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Association of HTRA1 and ARMS2 gene polymorphisms with response to intravitreal ranibizumab among neovascular age-related macular degenerative subjects.
Mohamad, NA, Ramachandran, V, Mohd Isa, H, Chan, YM, Ngah, NF, Ching, SM, Hoo, FK, Wan Sulaiman, WA, Inche Mat, LN, Mohamed, MH
Human genomics. 2019;(1):13
Abstract
BACKGROUND The association of HTRA1 rs11200638 and ARMS2 rs10490924 gene polymorphisms with response to intravitreal ranibizumab therapy among neovascular AMD (nAMD) subjects in Malaysia was determined in this study, followed by the expression of HTRA1 and ARMS2 genes. RESULTS Both single nucleotide polymorphisms (SNPs) recorded a significant association between nAMD and controls with HTRA1 rs11200638 at P = 0.018 (OR = 1.52, 95% CI = 1.07-215) and ARMS2 rs10490924 at P < 0.001 (OR = 2.44, 95% CI = 1.75-3.42). An association was also observed in response to ranibizumab for both SNPs in a logistic regression analysis (P < 0.001). The mRNA levels in the HTRA1 variant between responder and non-responder groups were significantly different for the homozygous non-risk GG genotype (P = 0.032). CONCLUSIONS The HTRA1 rs11200638 and ARMS2 rs10490924 gene polymorphisms are associated with nAMD among Malaysians. Both gene polymorphisms were also correlated with response to intravitreal ranibizumab therapy based on visual and anatomical outcomes especially the HTRA1 rs11200638 variant.
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Phenylbutyrate improves nitrogen disposal via an alternative pathway without eliciting an increase in protein breakdown and catabolism in control and ornithine transcarbamylase-deficient patients.
Marini, JC, Lanpher, BC, Scaglia, F, O'Brien, WE, Sun, Q, Garlick, PJ, Jahoor, F, Lee, B
The American journal of clinical nutrition. 2011;(6):1248-54
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Abstract
BACKGROUND Phenylbutyrate is a drug used in patients with urea cycle disorder to elicit alternative pathways for nitrogen disposal. However, phenylbutyrate administration decreases plasma branched-chain amino acid (BCAA) concentrations, and previous research suggests that phenylbutyrate administration may increase leucine oxidation, which would indicate increased protein degradation and net protein loss. OBJECTIVE We investigated the effects of phenylbutyrate administration on whole-body protein metabolism, glutamine, leucine, and urea kinetics in healthy and ornithine transcarbamylase-deficient (OTCD) subjects and the possible benefits of BCAA supplementation during phenylbutyrate therapy. DESIGN Seven healthy control and 7 partial-OTCD subjects received either phenylbutyrate or no treatment in a crossover design. In addition, the partial-OTCD and 3 null-OTCD subjects received phenylbutyrate and phenylbutyrate plus BCAA supplementation. A multitracer protocol was used to determine the whole-body fluxes of urea and amino acids of interest. RESULTS Phenylbutyrate administration reduced ureagenesis by ≈15% without affecting the fluxes of leucine, tyrosine, phenylalanine, or glutamine and the oxidation of leucine or phenylalanine. The transfer of (15)N from glutamine to urea was reduced by 35%. However, a reduction in plasma concentrations of BCAAs due to phenylbutyrate treatment was observed. BCAA supplementation did not alter the respective baseline fluxes. CONCLUSIONS Prolonged phenylbutyrate administration reduced ureagenesis and the transfer of (15)N from glutamine to urea without parallel reductions in glutamine flux and concentration. There were no changes in total-body protein breakdown and amino acid catabolism, which suggests that phenylbutyrate can be used to dispose of nitrogen effectively without adverse effects on body protein economy.
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Training does not affect protein turnover in pre- and early pubertal female gymnasts.
Boisseau, N, Persaud, C, Jackson, AA, Poortmans, JR
European journal of applied physiology. 2005;(3):262-7
Abstract
This study compared protein turnover in ten young female gymnasts [10.3 (0.5) years] engaged in regular intense physical training with ten age-matched controls [9.4 (0.6) years)]. Nitrogen flux ( Q), protein synthesis (PS), protein degradation (PD) and net protein turnover (NPB = PS-PD) were measured following a single oral dose of [(15)N]-glycine. The habitual dietary intake of each subject was assessed using a 7-day food record, with food portions being weighed before ingestion. The gymnasts had a low total energy intake which was unbalanced in the proportions of lipid, carbohydrate and protein. Protein flux was 7.19 (0.35) g.kg(-1).day(-1) in the gymnasts and 7.53 (0.81) g.kg(-1).day(-1) in the controls; protein synthesis was 6.06 (0.27) g.kg(-1).day(-1 )in the gymnasts and 6.53 (0.74) g.kg(-1).day(-1) in the controls; protein degradation was 5.45 (0.38) g.kg(-1).day(-1) in the gymnasts and 5.27 (0.74) g.kg(-1).day(-1) in the controls. All data are presented as means and standard errors of the mean (SEM). There were no statistical differences for protein flux, protein synthesis or protein degradation between the two groups. However, NPB was lower (-14%) in the trained gymnasts than in the control group ( P <0.05), which might be explained by a greater protein ingestion in the control group on the day of the protocol ( P <0.05). These results show that in pre- and early pubertal female gymnasts intense training does not exert a demonstrable effect on protein turnover.
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Adiponectin is independently associated with glycosylated haemoglobin.
Fernández-Real, JM, Botas-Cervero, P, López-Bermano, A, Casamitjana, R, Funahashi, T, Delgado, E, Kihara, S, Ricart, W
European journal of endocrinology. 2004;(2):201-5
Abstract
BACKGROUND In humans, adiponectin has been demonstrated to circulate in inverse proportion to the degree of insulin resistance. OBJECTIVE To investigate the association between adiponectin and glycosylated haemoglobin (HbA1c) in a population-based study. DESIGN AND METHODS Two hundred and ninety-seven individuals aged 30-75 years were enrolled in a cross-sectional study. They included patients with type 2 (non-insulin-dependent) diabetes mellitus and stable, good metabolic control (n=32) and individuals with glucose intolerance (n=54). Adiponectin was measured using a sandwich enzyme-linked immunosorbent assay (intra-assay and interassay coefficients of variation 3.3 and 7.4% respectively). RESULTS Adiponectin correlated with age (r=0.161; P=0.006), body mass index (r=-0.197; P=0.001), diastolic blood pressure (r=-0.181; P=0.005), fasting glucose and HbA1c (r=-0.251 and r=-0.22 respectively; P<0.0001), high-density lipoprotein cholesterol (r=0.442; P<0.001) and serum triglycerides (r=-362; P<0.001). In multiple regression analysis, sex, age, fasting and post-load glucose, and adiponectin independently contributed to 40% of the variance in HbA1c. Among individuals with normal glucose tolerance, fasting glucose (P=0.0033), post-load glucose (P=0.0015), age (P=0.001) and adiponectin (P=0.0083) independently contributed to 21% of the variance in HbA1c. CONCLUSION Adiponectin is significantly associated with altered glucose metabolism and independently contributes to the variance of HbA1c in a population-based manner.
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Plasma adiponectin response to acute exercise in healthy subjects.
Ferguson, MA, White, LJ, McCoy, S, Kim, HW, Petty, T, Wilsey, J
European journal of applied physiology. 2004;(2-3):324-9
Abstract
Adipose tissue secretes adiponectin, an adipocytokine that is involved in the regulation of insulin sensitivity. Following acute exercise, insulin sensitivity has been shown to increase. Increased adiponectin following exercise may be related to the change in insulin sensitivity. The purpose of the present study was to characterize the effect of a single cycle exercise session on adiponectin and to compare the exercise effects between healthy male and female subjects. Plasma concentrations of adiponectin, tissue necrosis factor-alpha (TNF-alpha), insulin, glucose, and leptin were assessed before and immediately after a 60-minute stationary cycle ergometry session at 65% of Vdot;O(2max). Male and female subjects were matched for cardiorespiratory fitness and body composition and dietary intake was controlled for the three days prior to the exercise trial. At rest, adiponectin concentration was not associated with percentage body fat, body mass index (BMI), fitness, or resting plasma variables ( P>0.05). Following exercise, neither male nor female subjects exhibited changes in adiponectin or leptin concentrations ( P>0.05). TNF-alpha exhibited a time main effect increase with exercise ( P<0.05), but there were no gender differences. These results suggest that plasma adiponectin concentrations do not change with exercise in healthy male or female subjects. Results are given as mean (SE).
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Decreased plasma concentration of a novel anti-inflammatory protein--adiponectin--in hypertensive men with coronary artery disease.
Dzielińska, Z, Januszewicz, A, Wiecek, A, Demkow, M, Makowiecka-Cieśla, M, Prejbisz, A, Kadziela, J, Mielniczuk, R, Florczak, E, Janas, J, et al
Thrombosis research. 2003;(5-6):365-9
Abstract
AIMS: Recent studies indicate that adiponectin may have anti-inflammatory and anti-atherogenic properties, suggesting that hypoadiponectinemia can play a role in the pathogenesis of cardiovascular disease. Therefore the aim of the study was to assess plasma adiponectin concentration in hypertensive male patients with coronary artery disease (CAD). Associations of adiponectinemia with other cardiovascular risk factors were also analysed. METHODS AND RESULTS The study included 99 consecutive male patients (median age 57 years) with hypertension and CAD who at the same time underwent coronary and renal angiography. The control group consisted of 62 BMI-matched healthy male blood donors (median age 48 years). Plasma adiponectin level was significantly lower in the CAD group as compared to the control group (4.01 +/- 0.18 vs. 4.88 +/- 0.24 microg/ml; p<0.01). There were no differences in plasma adiponectin concentration between hypertensive CAD patients with and without atherosclerotic renal artery stenosis. In the CAD group plasma adiponectin concentration correlated with levels of creatinine (r=0.56; p<0.001), HDL cholesterol (r=0.24; p<0.05), BMI (r=-0.33; p<0.001), glucose (r=-0.22; p<0.05) and triglycerides (r=-0.25; p<0.05). No correlation was found between plasma adiponectin and homocysteine concentrations. In a multivariate stepwise logistic regression model increasing concentrations of adiponectin were independently and significantly associated with a lower risk of CAD (OR 0.58 95% CI 0.42-0.81 p<0.001). CONCLUSIONS Our results showed decreased plasma adiponectin concentration in the studied group of hypertensive men with CAD as compared to normotensive healthy subjects. This may suggest that decreased plasma adiponectin concentration is associated with a higher risk of CAD.
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Metabolic effects of norepinephrine and dobutamine in healthy volunteers.
Ensinger, H, Geisser, W, Brinkmann, A, Wachter, U, Vogt, J, Radermacher, P, Georgieff, M, Träger, K
Shock (Augusta, Ga.). 2002;(6):495-500
Abstract
The objective of the present study was to evaluate the effects of norepinephrine (n = 9) and dobutamine (n = 7) on carbohydrate and protein metabolism in healthy volunteers in comparison with a control group (n = 9). Norepinephrine (0.1 microg/kg min), dobutamine (5 microg/kg min), or placebo was infused for 240 min. The plasma concentration of glucose, lactate, epinephrine, norepinephrine, insulin, and glucagon were determined. Glucose and urea production and leucine flux were measured using a tracer technique. Norepinephrine caused a persisting rise in plasma glucose concentration, whereas the increase in glucose production was only transient. A minor increase in plasma lactate concentration was observed, but it did not exceed the physiological range. No change in leucine flux, urea production, or plasma concentration of insulin, glucagon, or epinephrine was found. Dobutamine slightly decreased glucose production, whereas the plasma concentration of glucose and lactate did not change. The reduction in leucine flux was paralleled by a decrease in urea production. No change in the plasma concentration of insulin, glucagon, or the catecholamines was observed. In conclusion, both norepinephrine and dobutamine have only minor metabolic effects. Because glucose production is enhanced by alpha1- and beta2-adrenoceptor stimulation, we conclude that dobutamine is only a weak agonist at these adrenoceptors. These minor metabolic actions may make both compounds suitable for critically ill patients because no further increase in metabolic rate should be caused.
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Effects of lowering circulating free fatty acid levels on protein metabolism in adult growth hormone deficient patients.
Nielsen, S, Jørgensen, JO, Hartmund, T, Nørrelund, H, Nair, KS, Christiansen, JS, Møller, N
Growth hormone & IGF research : official journal of the Growth Hormone Research Society and the International IGF Research Society. 2002;(6):425-33
Abstract
Our study was conducted to define the roles of lowering circulating free fatty acids (FFA) and of growth hormone (GH) replacement on protein metabolism in GH deficient patients. To isolate the specific effects of FFA and GH we studied seven adult subjects with GH deficiency four times: (A) with administration of GH and Acipimox (an inhibitor of lipolysis), (B) with GH, without Acipimox, (C) without GH, with Acipimox and (D) without either. Each study included a 3 h basal period and a 3 h euglycemic clamp. Amino acid metabolism was assessed by stable isotope dilution technique at the whole body level and across the forearm. Overall, we saw no intervention effect on protein metabolism, but when the two situations in which Acipimox was given were combined, Acipimox decreased basal plasma FFA concentrations by 75% and increased serum urea concentrations by 20%, whole body appearance rates (reflecting protein degradation) of phenylalanine (by 7%) and tyrosine (by 11%) and protein synthesis rates for phenylalanine (by 7%), whereas phenylalanine-to-tyrosine conversion was unaffected. Acipimox more than doubled net forearm phenylalanine release during the clamp and increased basal forearm phenylalanine disappearance (reflecting muscle protein synthesis). During the clamp whole body amino acid fluxes and phenylalanine-to-tyrosine conversion decreased together with a decrease in forearm protein breakdown. GH replacement did not affect any of these metabolic parameters. Although we failed to show any role for GH, the results show that lowering of FFA concentrations with Acipimox has pronounced effects on protein metabolism, including increased whole body and forearm protein breakdown, together with increased protein synthesis systemically and locally in the forearm. The increase in serum urea and a doubling of net forearm phenylalanine release after lowering of FFA strongly indicate that the overall effect is catabolic and supports a pivotal protein conserving role of lipids.
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Influence of diuretics on the concentration of proteins and other components of pleural transudates in patients with heart failure.
Romero-Candeira, S, Fernández, C, Martín, C, Sánchez-Paya, J, Hernández, L
The American journal of medicine. 2001;(9):681-6
Abstract
PURPOSE Diuretic therapy increases the total protein and lactate dehydrogenase concentrations in pleural fluid in patients with transudates due to heart failure, but the effect of diuresis on other substances in pleural fluid constituents is not known. SUBJECTS AND METHODS Twenty-one patients with transudative pleural effusions due to congestive heart failure were prospectively studied. Repeated diagnostic thoracentesis (mean +/- SD = 3 +/- 1; range, 2 to 6) was performed until the effusions were radiographically unapparent (5 +/- 2 days). Thirty-one patients with congestive heart failure who underwent only a single thoracentesis after diuretic therapy served as controls. We measured the concentrations of various components of pleural effusions in the serum and in the pleural fluid, and determined the serum-pleural fluid gradient (serum concentration minus pleural fluid concentration) and ratio (serum concentration divided by pleural fluid concentration). RESULTS The pleural concentrations of most components increased significantly (P <0.001) from the initial specimen to the final specimen: total protein, from 23 +/- 7 g/L to 33 +/- 9 g/L; albumin, from 13 +/- 4 g/L to 18 +/- 6 g/L; lactate dehydrogenase, from 177 +/- 62 U/L to 288 +/- 90 U/L; cholesterol, from 31 +/- 16 mg/dL to 52 +/- 22 mg/dL; and cholinesterase, from 1,304 +/- 616 U/L to 1,884 +/- 674 U/L. Expressed as percentage change, the increases in the serum-pleural fluid gradients for albumin (12% +/- 22%) and total protein (11% +/- 12%) were significantly less than the increases in their concentrations in pleural fluid (albumin, 47% +/- 49%; total protein, 48% +/- 40%) or in their pleural fluid/serum ratios (albumin, 27% +/- 29%; total protein, 38% +/- 34%). CONCLUSIONS The concentrations of the biochemical components commonly measured in pleural fluid increase progressively during diuretic therapy. Calculation of the serum-pleural fluid gradients for protein and albumin may be the most useful way to distinguish transudates from exudates in patients with congestive heart failure who have undergone diuresis.
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Calcitonin gene- and parathyroid hormone-related peptides in preeclampsia: effects of magnesium sulfate.
Halhali, A, Wimalawansa, SJ, Berentsen, V, Avila, E, Thota, CS, Larrea, F
Obstetrics and gynecology. 2001;(6):893-7
Abstract
OBJECTIVE To determine whether circulating levels of calcitonin gene-related peptide (CGRP) and parathyroid hormone-related peptide (PTHrP) are altered in preeclampsia, and to assess the effects of magnesium sulfate therapy on circulating levels of these two peptides. METHODS The study population included 25 women with preeclampsia and 25 normotensive controls of similar gestational age. The effects of magnesium sulfate therapy were evaluated in 17 of the 25 preeclamptic women. Circulating levels of immunoreactive CGRP and PTHrP, including calcium, magnesium, and phosphate in the maternal and umbilical cord serum were measured. RESULTS The frequency of preeclampsia subjects with nondetectable PTHrP (under 3 pg/mL) was significantly higher (92% versus 48%, P <.001), whereas maternal serum CGRP levels were significantly lower (50 +/- 19 versus 90 +/- 23 pg/mL, P <.001). Similarly, the frequency of newborns with nondetectable PTHrP levels in umbilical serum was significantly higher (68% versus 36%, P <.05), whereas the levels of CGRP were significantly lower (67 +/- 17 versus 79 +/- 16 pg/mL, P <.05). Magnesium sulfate treatment resulted in a significant increase in maternal circulating CGRP levels (64 +/- 17 versus 47 +/- 18 pg/mL, P <.05) with no changes in PTHrP. CONCLUSION Maternal circulating PTHrP and CGRP concentrations were significantly lower in women with preeclampsia, which may contribute to the development and maintenance of hypertension during pregnancy. Furthermore, magnesium sulfate therapy increased the levels of CGRP in the maternal circulation.