Basal myokine levels are associated with quality of life and depressed mood in older adults.

In an aging society, late-life depression has become an increasing problem. There is evidence that physical activity ameliorates depressive symptoms and increases the quality of life (QoL). However, the underlying mechanisms are still poorly understood. Myokines are molecules secreted in response to muscle contraction. Some of them can cross the blood-brain barrier, making them promising candidates for mediating the beneficial effects of physical activity on mood. The present study aims to compare circulating myokine levels to depression/QoL in older athletes and controls. 55 athletes, 57 controls >59 years were enrolled. The assessment included ergometry, magnetic resonance imaging, blood withdrawal, and neuropsychological testing. Serum interleukin-6 (IL-6), irisin, brain-derived neurotrophic factor (BDNF), kynurenine, and cathepsin B were analyzed and compared to surrogates of depression and quality of life. Athletes presented with higher levels of Cathepsin B. Among controls, all myokines but irisin were associated with age. Also, among controls, kynurenine and IL-6 correlated inversely with specific dimensions of quality of life questionnaires, and IL-6 further with depressive symptoms and decreased physical performance. No such associations could be found among athletes. Irisin levels were inversely associated with mild depression and low-grade white matter-lesions in the brain and predicted impaired QoL. The circulating levels of several myokines/muscle activity-related factors appear to be associated with depressive symptoms and impaired QoL among older adults. However, in athletes, some of these connections seem ameliorated, suggesting additional stressors (as f.e. age) or a different pathomechanism among athletes.

Haem catabolism: a novel modulator of inflammation in Gilbert's syndrome.

BACKGROUND: Moderately elevated unconjugated bilirubin concentrations protect against inflammatory diseases and are present in individuals with Gilbert's syndrome. This study examined the relationship between circulating haem oxygenase catabolites, unconjugated bilirubin, carboxy haemoglobin, iron and inflammatory parameters. MATERIALS AND METHODS: Seventy-six matched individuals were allocated to Gilbert's syndrome (GS) or control group (unconjugated bilirubin ≥ or < 17.1 µM). Iron, carboxy haemoglobin and high-sensitivity C-reactive protein were analysed using routine diagnostic tests. Unconjugated bilirubin and haem were analysed using high-performance liquid chromatography. The cytokines IL-1ß, TNF-α and IL-6 were assessed using high-sensitivity enzyme-linked immunosorbent assays. RESULTS: Gilbert's syndrome subjects had significantly greater levels of unconjugated bilirubin (P < 0.05), carboxy haemoglobin (P < 0.05), iron (P < 0.05), IL-1ß (P < 0.05), a significantly lower body mass index (P < 0.05) and IL-6 concentrations (P < 0.05) vs. controls. Regression analysis revealed that unconjugated bilirubin mainly explained IL-1ß results (16%), and body mass index+IL-6 predicted 26% of the variance in C-reactive protein concentrations. CONCLUSIONS: A positive relationship between unconjugated bilirubin and free plasma haem, iron and carboxy haemoglobin indicated a positive feedback loop of haem oxygenase induction possibly mediated by unconjugated bilirubin. Furthermore, reduced body mass index in Gilbert's syndrome individuals was linked to reduced inflammation status, which could be influenced by circulating haem oxygenase catabolites and contribute to reduced risk of noncommunicable diseases in this population.

Mean platelet volume may represent a predictive parameter for overall vascular mortality and ischemic heart disease.

OBJECTIVE: An increased mean platelet volume (MPV), as an indicator of larger, more reactive platelets resulting from an increased platelet turnover, may represent a risk factor for overall vascular mortality, including myocardial infarction. We intended to identify patients at higher risk of dying from vascular disease in a large, hospital-based cohort. METHODS AND RESULTS: A total of 206 554 first-ever admissions to the Allgemeines Krankenhaus Wien for determination of MPV between January 1996 and July 2003 were included. Primary end points were overall vascular mortality and death due to ischemic heart disease. Multivariate Cox regression adjusted for sex, age, and platelet count was applied for analysis. MPV values were categorized into quintiles, with the lowest quintile serving as the reference category. Compared with individuals with lower MPV (<8.7 fL), hazard ratios for overall vascular mortality gradually increased to 1.5 in the highest category (≥11.01 fL). The relationship of MPV to ischemic heart disease was even stronger and increased from 1.2 (8.71 to 9.60 fL category) to 1.8 in the highest category (≥11.01 fL). CONCLUSIONS: Our results indicate that patients with an increased MPV (≥11.01 fL) are at higher risk of death due to ischemic heart disease, with hazard ratios comparable to those reported for obesity or smoking.

Coagulation factor VIII levels are associated with long-term survival - interactions with gender in a large hospital-based cohort.

INTRODUCTION: Elevated coagulation factor VIII activity has been associated with increased risk for both venous and arterial thrombosis. The current study evaluated the influence of Factor VIII levels and interactions with gender on all cause mortality in a large Austrian cohort. PATIENTS AND METHODS: During 1991 and 2003, 11203 individuals, first ever request for laboratory analyses of FVIII: C, age > or =18 years, were included in this study. The median observation period was 5 years covering a total of 46000 person-years. The death rate was 17.1%. RESULTS: Compared to individuals within the reference category (FVIII: C <94%) hazard ratios gradually increased from 1.4 (95% CI: 1.1-1.8) in the 152-170% category (5th decile) to finally 4.4 (95% CI: 3.5-5.5) in the >313% category (highest decile, all p < 0.05). The association between FVIII: C levels and mortality remained essentially unchanged when considering non-cancer mortality, all cause vascular mortality or mortality due to ischemic heart disease. Compared to males females with elevated FVIII: C had a worse outcome resulting in higher hazard ratios reaching 6.8 (95% CI: 4.6-9.9) within the highest decile compared to males (HR: 3.4 (95% CI: 2.6-4.5)). CONCLUSIONS: In our large patient cohort we might be able to demonstrate for the first time that FVIII: C plasma activity is strongly associated with all cause mortality. Additionally, FVIII: C appears to interact with gender. Especially in women FVIII: C might help identifying high-risk cohorts, which might benefit from individualized prevention strategies.

The EGF 61A/G polymorphism - a predictive marker for recurrence of liver metastases from colorectal cancer.

BACKGROUND: Epidermal growth factor (EGF) plays an important role in tumorigenesis. Variations in the DNA sequence of the gene EGF can lead to alterations in EGF activity, which is suspected to influence tumor progression. This retrospective study aimed to investigate the influence of EGF 61A/G polymorphism on the recurrence of liver metastases after hepatic surgery in patients with colorectal cancer. METHODS: EGF 61A/G polymorphism was determined in 268 consecutive patients (175 [65%] men and 93 [35%] women, mean age 62 +/- 10.3 years) who had liver metastases at primary diagnosis and were treated by surgery with curative intent (R0) for liver metastases from colorectal cancer. RESULTS: Overall, 81 of 268 (30%) patients exhibited wild-type EGF 61 A/A, 137 (51%) were heterozygous EGF 61 A/G and 50 (19%) were homozygous EGF 61 G/G. After adjusting for age, sex, UICC stage and tumor location, we observed a trend-wise 1.6-fold increased risk for hepatic recurrence (HR 1.6; 95% CI 1.0-2.5, P = 0.06) in individuals with the G/G genotype compared with carriers of the A-allele. The effect was much more pronounced in younger patients (or= 65 years). Interestingly, male patients with EGF G/G had a 1.6-fold higher risk of recurrence (HR 1.6; 95% CI 1.0-2.5, P = 0.07). A significant correlation (P = 0.033) was detected between Dukes classification and the homozygous 61 G/G genotype. CONCLUSION: Despite the limitations of our study, the retrospective results indicate that carriers of the EGF polymorphism might be at higher risk of developing liver recurrences. If confirmed in subsequent studies, genotyping for the EGF A/G variant might help in identification of patients at high risk of recurrence of liver metastases.

C-reactive protein and all-cause mortality in a large hospital-based cohort.

BACKGROUND: C-reactive protein (CRP), an acute-phase protein, is a sensitive systemic marker of inflammation and acute-phase reactions. Testing CRP concentrations at hospital admission may provide information about disease risk and overall survival. METHODS: All first-ever transmittals to the department of medical and chemical laboratory diagnostics for determination of low-sensitivity CRP (n = 274 515, 44.5% male, median age 51 years) between January 1991 and July 2003 were included [median follow-up time: 4.4 years (interquartile range, 2.3-7.4 years)]. The primary endpoint was all-cause mortality. Multivariate Cox regression adjusted for sex and age was applied for analysis. RESULTS: Compared to individuals within the reference category (CRP <5 mg/L), hazard ratios (HR) for all-cause mortality increased from 1.4 (5-10 mg/L category) to 3.3 in the highest category (>80 mg/L, all P <0.001). CRP was associated with various causes of death. The relation of CRP to cancer death was stronger than to vascular death. Younger patients with increased CRP had relatively far worse outcome than older patients (maximal HR: < or =30 years: 6.7 vs >60 years: 1.7-3.7). Interestingly, both short- and long-term mortality were associated with increasing CRP concentrations (>80 mg/L: HR 22.8 vs 1.4). CONCLUSION: Measurement of low-sensitivity CRP at hospital admission allowed for the identification of patients at increased risk of unfavorable outcome. Our findings indicate that close attention should be paid to hospitalized patients with high CRP not only because of very substantial short-term risk, but also long-term excess risk, the basis for which needs to be determined.

The tumor necrosis factor alpha -308 G/A polymorphism does not influence inflammation and coagulation response in human endotoxemia.

Tumor necrosis factor (TNF)-alpha plays a major role in the immune system. Release of proinflammatory cytokines, such as TNF-alpha and interleukin 6, by macrophages and other cells occurs in response to bacterial products. It has been reported that the TNF-alpha -308 G/A polymorphism in the TNF-alpha gene determines basal TNF-alpha levels. We hypothesized that it may also be associated with the degree of inflammatory response in a well-standardized model of systemic inflammation. Eighty-seven young men (age range, 19-35 years) received 2 ng/kg i.v. endotoxin (lipopolysaccharide [LPS]). The TNF-alpha promoter genotype was analyzed on a TaqMan genomic analyzer. Inflammation markers (interleukin 6, TNF-alpha), temperature, and coagulation markers (prothrombin fragment F1+2, D-dimer) were measured at 0, 2, 6, and 24 h after LPS infusion. Tumor necrosis factor-alpha plasma concentrations increased from a baseline 1.3 ng/L (range, 0.8-3.1 ng/L) before LPS infusion to a peak of 57.5 ng/L (range, 10.8-131.4 ng/L) at 2 h after LPS and then decreased continually to 10.8 ng/L (range, 4.7-16.5 ng/L) after 6 h and returned to baseline values after 24 h (1.9 ng/L [range, 1.1-3.9 ng/L]). We observed no significant differences in TNF-alpha baseline levels or in response to LPS after stratification of the data according to TNF-alpha genotype. Basal and peak values of selected inflammatory and coagulation markers were not different between wild-type TNF-alpha -308 individuals (GG) and carriers of the TNF-alpha -308 mutant allele (GA and AA). The TNF-alpha -308 G/A polymorphism does not contribute significantly to the individual variability of systemic TNF-alpha plasma concentrations after endotoxin challenge. Thus, if any, the impact of the TNF-alpha -308 G/A polymorphism on systemic endotoxin-triggered inflammation seems to be limited.

The fibrinogen -148 C/T polymorphism influences inflammatory response in experimental endotoxemia in vivo.

INTRODUCTION: The acute phase reactant fibrinogen plays a critical role in the coagulation system and inflammation. Recently several polymorphisms have been described regulating basal and peak fibrinogen expression. We evaluated the role of a frequent promoter polymorphism in the beta chain of the fibrinogen gene (-148 C/T) in a human in vivo model of experimental endotoxemia. MATERIAL AND METHODS: Healthy volunteers received 2 ng/kg endotoxin (LPS, n=73) as a bolus infusion over 2 min. Blood samples were collected by venipunctures into EDTA anticoagulated vacutainer tubes before LPS infusion. For determination of the fibrinogen promoter polymorphism, we developed a new mutagenic separated polymerase chain reaction assay. RESULTS: Carriers of the -148 T allele had significantly lower TNFalpha expression throughout the whole time course of LPS stimulation and Interleukin-6 levels were trendwise lower, however only basal levels reached statistical significance. No effects were observed on markers of coagulation activation (D-Dimer, Prothrombin F(1+2)). CONCLUSION: Our findings indicate, that the common -148 C/T polymorphism is associated with differences in the TNFalpha release in response to systemic LPS infusion in humans, and add to current evidence that gene-sequence changes in beta-fibrinogen locus can alter the ability of the host to respond to endotoxin.

A proinflammatory state is detectable in obese children and is accompanied by functional and morphological vascular changes.

BACKGROUND: Obesity is generally accepted as a risk factor for premature atherosclerosis. Subclinical inflammation as quantified by blood levels of C-reactive protein (CRP) contributes to the development and progression of atherosclerosis. We hypothesized that inflammation in obese children is related to functional and early morphological vascular changes. METHODS AND RESULTS: Blood levels of high sensitivity (hs) CRP, hsIL-6, the soluble intercellular adhesion molecule1 (ICAM-1), vascular cell adhesion molecule (VCAM)-1, and E-selectin were measured in 145 severely obese (body mass index [BMI], 32.2+/-5.8 kg/m2) and 54 lean (BMI, 18.9+/-3.2 kg/m2) children 12+/-4 years old. Flow-mediated dilation (FMD) of the brachial artery and carotid intima-media thickness (IMT) measured by high-resolution ultrasound as markers of early vascular changes were assessed in 92 (77 obese and 15 lean) and 59 (50 obese and 9 lean) children, respectively. Obese children had significantly higher levels of hsCRP, hsIL-6, and E-selectin than healthy controls (4.1+/-4.8 versus 0.9+/-1.5 mg/L, P<0.001 for hsCRP; 1.99+/-1.30 versus 1.42+/-1.01 pg/mL, P=0.05 for hsIL-6; and 78+/-38 versus 59+/-29 ng/mL, P=0.01 for E-selectin). There were no differences in the levels of ICAM-1 and VCAM-1 between groups. Obese children had lower peak FMD response (7.70+/-6.14 versus 11.06+/-3.07%, P=0.006) and increased IMT (0.37+/-0.04 versus 0.34+/-0.03 mm, P=0.03) compared with controls. Morbidly obese children (n=14, BMI 44.1+/-3.9 kg/m2) had highest levels of hsCRP (8.7+/-0.7 mg/L), hsIL-6 (3.32+/-1.1 pg/mL), and E-selectin (83+/-40 ng/mL). CONCLUSIONS: A proinflammatory state is detectable in obese children, which is accompanied by impaired vascular endothelial function and early structural changes of arteries, even in young subjects at risk. It remains to be determined whether high hsCRP in obese children predicts cardiovascular events.

The single nucleotide polymorphism Ser128Arg in the E-selectin gene is associated with enhanced coagulation during human endotoxemia.

The single nucleotide polymorphism (SNP) Ser128Arg in the E-selectin gene is overrepresented in certain patient groups with atherosclerosis or restenosis. We hypothesized and tested whether it may affect cytokine-induced levels of soluble (s) E-selectin, or be associated with proinflammatory or procoagulant properties in a well-standardized inflammation model. Healthy male volunteers (n = 157) received a lipopolysaccharide (LPS) infusion and were genotyped for the S128R SNP, and outcome parameters were measured by enzyme immunoassays and real-time polymerase chain reaction (RT-PCR, Taqman). The S128R SNP had no pronounced effects on basal or inducible sE-selectin levels, or levels of tumor necrosis factor or interleukin-6. However, carriers of the S128R SNP had 20% higher monocyte counts at 24 hours after LPS infusion. Importantly, the S128R allele enhanced thrombin generation by 50% to 80%, as measured by prothrombin fragment F(1+2) (P < .01), and hence fibrin formation (D-dimer) 2-fold (P = .01 to P = .002). However, tissue factor (TF) mRNA levels were not affected. The S128R E-selectin genotype is associated with procoagulant effects in a human model of endotoxin-induced, TF-triggered coagulation. This could contribute to its linkage with various thrombotic cardiovascular disorders.

PAI-1 4G/5G insertion/deletion promoter polymorphism and microvascular complications in type 2 diabetes mellitus.

BACKGROUND: Plasminogen activator inhibitor-1 (PAI-1) plays an important role in the regulation of fibrinolysis and extracellular matrix turnover. PAI-1 4G/5G insertion/deletion polymorphism in the PAI-1 promoter region has been shown to modulate PAI-1 plasma levels. We investigated the relationship between this polymorphism and the prevalence of diabetic nephropathy and retinopathy in patients with type 2 diabetes in the Austrian population. PATIENTS AND METHODS: 147 consecutive patients with type 2 diabetes mellitus (96 men, 51 women; median age, 65 years; IQR, 59-71) were analyzed for the PAI-1 4G/5G genotype. RESULTS: The genotype distribution in the individuals tested was as follows: 17% (n = 25) 5G/5G, 54% (n = 80) 4G/5G, and 29% (n = 42) 4G/4G. Patients homozygous for allele 4G had a significantly higher risk of diabetic proliferative retinopathy than patients without signs of diabetic retinopathy or nonproliferative retinopathy (OR, 7.3; 95% CI, 1.4-38.8; P = 0.02). No significant associations were observed between the PAI-1 genotype and the presence of albuminuria. CONCLUSION: According to our results, diabetic proliferative retinopathy might be associated with the prevalence of PAI-1 genotype 4G/4G.

The interleukin-6 G(-174)C promoter polymorphism does not determine plasma interleukin-6 concentrations in experimental endotoxemia in humans.

BACKGROUND: Interleukin 6 (IL-6) is a pleiotropic cytokine that plays an essential role in the pathogenesis of acute and chronic infections. As the role of the IL-6 G(-174)C polymorphism in determining serum concentrations of IL-6 is controversial, we studied the genotype-specific IL-6 response in a well-standardized model of systemic inflammation. METHODS: A total of 76 healthy young males (age range, 19-35 years) received a single bolus of 2 ng/kg endotoxin [lipopolysaccharide (LPS)] intravenously. Plasma IL-6 was measured by enzyme immunoassay at 0, 2, 6, and 24 h after LPS infusion, and the IL-6 promoter genotype was analyzed by a mutagenic separated PCR assay. RESULTS: IL-6 increased 300-fold 2 h after LPS challenge and returned almost to normal within 24 h. Neither basal IL-6 nor the IL-6 response to LPS was significantly affected by the IL-6 promoter genotype. CONCLUSIONS: The IL-6 G(-174)C promoter polymorphism does not significantly influence basal concentrations of IL-6 or peak IL-6 in human endotoxemia.