Reduced plasma PCSK9 response in patients with bacteraemia is associated with mortality.

BACKGROUND: The proprotein convertase subtilisin/kexin type 9 (PCSK9) enzyme controls blood cholesterol levels by downregulating the expression of the low-density lipoprotein receptor (LDLR). Pathogenic lipids (e.g. lipopolysaccharide) are removed from the circulation by an LDLR/PCSK9-dependent mechanism; thus, it has been suggested that PCSK9 inhibitors may be beneficial in the treatment of infections. We measured plasma PCSK9 levels in patients with culture-positive bacteraemia and explored pathogen-dependent and infection site-dependent effects as well as correlations between patient characteristics and outcome. METHODS: Proprotein convertase subtilisin/kexin type 9 in the plasma was measured with an enzyme-linked immunosorbent assay from 481 patients with blood culture-positive infection on days 0 to 4 after admission to the emergency department. Patient outcome and clinical and laboratory data were gathered retrospectively from patient records. RESULTS: The plasma PCSK9 level was elevated equally in patients with Gram-positive or Gram-negative bacterial infections; particularly high levels were seen in patients with a lower respiratory tract infection and Streptococcus pneumoniae bacteraemia. PCSK9 levels showed a significant positive correlation with C-reactive protein (CRP) level. Bacteraemia patients with liver disease or a history of alcohol abuse had significantly lower levels of plasma PCSK9. Reduced PCSK9 plasma responses in patients were significantly associated with mortality at days 7, 28 and 90. CONCLUSION: Proprotein convertase subtilisin/kexin type 9 is upregulated in blood culture-positive infections. Plasma PCSK9 resembles acute-phase proteins; its expression is induced during an infection, reduced in liver disease and correlates positively with CRP level. We have shown that PCSK9 levels are lower in patients with a fatal prognosis.

Plasma cell-free DNA and qSOFA score predict 7-day mortality in 481 emergency department bacteraemia patients.

BACKGROUND: A few studies have shown that both quick Sequential Organ Failure Assessment (qSOFA) score and cell-free DNA (cfDNA) have potential use as a prognostic marker in patients with infection. We studied these two markers alone and in combination to identify those emergency department (ED) patients with the highest risk of death. METHODS: Plasma cfDNA level was studied on days 0 to 4 after admittance to the ED from 481 culture-positive bloodstream infection cases. The qSOFA score was evaluated retrospectively according to Sepsis-3 definitions. The primary outcome was death by day 7. RESULTS: CfDNA on day 0 was significantly higher in nonsurvivors than in survivors (2.02 µg mL-1 vs. 1.35 µg mL-1 , P < 0.001). CfDNA level was high (>1.69 µg mL-1 ) in 134 (28%) of 481 cases, and the qSOFA score was ≥2 in 128 (28%) of 458 cases. High cfDNA and qSOFA score ≥2 had 70% and 77% sensitivity and 76% and 76% specificity in predicting death by day 7, respectively. High cfDNA alone had odds ratio (OR) of 7.7 (95% CI 3.9-15.3) and qSOFA score ≥2 OR of 11.6 (5.5-24.3), but their combination had OR of 20.3 (10.0-41.4) in predicting death by day 7 when compared with those with low cfDNA and qSOFA score <2. Amongst the five cases with the highest cfDNA levels, there were three patients with severe disseminated intravascular coagulation. CONCLUSION: CfDNA and qSOFA score can be used independently to identify those bacteraemia patients at high risk of death, and combining these two markers gives additional advantage.

The Plasma Level of Proprotein Convertase FURIN in Patients with Suspected Infection in the Emergency Room: A Prospective Cohort Study.

There is an increasing need for novel biomarkers that enable better diagnostic and prognostic stratification of patients with suspected infection. A proprotein convertase enzyme FURIN is upregulated upon immune cell activation, and it promotes infectivity by cleaving and activating pathogens. In this study, we determined FURIN levels in plasma using ELISA from 537 patients that were admitted to emergency room with suspected infection. Patients were sorted to high- and low-level FURIN groups with a cut-off level of 370 pg/ml. The study cohort included five diagnostic groups: Group 1, no systemic inflammatory response syndrome (SIRS, n = 59 patients); Group 2, bacterial infection without SIRS (n = 67); Group 3, SIRS, but no bacterial infection (n = 308); Group 4, sepsis without organ failure (n = 308); and Group 5, severe sepsis (n = 49). Statistically significant associations were not found between the plasma level of FURIN and the prevalence of sepsis (P = 0.957), diagnostic group of a patient (P = 0.737) or the bacteria in blood culture (P = 0.499). Additionally, the concentration of FURIN did not predict the severity or case fatality of the infectious disease. However, statistically significant associations were found between high plasma level of FURIN and diagnosed rheumatic disease (P < 0.001) as well as with the prevalence of non-smokers (P = 0.034). Thus, albeit the plasma level of FURIN does not predict the severity of infectious disease, it may be of use in the diagnostics of autoimmune diseases.

Evidence of streptococcal origin of acute non-necrotising cellulitis: a serological study.

Bacteriological diagnosis is rarely achieved in acute cellulitis. Beta-haemolytic streptococci and Staphylococcus aureus are considered the main pathogens. The role of the latter is, however, unclear in cases of non-suppurative cellulitis. We conducted a serological study to investigate the bacterial aetiology of acute non-necrotising cellulitis. Anti-streptolysin O (ASO), anti-deoxyribonuclease B (ADN) and anti-staphylolysin (ASTA) titres were measured from acute and convalescent phase sera of 77 patients hospitalised because of acute bacterial non-necrotising cellulitis and from the serum samples of 89 control subjects matched for age and sex. Antibiotic treatment decisions were also reviewed. Streptococcal serology was positive in 53 (69%) of the 77 cases. Furthermore, ten cases without serological evidence of streptococcal infection were successfully treated with penicillin. Positive ASO and ADN titres were detected in ten (11%) and three (3%) of the 89 controls, respectively, and ASTA was elevated in three patients and 11 controls. Our findings suggest that acute non-necrotising cellulitis without pus formation is mostly of streptococcal origin and that penicillin can be used as the first-line therapy for most patients.

Urine soluble urokinase-type plasminogen activator receptor levels correlate with proteinuria in Puumala hantavirus infection.

OBJECTIVES: Urokinase-type plasminogen activator receptor (uPAR) is upregulated during inflammation and known to bind to ß3 -integrins, receptors used by pathogenic hantaviruses to enter endothelial cells. It has been proposed that soluble uPAR (suPAR) is a circulating factor that causes focal segmental glomerulosclerosis and proteinuria by activating ß3 -integrin in kidney podocytes. Proteinuria is also a characteristic feature of hantavirus infections. The aim of this study was to evaluate the relation between urine suPAR levels and disease severity in acute Puumala hantavirus (PUUV) infection. DESIGN: A single-centre, prospective cohort study. SUBJECTS AND METHODS: Urinary suPAR levels were measured twice during the acute phase and once during convalescence in 36 patients with serologically confirmed PUUV infection. Fractional excretion of suPAR (FE suPAR) and of albumin (FE alb) was calculated. RESULTS: The FE suPAR was significantly elevated during the acute phase of PUUV infection compared to the convalescent phase (median 3.2%, range 0.8-52.0%, vs. median 1.9%, range 1.0-5.8%, P = 0.005). Maximum FE suPAR was correlated markedly with maximum FE alb (r = 0.812, P < 0.001) and with several other variables that reflect disease severity. There was a positive correlation with the length of hospitalization (r = 0.455, P = 0.009) and maximum plasma creatinine level (r = 0.780, P < 0.001) and an inverse correlation with minimum urinary output (r = -0.411, P = 0.030). There was no correlation between FE suPAR and plasma suPAR (r = 0.180, P = 0.324). CONCLUSION: Urinary suPAR is markedly increased during acute PUUV infection and is correlated with proteinuria. High urine suPAR level may reflect local production of suPAR in the kidney during the acute infection.

Genome-wide association study does not reveal major genetic determinants for anti-cytomegalovirus antibody response.

Cytomegalovirus (CMV) causes an infection, which is followed by a lifelong latency. CMV has received much attention in clinical studies, but little is known about the genetic basis of this common infection. To identify genetic polymorphisms associated with the susceptibility to and strength of anti-CMV immunoglobulin G (IgG) response to CMV infection, we conducted a genome-wide association study (GWAS) using an Illumina BeadChip containing 670 000 probes and participants from the Cardiovascular Risk in Young Finns Study, including 1486 anti-CMV IgG seropositive and 648 seronegative individuals. Statistical analyses were performed using logistic (for susceptibility) and linear regression (for strength of antibody response). None of single-nucleotide polymorphisms (SNPs) was found to be associated with susceptibility to CMV infection at the level of genome-wide significance (P<5 × 10(-8)). Also, none of the association signals identified reached genome-wide levels of statistical significance in the study of the strength of the antibody response to CMV although five SNPs in AGBL1 gene region displayed a suggestive association (lowest P-value=1.86 × 10(-6)). The results indicate that there is no strong evidence of major host genetic factors involved in either susceptibility to or the strength of antibody response to human CMV infection.

Soluble urokinase-type plasminogen activator receptor in patients with suspected infection in the emergency room: a prospective cohort study.

OBJECTIVES: The soluble form of urokinase-type plasminogen activator (suPAR) was evaluated as an early prognostic marker of sepsis in patients with suspected infection. DESIGN: A single-centre prospective cohort study. METHODS: The cohort comprised 539 patients in the emergency department with suspected infection: 59 without systemic inflammatory response syndrome (SIRS) and without bacterial infection (group 1), 68 with bacterial infection and without SIRS (group 2), 54 with SIRS and without bacterial infection (group 3), 309 with sepsis (SIRS and bacterial infection) and without organ failure (group 4) and 49 with severe sepsis (SIRS, bacterial infection and organ failure) (group 5). suPAR was measured on admission using a commercial solid-phase enzyme-linked immunosorbent assay. RESULTS: The median soluble form of the receptor (suPAR) concentrations in groups 1-5 were 4.7, 5.0, 4.4, 4.8 and 7.9 ng mL(-1) , respectively (P < 0.001). The levels were significantly higher in nonsurvivors compared with survivors (8.3 vs. 4.9 ng mL(-1) , P < 0.001) and in patients with severe sepsis (group 5) compared with those in the other groups (7.9 vs. 4.8 ng mL(-1) , P < 0.001). Area under the receiver operating characteristics curve (AUC(ROC) ) for the prediction of case fatality was 0.79 (95% confidence interval [CI]: 0.72-0.86, P < 0.0001) and 0.75 for severe sepsis (95% CI: 0.68-0.81, P < 0.0001). At a cut-off level of 6.4 ng mL(-1) , suPAR had 76% sensitivity and 69% specificity for fatal disease; at a cut-off level of 6.6 ng mL(-1) , the sensitivity and specificity for severe sepsis were 67% and 72%, respectively. In multivariate models, high suPAR remained an independent predictor of case fatality and severe sepsis after adjusting for potential confounders. CONCLUSIONS: A high suPAR level predicts case fatality and severe sepsis in patients with suspected infection.

Relation of high cytomegalovirus antibody titres to blood pressure and brachial artery flow-mediated dilation in young men: the Cardiovascular Risk in Young Finns Study.

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 < 0·001) and systolic (P = 0·053) and diastolic (P = 0·002) blood pressure elevation, and associated inversely with flow-mediated dilation (P = 0·014). In women, CMV antibody titres did not associate with any of the analysed parameters. In a multivariate regression model, which included traditional atherosclerotic risk factors, CMV antibody titres were independent determinants for systolic (P = 0·029) and diastolic (P = 0·004) blood pressure elevation and flow-mediated dilation (P = 0·014) in men. High CMV antibody titres are associated independently with blood pressure and brachial artery flow-mediated dilation in young men. This association supports the hypothesis that common CMV infection and/or an immune response to CMV may lead to impaired vascular function at a young age.

Plasma level of soluble urokinase-type plasminogen activator receptor as a predictor of disease severity and case fatality in patients with bacteraemia: a prospective cohort study.

OBJECTIVES: 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. DESIGN: A prospective cohort study. SUBJECTS AND METHODS: 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. RESULTS: The maximum suPAR values on days 1-4 were markedly higher in nonsurvivors compared to survivors (15.8 vs. 7.3 ng mL(-1) , P < 0.001) 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, P < 0.001). 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 pressure < 70 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. CONCLUSION: Plasma suPAR level is a sensitive and specific independent prognostic biomarker in patients with bacteraemia.

Relation among mannose-binding lectin 2 genotype, beta-cell autoantibodies, and risk for type 1 diabetes in Finnish children.

Mannose-binding lectin (MBL) is a key mediator of innate immunity, the insufficiency of which is caused by point mutations in the MBL2 gene. MBL insufficiency is associated with increased susceptibility to infections and certain autoimmune diseases, but its impact in the pathogenesis and risk of type 1 diabetes (T1D) is controversial. We investigated the significance of the MBL2 genotype on the risk of T1D in a Finnish study population comprising 470 diabetic children and 501 controls. Furthermore, the effect of MBL2 gene polymorphism on the emergence of beta-cell autoantibodies in 289 unaffected children with human leukocyte antigen-conferred susceptibility to T1D was assessed. MBL genotype had no significant effect on the risk or onset age of T1D. However, children with the biallelic variant genotype reflecting total MBL deficiency tested positive more frequently for > or =3 autoantibodies compared with children with another genotype (odds ratio = 6.0, 95% confidence interval 1.3-28; p = 0.013). In conclusion, the MBL2 genotype did not affect susceptibility to T1D in children, and this finding does not support previous reports implicating a role of the MBL2 genotype as a factor predisposing to T1D. The association of the biallelic variant genotype with positivity for multiple autoantibodies suggests that intermolecular epitope spreading may be linked with impaired clearance of autoantigens as a result of MBL deficiency.

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.

Serum mannan-binding lectin (MBL) in patients with infection: clinical and laboratory correlates.

In this study, we determined the serum levels of mannan-binding lectin (MBL) in patients with suspected or documented infection to characterize the possible role of MBL in the susceptibility to infection. We also investigated the kinetics of MBL during the infection and correlated the concentrations of MBL with those of acute-phase reactants C-reactive protein (CRP) and group II phospholipase A2 (PLA2-II) and cytokines interleukin-1(IL-1). interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-alpha). The frequency of MBL deficiency in the patients with signs of infection did not differ from that of controls. In four patients with MBL deficiency, the infections were caused by common pathogens and the outcome was normal. The mean MBL concentration in the patients with signs of infection was significantly higher than in the healthy controls (9.88 and 4.48 mg/l, respectively; p < 0.05). The highest mean MBL concentration was observed in patients with clinically or microbiologically documented bacterial infection. During follow-up, the MBL concentration altered individually in different patients, but no particular change in pattern in the MBL concentration could be demonstrated in any patient group. Of the acute-phase reactants in the circulation, only CRP and IL-1 showed a weak, albeit significant, negative correlation with the concentration of MBL. In conclusion, the deficiency of MBL was not shown to be an independent risk factor for infection in the adult population studied. The concentration of MBL did not follow the change in pattern of other acute-phase reactants and cytokines during the acute phase response. Therefore, measurement of the MBL concentration as an acute-phase reactant is not useful in the diagnosis or follow-up of infection. On the other hand, the deficiency of MBL can be detected reliably by serological methods even during an infection.

Opsonising immunoglobulins and mannan-binding lectin in chronic lymphocytic leukemia.

We investigated the influence of plasma concentrations of immunoglobulin G (IgG), IgA, IgM, IgG subclasses and mannan-binding lectin (MBL) on susceptibility to infection in patients with chronic lymphocytic leukemia (CLL). Of 28 patients with CLL, increased susceptibility to infection was recorded in nine. Four of them (44%) had hypogammaglobulinemia as opposed to only one (5%) of the 19 patients without increased susceptibility to infection (OR 14.4; 95% CI, 1.6-130). When the effect of IgG subclasses contributing to hypogammaglobulinemia was studied, only the decreased concentrations of IgG4 and IgG2 were associated with increased susceptibility to infection. They, in turn, were intercorrelated and also highly correlated with the concentration of IgA. In fact, when these parameters were studied by a multivariable model, only the decreased concentration of IgA was shown as an independent risk factor for infection (P = 0.03). The mean concentration of MBL was significantly higher in patients with infections than in those without (6.54 mg/l and 2.75 mg/l, respectively; P = 0.001). The monitoring of its concentrations might be useful in the follow-up of infectious morbidity in CLL.

Variant mannose-binding lectin 2 genotype is a risk factor for reactive systemic amyloidosis in rheumatoid arthritis.

OBJECTIVE: The aim of this study was to investigate whether polymorphism of the mannose-binding lectin 2 (MBL2) gene is related to the occurrence of systemic AA amyloidosis in patients with rheumatoid arthritis (RA). METHODS: MBL2 structural gene polymorphisms at codon 52 (CGT-->TGT, Arg-->Cys; D), codon 54 (GGC-->GAC, Gly-->Asp; B) and codon 57 (GGA-->GAA, Gly--> Glu; C), and MBL2 promoter region polymorphism at position -221 (G-->C) were examined in 57 patients with RA complicated by biopsy-proven reactive amyloidosis and 51 control RA patients without amyloid. RESULTS: A strong association was found between the presence of a structural MBL2 gene variant O (B, D or C) and the occurrence of amyloidosis in RA patients: 29 of 57 (50.9%) of the RA patients with amyloid had a variant allele compared with 12 of 51 (23.5%) of the RA patients without amyloid (OR 3.37, 95% CI 1.47-7.72; P = 0.004). CONCLUSION: We conclude that variant MBL2 structural genotype constitutes a significant risk factor for reactive amyloidosis in RA and that the increased risk is probably related to MBL-mediated impairment of mononuclear phagocyte function.

Allergic sensitization and microbial load--a comparison between Finland and Russian Karelia.

Epidemiological data have indicated that some infections are associated with a low risk of allergic diseases, thus supporting the idea (hygiene hypothesis) that the microbial load is an important environmental factor conferring protection against the development of allergies. We set out to test the hygiene hypothesis in a unique epidemiological setting in two socio-economically and culturally markedly different, although genetically related, populations living in geographically adjacent areas. The study cohorts included 266 schoolchildren from the Karelian Republic in Russia and 266 schoolchildren from Finland. The levels of total IgE and allergen-specific IgE for birch, cat and egg albumen were measured. Microbial antibodies were analysed against enteroviruses (coxsackievirus B4), hepatitis A virus, Helicobacter pylori and Toxoplasma gondii. Although total IgE level was higher in Russian Karelian children compared to their Finnish peers, the prevalence of allergen-specific IgE was lower among Russian Karelian children. The prevalence of microbial antibodies was, in turn, significantly more frequent in the Karelian children, reflecting the conspicuous difference in socio-economic background factors. Microbial infections were associated with lower risk of allergic sensitization in Russian Karelian children, enterovirus showing the strongest protective effect in a multivariate model. The present findings support the idea that exposure to certain infections, particularly in childhood, may protect from the development of atopy. Enterovirus infections represent a new candidate to the list of markers of such a protective environment. However, possible causal relationship needs to be confirmed in further studies.

Serum matrix metalloproteinase-9 and venous bypass graft occlusion.

OBJECTIVE: The primary results after coronary artery bypass grafting are good, but early clinical events as a result of graft occlusion are still a problem. Early occlusions are thought to be due to thrombosis or fibrointimal hyperplasia superimposed by thrombosis, but the etiology of these phenomena is not fully understood. Matrix metalloproteinase-9 has been suggested to have a role in graft occlusion ex vivo. MATERIAL AND METHODS: We investigated whether the level of serum matrix metalloproteinase-9 reflects its proposed role in occlusion of vein grafts. The study population consisted of 30 men with a history of myocardial infarction and 31 men without myocardial infarction who had undergone coronary artery bypass grafting. All the men were asymptomatic. RESULTS: Among the patients with no previous myocardial infarction, serum matrix metalloproteinase-9 level was significantly higher in those with graft occlusion than in those without occlusion (54.0+/-11.0 microg/L and 41.7+/-10.4 microg/L, respectively, p = 0.006), and it correlated positively with the number of occluded grafts (R = 0.55, p = 0.001). In the patients with myocardial infarction, this effect was not detected. CONCLUSIONS: Serum matrix metalloproteinase-9 reflected the occurrence of vein graft occlusion in subjects with no previous history of myocardial infarction.

Mannose-binding lectin 2 (MBL2) gene polymorphism in asthma and atopy among adults.

Mannose-binding lectin (MBL) insufficiency due to polymorphisms in the MBL2 gene causes an opsonization defect, which has been connected to infections and atopy. We investigated the significance of MBL2 genotypes with regard to persistent asthma and atopy among adults. The genotypes were determined in 243 adults with persistent asthma and 400 controls. Atopy was determined by skin-prick test. As a result, the carriage of -221 base pairs (bp) promoter region variant allele X (nucleotide change G-->C; alleles Y-->X, respectively) causing low MBL expression proved to be a significant risk factor for asthma in non-atopic males [odds ratio (OR) = 2.52, 95% confidence interval (CI) = 1.23-5.15; P = 0.01]. Furthermore, the X-allele carriage was associated with the decrease in lung function (forced expiratory volume at 1 s, FEV(1)) during follow-up in the patients with asthma (P = 0.033), the effect being strongest for non-atopic asthmatics (P = 0.042). The MBL2 genotype had no clear effect on the occurrence of atopy in adults. In conclusion, our results abrogate the previously suggested predisposing effect of MBL insufficiency on atopy at least in adults. However, as MBL is a complement component participating in immune defence against microbes, and as in the pathogenesis of non-atopic asthma infectious agents are probably involved, the gene-environment interactions between MBL and infections should be assessed further with regard to asthma.

Increased concentration of fecal alpha1-antitrypsin is associated with cow's milk allergy in infants with atopic eczema.

BACKGROUND: The use of fecal alpha1-antitrypsin in the monitoring of intestinal inflammation in infants with atopic eczema and food allergy was evaluated. METHODS: The study material comprised 26 atopic infants with confirmed food allergy. Fecal samples were collected before an elimination diet and 3 months later for the determination of alpha1-antitrypsin. RESULTS: Nine (35%) of the 26 patients demonstrated an increased fecal concentration of alpha1-antitrypsin (median 3 mg/g; range 2.8-6.4 mg/g). In all nine patients (100%) the oral cow's milk challenge was positive as opposed to only six (35%) in those with normal alpha1-antitrypsin concentration (P = 0.0024). No further connections between alpha1-antitrypsin and other food allergies were detected. As a result of an adequate elimination diet, the fecal concentration of alpha1-antitrypsin was normalized in seven patients, with a favourable clinical response in atopic eczema in six and no improvement in one patient. CONCLUSIONS: Our results indicate that serial determinations of fecal alpha1-antitrypsin provide a useful non-invasive tool for the detection and follow-up of intestinal inflammation in a certain group of atopic infants with cow's milk allergy and severe inflammation of the gut.

The significance of mannan-binding lectin gene alleles in patients with primary Sjögren's syndrome.

OBJECTIVE AND METHODS: To investigate the significance or mannan-binding lectin (MBL) gene alleles in patients with primary Sjogren's syndrome (pSS). Genotypes were determined in 65 pSS patients and 138 controls. RESULTS: No difference in MBL genotype or allele frequencies was detected between the pSS patients and controls. However, when the effect of MBL genotypes on the diagnostic findings in pSS patients was assessed, none of the eight patients with 52/w genotype fulfilled four (definite) Californian criteria (P = 0.007). Among these eight the Chisholm-Mason histological grade was > or = 3 in only three (P = 0.017). Furthermore, the MBL concentration was lower in patients with 52/w genotype compared to those with wild-type (w/w) genotype (P = 0.035). CONCLUSION: Our findings suggest that MBL structural gene polymorphisms do not influence on susceptibility to pSS. However, MBL may be associated with salivary gland destruction in pSS, and its concentration may be comparable with the intensity of inflammatory reaction. Further studies are warranted to clarify the possible mechanisms involved.

Early identification of bacteremia by biochemical markers of systemic inflammation.

Group II phospholipase A2 (PLA2-II), procalcitonin (PCT) and C-reactive protein (CRP) are useful indicators of the severity of inflammation in various infections. To compare their discriminatory abilities at an early phase of bacteremia, PLA2-II, PCT and CRP were measured upon admission and 24-48 h thereafter in 29 patients with bacteremia, non-bacteremic bacterial or viral infections. The levels of PLA2-II and PCT were higher in bacteremia than in non-bacteremic bacterial or viral infections. PCT was highest upon admission, PLA2-II peaked at 12-24h, whereas CRP peaked one day later. At < or =24h, the AUC(ROC)s of PLA2-II and PCT were superior to those of CRP. Thereafter, the AUC(ROC)s of PLA2-II and PCT decreased and those of CRP increased. PLA2-II at cut-off level of 150 microg/L and PCT at 2-6 microg/L showed high sensitivity and specificity for bacteremia within the first 24h. In conclusion, PLA2-II and PCT are useful markers for early diagnosis of bacteremia. Devising analytical methods suitable for point-of-care testing would further enhance the clinical utility of the measurement of serum PLA2-II and PCT.