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Increased levels of circulating cell-free DNA (cf-DNA) are associated with and predict poor health outcomes. However, its predictive ability for mortality in population-based samples remains understudied. We analysed the capability of cf-DNA to predict all-cause mortality and assessed whether it adds predictive value on top of the other risk factors in the Health 2000 survey (n = 1,257, 46–76 years of age, 15-years-follow-up, 18% deceased). When analysed in a multivariate model with the other factors that independently predicted mortality in the sample (age, gender, self-rated health, smoking and plasma levels of glucose and adiponectin), increases in cf-DNA levels were associated with increased risk of mortality (hazard ratio [HR] for 0.1 µg increase in cf-DNA: 1.017, 95% confidence interval [CI] 1.008–1.026, p = 0.0003). Inclusion of cf-DNA in the model improved the model fit and discrimination. Stratifying the analysis by cardiovascular disease (CVD) status indicated that cf-DNA predicted mortality equally well in individuals with (HR 1.018, 95% CI 1.008–1.026, p = 0.002) and without (HR 1.018, 95% CI 1.001–1.035, p = 0.033) CVD. In conclusion, our study indicates that cf-DNA level predicts mortality in middle-aged and older individuals, also among those with established CVD, and adds significant value to mortality prediction. Our results thus underscore the role of cf-DNA as a viable marker of health.

Objective. There is ample evidence demonstrating that accelerated atherosclerosis prevails in autoimmune rheumatic diseases, particularly in SLE, and that the risk is due not only to traditional cardiovascular risk factors but also to the disease itself. ANAs are a hallmark of SLE and are known even to antedate the development of SLE. Our aim was to investigate whether positive ANAs in young adults are associated with risk factors for atherosclerosis or subclinical markers of atherosclerosis. Methods. ANAs were examined by IIF using HEp-2 cells as substrate in 2278 participants in the Cardiovascular Risk in Young Finns Study for whom detailed data on cardiovascular risk factors and markers of subclinical atherosclerosis (including brachial flow-mediated dilatation, carotid compliance and carotid intima-media thickness) were available. Results. In multivariate analyses, adjusted for age, BMI, serum concentrations of CRP, triglycerides, high-density lipoprotein and low-density lipoprotein cholesterol, blood pressure and smoking habits, ANA positivity (titre > 160) was inversely associated (� ¼� 0.145; P ¼ 0.034) with carotid compliance in women. Conclusions. Our results indicate that ANA positivity is associated with decreased carotid elasticity in women, suggesting that mechanisms resulting in ANA production may be involved in the development of early atherosclerosis.

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.

BACKGROUND: Apolipoprotein E (apoE) polymorphism plays a central role in lipid metabolism, but has recently also been suggested to regulate inflammation, as judged by levels of serum C-reactive protein (CRP). OBJECTIVE: To establish whether polymorphism of the apoE genes affects susceptibility to primary Sjogren's syndrome (pSS), degree of inflammation or age of onset of pSS. METHODS: ApoE genotype distribution and allelic frequencies were analysed using PCR and the TaqMan system in 63 Finnish Caucasian patients with pSS and in 64 healthy controls matched for sex, ethnic origin and area of residence. The clinical and immunological data on the pSS patients were analysed in relation to the apoE genotypes. RESULTS: There was no difference between pSS patients and controls in apoE genotype and allelic frequencies. The apoE epsilon4 allele was significantly associated with early onset of pSS in the entire population and in female patients (Kaplan-Meier log rank test, P = 0.0407 and P = 0.0168, respectively). The average age (+/- S.D.) of onset of pSS in all apoE epsilon4 allele carriers was 46 +/- 12 and in other genotypes it was 53 +/- 10 yr (P = 0.031, t-test). ApoE polymorphism was not associated with signs of inflammation evaluated by such markers as concentration of plasma CRP, plasma interleukin-6, plasma TNF-alpha, immunoglobulin G and haemoglobin, or leucocyte count or ESR. CONCLUSIONS: ApoE polymorphism does not affect susceptibility to pSS or levels of plasma inflammatory indices in patients with pSS. However, a clear association prevails between apoE epsilon4 and early onset of pSS.

Objectives To determine whether plasma matrix metalloproteinase 9 (MMP-9) and MMP9 (-1562C-->T) polymorphism have an effect on the disease phenotype in primary Sjogren's syndrome (pSS). Methods Plasma MMP-9 concentrations and polymorphism of the MMP9 gene were analysed in 66 patients with pSS. These data were studied in relation to the clinical data of the patients. The genetic data of patients were compared with the data of 66 healthy subjects. Results Plasma MMP-9 was higher in patients with definite pSS than in patients with possible pSS. This association was principally caused by higher plasma MMP-9 in patients with a positive Schirmer test and keratoconjunctivitis sicca. pSS patients with purpura, SS-A autoantibodies and RF had significantly lower plasma MMP-9 than patients without these characteristics. The overall MMP9 (-1562C-->T) allele frequencies were similar in patients and control subjects. The frequency of the allele T was higher in patients without Raynaud's phenomenon than in the control group. Conclusions MMP9 (-1562C-->T) could not be used for risk assessment in pSS. The presence of the rarer allele T may decrease the risk of Raynaud's phenomenon in pSS. High plasma MMP-9 is indicative of definite pSS but may paradoxically have a preventive effect on the eruption of purpura and on the development of autoantibody reaction in pSS.

Objectives. To determine whether plasma interleukin-6 (IL-6) and G/C base exchange polymorphism at position -174 of the IL6 gene have an effect on the clinical manifestations of primary Sjogren's syndrome (pSS). Methods. Levels of circulating IL-6 protein and polymorphism of the IL6 gene were analysed in 66 patients with pSS and in 400 healthy subjects. These data were studied in relation to clinical data on the pSS patients. Results. Plasma IL-6 was elevated in pSS patients compared with healthy controls, pSS patients with coeliac disease, pulmonary fibrosis or alveolitis or peripheral nervous system symptoms had significantly higher IL-6 levels than patients without these manifestations. IL-6 levels increased in parallel with the histological grade of minor salivary gland biopsy and the number of pSS criteria fulfilled. IL6 allele frequencies were similar in patients and normal subjects. Plasma IL-6 levels were regulated by the IL6 genotype in pSS patients. Conclusions. The G/C polymorphism of the IL6 gene does not predispose patients to pSS, but the circulating IL-6 concentration is related to specific manifestations of the disease and the levels of IL-6 are regulated by the IL6 promoter polymorphism in pSS.

Summary Human cytomegalovirus (CMV) infection is associated with a higher risk of cardiovascular disease in immunocompromised organ transplant patients. It has been linked with the pathogenesis of elevated arterial blood pressure. However, controversy exists as to whether CMV infection is associated with endothelial function, and little is known about its role as a potential risk factor for early atherosclerosis development at a young age. We aimed to discover if CMV antibody titres are associated with early vascular changes (carotid intima-media thickness, carotid artery distensibility and brachial artery flow-mediated dilation), blood pressure elevation or other traditional cardiovascular risk factors. CMV antibody titres were measured in 1074 women and 857 men (aged 24–39 years) taking part in the Cardiovascular Risk in Young Finns study. CMV antibody titres were significantly higher in women compared to men. In men, high CMV antibody titres were associated directly with age (P

Alzheimer's disease (AD) and Parkinson's disease (PD) are the two most common neurodegenerative conditions characterised by the presence of abnormal accumulation of proteins and loss of neurones in specific regions of the brain. The aetiology and pathogenesis of AD and PD still remain largely unknown. Evidence has emerged that immune mediated mechanisms may be important in the development of these disorders,1,2 and cytokine interleukin 1 (IL1) is one of the mediators suggested to be involved. The IL1 family comprises three proteins, the proinflammatory IL1α and IL1β and their inhibitor IL1 receptor antagonist (IL1Ra), which are encoded by the IL1A , IL1B , and IL1RN genes respectively.3 Since IL1 may have a role in AD4–8 and in PD,9,10 variation in the IL1A , IL1B , and IL1RN genes may be of importance in the development of these disorders. There is already some evidence in support of this, including the postulated association of the IL1A (−889) \*2/\*2 genotype with AD11 and the influence of the IL1B (−511) \*1/\*1 genotype on age at onset of PD.12 However, validation in different population groups is needed to determine whether polymorphisms located in the IL1A , IL1B , and IL1RN genes represent actual susceptibility factors for AD and PD. In the present study, our purpose was to investigate whether polymorphisms of the IL1 cluster genes are associated with the risk of AD or PD in Finnish patients. Ethical approval for the investigation was obtained from the local Hospital Ethical Committees. All patients and controls enrolled in the study were from western Finland. The AD group consisted of 92 sporadic late onset (>65 years) patients (63 women, 29 men). Thirty-eight patients (mean age at onset 73.7 years (SD 4.9)) met the clinical diagnostic criteria of the NINCDS-ADRDA Work …

Urokinase-type plasminogen activator receptor (uPAR) is expressed on a variety of different immune cells and vascular endothelial cells during inflammation. Previous studies indicate that a high plasma concentration of the soluble form of the receptor (suPAR) predicts poor outcome in infectious diseases.A prospective cohort study.Plasma suPAR levels were measured in 132 patients with bacteraemia caused by Staphylococcus aureus, Streptococcus pneumoniae, ß-haemolytic streptococcae or Escherichia coli using a commercial enzyme-linked immunosorbent assay (ELISA). Values were measured on days 1-4 after a positive blood culture, on days 13-18 and on recovery.The maximum suPAR values on days 1-4 were markedly higher in nonsurvivors compared to survivors (15.8 vs. 7.3 ng mL(-1) , P0.001) and the area under the receiver operating characteristic curve (AUC(ROC) ) in the prediction of case fatality was 0.84 (95% confidence interval (CI) 0.76-0.93, P0.001). At a cut-off level of 11.0 ng mL(-1) , the sensitivity and specificity of suPAR for fatal disease was 83% and 76%, respectively. A high level of suPAR (≥ 11 ng mL(-1) ) was associated with hypotension (mean arterial pressure70 mmHg) (odds ratio (OR) 6.5; 95% CI 2.9-14.6) and high sequential organ failure assessment score (≥ 4) (OR 9.3; 95% CI 4.0-21.9). A high suPAR level remained an independent risk factor for case fatality in a logistic regression model adjusted for potential confounders.Plasma suPAR level is a sensitive and specific independent prognostic biomarker in patients with bacteraemia.

Activin A/erythroid differentiation factor (EDF), a dimeric polypeptide hormone composed of two beta A subunits, regulates growth and erythroid differentiation of human hematopoietic progenitor and erythroleukemia cells. We have identified activated human peripheral blood monocytes as a natural source of activin A/EDF. In these cells, lipopolysaccharide (LPS) induced rapidly the expression of the beta A subunit mRNAs through protein kinase C-dependent transcriptional regulation. The beta A subunit mRNA expression was also increased by 1,25-dihydroxyvitamin D3, an inducer of macrophage maturation of monocytes. Western analysis with an anti-beta A antibody and an erythroid differentiation bioassay confirmed that the conditioned media of LPS-activated monocytes contained the activin A/EDF protein. We suggest that monocyte/macrophage-derived activin A/EDF may not only modulate hematopoiesis but may also act as a mediator molecule in the diverse physiologic and pathogenetic events in which these cells are involved.

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.

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.

Both genetic and environmental factors, e.g. early childhood infections, have a role in the pathogenesis of atopic diseases.To examine simultaneously the strength and possible interactions of two known such factors, IL4 genetics and Helicobacter pylori infection, on the risk of atopy and asthma.Gene polymorphism analyses and skin prick tests (SPT) were determined in 245 adult asthmatics and 405 nonasthmatic controls of population-based case-control study. SPTs were used as an indicator of atopy. H. pylori infection was verified by detecting anti-H. pylori IgG antibodies in sera.A significant negative association was seen between the presence H. pylori antibodies and SPT positivity (or =1 positive reactions) in both asthmatics and controls (p = 0.002 and p = 0.025, respectively) but the effect of IL-4 polymorphism (SNP -590C/T) was nonsignificant in both groups (p = 0.071 and p = 0.072, respectively). However, IL4 genetics had an effect on susceptibility to H. pylori: asthmatics carrying the IL4 -590 allele T had a diminished risk to be H. pylori infected (OR 0.485 95%CI 0.287-0.819). This effect was not seen in controls. Logistic regression analysis indicated that H. pylori and IL4 effects on atopy risk are not interdependent.This study showed that the effect of H. pylori infection on atopy risk is stronger than that of IL4 genetics. There is no interaction between these factors on the pathogenesis of atopy suggesting that these factors have distinct immunopathogenetic mechanisms. However, the genetic effect may modify the role of infective agents by effecting on susceptibility to disease.

Functional polymorphisms of the genes for interleukin-10 (IL-10; promoter position -1082), chemokine receptor-5 (CCR5 32 bp deletion), tumor necrous factor-alpha (TNFalpha promoter position -308) and cytotoxic T-lymphocyte antigen-4 (CTLA-4 exon 1 position 49) were investigated for possible influence on susceptibility and outcome of multiple sclerosis (MS). The polymorphisms were typed by polymerase chain reaction based methods or by direct sequencing in MS patients (n=93-116) and controls (n=109-400). The studied genes were not associated with MS susceptibility. Patients were classified as suffering from a mild/moderate [Expanded Disability Status Scale (EDSS) 0-5.5] or severe (EDSS 6-8.0) form of MS. The AG genotype of IL-10 proved to be protective against severe MS in all patients (OR=0.32, P=0.010), the effect being increased over the years (10 years; OR=0.33, P=0.043, 15 years; OR=0.21, P=0.025 or 20 years; OR=0.14, P=0.026). Our results suggest that differential production of IL-10 might be a factor in the severity of MS.

The production of proinflammatory cytokines activates the systemic inflammatory response in sepsis. Patients also develop a compensatory anti-inflammatory reaction, which may have an important down-regulatory effect on the overactive inflammation. However, the role of this anti-inflammatory response in sepsis is not completely clarified. In this prospective study, we investigated the relationship between the pro- and anti-inflammatory cytokine profiles in severe sepsis and their role in the development of multiple organ failure (MOF).Thirty-eight patients meeting the criteria for severe sepsis were studied. MOF was defined as a maximum SOFA score of 10 or higher. Serial measurements of the proinflammatory IL-6 and IL-1beta and the anti-inflammatory IL-10 and IL-1ra were used. The cytokine samples were taken at the onset of sepsis and on the third and fifth day during the ICU period.The initial IL-10 and IL-1ra responses were identical in patients with or without MOF. The anti-inflammatory cytokine levels remained elevated in the MOF patients, whereas in patients without MOF the levels declined. The IL-6/IL-10 ratio was significantly higher in the MOF patients on days 1 and 3 compared with patients without MOF.We could not demonstrate overproduction of anti-inflammatory IL-10 in MOF patients. On the contrary, the high IL-6/IL-10 ratio indicates that IL-10 deficiency may contribute to the development of MOF in severe sepsis.

IL-10 has several functional effects relevant to asthma. It can modulate IgE production and induce apoptosis in eosinophils. Polymorphisms of IL-10 gene have been shown to affect IL-10 production.To establish whether IL-10 polymorphisms are associated with asthma and phenotype-related characteristics.The frequency of three single base exchange polymorphisms (at positions - 1082, - 819 and - 592) and corresponding haplotypes of the IL-10 gene were analysed in 245 adult asthmatic subjects and 405 controls using PCR and restriction fragment length polymorphism (RFLP). The data were assessed for correlations with the eosinophil count, serum IgE and lung function.The IL-10 haplotype frequencies were similar in asthmatics and controls. Eosinophil count median was 2.0- to 3.2-fold higher among asthmatics with rare ATA/ATA genotype than in asthmatics with other genotypes. No such difference was seen in the control group. When analysed by IL-10 haplotype carrier state and gender, male asthmatics with ATA haplotype had 2.8-fold higher serum IgE than those without ATA. A converse association was found in male controls with ATA haplotype, who had 1.9-fold lower serum IgE than their ATA-negative counterparts. The high IL-10-producing GCC haplotype was associated with impaired lung function in smoking male controls while in asthmatics no clear effect on lung function was found with any of the haplotypes studied.These results suggest that the eosinophil counts and serum IgE are differently regulated by IL-10 genotype in asthmatic and in normal subjects. However, IL-10 polymorphism is not related to susceptibility in asthma.

Oral Lactobacillus rhamnosus GG ingestion for 5 days to 4 weeks has been shown to alleviate clinical symptoms of gastrointestinal inflammation and atopic dermatitis. To determine whether oral Lactobacillus rhamnosus GG may act by generating immunosuppressive mediator in atopic children. Lactobacillus rhamnosus GG (ATCC 53103) at a daily dose of 2 x 1010 cfu was added for 4 weeks to the diets of nine children (mean age, 21 months) with atopic dermatitis. Blood and faecal samples were collected before supplementation and at early (2 weeks) and late stage (4 and 8 weeks from the beginning). The concentrations of interleukin-6 (IL-6), IL-10, IL-12, tumour necrosis factor-alpha (TNFalpha) and interferon-gamma (IFNgamma) in sera, as well as the production of IL-2, IL-4, IL-10 and IFNgamma in mitogen-induced peripheral blood mononuclear cells, were assessed. Secretory IgA and TNFalpha were also determined in faeces. The serum IL-10 concentration differed significantly between before, early and late samples (P0.001) due to the elevation of serum IL-10 in the later phase of oral Lactobacillus rhamnosus GG ingestion. The enhancement of IL-10 production in mitogen-induced cultures preceded the rise in serum IL-10. The enhanced IL-10 generation in vivo substantiates the anti-inflammatory properties of specific probiotic bacteria strains, and provides an additional reason for considering such treatments for patients with intestinal inflammation.

We tested the effects of interleukin-2 (IL-2), human recombinant tumor necrosis factor alpha (TNF-alpha), Staphylococcus aureus Cowan I (SAC), TPA, and their combinations, using a standard thymidine incorporation assay, in order to identify an optimal mitogen combination (OMC) for 24 consecutive patients with B-cell chronic lymphocytic leukemia (B-CLL). The combination that induced the highest thymidine incorporation was chosen as the OMC for each patient. Among 14 mitogen combinations tested, there were six different OMCs, of which the most frequent was TNF-alpha + IL-2. It was the OMC in 9 of 24 cases. The other OMCs were TNF-alpha + TPA1 (5/24), SAC + IL-2 (5/24), TPA1 + IL-2 (3/24), TPA10 + IL-2 (1/24), and TNF-alpha + TPA10 + IL-1 (1/24). The mitogenic power of the selected OMC in each case was then evaluated both by the combination of immunophenotyping and molecular cytogenetic techniques known as MAC (Morphology, Antibody, Chromosomes) and standard chromosome analysis. After OMC stimulation, the levels of DNA synthesis and B-cell proliferation (mitotic index) were, on average, 10-fold higher than those observed after standard TPA stimulation (P0. 0001). The proportion of mitotic B cells exceeded the proportion of mitotic T cells in 70.1% of the cases after OMC stimulation. After TPA stimulation, 7.7% +/- 2.5% of all mitoses were B-cell mitoses, whereas after OMC stimulation this proportion rose to 57.9% +/- 5.3%. The frequency of clonal chromosomal aberrations increased from 46% after TPA stimulation to 79% after OMC stimulation. The clonal aberrations del(6q), del(11q), and/or del(13q) were observed in 26%, 32%, and 42% of the patients with the respective clonal chromosomal aberrations, whereas the corresponding frequencies after TPA stimulation were only 4%, 21%, and 17%. When the lineage involvement of cells with clonal chromosomal aberrations from three patients was analyzed, the aberrations were found to be restricted to B cells only, and in one patient to a minor subset of B cells. The results demonstrate that an individually chosen OMC induces a high rate of proliferation in neoplastic B cells. We found deletions in 6q, 11q, and 13q at higher frequencies than reported previously, most probably as a result of an improved mitogenic response. The identification of an optimal mitogen stimulation for each patient, prior to chromosome analysis, can well be expected to reduce the rate of false-normal results in the future. This is essential for accurate evaluation of the prognostic significance of chromosomal aberrations in B-CLL.

The genes in the IL-1 complex code for three proteins, IL-1alpha, IL-1beta and the IL-1 receptor antagonist (IL-1 Ra). The severity of a given infection is influenced by the balance between the levels of IL-1beta, the major extracellular agonist, and that of IL-1 Ra. In healthy individuals, IL-1 Ra is readily detectable in plasma but IL-1beta levels are usually undetectable. As there are polymorphisms in both of these genes, we have now analyzed whether there are allelic associations between these loci and whether these would have an influence on plasma IL-1 Ra levels. In 200 healthy blood donors, the mean plasma IL-1 Ra concentration was 681 pg/ ml. The IL-1Ra allele 2 (IL1RN*2) had a clear influence on IL-1Ra levels: its carriers had higher levels than the non-carriers (745 ng/ml vs. 627 pg/ml, p0.05, t-test). As marker alleles for IL-1beta we used two biallelic base-exchange polymorphisms (at positions -511 and +3953 relative to the transcriptional start site). The more rare allele of IL-1beta -511 (allele 2) was significantly associated with the presence of IL-1 Ra allele 2, but in the case of the IL-1beta +3953, the more rare allele (allele 2) was less frequent in the carriers of the IL-1 Ra allele 2. These IL-1beta allelisms did not have a direct influence on plasma IL-1Ra levels, but the enhancing effect of IL-1 Ra allele 2 on IL-1 Ra plasma levels required the presence of the IL-1beta -511 allele 2 or absence of the IL-1beta +3953 allele 2. Taken together, these results indicate that the IL-1beta gene participates in the regulation of IL-1 Ra production in vivo and that the alleles of IL-1beta and IL-1 Ra which demonstrate this cooperative effect are often associated.

The capacity of neonatal T cells to secrete interleukin-2 (IL-2) has been reported to be variable. We analysed IL-2 production in purified neonatal and adult T cells using polyclonal activator phorbol ester + calcium ionophore (PDBu + iono) or receptor-mediated anti-CD3/anti-CD3+ anti-CD28 stimulation. PDBu + iono induced equally high IL-2 levels in both groups and, when stimulated with plate-bound anti-CD3 monoclonal antibody (mAb), the IL-2 secretion by neonatal cells was undetectable and adult cells produced low amounts of IL-2 (mean 331 +/- 86 pg/ml). The addition of anti-CD28 mAb to anti-CD3-stimulated cells markedly increased IL-2 production in both cell types, but levels of IL-2 in neonatal T cells remained clearly lower than those of adult T cells (respective mean values: 385 +/- 109 pg/ml and 4494 +/- 1199 pg/ml). As NF-kappa B is a critical transcription factor in the control of IL-2 expression, we next analysed its nuclear translocation in neonatal and adult T cells using the electrophoretic mobility shift assay and, because induction of reactive oxygen intermediates (ROI) is required for the activation of NF-kappa B, we also analysed levels of intracellular ROI in these cells using the ROI-reactive fluorochrome DCFH-DA and flow cytometry. In neonatal T cells NF-kappa B activation and ROI formation after anti-CD3 stimulation were low compared with adult T cells and, although addition of anti-CD28 mAb increased induction of NF-kappa B and ROI formation, levels similar to those of adults were not achieved. After PDBu + iono stimulation, the cells showed similar ROI formation and IL-2 secretion. Our results suggest that reduced IL-2 production by neonatal T cells is specific for anti-CD3 and anti-CD3+ anti-CD28-mediated stimulation and that these activators cannot effectively activate the ROI-NF-kappa B signalling pathway in neonatal T cells.

The production of the cytokines interleukin-6 (IL-6) and tumour necrosis factor-alpha (TNF-alpha) in B-CLL cells from 24 patients at different stages of chronic lymphocytic B-cell leukaemia (B-CLL) was investigated in vitro. In the majority of these cases, low spontaneous IL-6 production was measured. Mitogenic stimulation with phorbol 12-myristate 13-acetate (PMA) or PMA plus interleukin-2 (IL-2) resulted in a tremendous increase in TNF-alpha and IL-6 production in cells representing early stage (Binet A) disease. In contrast, very little, if any, production took place in cells from patients with advanced stage (Binet C) B-CLL. The results from stage B patients were intermediate. The most remarkable difference was recorded in PMA-stimulated (1 ng/ml) IL-6 production. In stimulated 72 h cultures, IL-6 concentrations were 1280 +/- 1080 pg/ml for Binet A (n = 11), 757 +/- 597 pg/ml for Binet B (n = 8) and 46.0 +/- 84.0 pg/ml for Binet C (n = 5). The differences in IL-6 production between stage C v B and stage C v A were both statistically significant (P=0.025). Similar effects, but to a lesser extent, were observed in TNF-alpha production. These results suggest that the varying capacity to produce IL-6 and TNF-alpha may play a role in B-CLL progression and in clinical manifestations of the disease.

A major feature of atopic dermatitis (AD) is the propensity to generate IgE to environmental antigens. Despite extensive information on IgE dysregulation in AD, the nature of immune responses to ingested allergens is poorly characterized.To determine the clinical and immunological responses to food in AD patients.To characterize the type and timing of clinical reactions to oral cow milk, 83 AD patients aged 2 to 60 months were subjected to double-blind placebo-controlled food challenge (DBPCFC). IFN-gamma and IL-4 production by their peripheral blood mononuclear cells (PBMC) was determined before and after DBPCFC.Of 50 patients positive to DBPCFC. 46% manifested exanthematous-type immediate-onset reactions and 54% eczematous-type late-onset reactions. In either group, the production of IL-4 and IFN-gamma by Concanavalin A-stimulated PBMC was comparable before and after DBPCFC. For immediate-reacting patients, the median IFN-gamma production by milk-stimulated PBMC was 11.5 (4.2-17.2) pg/ml as against 2.3 (0.2-5.7) pg/ml by unstimulated PBMC, P = 0.0008 before DBPCFC, and 4.6 (2.8-10.3) pg/ml. vs 4.2 (1.7-9.0) pg/mL, p = 0.40, correspondingly after DBPCFC.Before DBPCFC, immediate-reacting but not late-reacting patients were found to be capable of allergen-specific IFN-gamma production in vitro, indicating the heterogeneity in AD patients. After DBPCFC, the IFN-gamma generation abolished, indicating the effect of oral allergen exposure on IFN-gamma producing responses of AD patients.

This study involved 342 patients hospitalized because of severe, persistent sciatica suggestive of a lumbar intervertebral disc herniation. After standard clinical evaluation. EMG and myelography, 220 patients underwent lumbar discectomy. The remaining 122 patients were treated conservatively. Follow-up examinations were arranged after 1, 5 and 13 years. The study focused on the rehabilitation outcome in general and differences in outcome between the two treatment groups. Several indicators showed a rather poor outcome for sciatica patients during the 13-year follow-up period. In the operated group 16% had been re-operated because of lumbar disc herniation. True recurrence of herniation (same level and side) occurred in 8%. In the conservatively treated group 14% had undergone spinal surgery. Nearly 70% of the patients still reported sciatica. Self-assessed levels of low back pain were “no change/worse” for 19% in the operated group and for 44% in the conservatively treated group. In both the study groups, nearly 40% of the subjects had retired on disability pensions.

Interleukin (IL)-1 beta and IL-6 levels in plasma and cerebrospinal fluid (CSF) of 14 medicated schizophrenic patients and 9 controls were measured by enzyme-linked immunosorbent assay. Almost no detectable levels of IL-6 in plasma or CSF from patients or controls were found. With regard to mean plasma or CSF levels of IL-1 beta there were no statistically significant differences between the two groups investigated. The dose of neuroleptic medication the patients used did not correlate with the IL-1 beta plasma levels. For the whole series of subjects (n = 23) or for the schizophrenic patients (n = 14) no correlation between the plasma and CSF levels of IL-1 beta was found.

The signal transduction pathways leading to the expression of IL-1 beta in human monocytes via HLA-DR stimulation were investigated. SEB, a staphylococcal enterotoxin that binds to HLA-DR molecules, induced IL-1 beta expression in human monocytes. Protein synthesis inhibition by cycloheximide did not inhibit SEB-mediated IL-1 beta signal, indicating that protein synthesis is not required for the MHC class-II-mediated IL-1 beta expression. The effect of PKC, PKA, and tyrosine kinase inhibitors on HLA-DR-mediated IL-1 beta mRNA expression was then determined. H7, a preferential PKC inhibitor, completely inhibited IL-1 beta signal induced by SEB. The role of PKC on HLA-DR-mediated IL-1 beta induction was further confirmed by the ability of SEB to activate PKC on monocytes directly when measured with labeled phorbol ester ([3H]Pbt2)-binding capacity of whole cells. HA 1004, a preferential PKA inhibitor, and isobutyl-methyl-xanthine (IBMX), which inhibits the degradation of cAMP, had no effect on SEB-induced IL-1 beta signal, excluding the role of cAMP on HLA-DR-mediated IL-1 beta expression. Two tyrosine kinase inhibitors, genistein and dihydroxycinnamate, both inhibited SEB-induced IL-1 beta mRNA in monocytes. SEB also induced enhanced tyrosine phosphorylation of several proteins in human monocytes when determined with antiphosphotyrosine immunoblotting. Our results demonstrate that both PKC and protein tyrosine kinases are involved in HLA-DR-induced IL-1 beta expression in human monocytes.

The prognostic value of EMG in patients treated for lumbar disc herniation was evaluated in 80 patients, 55 were operated and 25 treated conservatively. All patients had an EMG examination before the initial hospitalization or operation. The patients were followed up one year and five years later. The outcome of the treatment was evaluated using a modified WHO handicap classification. The initial EMG finding had no prognostic significance in determining the outcome five years later. A normal EMG finding both at the one year and five year follow-ups was related to a good outcome. Signs of old neuropathy, large motor unit potentials and reduced interference pattern muscles were related to a poor outcome. The EMG findings predict the outcome for these patients only to a limited extent. The overall outcome seems to be influenced to a greater extent by psycho-social aspects than by qualitative aspects of the nerve root lesion detected by the EMG.

Social factors of 179 operated and 97 non-operated patients one year after hospitalization due to low back pain and sciatica were tested by multi-variate regression analysis in relation to the five-year outcome evaluated according to the WHO Handicap Classification. For operated men a subjective working incapacity (relative risk RR = 4.6) and co-morbidity (RR = 2.7) predicted a poor outcome. For operated women the predictive factors were subjective working incapacity (RR = 3.2) and older age (RR = 1.9). For non-operated men an increased occurrence of occupational hazards (RR = 3.6) and for non-operated women co-morbidity (RR = 7.1) indicated a poor outcome.

Based on a prospective study on 342 sciatica patients examined with rhizography, the aim was to determine which factors others than the rhizography finding and the grade and duration of symptoms were related to the selection of patients to undergo operation. Compared with surgically treated patients, conservatively treated patients who did not undergo operation and who had pathologic rhizography findings had pessimistic attitudes to possible surgery, often expressed a desire to retire, and considered their work as physically stressful. The women in this group were older and had lower pain indices than women who underwent operation. Conservatively treated patients with negative rhizography had more severe occupational handicaps, minor expectations of possible surgery, physically more strenuous jobs requiring difficult physical positions, and lower indices for pain and ADL than did the operated patients. The social and ergonomic background problems are emphasized in sciatica patients conservatively treated after rhizography.

The interleukin (IL)-1 gene cluster within chromosome 2 contains genes coding for both anti- and proinflammatory cytokines, including IL-1alpha, IL-1beta, IL-1Ra, and several novel cytokines designated IL-1F5 - IL-1F10.1 Proinflammatory cytokines IL-1alpha and beta are involved in the enhancement of inflammation and host defence. Anti-inflammatory IL-1Ra counteracts the function of IL-1alpha and IL-1beta. These cytokines are produced by a variety of cell types, for example, monocytes, magrophages, and keratinocytes. All IL-1 family genes are polymorphic and several of these polymorphisms have been shown to be associated with either susceptibility to or severity of inflammatory conditions and diseases.2 Atopy is a familial syndrome underlying atopic eczema, allergic rhinoconjuctivitis, and bronchial asthma. The skin prick test (SPT) is used to examine specific IgE mediated allergic responses and the results are generally in line with anamnestic data on atopy.3 Both IL-1alpha and beta have been shown to play a role in the regulation of allergen induced early and late reactions.4,5 IL-1alpha has also been found to accelerate cutaneous inflammation,6 whereas IL-1beta is involved in the regulation of contact sensitisation.7 In asthmatic bronchial epithelium, the expression of both IL-1beta and IL-1Ra is increased.8 Cytokines function as a network and thus the net effect on allergic inflammation may be dependent on allele combinations of individual cytokine genes. Recently in our population based case control study, we showed that IL1A (SNP +4845) genotype influences the SPT results.9 The carriers of the rarer allele 2 had a significantly lower SPT positive rate than that of non-carriers. Now we have expanded the study by analysing two additional SNPs ( IL1B SNP +3954 C>T and IL1RN VNTR in intron 2) in the IL-1 gene cluster from the same cohort. Altogether 254 females and 151 males (mean age 60 years, age range …

Mouse monoclonal antibodies to carcinoembryogenic antigen (CEA) obtained by the somatic cell hybridization technique of Köhler and Milstein were used in a modified enzyme bridge immunoperoxidase staining method. Both high and low affinity antibodies were tested and their staining properties compared with those of a commercial polyvalent rabbit antiserum. The staining pattern of neoplastic epithelial cells in all seven antibodies in samples of primary adenocarcinoma of the colon was similar, indicating that no gross differences were found in the exposure of the different antigenic determinants of CEA in formalin fixed tissue. The background staining of the monoclonal antibodies are negligible. It is concluded that monoclonal antibodies are superior to conventional antisera in immunoperoxidase staining of CEA.

A series of surgically treated patellar tendon lesions among athletes is presented. The material was collected during 5 years from three sports injury clinics and from two hospitals. During this period the authors treated about 150 cases of jumper's knee, of which 34 cases were treated by operation. The athletes were mostly volley ball players, jumpers or runners. The operation revealed a necrotic focus of the patellar tendon in 21 cases, the retinaculum was thick and adherent in 16 patients and an exostosis of the patellar insertion was seen in two cases. The necrotic areas were excised, the thick and adherent retinaculum was divided and the exostoses were excised and drilled. Surgical treatment of chronic patellar tendon pains may give good results in selected cases.

Seven measures at the three lowest lumbar interspaces were recorded from conventional radiographs of the lumbar spines of 160 consecutive patients with low back pain and sciatica admitted for myelography and possible surgery. Eighty-eight patients were operated upon for disc herniation, and of the conservatively-treated 72 patients, 18 had a pathologic and 54 a normal myelogram. The results were evaluated after one year using the occupational handicap scales of WHO. Correlations of radiographic measures to stature were moderate and to age small. After adjusting for stature and age, only the male interpedicular distances and the antero-posterior diameter of intervertebral foramen at L3 were greater than those of females. The males with a pathologic myelogram had smaller posterior disc height at L3 and a smaller interarticular distance at L3 and L4 than those with normal myelogram, likewise the midsagittal diameter at L3 and L4 in females. In all patients other measures besides posterior disc height were smaller than those for low back pain patients (p less than 0.001) or for cadavers (p less than 0.001). The only correlation between measures and clinical manifestations was between pedicular length at L3 and limited straight leg raising. Where the disc material had been extruded into the spinal canal, the interpedicular distance was significantly wider. Only anterior disc height at L3 revealed differences between good and poor outcome one year after surgery, as did the interarticular distance at S1 in patients with normal myelogram after conservative treatment.

The concentration of free and conjugated diazepam, of its major demethylated metabolite, N-demethyldiazepam, and of its hydroxylated metabolites, N-methyloxazepam and oxazepam, were measured by a GLC-method in plasma, bile and urine following four nightly doses of diazepam 10 mg. Ten patients with a T-tube in the common bile duct after choledochotomy (Group I) were studied and 12 patients after cholecystectomy (Group II). Twelve hours after drug administration, the mean total concentration of diazepam in bile was 1/23 that in plasma. Similarly, during 9–10 h only low concentrations of diazepam were found in the urine, and in both urine and bile only the unconjugated drug was found. The principal metabolite of diazepam in plasma was N-demethyldiazepam. In bile an average of 77% of the total amount of N-demethyldiazepam was in the conjugated form, and its total concentration was half that in plasma. In urine N-demethyldiazepam was mainly in the conjugated form. No hydroxylated metabolites of diazepam were found in plasma. Oxazepam was the metabolite found in bile and urine in the next highest concentration after N-demethyldiazepam. In the urine it was mainly conjugated, but in bile only a mean of 35% was conjugated. Both in bile and urine, N-methyloxazepam was found only intermittently and in low concentration. Diazepam and all of its common metabolites were measured in human bile, and the concentrations found were too low to produce a clinically significant enterohepatic circulation.

A total of 753 patients (328 women, 425 men) below 65 years of age and without previous pension living in the South-West of Finland, were operated on for the first time for lumbar disc herniation during the period 1975-1979. The frequency of a new invalidity pension was observed during a follow up period of two years. Of the 753 patients there were 100 new invalidity pensioners (13%) during one year and 133 (18%) during two years after the first operation. According to a statistical model for the impact of age and nature of work on invalidity pension the greatest risk of pensioning for women was associated with age, pensioning being more than five times higher in the age group 45-54 years than below 35 years. Moderate and heavy work by women constituted a minor risk factor, increasing the risk by less than two times compared with light work. In men the risk correlated clearly to both age and nature of work. Moderate and heavy work increased the risk nearly three times compared with light work. The frequency of pensions among 45-64 year old men was even 6-8 times higher, than the risk for men below 35 years. A second operation increased the risk on average two to three times. Cauda equina syndrome was not a risk factor for receiving an invalidity pension. The primary diagnosis for an invalidity pension was something other than lumbar disc herniation in 20%. Patients with unsatisfactory results after lumbar disc operations account for about 10% of all the new invalidity pensions due to some form of back disease in Finland.

An open trial with diflunisal (500 mg twice daily) in 766 outpatients consulting their doctor for low back pain, was carried out as part of the project "Back Pain 1981" in Finland. Of the patients (mean age 41 years), 460 had acute lumbago, 144 sciatica and 162 had chronic low back pain as a clinical diagnosis. In each diagnostic group there was a control group of patients receiving no drug therapy. Of the patients 65 percent were men and 35 percent women and the groups did not differ from this distribution in any diagnosis. The efficacy of the treatment was evaluated using four criteria: change of pain at rest and during exercise, patient's evaluation of the efficacy of the treatment, and the need for any supportive treatment. Side-effects of the drug therapy were registered. In all diagnostic groups the relief of pain both at rest and during exercise was greater in patients receiving diflunisal than in the controls. The greatest difference was found in lumbago. The patient's evaluation did not differ between the groups. The drug therapy diminished the need for supportive physical therapy. The frequency of side-effects was 8.6%. They led to the discontinuation of medication in 14 cases (3%). No severe side-effects were found. Diflunisal therapy for the relief of low back pain is therefore considered to be indicated in outpatient care.

The aim of this study was to elucidate the consequences of leisure time physical activities on the one-year results of surgery of lumbar intervertebral disc herniation. Pre- and postoperative leisure time physical activities and severity of occupation handicap were analyzed from 212 patients. Only to a certain degree the findings support the claim that a high preoperative level of physical activities during leisure time is linked with good postoperative results.

Two cases of traumatic bilateral Achilles tendon rupture are reported. One of the patients was a healthy middle-aged man, who had been an active national-level gymnast 20 years earlier. He had not suffered any complaints of Achilles tendons before. The ruptures occurred when, after a sauna, he showed his guests a vault forwards, which he had been able to perform easily. This time the landing took place on the toes, causing a high peak stretch to the calf muscles and Achilles tendons. The total rupture of both Achilles tendons was treated surgically, with an excellent result 2 days after the trauma. End-to-end suturation and a fascial flap plasty were made on both sides. No macroscopic degeneration could be detected on the rupture sites. He was allowed to walk freely 6 weeks after the surgery. The second case was a 54-year-old woman, who had suffered from Achilles tendinitis and peritendinitis for 2 years. Both tendons had been surgically treated, and severe adhesions and local degenerative changes had been found. The tendon rupture occurred when she injured her left ankle while getting out of the car. Two days later she fell at home, because of the weakness of the left side, and consequently the right Achilles tendon was injured. She was treated conservatively for 10 days, before the surgery was performed. Both tendons were ruptured and an extensive degeneration of the area was observed. The right side suffered from a rerupture, which was again treated surgically. After surgery the recovery was slow, but the final result 3 years later was moderate. Neither of the patients had any systemic diseases.

A redox steady state is important in maintaining vital cellular functions and is therefore homeostatically controlled by a number of antioxidative agents, the most important of which are enzymes. Oxidative Stress (OS) is associated with (or/and caused by) excessive production of damaging reactive oxygen and/or nitrogen species (ROS, RNS), which play a role in many pathologies. Because OS is a risk factor for many diseases, much effort (and money) is devoted to early diagnosis and treatment of OS. The desired benefit of the “identify (OS) and treat (by low molecular weight antioxidants, LMWA)” approach is to enable selective treatment of patients under OS. The present work aims at gaining understanding of the benefit of the antioxidants based on interrelationship between the concentration of different OS biomarkers and LMWA. Both the concentrations of a variety of biomarkers and of LMWA were previously determined and some analyses have been published by the MARK-AGE team. For the sake of simplicity, we assume that the concentration of an OS biomarker is a linear function of the concentration of a LMWA (if the association is due to causal relationship). A negative slope of this dependence (and sign of the correlation coefficient) can be intuitively expected for an antioxidant, a positive slope indicates that the LMWA is pro-oxidative, whereas extrapolation of the OS biomarker to [LMWA] = 0 is an approximation of the concentration of the OS biomarker in the absence of the LMWA. Using this strategy, we studied the effects of 12 LMWA (including tocopherols, carotenoids and ascorbic acid) on the OS status, as observed with 8 biomarkers of oxidative damage (including malondialdehyde, protein carbonyls, 3-nitrotyrosine). The results of this communication show that in a cross-sectional study the LMWA contribute little to the redox state and that different “antioxidants” are very different, so that single LMWA treatment of OS is not scientifically justified assuming our simple model. In view of the difficulty of quantitating the OS and the very different effects of various LMWA, the use of the “identify and treat” approach is questionable.