steroid hormones in a subsample of 30 subjects. Regardless of sex, amygdala and hippocampal volumes varied as a function of TS and were associated with circulating testosterone (TEST) levels. By contrast, striatal GM volumes were unrelated to pubertal development and circulating steroid hormones. Whole-brain regression analyses revealed positive associations between circulating estrogen levels and parahippocampal GM volumes as well as between TEST levels and diencephalic brain structures. In addition, a negative association was found between circulating TEST and left parietal GM volumes. These data suggest that GM development in certain brain regions is associated with sexual maturation and that pubertal hormones might have organizational effects on the developing human brain.

Functional Characterization of Promoter Variants of the Adiponectin Gene Complemented by Epidemiological Data

PubMed Central

Laumen, Helmut; Saningong, Akuma D.; Heid, Iris M.; Hess, Jochen; Herder, Christian; Claussnitzer, Melina; Baumert, Jens; Lamina, Claudia; Rathmann, Wolfgang; Sedlmeier, Eva-Maria; Klopp, Norman; Thorand, Barbara; Wichmann, H.-Erich; Illig, Thomas; Hauner, Hans

2009-01-01

OBJECTIVE Adiponectin (APM1, ACDC) is an adipocyte-derived protein with downregulated expression in obesity and insulin-resistant states. Several potentially regulatory single nucleotide polymorphisms (SNPs) within the APM1 gene promoter region have been associated with circulating adiponectin levels. None of them have been functionally characterized in adiponectin-expressing cells. Hence, we investigated three SNPs (rs16861194, rs17300539, and rs266729) for their influence on adiponectin promoter activity and their association with circulating adiponectin levels. RESEARCH DESIGN AND METHODS Basal and rosiglitazone-induced promoter activity of different SNP combinations (haplotypes) was analyzed in 3T3-L1 adipocytes using luciferase reporter gene assays and DNA binding studies comparing all possible APM1 haplotypes. This functional approach was complemented with analysis of epidemiological population-based data of 1,692 participants of the MONICA/KORA S123 cohort and 696 participants from the KORA S4 cohort for SNP and haplotype association with circulating adiponectin levels. RESULTS Major to minor allele replacements of the three SNPs revealed significant effects on promoter activity in luciferase assays. Particularly, a minor variant in rs16861194 resulted in reduced basal and rosiglitazone-induced promoter activity and hypoadiponectinemia in the epidemiological datasets. The haplotype with the minor allele in all three SNPs showed a complete loss of promoter activity, and no subject carried this haplotype in either of the epidemiological samples (combined P value for statistically significant difference from a random sample was 0.006). CONCLUSIONS Our results clearly demonstrate that promoter variants associated with hypoadiponectinemia in humans substantially affect adiponectin promoter activity in adipocytes. Our combination of functional experiments with epidemiological data overcomes the drawback of each approach alone. PMID:19074982

A tumor specific antibody to aid breast cancer screening in women with dense breast tissue

PubMed Central

Roy, Lopamudra Das; Dillon, Lloye M.; Zhou, Ru; Moore, Laura J.; Livasy, Chad; El-Khoury, Joe M.; Puri, Rahul; Mukherjee, Pinku

2017-01-01

Screening for breast cancer has predominantly been done using mammography. Unfortunately, mammograms miss 50% cancers in women with dense breast tissue. Multi-modal screenings offer the best chance of enhancing breast cancer screening effectiveness. We evaluated the use of TAB004, an antibody that recognizes the tumor form of the glycoprotein MUC1 (tMUC1), to aid early detection of breast cancer. Our experimental approach was to follow tMUC1 from the tissue into circulation. We found that 95% of human breast cancer tissues across all subtypes stained positive for TAB004. In breast cancer cell lines, we showed that the amount of tMUC1 released from tumor cells is proportional to the cell's tMUC1 expression level. Finally, we showed that TAB004 can be used to assess circulating tMUC1 levels, which when monitored in the context of cancer immunoediting, can aid earlier diagnosis of breast cancer regardless of breast tissue density. In a blinded pilot study with banked serial samples, tMUC1 levels increased significantly up to 2 years before diagnosis. Inclusion of tMUC1 monitoring as part of a multi-modal screening strategy may lead to earlier stage diagnosis of women whose cancers are missed by mammography. PMID:28680538

Association Between Circulating Baseline Proprotein Convertase Subtilisin Kexin Type 9 Levels and Efficacy of Evolocumab.

PubMed

Desai, Nihar R; Giugliano, Robert P; Wasserman, Scott M; Gibbs, John P; Liu, Thomas; Scott, Rob; Sabatine, Marc S

2017-05-01

Levels of proprotein convertase subtilisin kexin type 9 (PCSK9) vary markedly across the population and are influenced by genetic and nongenetic factors. Evolocumab is a fully human, monoclonal antibody against PCSK9 that reduces low-density lipoprotein cholesterol (LDL-C) levels by 55% to 75%. Whether the efficacy of evolocumab varies based on an individual's baseline PCSK9 level remains unknown. To characterize variability in PCSK9 levels and determine whether the LDL-C level reduction achieved with evolocumab differs based on PCSK9 levels. This study included pooled data from 3016 patients from 4 phase 3 randomized clinical trials of evolocumab as part of the Program to Reduce LDL-C and Cardiovascular Outcomes Following Inhibition of PCSK9 in Different Populations. Circulating PCSK9 levels were measured at baseline using quantitative enzyme-linked immunosorbent assays and used to stratify patients into quartiles, and LDL-C level was measured at baseline and weeks 10 and 12. In an additional 138 patients enrolled in a pharmacokinetic and pharmacodynamic substudy from 4 phase 2 trials, circulating PCSK9 levels were measured at baseline and then weekly at weeks 8 through 12. Placebo-controlled percentage change in LDL-C level with evolocumab, 140 mg every 2 weeks and 420 mg once monthly, across quartiles of baseline PCSK9 levels. Of the 3016 patients, 1492 (49.5%) were female and 2758 (91.4%) were white. The median baseline circulating PCSK9 level was 323 ng/mL (interquartile range, 258-406 ng/mL). Patients with higher levels of PCSK9 were more likely to be receiving intensive statin therapy (56%, 36%, 25%, and 13% in the fourth through first quartiles; P < .001) and had significantly lower baseline LDL-C level (123 mg/dL, 124 mg/dL, 128 mg/dL, and 137 mg/dL in the fourth through first quartiles; P < .001). After stratifying by statin use, there was no correlation between PCSK9 levels and LDL-C levels (ρ = 0.03 [95% CI, -0.04 to 0.10] for nonstatin users, P = .39, and ρ = 0.03 [95% CI, -0.01 to 0.08] for statin users, P = .12). Across all quartiles of baseline PCSK9 levels, both evolocumab 140 mg every 2 weeks and 420 mg once monthly suppressed circulating PCSK9 levels by 90% to 100% within 1 week of administration. Both evolocumab 140 mg every 2 weeks and 420 mg once monthly were associated with significant reductions in LDL-C levels between 64% and 71% (P < .001), regardless of PCSK9 levels (P for interaction = .76 and .21, respectively). Regardless of baseline PCSK9 levels, the doses of evolocumab being studied in a large cardiovascular outcomes trial suppress PCSK9 levels and consistently and substantially reduce LDL-C levels.

PATHOGENESIS OF FEVER: EFFECTS OF VARIOUS ENDOGENOUS PYROGENS UPON THE LEVEL OF CIRCULATING GRANULOCYTES IN NORMAL RABBITS

PubMed Central

King, M. K.

1960-01-01

The endogenous pyrogen in the serum or plasma of rabbits 2 hours after the intravenous injection of typhoid vaccine had a marked effect on the circulating leucocytes of normal rabbits. Immediately following intravenous injection there was a brief, but marked, granulocytopenia which was quickly followed by a granulocytosis. Under the same circumstances pooled heterologous serum or plasma from normal rabbits produced no fever or significant change in the level of circulating leucocytes. The cell-free fluid of sterile peritoneal exudates produced a marked leucocytosis without a preceding leucopenia when injected intravenously into normal rabbits. When comparably pyrogenic doses of typhoid vaccine were injected in the same manner no significant change in the level of circulating leucocytes occurred. The relevance of these findings to the pathogenesis of fever is discussed. PMID:13756095

Pathogenesis of fever: effects of various endogenous pyrogens upon the level of circulating granulocytes in normal rabbits.

PubMed

KING, M K

1960-11-01

The endogenous pyrogen in the serum or plasma of rabbits 2 hours after the intravenous injection of typhoid vaccine had a marked effect on the circulating leucocytes of normal rabbits. Immediately following intravenous injection there was a brief, but marked, granulocytopenia which was quickly followed by a granulocytosis. Under the same circumstances pooled heterologous serum or plasma from normal rabbits produced no fever or significant change in the level of circulating leucocytes. The cell-free fluid of sterile peritoneal exudates produced a marked leucocytosis without a preceding leucopenia when injected intravenously into normal rabbits. When comparably pyrogenic doses of typhoid vaccine were injected in the same manner no significant change in the level of circulating leucocytes occurred. The relevance of these findings to the pathogenesis of fever is discussed.

Assessing Positivity and Circulating Levels of NS1 in Samples from a 2012 Dengue Outbreak in Rio de Janeiro, Brazil

PubMed Central

Allonso, Diego; Meneses, Marcelo D. F.; Fernandes, Carlos A.; Ferreira, Davis F.; Mohana-Borges, Ronaldo

2014-01-01

Dengue virus (DENV) represents a major threat to public health worldwide. Early DENV diagnosis should not only detect the infection but also identify patients with a higher likelihood to develop severe cases. Previous studies have suggested the potential for NS1 to serve as a viral marker for dengue severity. However, further studies using different sera panels are required to confirm this hypothesis. In this context, we developed a lab-based ELISA to detect and quantitate NS1 protein from the four DENV serotypes and from primary and secondary cases. This approach was used to calculate the circulating NS1 concentration in positive samples. We also tested the NS1 positivity of DENV-positive samples according to the Platelia Dengue NS1 Ag assay. A total of 128 samples were positive for DENV infection and were classified according to the WHO guidelines. The overall NS1 positivity was 68% according to the Platelia assay, whereas all samples were NS1-positive when analyzed with our lab-based ELISA. Fifty-four samples were positive by PCR, revealing a co-circulation of DENV1 and DENV4, and the NS1 positivity for DENV4 samples was lower than that for DENV1. The circulating NS1 concentration ranged from 7 to 284 ng/mL. Our results support previous data indicating the low efficiency of the Platelia assay to detect DENV4 infection. Moreover, this work is the first to analyze NS1 antigenemia using retrospective samples from a Brazilian outbreak. PMID:25412084

Mediterranean diet cools down the inflammatory milieu in type 2 diabetes: the MÉDITA randomized controlled trial.

PubMed

Maiorino, Maria Ida; Bellastella, Giuseppe; Petrizzo, Michela; Scappaticcio, Lorenzo; Giugliano, Dario; Esposito, Katherine

2016-12-01

Mediterranean-style diets provide cardiovascular benefits and increase insulin sensitivity. There is little evidence that adherence to Mediterranean diet may influence the levels of the inflammatory milieu in type 2 diabetes. The aim of this study was to assess whether Mediterranean diet influences both C-reactive protein (CRP) and adiponectin in newly diagnosed type 2 diabetes, and whether adherence to Mediterranean diet affects their circulating levels. In a two-arm, single-center trial, 215 men and women with newly diagnosed type 2 diabetes were randomized to a Mediterranean diet (n = 108, 54 males and 54 females) or a low-fat diet (n = 107, 52 males and 55 females), with a total follow-up of 8.1 years. At baseline visit and at 1 year, body weight, HOMA index, CRP, and adiponectin and its fractions were assessed. Adherence to the diets was assessed by calculating the Mediterranean-diet score. At 1 year, CPR fell by 37 % and adiponectin rose by 43 % in the Mediterranean diet group, while remaining unchanged in the low-fat diet group. The pattern of adiponectin fractions (high and non-high molecular weight) showed a response similar to that of total adiponectin. Diabetic patients with the highest scores (6-9 points) of adherence to Mediterranean diet had lower circulating CRP level and higher circulating total adiponectin levels than the diabetic patients who scored <3 points on the scale (P = 0.001). The results of this randomized controlled trial demonstrate that Mediterranean diet cools down the inflammatory milieu of type 2 diabetes.

Dissociation of a ferric maltol complex and its subsequent metabolism during absorption across the small intestine of the rat.

PubMed Central

Barrand, M. A.; Callingham, B. A.; Dobbin, P.; Hider, R. C.

1991-01-01

1. The fate and disposition of [59Fe]-ferric [3H]-maltol after intravenous administration were investigated in anaesthetized rats. Immediate dissociation of ferric iron from maltol took place in the circulation even with high doses of ferric maltol (containing 1 mg elemental iron). In plasma samples withdrawn within 1 min of injection and subjected to gel filtration, 59Fe eluted with the high molecular weight proteins whilst the tritium was associated with low molecular weight material. 2. The rates of elimination of 59Fe and of tritium from the plasma and their ultimate fate were very different. The half life for 59Fe in the plasma was around 70 min and 59Fe appeared mainly in the bone marrow and liver. There was an initial rapid exit of tritium from the plasma with a half life of around 12 min. This was followed either by a plateau or by a rise in tritium levels, involving entry of maltol metabolites into the circulation. These metabolites could be recovered in the urine. 3. Entry of 59Fe and of tritium into the blood plasma after intraduodenal administration of [59Fe]-ferric [3H]-maltol was also very different. At low doses of ferric maltol (containing 100 micrograms elemental iron), the tritium appeared in the plasma in highest amounts within seconds and then decreased whilst there was a slow rise in 59Fe levels. At higher doses of ferric maltol (containing 7 mg elemental iron), levels of 59Fe in the plasma were highest at 5 min and then fell whereas tritium levels rose steadily. Mucosal processing of 59Fe prevented further entry of iron at high dose into the circulation.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:1364845

Circulating endothelial progenitor cells, Th1/Th2/Th17-related cytokines, and endothelial dysfunction in resistant hypertension.

PubMed

Magen, Eli; Feldman, Arie; Cohen, Ziona; Alon, Dora Ben; Minz, Evegeny; Chernyavsky, Alexey; Linov, Lina; Mishal, Joseph; Schlezinger, Menacham; Sthoeger, Zev

2010-02-01

A possible link between chronic vascular inflammation and arterial hypertension is now an object of intensive studies. To compare Th1/Th2/Th17 cells-related cytokines, circulating endothelial progenitor cells (EPC), and endothelial function in subjects with resistant arterial hypertension (RAH) and controlled arterial hypertension (CAH). Blood pressure was measured by electronic sphygmomanometer. EPC were identified as CD34+/CD133+/kinase insert domain receptor (KDR)+ cells by flow cytometry. Th1/Th2/Th17 cells-related cytokines were identified using the Human Th1/Th2/Th17 Cytokines MultiAnalyte ELISArray Kit. Endothelium-dependent (FMD) vasodilatation of brachial artery was measured by Doppler ultrasound scanning. RAH group (n = 20) and CAH group (n = 20) and 17 healthy individuals (control group) were recruited. In the RAH group, lower blood levels of EPC number (42.4 +/- 16.7 cells/mL) and EPC% (0.19 +/- 0.08%) were observed than in the CAH group (93.1 +/- 88.7 cells/mL; P = 0.017; 0.27 +/- 0.17; P = 0.036) and control group (68.5 +/- 63.6 cells/mL; P < 0.001; 0.28 +/- 0.17%; P = 0.003), respectively. Plasma transforming growth factor-beta1 levels were significantly higher in the RAH group (1767 +/- 364 pg/mL) than in the CAH group (1292 +/- 349; P < 0.001) and in control group (1203 +/- 419 pg/mL; P < 0.001). In the RAH group, statistically significant negative correlation was observed between systolic blood pressure and EPC% (r = -0.72, P < 0.01). FMD in the RAH group was significantly lower (5.5 +/- 0.8%) than in the CAH group (9.2 +/- 1.4; P < 0.001) and in healthy controls (10.1 +/- 1.1%; P < 0.001). RAH is characterized by reduced circulating EPC, substantial endothelial dysfunction, and increased plasma transforming growth factor-beta1 levels.

Leptin administered in physiological or pharmacological doses does not regulate circulating angiogenesis factors in humans.

PubMed

Aronis, K N; Diakopoulos, K N; Fiorenza, C G; Chamberland, J P; Mantzoros, C S

2011-09-01

Leptin has been shown to regulate angiogenesis in animal and in vitro studies by upregulating the production of several pro-angiogenic factors, but its role in regulating angiogenesis has never been studied in humans. The potential angiogenic effect of two doses of metreleptin (50 and 100 ng/ml) was evaluated in vitro, using a novel three-dimensional angiogenesis assay. Fifteen healthy, normoleptinaemic volunteers were administered both a physiological (0.1 mg/kg) and a pharmacological (0.3 mg/kg) single dose of metreleptin, in vivo, on two different inpatient admissions separated by 1-12 weeks. Serum was collected at 0, 6, 12 and 24 h after metreleptin administration. Twenty lean women, with leptin levels <5 ng/ml, were randomised in a 1:1 fashion to receive either physiological replacement doses of metreleptin (0.04-0.12 mg/kg q.d.) or placebo for 32 weeks. Serum was collected at 0, 8, 20 and 32 weeks after randomisation. Proteomic angiogenesis array analysis was performed to screen for angiogenic factors. Circulating concentrations of angiogenin, angiopoietin-1, platelet derived endothelial factor (PDGF)-AA, matrix metalloproteinase (MMP) 8 and 9, endothelial growth factor (EGF) and vascular EGF (VEGF) were also measured. Both metreleptin doses failed to induce angiogenesis in the in vitro model. Although leptin levels increased significantly in response to both short-term and long-term metreleptin administration, circulating concentrations of angiogenesis markers did not change significantly in vivo. This is the first study that examines the effect of metreleptin administration in angiogenesis in humans. Metreleptin administration does not regulate circulating angiogenesis related factors in humans. ClinicalTrials.gov NCT00140205 and NCT00130117. This study was supported by National Institutes of Health-National Center for Research Resources grant M01-RR-01032 (Harvard Clinical and Translational Science Center) and grant number UL1 RR025758. Funding was also received from the National Institute of Diabetes and Digestive and Kidney Diseases grants 58785, 79929 and 81913, and AG032030.

The time course of follicle-stimulating hormone suppression by recombinant human inhibin A in the adult male rhesus monkey (Macaca mulatta).

PubMed

Ramaswamy, S; Pohl, C R; McNeilly, A S; Winters, S J; Plant, T M

1998-08-01

In higher primates, FSH secretion appears to be regulated by a control system consistent with that described by the classical inhibin hypothesis. The purpose of the present experiment was to examine the time course of inhibin's action to suppress FSH secretion in the intact adult male rhesus monkey. To this end, five adult males implanted with indwelling venous catheters and exhibiting typical episodic patterns of LH and testosterone (T) secretion received a 4-day i.v. infusion of recombinant human (rh) inhibin A (832 ng/h x kg) followed, after a 4-week interval, by vehicle infusion of similar duration. Changes in circulating FSH concentrations during the inhibin and vehicle infusions were determined using a sensitive homologous macaque RIA, whereas enzyme-linked immunosorbent assays were employed to track inhibin A, inhibin B, and inhibin pro-alpha-C levels during the experiment. Normal pulsatile activity in the hypothalamic-pituitary-Leydig cell axis was confirmed by monitoring changes in circulating concentrations of LH and T in 12-h windows of sequential blood collection (1200-2400 h; every 20 min) before, during, and after the rh inhibin A and vehicle infusions. Although infusion of rh inhibin A, which led to a 12 ng/ml square wave increment in circulating levels of this inhibin dimer, produced a marked decline in circulating FSH concentrations, significant suppression of the secretion of this gonadotropin was not manifest until 54 h after initiation of the infusion. Despite the marked decline in FSH secretion during the last 24 h of the 4-day infusion of recombinant hormone, circulating inhibin B and pro-alpha-C concentrations were maintained at preinfusion control levels (1 ng/ml). The finding that imposition of an exaggerated circulating inhibin signal led to suppression of FSH secretion in the male monkey only after 2 days of exposure to the hormone indicates that in this species the feedback action of testicular inhibin on FSH secretion is heavily lagged. Moreover, as the decrease in FSH did not lead to changes in native inhibin secretion, it seems reasonable to propose that the FSH-inhibin feedback loop that governs testicular function in higher primates operates with considerable hysteresis at both the pituitary and gonadal levels. The failure of dramatically elevated inhibin A levels to influence the pulsatile secretion of LH in the monkey reinforces the idea that in this species the pituitary action of testicular inhibin is specific for FSH and does not involve modulation of GnRH receptor levels.

Large-scale circulation departures related to wet episodes in north-east Brazil

NASA Technical Reports Server (NTRS)

Sikdar, Dhirendra N.; Elsner, James B.

1987-01-01

Large scale circulation features are presented as related to wet spells over northeast Brazil (Nordeste) during the rainy season (March and April) of 1979. The rainy season is divided into dry and wet periods; the FGGE and geostationary satellite data was averaged; and mean and departure fields of basic variables and cloudiness were studied. Analysis of seasonal mean circulation features show: lowest sea level easterlies beneath upper level westerlies; weak meridional winds; high relative humidity over the Amazon basin and relatively dry conditions over the South Atlantic Ocean. A fluctuation was found in the large scale circulation features on time scales of a few weeks or so over Nordeste and the South Atlantic sector. Even the subtropical High SLPs have large departures during wet episodes, implying a short period oscillation in the Southern Hemisphere Hadley circulation.

Large-scale circulation departures related to wet episodes in northeast Brazil

NASA Technical Reports Server (NTRS)

Sikdar, D. N.; Elsner, J. B.

1985-01-01

Large scale circulation features are presented as related to wet spells over northeast Brazil (Nordeste) during the rainy season (March and April) of 1979. The rainy season season is devided into dry and wet periods, the FGGE and geostationary satellite data was averaged and mean and departure fields of basic variables and cloudiness were studied. Analysis of seasonal mean circulation features show: lowest sea level easterlies beneath upper level westerlies; weak meridional winds; high relative humidity over the Amazon basin and relatively dry conditions over the South Atlantic Ocean. A fluctuation was found in the large scale circulation features on time scales of a few weeks or so over Nordeste and the South Atlantic sector. Even the subtropical High SLP's have large departures during wet episodes, implying a short period oscillation in the Southern Hemisphere Hadley circulation.

[Effect of extracts from Dendrobii ifficinalis flos on hyperthyroidism Yin deficiency mice].

PubMed

Lei, Shan-shan; Lv, Gui-yuan; Jin, Ze-wu; Li, Bo; Yang, Zheng-biao; Chen, Su-hong

2015-05-01

Some unhealthy life habits, such as long-term smoking, heavy drinking, sexual overstrain and frequent stay-up could induce the Yin deficiency symptoms of zygomatic red and dysphoria. Stems of Dendrobii officinalis flos (DOF) showed the efficacy of nourishing Yin. In this study, the hyperthyroidism Yin deficiency model was set up to study the yin nourishing effect and action mechanism of DOF, in order to provide the pharmacological basis for developing DOF resources and decreasing resource wastes. ICR mice were divided into five groups: the normal control group, the model control group, the positive control group and DOF extract groups (6.4 g · kg(-1)). Except for the normal group, the other groups were administrated with thyroxine for 30 d to set up the hyperthyroidism yin deficiency model. At the same time, the other groups were administrated with the corresponding drugs for 30 d. After administration for 4 weeks, the signs (facial temperature, pain domain, heart rate and autonomic activity) in mice were measured, and the facial and ear micro-circulation blood flow were detected by laser Doppler technology. After the last administration, all mice were fasted for 12 hours, blood were collected from their orbits, and serum were separated to detect AST, ALT, TG and TP by the automatic biochemistry analyzer and test T3, T4 and TSH levels by ELISA. (1) Compared with the normal control group, the model control group showed significant increases in facial and ear micro-circulation blood flow, facial temperature and heart rate (P < 0.05, P < 0.01), serum AST, ALT (P < 0.01), T3 level (P < 0.05), TSH level (P < 0.05) and notable deceases in pain domain (P < 0.01), TG level (P < 0.01). (2) Compared with the model control group, extracts from DOF (6 g · kg(-1)) could notably reduce facial and ear micro-circulation blood flow, facial temperature and heart rate (P < 0.05, P < 0.01) and AST (P < 0.05) and enhance pain domain (P < 0.01) and TG (P < 0.01). Extracts from DOF (4 g · kg(-1)) could remarkably reduce AST and ALT levels (P < 0.01, 0.05). Extracts from DOF (6 g · kg(-1) 4 g · kg(-1)) could significantly reduce T3 and increase serum TSH level (P < 0.05). DOF could improve Yin deficiency symptoms of zygomatic red and dysphoria in mice as well as liver function injury caused by overactive thyroid axis. According to its action mechanism, DOF may show yin nourishing and hepatic protective effects by impacting thyroxin substance metabolism, improving micro-circulation and reducing heart rate.

The effect of vasopressin 1b receptor (V1bR) blockade on HPA axis activity in rats exposed to acute heat stress.

PubMed

Jasnic, Nebojsa; Djordjevic, Jelena; Vujovic, Predrag; Lakic, Iva; Djurasevic, Sinisa; Cvijic, Gordana

2013-06-15

Thermal stressors such as low and high ambient temperature elicit an abundance of neuroendocrine responses including activation of the hypothalamo-pituitary-adrenal (HPA) axis and arginine vasopressin (AVP) release. The exposure to heat is a particularly interesting model for studying AVP action because this kind of stressor represents not only an unpleasant experience but also a threat to osmotic homeostasis. As AVP has long been recognized as a hormone involved in the modulation of HPA axis activity, the aim of this study was to elucidate the role of AVP in acutely heat-exposed rats using Nelivaptan, a selective vasopressin 1b receptor (V1bR) antagonist. Rats were exposed to high ambient temperature (38°C) for 60 min. The circulating hormones were determined by ELISA or chemiluminescence, and intrapituitary adrenocorticotropic hormone (ACTH) and V1bR level were determined by western blot. The results obtained show that V1bR blockade negatively affected the increase in blood ACTH caused by heat exposure. This treatment alone, or in combination with Nelivaptan, decreased intrapituitary V1bR levels while circulating AVP concentration was increased under the same conditions. Furthermore, a strong correlation was observed between blood ACTH and corticosterone concentration. In conclusion, our results directly confirm the positive role of AVP in the regulation of ACTH secretion from the pituitary in animals exposed to heat. Moreover, the results suggest that AVP from the general circulation influences pituitary V1bR.

Genome-wide identification of microRNAs regulating cholesterol and triglyceride homeostasis.

PubMed

Wagschal, Alexandre; Najafi-Shoushtari, S Hani; Wang, Lifeng; Goedeke, Leigh; Sinha, Sumita; deLemos, Andrew S; Black, Josh C; Ramírez, Cristina M; Li, Yingxia; Tewhey, Ryan; Hatoum, Ida; Shah, Naisha; Lu, Yong; Kristo, Fjoralba; Psychogios, Nikolaos; Vrbanac, Vladimir; Lu, Yi-Chien; Hla, Timothy; de Cabo, Rafael; Tsang, John S; Schadt, Eric; Sabeti, Pardis C; Kathiresan, Sekar; Cohen, David E; Whetstine, Johnathan; Chung, Raymond T; Fernández-Hernando, Carlos; Kaplan, Lee M; Bernards, Andre; Gerszten, Robert E; Näär, Anders M

2015-11-01

Genome-wide association studies (GWASs) have linked genes to various pathological traits. However, the potential contribution of regulatory noncoding RNAs, such as microRNAs (miRNAs), to a genetic predisposition to pathological conditions has remained unclear. We leveraged GWAS meta-analysis data from >188,000 individuals to identify 69 miRNAs in physical proximity to single-nucleotide polymorphisms (SNPs) associated with abnormal levels of circulating lipids. Several of these miRNAs (miR-128-1, miR-148a, miR-130b, and miR-301b) control the expression of key proteins involved in cholesterol-lipoprotein trafficking, such as the low-density lipoprotein (LDL) receptor (LDLR) and the ATP-binding cassette A1 (ABCA1) cholesterol transporter. Consistent with human liver expression data and genetic links to abnormal blood lipid levels, overexpression and antisense targeting of miR-128-1 or miR-148a in high-fat diet-fed C57BL/6J and Apoe-null mice resulted in altered hepatic expression of proteins involved in lipid trafficking and metabolism, and in modulated levels of circulating lipoprotein-cholesterol and triglycerides. Taken together, these findings support the notion that altered expression of miRNAs may contribute to abnormal blood lipid levels, predisposing individuals to human cardiometabolic disorders.

Brain regions involved in the development of acute phase responses accompanying fever in rabbits.

PubMed Central

Morimoto, A; Murakami, N; Nakamori, T; Sakata, Y; Watanabe, T

1989-01-01

1. The effects of microinjection of rabbit endogenous pyrogen and human recombinant interleukin-1 alpha on rectal temperature and acute phase responses were extensively examined in forty different brain regions of rabbits. The acute phase responses that were investigated were the changes in plasma levels of iron, zinc and copper concentration and the changes in circulating leucocyte count. 2. The rostral hypothalamic regions, such as nucleus broca ventralis, preoptic area and anterior hypothalamic region, responded to the microinjection of endogenous pyrogen or interleukin-1 by producing both fever and acute phase responses. 3. The microinjection of endogenous pyrogen or interleukin-1 into the rostral hypothalamic regions significantly decreased the plasma levels of iron and zinc concentration 8 and 24 h after injection. The circulating leucocyte count increased 8 h after injection. However, neither the injections of endogenous pyrogen nor interleukin-1 affected the number of red blood cells. 4. The present results show that the rostral hypothalamic regions respond directly to endogenous pyrogen or interleukin-1 with the consequent development of fever and acute phase responses. PMID:2514261

Adipose tissue branched chain amino acid (BCAA) metabolism modulates circulating BCAA levels.

PubMed

Herman, Mark A; She, Pengxiang; Peroni, Odile D; Lynch, Christopher J; Kahn, Barbara B

2010-04-09

Whereas the role of adipose tissue in glucose and lipid homeostasis is widely recognized, its role in systemic protein and amino acid metabolism is less well-appreciated. In vitro and ex vivo experiments suggest that adipose tissue can metabolize substantial amounts of branched chain amino acids (BCAAs). However, the role of adipose tissue in regulating BCAA metabolism in vivo is controversial. Interest in the contribution of adipose tissue to BCAA metabolism has been renewed with recent observations demonstrating down-regulation of BCAA oxidation enzymes in adipose tissue in obese and insulin-resistant humans. Using gene set enrichment analysis, we observe alterations in adipose-tissue BCAA enzyme expression caused by adipose-selective genetic alterations in the GLUT4 glucose-transporter expression. We show that the rate of adipose tissue BCAA oxidation per mg of tissue from normal mice is higher than in skeletal muscle. In mice overexpressing GLUT4 specifically in adipose tissue, we observe coordinate down-regulation of BCAA metabolizing enzymes selectively in adipose tissue. This decreases BCAA oxidation rates in adipose tissue, but not in muscle, in association with increased circulating BCAA levels. To confirm the capacity of adipose tissue to modulate circulating BCAA levels in vivo, we demonstrate that transplantation of normal adipose tissue into mice that are globally defective in peripheral BCAA metabolism reduces circulating BCAA levels by 30% (fasting)-50% (fed state). These results demonstrate for the first time the capacity of adipose tissue to catabolize circulating BCAAs in vivo and that coordinate regulation of adipose-tissue BCAA enzymes may modulate circulating BCAA levels.

Sclerostin serum levels in patients with systemic autoimmune diseases

PubMed Central

Fernández-Roldán, Concepción; Genre, Fernanda; López-Mejías, Raquel; Ubilla, Begoña; Mijares, Verónica; Cano, Daniel Sánchez; Robles, Concepción López; Callejas-Rubio, José Luis; Fernández, Raquel Ríos; Ruiz, Manuela Expósito; González-Gay, Miguel Á; Centeno, Norberto Ortego

2016-01-01

Systemic autoimmune diseases (SADs) are associated with lower bone mass and an increased risk of fractures. Sclerostin has a pivotal role in bone metabolism. Available data on circulating sclerostin levels in healthy subjects are limited, whereas those in SAD patients are absent. Our objective was to determine circulating sclerostin concentrations in systemic lupus erythematosus (SLE), systemic sclerosis (SSc) and Crohn's disease (CD) patients, and to analyze the factors associated with sclerostin concentrations. In this cross-sectional case–control study, serum sclerostin levels were measured in 38 SLE patients, 20 CD patients, 8 SSc patients and 20 healthy controls using a sclerostin ELISA. The mean values of the sclerostin (95% confidence interval) were 35.36 pmol l−1 (12–101) in patients and 33.92 pmol l−1 (2.31–100) in control subjects. The mean sclerostin value was 36.4 pmol l−1 (22.1–48.5) in SLE patients, 26.7 pmol l−1 (17.3–36.3) in CD patients and 51.8 pmol l−1 (26.5–77.1) in SSc patients (P=0.001). Serum sclerostin levels were positively correlated with age (P<0.001), body mass index (BMI) (P=0.01) and lumbar spine Z-score (P=0.001) and negatively with creatinine clearance (P=0.001). Glucocorticoid treatment did not affect sclerostin levels. Sclerostin levels seem to have a heterogeneous pattern in different autoimmune diseases. SLE and SSc patients did not differ from healthy controls regarding sclerostin levels. The CD group had significantly lower values compared with SSc patients. Factors associated with sclerostin levels in autoimmune diseases seem to be the same than in the general population. PMID:26909149

Sclerostin serum levels in patients with systemic autoimmune diseases.

PubMed

Fernández-Roldán, Concepción; Genre, Fernanda; López-Mejías, Raquel; Ubilla, Begoña; Mijares, Verónica; Cano, Daniel Sánchez; Robles, Concepción López; Callejas-Rubio, José Luis; Fernández, Raquel Ríos; Ruiz, Manuela Expósito; González-Gay, Miguel Á; Ortego Centeno, Norberto

2016-01-01

Systemic autoimmune diseases (SADs) are associated with lower bone mass and an increased risk of fractures. Sclerostin has a pivotal role in bone metabolism. Available data on circulating sclerostin levels in healthy subjects are limited, whereas those in SAD patients are absent. Our objective was to determine circulating sclerostin concentrations in systemic lupus erythematosus (SLE), systemic sclerosis (SSc) and Crohn's disease (CD) patients, and to analyze the factors associated with sclerostin concentrations. In this cross-sectional case-control study, serum sclerostin levels were measured in 38 SLE patients, 20 CD patients, 8 SSc patients and 20 healthy controls using a sclerostin ELISA. The mean values of the sclerostin (95% confidence interval) were 35.36 pmol l(-1) (12-101) in patients and 33.92 pmol l(-1) (2.31-100) in control subjects. The mean sclerostin value was 36.4 pmol l(-1) (22.1-48.5) in SLE patients, 26.7 pmol l(-1) (17.3-36.3) in CD patients and 51.8 pmol l(-1) (26.5-77.1) in SSc patients (P=0.001). Serum sclerostin levels were positively correlated with age (P<0.001), body mass index (BMI) (P=0.01) and lumbar spine Z-score (P=0.001) and negatively with creatinine clearance (P=0.001). Glucocorticoid treatment did not affect sclerostin levels. Sclerostin levels seem to have a heterogeneous pattern in different autoimmune diseases. SLE and SSc patients did not differ from healthy controls regarding sclerostin levels. The CD group had significantly lower values compared with SSc patients. Factors associated with sclerostin levels in autoimmune diseases seem to be the same than in the general population.

Plasma serpinB1 is related to insulin sensitivity but not pancreatic β-Cell function in non-diabetic adults.

PubMed

Glicksman, Michael; Asthana, Asha; Abel, Brent S; Walter, Mary F; Skarulis, Monica C; Muniyappa, Ranganath

2017-03-01

Pancreatic β -cell dysfunction because of reduced β -cell mass and function is a primary determinant in the progression of diabetes. Increase in β -cell mass and compensatory hyperinsulinaemia is frequently associated with insulin-resistant states. Although the humoral factors mediating this compensatory response are unknown, serpinB1, a protease inhibitor, has recently been proposed to be one such factor. In this study, we examine the relationships between plasma serpinB1, insulin sensitivity, and pancreatic β -cell function in non-diabetic individuals. 117 subjects (women, n  = 50, men, n  = 67; age= 37.6 ± 10.8; BMI=31.1 ± 7.7 kg/m 2 ) underwent an insulin-modified frequently sampled intravenous glucose tolerance test (FSIVGTT) at the NIH Clinical Research Center. Acute insulin response (AIR) and insulin sensitivity index (SI) were obtained from the FSIVGTT with MINMOD analysis. The Quantitative Insulin Sensitivity Check Index (QUICKI) was calculated from fasting insulin and glucose values. Plasma serpinB1 levels were measured using an ELISA assay. Simple linear correlation analyses were performed to evaluate the relationship between serpinB1 and measures of insulin sensitivity and β -cell function. Circulating serpinB1 levels were unrelated to age, sex, race, BMI, or percent body fat. SI but not AIR significantly correlated with circulating serpinB1 levels ( r  = 0.23, P  < 0.05). QUICKI tended to positively correlate with serpinB1 ( r  = 0.16, P  = 0.09). Circulating serpinB1 is directly associated with insulin sensitivity but not β -cell function in non-diabetic adults. Whether this modest association plays a role in insulin sensitivity in humans remains to be clarified. Published [2017]. This article is a U.S. Government work and is in the public domain in the USA.