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A low cartilage formation and repair endotype predicts radiographic progression of symptomatic knee osteoarthritis.
Luo, Y, Samuels, J, Krasnokutsky, S, Byrjalsen, I, Kraus, VB, He, Y, Karsdal, MA, Abramson, SB, Attur, M, Bay-Jensen, AC
Journal of orthopaedics and traumatology : official journal of the Italian Society of Orthopaedics and Traumatology. 2021;(1):10
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Abstract
BACKGROUND Osteoarthritis (OA) is a disease with multiple endotypes. A hallmark of OA is loss of cartilage; however, it is evident that the rate of cartilage loss differs among patients, which may partly be attributed to differential capacity for cartilage repair. We hypothesize that a low cartilage repair endotype exists and that such endotypes are more likely to progress radiographically. The aim of this study is to examine the associations of level of cartilage formation with OA severity and radiographic OA progression. We used the blood-based marker PRO-C2, reflecting type II collagen formation, to assess levels of cartilage formation. MATERIALS AND METHODS The type II collagen propeptide PRO-C2 was measured in the serum/plasma of knee OA subjects from New York University (NYU, n = 106) and a subcohort of the phase III oral salmon calcitonin (sCT) trial SMC021-2301 (SMC, n = 147). Risk of radiographic medial joint space narrowing (JSN) over 24 months was compared between quartiles (very low, low, moderate, and high) of PRO-C2. Associations were adjusted for age, gender, BMI, race, baseline pain levels, and baseline joint space width. RESULTS In both the NYU and SMC cohorts, subjects with low PRO-C2 levels had greater JSN compared with subjects with high PRO-C2. Mean difference in JSN between subjects with very low and high levels of PRO-C2 was 0.65 mm (p = 0.002), corresponding to a 3.4 (1.4-8.6)-fold higher risk of progression. There was no significant effect of sCT treatment, compared with placebo, on JSN over 2 years before stratification based on baseline PRO-C2. However, there were proportionately fewer progressors in the sCT arm of the very low/low PRO-C2 group compared with the moderate/high group (Chi squared = 6.5, p = 0.011). CONCLUSION Serum/plasma level of type II collagen formation, PRO-C2, may be an objective indicator of a low cartilage repair endotype, displaying radiographic progression and superior response to a proanabolic drug. LEVEL OF EVIDENCE Level III post hoc exploratory analysis of one longitudinal cohort and a sub-study from one phase III clinical trial.
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Effects of upper-body resistance exercise training on serum nesfatin-1 level, insulin resistance, and body composition in obese paraplegic men.
Mogharnasi, M, TaheriChadorneshin, H, Papoli-Baravati, SA, Teymuri, A
Disability and health journal. 2019;(1):29-34
Abstract
BACKGROUND As a recently discovered adipokine, nesfatin-1 is conducive to insulin sensitivity, lipid profile, energy balance, and probably obesity. OBJECTIVE The aim of the present study was to investigate the effect of upper-body resistance exercise training (RET) on nesfatin-1 levels, insulin resistance, lipid profile, and body composition in obese paraplegic men. METHODS Twenty obese paraplegic men were randomly assigned into control and upper-body RET groups. Upper-body RET was performed for 8 weeks, 3 sessions per week at an intensity corresponding to 60-80% maximum amount of force that can be generated in one maximal contraction in 5 stations (bench press, seated rows, sitting lat pulldown, arm extension, and arm curls). Body fat percentage was determined according to 4-sites skinfold protocol of Durnin and Womersley and Siri equation. Obesity for spinal cord injury patients in the current study was set at BMI >22 kg/m2. Data were statistically analyzed by paired and independent t-test (P < 0.05). RESULTS We found significant improvements in serum levels of nesfatin-1 (21.13%), insulin sensitivity (8.95%), and high-density lipoprotein (10.87%). Other lipid profile markers, i.e. low-density lipoprotein (4.32%), cholesterol (8.20%), and triglyceride (15.10%) reduced significantly after upper-body RET. Moreover, upper-body RET led to a significant reduction in body mass index (2.36%), body fat percentage (2.79%), and waist-to-hip ratio (2.40%). CONCLUSION Upper-body RET improved insulin sensitivity, lipid profile, and body composition in paraplegic men. Serum nefastin-1 may be a potential marker of success in weight management in this population.
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The effects of Nigella sativa on thyroid function, serum Vascular Endothelial Growth Factor (VEGF) - 1, Nesfatin-1 and anthropometric features in patients with Hashimoto's thyroiditis: a randomized controlled trial.
Farhangi, MA, Dehghan, P, Tajmiri, S, Abbasi, MM
BMC complementary and alternative medicine. 2016;(1):471
Abstract
BACKGROUND Hashimoto's thyroiditis is an autoimmune disorder and the most common cause of hypothyroidism. The use of Nigella sativa, a potent herbal medicine, continues to increase worldwide as an alternative treatment of several chronic diseases including hyperlipidemia, hypertension and type 2 diabetes mellitus (T2DM). The aim of the current study was to evaluate the effects of Nigella sativa on thyroid function, serum Vascular Endothelial Growth Factor (VEGF) - 1, Nesfatin-1 and anthropometric features in patients with Hashimoto's thyroiditis. METHODS Forty patients with Hashimoto's thyroiditis, aged between 22 and 50 years old, participated in the trial and were randomly allocated into two groups of intervention and control receiving powdered Nigella sativa or placebo daily for 8 weeks. Changes in anthropometric variables, dietary intakes, thyroid status, serum VEGF and Nesfatin-1 concentrations after 8 weeks were measured. RESULTS Treatment with Nigella sativa significantly reduced body weight and body mass index (BMI). Serum concentrations of thyroid stimulating hormone (TSH) and anti-thyroid peroxidase (anti-TPO) antibodies decreased while serum T3 concentrations increased in Nigella sativa-treated group after 8 weeks. There was a significant reduction in serum VEGF concentrations in intervention group. None of these changes had been observed in placebo treated group. In stepwise multiple regression model, changes in waist to hip ratio (WHR) and thyroid hormones were significant predictors of changes in serum VEGF and Nesgfatin-1 values in Nigella sativa treated group (P < 0.05). CONCLUSIONS Our data showed a potent beneficial effect of powdered Nigella sativa in improving thyroid status and anthropometric variables in patients with Hashimoto's thyroiditis. Moreover, Nigella sativa significantly reduced serum VEGF concentrations in these patients. Considering observed health- promoting effect of this medicinal plant in ameliorating the disease severity, it can be regarded as a useful therapeutic approach in management of Hashimoto's thyroiditis. TRIAL REGISTRATION Iranian registry of clinical trials (registration number IRCT2015021719082N4 - Registered March-15-2015).
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Low-dose spironolactone reduces plasma fibulin-1 levels in patients with type 2 diabetes and resistant hypertension.
Oxlund, CS, Cangemi, C, Henriksen, JE, Jacobsen, IA, Gram, J, Schousboe, K, Tarnow, L, Argraves, WS, Rasmussen, LM
Journal of human hypertension. 2015;(1):28-32
Abstract
Diabetic patients with hypertension are at particularly high risk of vascular damage and consequently cardiovascular and renal disease. Fibulin-1, an extracellular matrix glycoprotein, is increased in arterial tissue and plasma from individuals with type 2 diabetes. This study aimed to evaluate whether antihypertensive treatment with spironolactone changes plasma fibulin-1 levels. In a multicenter, double-blind, randomized, placebo-controlled study, 119 patients with type 2 diabetes and resistant hypertension were included. A dose of spironolactone 25 mg or matching placebo was added to previous treatment at randomization. Blood pressure (BP) and plasma fibulin-1 were measured at baseline and at 16 weeks follow-up. Overall, 112 patients completed the study. All measures of BP were reduced in the spironolactone group at follow-up. Plasma fibulin-1 was significantly reduced after spironolactone treatment (P=0.009), but increased after placebo (P=0.017). Baseline plasma fibulin-1 correlated with BP and estimated glomerular filtration rate. Increased levels of plasma fibulin-1 (P=0.004) were observed in diabetic participants reporting erectile dysfunction as compared with participants who did not. Treatment with low-dose spironolactone reduced plasma fibulin-1 levels in patients with type 2 diabetes and resistant hypertension. This supports the hypothesis that the antihypertensive effect of the mineralocorticoid receptor blocker in part may be due to regression of vascular remodeling.
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Vitamin K2 supplementation in haemodialysis patients: a randomized dose-finding study.
Caluwé, R, Vandecasteele, S, Van Vlem, B, Vermeer, C, De Vriese, AS
Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association. 2014;(7):1385-90
Abstract
BACKGROUND Haemodialysis patients suffer from accelerated vascular calcification. The vitamin K-dependent matrix Gla protein (MGP) is one of the most powerful inhibitors of vascular calcification. Haemodialysis patients have high levels of the inactive form of MGP (desphosphorylated-uncarboxylated-MGP, dp-uc-MGP) and may benefit from pharmacological doses of vitamin K2 (menaquinone) to improve the calcification inhibitory activity of MGP. METHODS To determine the optimal dose of menaquinone-7 (MK-7) for MGP activation, 200 chronic haemodialysis patients were recruited to randomly receive 360, 720 or 1080 µg of MK-7 thrice weekly for 8 weeks. Dp-uc-MGP was measured at baseline and after 8 weeks. Dietary intake of vitamin K1 (phylloquinone) and menaquinone was estimated based on a detailed questionnaire. RESULTS At baseline, dp-uc-MGP was not associated with phylloquinone intake (P = 0.92), but correlated inversely with menaquinone intake (P = 0.023). MK-7 supplementation dose dependently reduced dp-uc-MGP. The levels decreased by 17, 33 and 46% in the respective groups. Drop-outs were mainly due to gastrointestinal side-effects related to the unpleasant smell of the tablets. CONCLUSIONS Chronic haemodialysis patients have high levels of inactive MGP, possibly related to a low dietary vitamin K intake. Pharmacological doses of MK-7 dose-dependently reduce dp-uc-MGP. Menaquinone supplementation may be a novel approach to prevent vascular calcifications in chronic haemodialysis patients.
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Genetic modifiers of cardiorespiratory fitness response to lifestyle intervention.
Peter, I, Papandonatos, GD, Belalcazar, LM, Yang, Y, Erar, B, Jakicic, JM, Unick, JL, Balasubramanyam, A, Lipkin, EW, Delahanty, LM, et al
Medicine and science in sports and exercise. 2014;(2):302-11
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Abstract
PURPOSE Numerous prospective studies indicate that improved cardiorespiratory fitness reduces type 2 diabetes risk and delays disease progression. We hypothesized that genetic variants modify fitness response to an intensive lifestyle intervention (ILI) in the Action for Health in Diabetes (Look AHEAD) randomized clinical trial, aimed to detect whether ILI will reduce cardiovascular events in overweight/obese subjects with type 2 diabetes compared with a standard of care. METHODS Polymorphisms in established fitness genes and in all loci assayed on the Illumina CARe iSelect chip were examined as predictors of change in MET level, estimated using a treadmill test, in response to a 1-yr intervention in 3899 participants. RESULTS We identified a significant signal in previously reported fitness-related gene RUNX1 that was associated with 1-yr METs response in ILI (0.19 ± 0.04 MET less improvement per minor allele copy; P = 1.9 × 10(-5)) and genotype-intervention interaction (P = 4.8 × 10(-3)). In the chipwide analysis, FKBP7 rs17225700 showed a significant association with ILI response among subjects not receiving beta-blocker medications (0.47 ± 0.09 METs less improvement; P = 5.3 × 10(-5)) and genotype-treatment interaction (P = 5.3 × 10(-7)). The Gene Relationships Among Implicated Loci pathway-based analysis identified connections between associated genes, including those influencing vascular tone, muscle contraction, cardiac energy substrate dynamics, and muscle protein synthesis. CONCLUSIONS This is the first study to identify genetic variants associated with fitness responses to a randomized lifestyle intervention in overweight/obese diabetic individuals. RUNX1 and FKBP7, involved in erythropoesis and muscle protein synthesis, respectively, are related to change in cardiorespiratory fitness in response to exercise.
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TGF-β1-induced phospholamban expression alters esophageal smooth muscle cell contraction in patients with eosinophilic esophagitis.
Beppu, LY, Anilkumar, AA, Newbury, RO, Dohil, R, Broide, DH, Aceves, SS
The Journal of allergy and clinical immunology. 2014;(5):1100-1107.e4
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Abstract
BACKGROUND Eosinophilic esophagitis (EoE) is a chronic antigen-mediated disease characterized by esophageal eosinophilia, remodeling, and fibrosis. TGF-β1 is a central regulator of EoE remodeling and increases esophageal smooth muscle (ESM) cell contraction. OBJECTIVE In this study we aimed to understand the molecular mechanisms by which TGF-β1 could induce ESM cell contraction. METHODS We used primary human ESM cells and esophageal myofibroblasts (EMFs) to assess the mechanisms of TGF-β1-induced contraction. We analyzed the expression, phosphorylation, and function of phospholamban (PLN), a sarcoendoplasmic reticulum regulatory protein induced by TGF-β1. Expression of PLN, phospho-PLN, and its regulatory pathway was analyzed in the ESM of biopsy specimens from patients with EoE and control subjects. Gene silencing in EMFs from patients with EoE was used to understand the role of PLN in contraction. RESULTS TGF-β1 induced and phosphorylated PLN in primary human ESM cells and EMFs from patients with EoE. PLN and phospho-PLN levels were increased in smooth muscle from patients with EoE compared with that seen in smooth muscle from control subjects in vivo. PLN inhibition significantly diminished TGF-β1-induced EMF contraction in patients with EoE. PLN expression and ESM/EMF contraction depended on TGF-β receptor I signals. CONCLUSION We describe a previously unrecognized mechanism for ESM cell contraction that depends on TGF-β1, its receptors, and PLN. Because PLN levels are increased in smooth muscle from patients with EoE and PLN silencing diminishes contraction, we provide a novel potential mechanistic framework and therapeutic target for ESM dysfunction in patients with EoE.
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SPARCL1 expression increases with preoperative radiation therapy and predicts better survival in rectal cancer patients.
Kotti, A, Holmqvist, A, Albertsson, M, Sun, XF
International journal of radiation oncology, biology, physics. 2014;(5):1196-202
Abstract
PURPOSE The secreted protein acidic and rich in cysteine-like 1 (SPARCL1) is expressed in various normal tissues and many types of cancers. The function of SPARCL1 and its relationship to a patient's prognosis have been studied, whereas its relationship to radiation therapy (RT) is not known. Our aim was to investigate the expression of SPARCL1 in rectal cancer patients who participated in a clinical trial of preoperative RT. METHODS AND MATERIALS The study included 136 rectal cancer patients who were randomized to undergo preoperative RT and surgery (n=63) or surgery alone (n=73). The expression levels of SPARCL1 in normal mucosa (n=29), primary tumor (n=136), and lymph node metastasis (n=35) were determined by immunohistochemistry. RESULTS Tumors with RT had stronger SPARCL1 expression than tumors without RT (P=.003). In the RT group, strong SPARCL1 expression was related to better survival than weak expression in patients with stage III tumors, independent of sex, age, differentiation, and margin status (P=.022; RR = 18.128; 95% confidence interval, 1.512-217.413). No such relationship was found in the non-RT group (P=.224). Further analysis of interactions among SPARCL1 expression, RT, and survival showed statistical significance (P=.024). In patients with metastases who received RT, strong SPARCL1 expression was related to better survival compared to weak expression (P=.041) but not in the non-RT group (P=.569). CONCLUSIONS SPARCL1 expression increases with RT and is related to better prognosis in rectal cancer patients with RT but not in patients without RT. This result may help us to select the patients best suited for preoperative RT.
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Circulating levels of matrix gla protein and progression of aortic stenosis: a substudy of the Aortic Stenosis Progression Observation: Measuring Effects of rosuvastatin (ASTRONOMER) trial.
Capoulade, R, Côté, N, Mathieu, P, Chan, KL, Clavel, MA, Dumesnil, JG, Teo, KK, Tam, JW, Fournier, D, Després, JP, et al
The Canadian journal of cardiology. 2014;(9):1088-95
Abstract
BACKGROUND Matrix γ-carboxyglutamate protein is an inhibitor of cardiovascular calcification. The objective of this substudy of the Aortic Stenosis Progression Observation: Measuring Effects of Rosuvastatin (ASTRONOMER) trial was to examine the relationship between total (ie, carboxylated [active] form + uncarboxylated [inactive] form) circulating desphosphorylated matrix γ-carboxyglutamate protein (dpMGP) level and the progression rate of aortic stenosis (AS). METHODS Among the patients included in the ASTRONOMER trial, 215 patients had measures of baseline circulating total dpMGP level and an echocardiographic follow-up (mean follow-up: 3.5 ± 1.3 years). Progression of AS was assessed according to the measurement of the annualized increase in peak aortic jet velocity. RESULTS In the whole cohort, baseline dpMGP level was associated with faster progression rate of peak aortic jet velocity (r = 0.16; P = 0.02) in individual analysis but not in multivariable analysis (P = 0.40). However, there was a significant interaction (P = 0.03) between dpMGP level and age, with respect to the effect on AS progression. After dichotomization according to median value of age (ie, 57 years old), total dpMGP level was associated with faster AS progression rate (r = 0.24; P = 0.008) in the younger patients, and this association remained significant in multivariable analysis (P = 0.04), but not in the older ones. The independent correlates of dpMGP level were fasting glucose (P = 0.009) and oxidized low-density lipoprotein (P = 0.01). CONCLUSIONS This is the first prospective study to demonstrate a relationship between increased circulating levels of total dpMGP and faster progression rate of AS in younger individuals. Future studies are needed to determine if dpMGP is simply a marker or a contributing factor to ectopic mineralization of aortic valve.
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Plasma nesfatin-1 level in obese patients after acupuncture: a randomised controlled trial.
Guo, Y, Xing, M, Sun, W, Yuan, X, Dai, H, Ding, H
Acupuncture in medicine : journal of the British Medical Acupuncture Society. 2014;(4):313-7
Abstract
BACKGROUND Nesfatin-1 is an anorexigenic hormone suggested to regulate obesity. OBJECTIVE To investigate the relationship between nesfatin-1 level and anthropometric and metabolic parameters in obese patients, and examine the change in plasma nesfatin-1 level after acupuncture treatment. METHODS 64 obese adult patients without diabetes and 58 normal weight control subjects were enrolled in this study. The obese patients were randomly divided into an acupuncture plus diet group (n=32) and a diet only group (n=32). Measurements were repeated after 45 days. RESULTS Body mass index (BMI), waist and hip circumferences, serum insulin, lipoprotein and insulin resistance measures were significantly higher, and plasma nesfatin-1 level was significantly lower, in obese patients than in normal weight controls. In addition, negative correlations were found between plasma nesfatin-1 level and BMI, waist and hip circumferences. Weight reduction in participants after acupuncture and diet restriction was 7.0% and 4.3%, respectively. Plasma nesfatin-1 level increased from 2.75±1.16 to 3.44±1.28 ng/mL and from 2.86±1.07 to 3.23±1.06 ng/mL in acupuncture and diet groups, respectively; the difference was significant, p<0.05. CONCLUSIONS Plasma nesfatin-1 level is reduced in obese adults, and is increased after acupuncture. The beneficial effect of acupuncture on obesity is associated with increased plasma nesfatin-1 level.