False-positive prostate cancer markers in a man with symptomatic urethral Chlamydia trachomatis infection.

Symptomatic male urethral Chlamydia trachomatis infection resulted in inflammation of the prostate, with associated increases in both prostate-specific (PSA) and prostate cancer-specific (PCA3) markers with prostate biopsies showing no evidence of malignancy.

Physiologically Based Pharmacokinetic (PBPK) Modeling of Metabolic Pathways of Bromochloromethane in Rats.

Bromochloromethane (BCM) is a volatile compound and a by-product of disinfection of water by chlorination. Physiologically based pharmacokinetic (PBPK) models are used in risk assessment applications. An updated PBPK model for BCM is generated and applied to hypotheses testing calibrated using vapor uptake data. The two different metabolic hypotheses examined are (1) a two-pathway model using both CYP2E1 and glutathione transferase enzymes and (2) a two-binding site model where metabolism can occur on one enzyme, CYP2E1. Our computer simulations show that both hypotheses describe the experimental data in a similar manner. The two pathway results were comparable to previously reported values (V(max⁡) = 3.8 mg/hour, K(m) = 0.35 mg/liter, and k(GST) = 4.7 /hour). The two binding site results were V(max⁡(1) ) = 3.7 mg/hour, K(m⁡(1) ) = 0.3 mg/hour, CL(2) = 0.047 liter/hour. In addition, we explore the sensitivity of different parameters for each model using our obtained optimized values.

Serum amyloid A is independently associated with metabolic risk factors but not with early atherosclerosis: the Cardiovascular Risk in Young Finns Study.

BACKGROUND: Serum amyloid A (SAA) is a sensitive marker of inflammation and its elevation has been implicated in obesity and in cardiovascular disease, yet data on its regulation in young adults or on its role in early atherosclerosis is scarce. We investigated which factors explain the variation in SAA and analysed whether SAA could be associated with preclinical atherosclerosis. METHODS: Serum amyloid A levels were measured in participants of the Cardiovascular Risk in Young Finns Study (n = 2280, n = 1254 women, n = 1026 men). Correlates and determinants of SAA were analysed and the effect of SAA on subclinical atherosclerosis, measured as intima-media thickness (IMT) and carotid artery compliance, was evaluated with risk-factor adjusted models. RESULTS: Serum amyloid A correlated directly and independently of BMI with C-reactive protein (CRP), waist circumference and leptin in both sexes, with total cholesterol, LDL cholesterol and ApolipoproteinA1 (ApoA1) in women and with triglycerides, insulin levels and insulin resistance in men. Use of combined oral contraceptives and intrauterine device was also associated with SAA levels. Determinants for SAA included CRP, leptin and ApoA1 in women, and CRP, leptin and HDL cholesterol in men. SAA levels correlated with carotid compliance in both sexes and with IMT in men, yet SAA had no independent effect on IMT or carotid compliance in multivariable analysis. CONCLUSIONS: Serum amyloid A was associated with several metabolic risk factors but was not an independent predictor of IMT or carotid artery compliance. Further longitudinal studies will show whether SAA holds a prognostic value as a risk marker, analogously to CRP.

Association of C-reactive protein (CRP) gene allelic variants with serum CRP levels and hypertension in Turkish adults.

OBJECTIVE: Serum C-reactive protein (CRP) is an independent risk factor for cardiovascular disease and metabolic syndrome (MetS). The aim of this study was to analyze the CRP gene allelic variations in the Turkish adult risk factor (TARF) study and relate them with serum CRP levels as well as MetS and its components. METHODS: We analyzed CRP gene polymorphisms (-286C>T>A [rs3091244], +1444C>T [rs1130864], +1059G>C [rs1800947], and +1846G>A [rs1205]) as well as their haplotypes, in addition to measuring CRP levels (n=1138) and collecting risk factor data from 1987 adults (mean age 54.3+/-11.9 years, 51.3% women) participating in the TARF Study. MetS was defined by using the criteria of the National Cholesterol Education Program modified for pre-diabetes and in men for abdominal obesity. RESULTS: After adjustment for the major cardiovascular risk factors, four CRP SNPs (-286C>T>A, +1059G>C, +1444C>T, and +1846G>A) were significantly associated with serum CRP levels in women (p<0.05), whereas the -286C>T>A and +1444C>T polymorphisms were associated with CRP levels in men (p<0.05). The haplotype analyses revealed four common CRP haplotypes. The haplotype 1 (CGCA) in women and the haplotype 3 (TGTG) in men were associated with serum CRP levels and hypertension (p<0.05). However, no haplotype association was observed for MetS or its components. CONCLUSION: CRP gene allelic variation is associated with serum CRP levels as well as hypertension in Turkish adults.

C-reactive protein haplotype is associated with high PSA as a marker of metastatic prostate cancer but not with overall cancer risk.

Growing evidence points to a role for inflammation in prostate carcinogenesis. The significance of C-reactive protein (CRP), an inflammatory and innate immunity molecule, has not been evaluated thoroughly in prostate cancer (PC). In this study of 739 Finnish patients with PC and 760 healthy men, we evaluated the associations of CRP genotypes and haplotypes with total PC risk and PC progression, using prostate-specific antigen (PSA) as a marker of metastatic disease. Although the haplotype frequencies were similar in patients and controls, an association between haplotype ACCCA and patients' PSA levels was found. The carriers more often had a high PSA than non-carriers (P=0.0002) and the SNP rs2794521 A-allele and rs1800947 C-allele carriers had a higher PSA than non-carriers (P=0.009 and P=0.0004, respectively). A trend for a younger age at diagnosis was found among the carriers of ACCCA (P=0.07) and the rs1800947 C-allele (P=0.06), as well as a trend for the latter to have more likely metastases (P=0.06), but not after Bonferroni correction (alpha=0.00208). This is the first study to suggest association between PSA and CRP variants in PC and, therefore, further studies are warranted. CRP alleles previously found to protect against increased CRP levels are now suggested to be associated with metastatic PC, indicated by elevated PSA.

CRP and FCGR2A genes have an epistatic effect on carotid artery intima-media thickness: the Cardiovascular Risk in Young Finns Study.

The role of the inflammatory mediator C-reactive protein (CRP) in atherosclerosis is recognized although its specific functions are not entirely clear. CRP binds to the Fcgamma receptor2A (FcgammaR2A) and its polymorphism, FCGR2A (Arg131His), strongly influences the binding. We wanted to evaluate the CRP-mediated proatherogenic process on early atherosclerosis and investigated whether CRP and FCGR2A show an interactive effect on carotid intima-media thickness (IMT). Polymorphisms of FCGR2A (Arg131His) and CRP (-717A > G, -286C > T > A, +1059G > C, +1444C > T and +1846G > A) were genotyped and their effects on IMT were analyzed in 2260 young adults participating in the Cardiovascular Risk in Young Finns Study. CRP haplotypes were constructed based on the CRP polymorphisms. The FCGR2A(Arg131His) polymorphism did not have an independent effect on IMT but a significant gene-gene interaction, epistasis, between FCGR2A and CRP genetics on IMT was found. The epistatic effect was seen in men at haplotype and genotypic level; both CRP haplotype GCGCG (-717, -286, +1059, +1444 and +1846) and CRP-717A > G polymorphism interacted with FCGR2A(Arg131His) on IMT. After adjustment with classical risk factors the P-values for interaction were P = 0.013 and P = 0.010, respectively. No associations were observed in women. In conclusion, this study showed that the effect of CRP genetics on early atherosclerotic changes is modulated by the FCGR2A genetics.

Genetics of C-reactive protein and complement factor H have an epistatic effect on carotid artery compliance: the Cardiovascular Risk in Young Finns Study.

Atherosclerosis is characterized by a prominent inflammatory component and C-reactive protein (CRP) has been implicated to modulate the complement activity in atherosclerotic arteries via complement factor H (CFH) binding. In this study, we examined whether the gene-gene interactions between CRP haplotypes and CFH Tyr402His functional polymorphism exerted an effect on early atherosclerosis. Single nucleotide polymorphisms (SNPs) in CFH (Tyr402His) and CRP (-717A>G, -286C >T>A, +1059G>C, +1444C>T and +1846G>A) were genotyped in the participants of the Cardiovascular Risk in Young Finns Study (n=1698, aged 24-39 years). The CRP SNPs were further constructed into haplotypes and their interactive effects with the CFH Tyr402His polymorphism on the early atherogenic vascular changes [i.e. carotid artery compliance (CAC) and intima-media thickness (IMT)] were examined. After risk factor adjustment, a significant gene-gene interaction (P=0.007) on CAC was observed between CRP haplotype ATGTG and CFH Tyr402His polymorphism in males. Furthermore, logistic regression analysis verified the risk-modifying interactive effect on CAC between these loci (OR 3.70, 95% CI 1.37-10.02, P=0.010). No effects on CAC were observed in females and no effects on IMT were detected in either sex. We conclude that the combined presence of CRP haplotype ATGTG and CFH 402His allele may be disadvantageous to carotid artery elasticity in males.

Gene-environment interaction between MBL2 genotype and smoking, and the risk of gram-positive bacteraemia.

Mannose-binding lectin (MBL) insufficiency caused by point mutations in the MBL2 gene has been associated with increased susceptibility to bacteraemic infections. We here investigated the effect of MBL2 polymorphisms on the susceptibility and clinical course of bacteraemia. The study cohort comprised 145 patients with bacteraemia and 400 controls. In the case of patients with bacteraemia, laboratory findings and clinical data were registered on admission and during six consecutive days. MBL2 structural polymorphisms at codons 52 (CGT-->TGT; designated D or O), 54 (GGC-->GAC; B or O) and 57 (GGA-->GAA; C or O) in exon 1 of the MBL2 gene and promoter region polymorphisms at position -221 (G-->C, designated Y or X alleles) were determined. No difference in MBL2 genotype frequencies between the bacteraemic patients and controls was detected, and MBL2 genotype had no independent effect on mortality, nor disease severity. However, smoking proved a significant risk factor for Gram-positive (Staphylococcus aureus, Streptococcus pneumoniae or beta-haemolytic streptococci) bacteraemia in patients carrying the variant O allele (53% current smokers in Gram-positive bacteraemia patients compared with only 21% in controls, odds ratios 4.2, 95% confidence intervals 2.0-9.0; P < 0.001), while it did not have an effect in those homozygous for the A allele. The same effect was not detected in Escherichia coli bacteraemia. In conclusion, MBL2 genotypes representing MBL insufficiency were not associated with the overall risk of bacteraemia or disease severity, but smoking in carriers of the structural variant O allele may have a deleterious effect increasing the risk of Gram-positive bacteraemia.

C-reactive protein genetics is associated with carotid artery compliance in men in The Cardiovascular Risk in Young Finns Study.

Although C-reactive protein (CRP) is known to predict cardiovascular events, its status as a causal risk factor is still controversial. CRP gene single nucleotide polymorphisms (SNPs) have been shown to associate with CRP concentration, but no direct independent effect on early atherosclerotic changes has been demonstrated. We aimed to determine if CRP gene polymorphisms or haplotypes are associated with CRP concentration or carotid artery compliance (CAC), an indicator of subclinical atherosclerosis. We genotyped CRP gene polymorphisms -717A>G, -286C>T>A, +1059G>C, +1444C>T and +1846G>A and measured CRP concentration and CAC in 2283 young adults participating in The Cardiovascular Risk in Young Finns Study. A strong association was found between CRP genotypes and CRP concentration, which was also seen at the haplotype level. Linear regression analysis showed an independent effect of each SNP on CRP concentration after adjustment for risk factors, except for +1444 in males. Moreover, -286C>T>A, +1444C>T and +1846G>A were associated with CAC in males, but not in females. Men carrying the SNP -286 allele C had increased CAC after adjusting for risk factors. These data suggest that the presence of high producer CRP genotype is deleterious to carotid elasticity in men.

When do social inequalities in C-reactive protein start? A life course perspective from conception to adulthood in the Cardiovascular Risk in Young Finns Study.

BACKGROUND: It is unclear when in the life course do social inequalities in inflammation emerge. We examined whether the association between socioeconomic position (SEP) and C-reactive protein (CRP) is determined at conception, in childhood, adolescence or adulthood in 1484 participants from the population-based Cardiovascular Risk in Young Finns Study. METHODS: Five variants of the CRP gene were used to investigate whether SEP differences in CRP levels are determined at conception. SEP and serum CRP were assessed in childhood (age 3-9), adolescence (age 12-18) and in adulthood (age 24-39). SEP was measured using parental education and occupational status in childhood and adolescence, and participants' own education and occupational status in adulthood. Participants with CRP > 10 mg/l were excluded. RESULTS: All CRP gene variants were associated with circulating CRP concentrations in childhood, but there were no differences in the distribution of these variants by SEP. No strong evidence was found of associations between parental SEP and CRP. A graded association between higher SEP and lower CRP was observed in adulthood for education (P = 0.0005) but not for occupational status. Trajectories that led to high educational achievement both in the participants and their parents were associated with lower (P

CRP gene is involved in the regulation of human longevity: a follow-up study in Finnish nonagenarians.

Chronic low-grade inflammation is involved in the pathogenesis of many disease conditions in humans and it is frequently quantified by measuring the blood concentration of C-reactive protein (CRP). Here we show that the CRP concentration in old people (nonagenarians) is, at least partially, genetically determined, and that the high producer genotype is associated with a shorter life expectancy during follow-up. Thus, the data imply that the CRP gene may be a longevity gene in humans.

Increased lipolysis in LCHAD deficiency.

An increasing number of fatty acid oxidation defects are being detected owing to diagnostic improvements and a greater awareness among clinicians. The metabolic block leads to energy disruption, fatty infiltration, and toxic effects on organ functions exerted by beta-oxidation metabolites. This investigation was undertaken to assess the influence of long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency on lipolysis and energy turnover. We addressed the question whether the lipolysis and glucose production rates would be altered in the fasting state in a child with this disease. Lipolysis, glucose production and resting energy expenditure (REE) were studied in a 17-month-old girl with LCHAD deficiency and her healthy twin sister. Lipolysis and glucose production were determined after a 4-6 h fast by constant-rate infusion of [1,1,2,3,3-(2)H(5)]glycerol and [6,6-(2)H(2)]glucose and analysis by gas chromatography-mass spectrometry. REE was estimated by indirect calorimetry. The affected girl showed 50% higher lipolysis than did her sister, whereas the glucose production rates were similar. Plasma levels of dicarboxylic acids of 6-12 carbon atoms chain length, 3-hydroxy fatty acids of 6-18 carbon atoms chain length, total free fatty acids, and acylcarnitines were increased in the patient, as was REE. Since glucose production rates and plasma glucose levels were similar in the two girls, the increased lipolysis observed in the patient probably represents a compensatory mechanism for energy generation. This is achieved at the price of an augmented risk for fatty acid infiltration and toxic effects of beta-oxidation intermediates. This highlights the importance of avoiding fasting in these patients.

Toll-like receptor 4 polymorphism is associated with coronary stenosis but not with the occurrence of acute or old myocardial infarctions.

OBJECTIVE: Atherosclerosis is considered to be a chronic inflammatory disease. Toll-like receptor 4 (TLR-4), a key mediator in activating inflammatory cascade, has an A-to-G functional polymorphism that changes aspartic acid to glycine at position 299. TLR-4 is activated by, for example, lipopolysaccharides. The purpose of this study was to investigate the role of a common Asp299Gly polymorphism of the TLR-4 gene in atherosclerosis. MATERIAL AND METHODS: The study comprised autopsy material from 657 men (the Helsinki Sudden Death Study; mean age 53, range 33-70 years). RESULTS: Fewer G-allele carriers had 3-vessel coronary artery disease compared with AA homozygotes (OR 0.32; 95 % CI, 0.12-0.88, p = 0.027), and they also had a lower mean value for maximal coronary stenosis (p = 0.019). TLR-4 polymorphism was not significantly associated with the occurrence of acute or old myocardial infarction (MI). CONCLUSIONS: The G allele of the TLR-4 gene, which is associated with a lower inflammation response, was associated with a lower risk of coronary stenosis but not with the occurrence of MI and hence is not a major factor in the development of coronary atherosclerosis.

Multiferroic domain dynamics in strained strontium titanate.

Multiferroicity can be induced in strontium titanate by applying biaxial strain. Using optical second harmonic generation, we report a transition from 4/mmm to the ferroelectric mm2 phase, followed by a transition to a ferroelastic-ferroelectric mm2 phase in a strontium titanate thin film. Piezoelectric force microscopy is used to study ferroelectric domain switching. Second harmonic generation, combined with phase-field modeling, is used to reveal the mechanism of coupled ferroelectric-ferroelastic domain wall motion. These studies have relevance to multiferroics with coupled polar and axial phenomena.

Epistatic effect of C-reactive protein (CRP) single nucleotide polymorphism (SNP) +1059 and interleukin-1B SNP +3954 on CRP concentration in healthy male blood donors.

Baseline C-reactive protein (CRP) concentrations are indicative of persons prone to cardiovascular diseases and are about 40-50% heritable. We have previously shown that interleukin (IL)-1B +3954 allele T is associated with lower CRP concentration. In this study, we aimed to examine the effect of this polymorphism together with the CRP +1059 gene polymorphism on baseline CRP concentrations, and genotyped 336 healthy blood donors for CRP +1059 (G-->C) and IL-1B +3954 (C-->T) polymorphisms. In men, the carriers of the CRP +1059 C-allele had significantly lower CRP values than GG homozygotes (0.66 versus 0.43 mg l(-1), up to -35%, P = 0.009). No significant difference was found in women. When the data were stratified for both of these polymorphisms in men, CRP +1059 GG homozygotes had low CRP concentrations only if they were allele-T carriers of IL-1B +3954 simultaneously (0.93 versus 0.50 mg l(-1), P = 0.013). Genotype CRP +1059 GG/IL-1B +3954 CC was associated with an almost 3-fold risk of a higher baseline CRP value [odds ratio (OR) 2.84 (CI 1.03-6.07)]. Thus, both IL-1B +3954 (C-->T) and CRP +1059 (G-->C) polymorphisms influence baseline CRP values and act independently of each other in male subjects. These polymorphisms might be predictive markers of persons prone to cardiovascular diseases.

HEMA bound to self-protein promotes auto-antibody production in mice.

While several studies report that acrylic monomers contained in dental materials may cause hypersensitivity reactions, little is known of the associated immune response. Here we address the potential of 2-hydroxyethyl-methacrylate (HEMA) to bind to endogenous protein and elicit auto-antibody production in vivo. Albumin was incubated with HEMA at various times and pH. Following confirmation of the conjugation by inhibition of trinitrophenyl (TNP) binding, female Balb/c mice received HEMA conjugated to mouse serum albumin (MSA) in Freund's incomplete adjuvant or saline subcutaneously. ELISA was used to determine the serum antibody responses to native and modified MSA. IL-2 production in spleen cell cultures stimulated with HEMA-conjugated MSA was measured. HEMA reacted with serum albumin at physiological conditions. HEMA-conjugated MSA induced IL-2 secretion and production of IgG antibodies to native MSA. The results suggest that modification of an endogenous protein like serum albumin with HEMA may defeat the control of immune responses to this self-protein.

p53, CHK2, and CHK1 genes in Finnish families with Li-Fraumeni syndrome: further evidence of CHK2 in inherited cancer predisposition.

Germ-line mutations in the p53 gene predispose individuals to Li-Fraumeni syndrome (LFS). The cell cycle checkpoint kinases CHK1 and CHK2 act upstream of p53 in DNA damage responses, and recently rare germ-line mutations in CHK2 were reported in LFS families. We have analyzed CHK1, CHK2, and p53 genes for mutations in 44 Finnish families with LFS, Li-Fraumeni-like syndrome, or families phenotypically suggestive of LFS with conformation-sensitive gel electrophoresis. Five different disease-causing mutations were observed in 7 families (7 of 44 families; 15.9%): 4 in the p53 gene (5 of 44 families; 11.4%) and 1 in the CHK2 gene (2 of 44 families; 4.5%). Interestingly, the other CHK2-mutation carrier also has a mutation in the MSH6 gene. The cancer phenotype in the CHK2-families was not characteristic of LFS, and may indicate variable phenotypic expression in the rare families with CHK2 mutations. No mutations in the CHK1 gene were identified. Additional work is necessary to completely unravel the molecular background of LFS.

Cross-reactivity of antibodies to type 6B and 6A polysaccharides of Streptococcus pneumoniae, evoked by pneumococcal conjugate vaccines, in infants.

Streptococcus pneumoniae serotypes 6B and 6A are important causes of infections, yet only 6B is included in current vaccines. It is, therefore, crucial to evaluate whether functional antibodies are produced against both types after vaccination. Concentration and opsonophagocytic activity (OPA) of antibodies to 6B and 6A polysaccharides were determined in serum samples from infants immunized with 3 different pneumococcal conjugate vaccines containing serotype 6B. In all vaccine groups, a significant correlation was found between the anti-6B and -6A antibody concentration and OPA. However, OPA to the vaccine serotype was detectable more commonly than OPA to the cross-reactive type. Furthermore, 5%-15% of the serum samples showed high OPA against the 6B but not the 6A strain. On average, 2-6 times more anti-6B antibodies were needed for 50% opsonophagocytic killing of the type 6A than the type 6B strain. Although pneumococcal type 6B conjugate vaccines elicit antibodies that cross-react with type 6A, not all anti-6B antibodies are functionally cross-reactive.

Type specificity and significance of different isotypes of serum antibodies to human papillomavirus capsids.

Isotype-specific serum antibody responses against human papillomavirus (HPV) type 16 were evaluated by use of cross-sectional, prospective, and population-based seroepidemiologic studies. IgG1 and IgA were the most abundant isotypes. No sample contained IgG2, and <25 samples contained IgG3 or IgM. Total IgG, IgA, and IgG1 were HPV type specific and were associated with HPV-16 DNA (odds ratios [ORs], 5.4, 5.0, and 5.9, respectively; P<.001) but not with other HPV DNA (ORs, 1.2, 1.2, and 0.8, respectively; P value was not significant). Total IgG and IgG1 were strongly associated with number of lifetime sex partners (P<.001); IgA was only associated with number of recent sex partners and lifetime sex partners among younger women. Total IgG, IgG1, and IgA were associated with cervical intraepithelial neoplasia type III and also predicted risk of future cervical neoplasia. IgG and IgG1 appeared to mark lifetime cumulative exposure, whereas IgA may mark recent or ongoing infection.

Distribution of interleukin-2, -4, -10, tumour necrosis factor-alpha and transforming growth factor-beta mRNAs in oral lichen planus.

In the present study, MRNA for the cytokines interleukin-2 (IL-2), IL-4, IL-10 tumour necrosis factor-alpha (TNF-alpha) and transforming growth factor beta-1 (TGF-beta-1) were investigated in oral lichen planus (OLP) lesions using in situ hybridization with 35S-labelled oligonucleotide probes on frozen tissue sections. In addition, the expression of interferon-gamma (IFN-gamma), IL-10 and IL-4 mRNAs was analysed in cultured lesional T lymphocytes from oral lichen planus by polymerase chain reaction. Cells expressing mRNA for IL-2, IL-4, IL-10, TNF-alpha and TGF-beta 1 were found in all the biopsies studied. Approximately 1-2% of the total number of infiltrating cells in the lesions were positive for each of the different cytokine mRNAs. Most biopsies contained basement membrane-oriented, mRNA-positive cells. In the cultured T-cell lines, message for IFN-gamma was detected in all the patients, IL-10 in all but one, and IL-4 in just one of the seven patients investigated. The results suggest that mRNA for both pro- and anti-inflammatory cytokines, i.e., mixed T-helper 1 (TH1) and TH2 cytokine profiles, are generated simultaneously by a limited number of cells in chronic lesions of OLP.