Interleukin 1B gene polymorphism is associated with baseline C-reactive protein levels in healthy individuals

C-reactive protein (CRP) is a sensitive marker of inflammation induced by both IL-6 and IL-1. Thus, genetic variation in these genes could be associated with the variety in C-reactive protein levels, and therefore with the severity of the entire inflammatory response. Even a subtle elevation in baseline CRP levels in healthy individuals has been found to significantly increase the risk for cardiovascular diseases. Therefore, to find out the possible role of pro-inflammatory cytokines in CRP baseline regulation we conducted a study of 338 healthy blood donors whose CRP levels were determined and whose single nucleotide polymorphisms of IL1A(C/T)-889, IL1B(C/T)-511, IL1B(C/T) + 3954, IL6(G/C)-174 and ILRN (a VNTR) both genotyped and haplotyped. The data revealed an association between CRP levels and the IL1B + 3954 genotype. Also, the bilocus haplotype IL1B-511*1/IL1B + 3954*2 was more frequent in subjects with below median CRP levels (< 0.72 mg/l), and composite genotype analysis of IL1B-511/IL1B + 3954 supported this finding. Our findings suggest that in healthy people, basal CRP levels are regulated by IL1B but not by IL6 genetics.     

Serum aspartate and alanine aminotransferase activities in protein energy malnutrition

The activities of serum aspartate and alanine aminotransferases were measured in protein energy malnutrition (PEM). These enzyme activities were both increased in PEM and fell as recovery was established. There was a marked reduction in the serum albumin level, and an inverse relationship was observed between the serum albumin levels and the enzyme activities. The relationship is discussed in the light of the hepatocellular damage of PEM. The assay of these enzyme activities along with estimation of serum albumin in PEM will prove very useful in the diagnosis of the liver damage that may occur in PEM before clinical manifestations are established.     

Gender differences in healthy ranges for serum alanine aminotransferase levels in adolescence

Background & Aims

There is a worldwide epidemic of obesity among adolescents who subsequently are at increased risk for the development of non alcoholic fatty liver disease (NAFLD). The serum alanine aminotransferase (ALT) is the most frequently used test for screening these individuals, but no age and gender-specific upper limits of normal (ULN) based on healthy population data in children are available. The objective of the present study was to define ULN for ALT in healthy children in order to use this as a tool for case finding.

Methods

A total of 975 school children (aged 7–18 years) were included in the study cohort. Highly significant correlations (all p<0.001) were noted between ALT values and measures of BMI, systolic and diastolic blood pressure, insulin levels, HOMA-IR, total cholesterol and triglyceride concentrations. In order to define the population with no risk factors, we excluded subjects having abnormal values for factors that correlated with ALT. This population comprised 186 boys and 185 girls.

Results

In boys, median serum ALT levels were 16 IU/L and 9, 11, 18, and 30 IU/L for the 5th, 25th, 75th, and 95th percentiles. In girls, median serum ALT was 13, and 7, 9, 16, and 21 IU/L for the 5th, 25th, 75th, and 95th percentiles, respectively. The ULNs for ALT were 30 IU/L and 21 IU/L for boys and girls respectively. We found a linear relationship between age and ALT in females (p<0.001) but not in males. By multiple logistic regression, independent predictors of an elevated ALT included the BMI, waist hip ratio and levels of serum total cholesterol. In females, age was an additional inverse predictor.

Conclusions

In children and adolescents, these normal limits for ALT should be applied. Those with persistent elevations should be investigated further.     

Testosterone-induced muscle hypertrophy is associated with an increase in satellite cell number in healthy,young men

Testosterone (T) supplementation in men induces muscle fiber hypertrophy. We hypothesized that T-induced increase in muscle fiber size is associated with a dose-dependent increase in satellite cell number. We quantitated satellite cell and myonuclear number by using direct counting and spatial orientation methods in biopsies of vastus lateralis obtained at baseline and after 20 wk of treatment with a gonadotropin-releasing hormone agonist and a 125-, 300-, or 600-mg weekly dose of T enanthate. T administration was associated with a significant increase in myonuclear number in men receiving 300- and 600-mg doses. The posttreatment percent satellite cell number, obtained by direct counting, differed significantly among the three groups (ANCOVA P < 0.000001); the mean posttreatment values (5.0 and 15.0%) in men treated with 300- and 600-mg doses were greater than baseline (2.5 and 2.5%, respectively, P < 0.05 vs. baseline). The absolute satellite cell number measured by spatial orientation at 20 wk (1.5 and 4.0/mm) was significantly greater than baseline (0.3 and 0.6/mm) in men receiving the 300- and 600-mg doses (P < 0.05). The change in percent satellite cell number correlated with changes in total (r = 0.548) and free T concentrations (r = 0.468). Satellite cell and mitochondrial areas were significantly higher and the nuclear-to-cytoplasmic ratio lower after treatment with 300- and 600-mg doses. We conclude that T-induced muscle fiber hypertrophy is associated with an increase in satellite cell number, a proportionate increase in myonuclear number, and changes in satellite cell ultrastructure.     

Testosterone-induced increase in muscle size in healthy young men is associated with muscle fiber hypertrophy

Administration of replacement doses of testosterone to healthy hypogonadal men and supraphysiological doses to eugonadal men increases muscle size. To determine whether testosterone-induced increase in muscle size is due to muscle fiber hypertrophy, 61 healthy men, 18-35 yr of age, received monthly injections of a long-acting gonadotropin-releasing hormone (GnRH) agonist to suppress endogenous testosterone secretion and weekly injections of 25, 50, 125, 300, or 600 mg testosterone enanthate (TE) for 20 wk. Thigh muscle volume was measured by magnetic resonance imaging (MRI) scan, and muscle biopsies were obtained from vastus lateralis muscle in 39 men before and after 20 wk of combined treatment with GnRH agonist and testosterone. Administration of GnRH agonist plus TE resulted in mean nadir testosterone concentrations of 234, 289, 695, 1,344, and 2,435 ng/dl at the 25-, 50-, 125-, 300-, and 600-mg doses, respectively. Graded doses of testosterone administration were associated with testosterone dose and concentration-dependent increase in muscle volume measured by MRI (changes in vastus lateralis volume, -4, +7, +15, +32, and +48 ml at 25-, 50-, 125-, 300-, and 600-mg doses, respectively). Changes in cross-sectional areas of both type I and II fibers were dependent on testosterone dose and significantly correlated with total (r = 0.35, and 0.44, P < 0.0001 for type I and II fibers, respectively) and free (r = 0.34 and 0.35, P < 0.005) testosterone concentrations during treatment. The men receiving 300 and 600 mg of TE weekly experienced significant increases from baseline in areas of type I (baseline vs. 20 wk, 3,176 +/- 186 vs. 4,201 +/- 252 microm(2), P < 0.05 at 300-mg dose, and 3,347 +/- 253 vs. 4,984 +/- 374 microm(2), P = 0.006 at 600-mg dose) muscle fibers; the men in the 600-mg group also had significant increments in cross-sectional area of type II (4,060 +/- 401 vs. 5,526 +/- 544 microm(2), P = 0.03) fibers. The relative proportions of type I and type II fibers did not change significantly after treatment in any group. The myonuclear number per fiber increased significantly in men receiving the 300- and 600-mg doses of TE and was significantly correlated with testosterone concentration and muscle fiber cross-sectional area. In conclusion, the increases in muscle volume in healthy eugonadal men treated with graded doses of testosterone are associated with concentration-dependent increases in cross-sectional areas of both type I and type II muscle fibers and myonuclear number. We conclude that the testosterone induced increase in muscle volume is due to muscle fiber hypertrophy.     

Serum adiponectin is positively associated with lung function in young adults,independent of obesity: The CARDIA study

Rationale

Adipose tissue produces adiponectin, an anti-inflammatory protein. Adiponectin deficiency in mice is associated with abnormal post-natal alveolar development.

Objective

We hypothesized that lower serum adiponectin concentrations are associated with lower lung function in humans, independent of obesity. We explored mediation of this association by insulin resistance and systemic inflammation.

Methods and Measurements

Spirometry testing was conducted at years 10 and 20 follow-up evaluation visits in 2,056 eligible young adult participants in the Coronary Artery Risk Development in Young Adults (CARDIA) study. Body mass index, serum adiponectin, serum C-reactive protein (a marker of systemic inflammation), and insulin resistance were assessed at year 15.

Main Results

After controlling for body mass index, years 10 and 20 forced vital capacity (FVC) were 81 ml and 82 ml lower respectively (p = 0.004 and 0.01 respectively) in the lowest vs. highest adiponectin quartiles. Similarly, years 10 and 20 forced expiratory volume in one second (FEV₁) were 50 ml and 38 ml lower (p = 0.01 and 0.09, respectively) in the lowest vs. highest adiponectin quartiles. These associations were no longer significant after adjustment for insulin resistance and C-reactive protein. Serum adiponectin was not associated with FEV₁/FVC or peak FEV₁.

Conclusions

Independent of obesity, lower serum adiponectin concentrations are associated with lower lung function. The attenuation of this association after adjustment for insulin resistance and systemic inflammation suggests that these covariates are on a causal pathway linking adiponectin and lung function.     

Soluble serum CD81 is elevated in patients with chronic hepatitis C and correlates with alanine aminotransferase serum activity

Aim

Cellular CD81 is a well characterized hepatitis C virus (HCV) entry factor, while the relevance of soluble exosomal CD81 in HCV pathogenesis is poorly defined. We performed a case-control study to investigate whether soluble CD81 in the exosomal serum fraction is associated with HCV replication and inflammatory activity.

Patients and Methods

Four cohorts were investigated, patients with chronic hepatitis C (n = 37), patients with chronic HCV infection and persistently normal ALT levels (n = 24), patients with long term sustained virologic response (SVR, n = 7), and healthy volunteers (n = 23). Concentration of soluble CD81 was assessed semi-quantitatively after differential centrifugation ranging from 200 g to 100,000 g in the fifth centrifugation fraction by immunoblotting and densitometry.

Results

Soluble CD81 was increased in patients with chronic hepatitis C compared to healthy subjects (p = 0.03) and cured patients (p = 0.017). Patients with chronic HCV infection and persistently normal ALT levels and patients with long term SVR had similar soluble CD81 levels as healthy controls (p>0.2). Overall, soluble CD81 levels were associated with ALT levels (r = 0.334, p = 0.016) and severe liver fibrosis (p = 0.027).

Conclusion

CD81 is increased in the exosomal serum fraction in patients with chronic hepatitis C and appears to be associated with inflammatory activity and severity of fibrosis.     

Obesity is an independent determinant of elevated C-reactive protein in healthy women but not men

Background and aims: High-sensitivity C-reactive protein (hs CRP) has emerged as an inflammatory biomarker to predict metabolic syndrome. Here, we investigate the association of hs CRP with metabolic variables and determine the risks for elevated hs CRP levels in healthy Singaporean adults.

Methods: We conducted a cross-sectional study of 225 participants (104 men). The levels of hs CRP and fasting lipid parameters were analyzed by COBAS. Body composition was determined with dual-energy X-ray absorptiometry.

Results: Twenty-one (9?%) participants had elevated hs CRP levels (>3?mg/mL). The levels of hs CRP had significant correlations (p?<0.05) with obesity and metabolic variables among women. Stepwise multivariate regression analysis identified FM (%) (accounted for 22.5% of the variability in hs CRP levels) as a major determinant of hs CRP levels. On multivariate regression, FM (%) was the independent determinant of intermediate and elevated hs CRP in women after adjustment for the potential confounders.

Conclusions: Obesity may play a direct role in the elevated hs CRP levels in women, but not men living in Singapore. This is probably due to different body composition or different effects of sex hormones on adipose tissue between men and women.     

Serum adipocyte-specific fatty acid-binding protein is associated with nonalcoholic fatty liver disease in apparently healthy subjects

Adipocyte-specific fatty acid-binding protein (A-FABP) is a cytoplasmic protein that is expressed in adipocytes and is closely associated with insulin resistance, metabolic syndrome, and Type 2 diabetes. We investigated the relationship between A-FABP as a surrogate marker of metabolic syndrome and non-alcoholic fatty liver disease (NAFLD) in apparently healthy subjects. We assessed clinical and biochemical metabolic parameters and measured serum levels of A-FABP, high-sensitivity C-reactive protein and tumor necrosis factor-α (TNF-α) in 494 subjects who were divided into two groups according to the presence of NAFLD by abdominal ultrasonography. All parameters associated with metabolic syndrome were significantly higher in patients with NAFLD (P<.001). A-FABP showed positive correlation with TNF-α, homeostasis model assessment index of insulin resistance (HOMA-IR), and metabolic syndrome (P<.001) when adjusted for age and sex. The odds ratio for the risk of NAFLD in the highest tertile of A-FABP compared with the lowest tertile was 7.36 (CI 3.80-14.27, P<.001) after adjustment for age and sex; 4.52 (CI 2.22-9.20, P<.001) after adjustment for age, sex, HOMA-IR and metabolic syndrome and 2.86 (CI 1.11-7.35, P<.05) after further adjustment for all metabolic parameters including TNF-α. The serum level of A-FABP was independently associated with NAFLD and showed significant correlation with TNF-α, HOMA-IR, and metabolic syndrome.     

Serum alanine aminotransferase to aspartate aminotransferase ratio and degree of fatty liver in morbidly obese patients

We evaluated the change in serum alanine aminotransferase (ALT; EC 2.6.1.2) to serum aspartate aminotransferase (AST; EC 2.6.1.; ALT/AST) ratio with the degree of fatty liver in morbidly obese patients. A total of 31 patients were included in the study. Fatty liver was graded as 0 to 4+. The mean and SD of AST and ALT were not significantly different between groups of patients with various grades of fatty liver. There was, however, a significant correlation between the ALT/AST ratio and the degree of fatty infiltration of the liver. This, we believe, implies damage mainly to the plasma membrane allowing loss of cytoplasmic enzymes rather than loss of mitochondrial enzymes.     

Dimethylarginine:pyruvate aminotransferase in rats. Purification, properties, and identity with alanine:glyoxylate aminotransferase 2

Dimethylarginine:pyruvate aminotransferase, which plays a role in the metabolism of dimethylarginines, has been purified to homogeneity from rat kidney. The enzyme has a molecular weight of approximately 200,000 and an isoelectric point at about pH 6.3. The enzyme consists of four similar subunits having a molecular weight of about 50,000. The enzyme catalyzes the effective transaminations of guanidino-N methylated L-arginines (e.g. NG,NG-dimethyl-L-arginine, NG,N'G-dimethyl-L-arginine and NG-monomethyl-L-arginine) and the alpha-amino group of L-ornithine to pyruvate or glyoxylate. The enzyme was always accompanied by the known alanine:glyoxylate amino-transferase activity with the ratios of their specific activities remaining constant during the purification steps. The physicochemical and immunological properties of the purified enzyme were shown to be identical with those of the isozyme of alanine:glyoxylate aminotransferase (EC 2.6.1.44), designated as alanine:glyoxylate aminotransferase 2 (Noguchi, T. (1987) in Peroxisomes in Biology and Medicine (Fahimi, H. D., and Sies, H., eds) pp. 234-243, Springer-Verlag, Heidelberg). The distribution profiles in tissues and the negative response to glucagon treatment further supported the identity of the two enzymes. The present data show that alanine:glyoxilate aminotransferase 2 functions in dimethylarginine metabolism in vivo in rats.     

Serum copper,zinc and high-sensitivity C-reactive protein in short and long sleep duration in ageing men

BackgroundSerum levels of zinc and copper have been proposed to associate with sleep duration. Mechanisms, such as inflammatory processes, have been suggested to relate this association. However, earlier studies have been conducted in small sample sizes. Human studies investigating the suggested associations while controlling for potential confounding factors are lacking.MethodsPopulation-based data consisted of 2570 men (aged 42–60 years) from Eastern Finland. The participants reported an estimate of their sleep duration. The serum levels of zinc (S–Zn), copper (S–Cu) and high-sensitivity C-reactive protein (hs-CRP) were measured. Analysis of covariance was used for multivariate analyses.ResultsS–Zn levels and Zn/Cu ratio were lowest in ≤6 h sleep. S–Cu levels were highest in ≥10 h sleep. Elevated levels (>3.0 mmol/l) of hs-CRP were observed in ≤6 h and ≥10 h sleep. After adjustments for age, cumulative smoking history (pack-years), alcohol consumption (g/week), Human Population Laboratory depression scale scores, physical activity (kcal/day), cardiometabolic syndrome, and cardiovascular disease history, sleep duration was significantly associated with levels of both S–Cu and hs-CRP. The association with S–Cu remained statistically significant following further adjustment for hs-CRP in the same model.ConclusionsOur data suggests an association between S–Cu and sleep duration in ageing men. Elevated inflammation (measured as serum hs-CRP) does not explain this relationship. Mechanisms underlying the relationship require further investigation, as S–Cu may contribute to sleep regulation through pro-oxidative processes and copper-dependent N-methyl-d-aspartate receptor activity.     

The influence of hormones and inflammatory agents on C-reactive protein, cortisol and alanine aminotransferase in the plaice (Pleuronectes platessa L.)

Endotoxin stimulates production of both C-reactive protein (CRP) and cortisol in the plaice within 24 hr. Cortisol alone (optimum dose i.p. 500 micrograms/300 g wt fish) also stimulates CRP production and the possibility that endotoxin acts through cortisol was examined. Dexamethasone suppresses cortisol production but elevates CRP. Cortisol levels are restored to normal within 24 hr of endotoxin injection. Turpentine and ACTH which stimulate cortisol do not affect CRP. Endotoxin and cortisol have no significant effect on alanine aminotransferase activity in the serum and liver although it is elevated in the serum within 24 hr of the administration of adrenalin or turpentine.     

Determination of alanine aminotransferase in human serum in an open-closed flow injection configuration.

Open-closed flow injection systems allow the development of methods based on multidetection by using conventional detectors. The methods proposed here for the determination of alanine aminotransferase (ALT) utilize a photometric detector included in the closed circuit, which allows one to perform fixed-time and reaction-rate measurements whose sensitivity can be increased by using the sum of the analytical signals. The methods, with determination ranges between 1 and 500 U l-1 of ALT, feature sampling frequencies up to 60 h-1. Their application to serum samples provided excellent results, with recoveries between 95 and 106% and averaging at 99.9%.     

Serum prolactin is associated with apoptosis in men with human immunodeficiency virus infection

We examined the in vivo and in vitro production of prolactin (PRL) in 20 untreated HIV-infected men compared to 14 uninfected men and its association with the cell cycle and apoptosis. Compared to uninfected men, the HIV-infected men had: (i) higher fasting serum bioactive (BIO) PRL; (ii) lower serum immunoreactive (RIA) and BIO-PRL responses to intravenous metoclopramide; (iii) greater BIO-RIA PRL ratio both fasting and during intravenous metoclopramide; (iv) lower percentage of non-stimulated PBMC in the G0/G1 phase, but a higher percentage in the S phase, of the cell cycle with normal response to Concanavalin-A; and (v) higher in vitro production of BIO-PRL by non-stimulated PBMC, which was blocked after Concanavalin-A. Fasting serum BIO-PRL positively correlated with the percent of non-stimulated PBMC in S + G2/M phases. The percentage of apoptotic PBMC negatively correlated with CD4+ T lymphocytes and with the area under the serum RIA-PRL curve, but positively correlated with the area under the curve for the BIO/RIA ratio. These results suggest that in these HIV-infected men: (i) a diminished dopaminergic tone may exist, as an adaptive mechanism attempting to survive; and (ii) BIO-PRL may participate as a cofactor in the stimulation of T-cell proliferation.     

Common variants in the CRP gene are associated with serum C-reactive protein levels and body mass index in healthy individuals in Mexico

Variants in the C-reactive protein (CRP) gene have been found to be associated with various phenotypic traits. We evaluated the effect of four SNPs in the CRP gene on serum levels of protein and body mass index (BMI) in 150 unrelated Mexican subjects from 18 to 25 years old, without hypertension, non-overweight, and without inflammatory diseases, non-smoking and non-consumers of alcohol. Subjects were measured for BMI, waist circumference, blood pressure, and serum glucose and triglycerides. The identification of SNPs was performed by PCR-RFLP. Three of the four SNPs were associated with variation in serum levels of CRP, increased in TT (rs1130864) and GG (rs2794521) genotypes, and decreased in the AA genotype of rs1205. The TT genotype was associated with a significant increase in BMI (β = 1.1 kg/m(2), P = 0.04). Two haplotypes were significantly associated with increased serum levels of CRP, but not with BMI. We conclude that variation in the CRP gene affects serum protein levels.     

Kidneys extract BNP and NT-proBNP in healthy young men.

Renal metabolism of the cardiac marker NH2-terminal-pro-brain natriuretic peptide (NT-proBNP) has been suggested. Therefore, we determined the renal extraction ratios of NT-proBNP and its bioactive coproduct brain natriuretic peptide (BNP) at rest and during exercise. In addition, the cerebral ratios were evaluated. Ten young healthy men were investigated at baseline, during moderate cycle exercise (heart rate: 140, Borg scale: 14-15), and in the recovery with BNP and NT-proBNP measured from the brachial artery and the jugular and renal veins, and the renal and cerebral extraction ratios (Ext-Ren and Ext-Cer, respectively) were calculated. Cardiac output, stroke volume, heart rate, mean arterial pressures, and estimated glomerular filtration were determined. BNP and NT-proBNP were extracted by the kidneys but not by the brain. We observed no effect of exercise. The mean values (+/- SE) of Ext-Ren of NT-proBNP were similar (0.19 +/- 0.05, 0.21 +/- 0.06, and 0.12 +/- 0.03, respectively) during the three sessions (P > 0.05). Also the Ext-Ren of BNP were similar (0.18 +/- 0.07, 0.15 +/- 0.11, and 0.14 +/- 0.06, respectively; P > 0.05). There were no significant differences between Ext-Ren of BNP and NT-proBNP during the three sessions (P > 0.05). The Ext-Cer of both peptides varied insignificantly between -0.21 +/- 0.15 and 0.11 +/- 0.08. The renal extraction ratio of both BNP and NT-proBNP is approximately 0.15-0.20. There is no cerebral extraction, and short-term moderate exercise does not affect these values. Our findings suggest that the kidneys extract BNP and NT-proBNP to a similar extent in healthy young men.     

Emotion recognition accuracy in healthy young females is associated with cycle phase

Several studies reported a significant influence of ovarian hormone status on cognition and person perception. In particular, it has been stated that female mating preferences are shifted during the menstrual cycle. It remains, however, unclear if facial emotion recognition, a prerequisite for successful social interaction, is also influenced by estradiol and progesterone levels. Hence, we investigated 32 healthy right-handed females, 15 during their follicular phase and 17 during their luteal phase and compared their recognition accuracy. Hormone levels were correlated with several neuropsychological parameters. Subjects were matched for age and education and did not differ in any neuropsychological function. Analysis of emotion recognition performance (ANOVA) revealed a significant effect of phase, showing higher accuracy in the follicular group. Furthermore, a significant negative correlation between progesterone level and emotion recognition performance emerged, indicating higher accuracy with lower progesterone levels, hence supporting the group differences. Our results indicate a significant association of menstrual cycle phase and thus ovarian hormone concentration on facial emotion recognition, with progesterone exerting a special influence on this social-emotional ability.     

Late bedtime is associated with decreased hippocampal volume in young healthy subjects

Sleep and Biological Rhythms - Hippocampal volume loss has been described in several pathological conditions including sleep disorders. Whether differences in normal sleep are associated with...