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A prospective study was conducted over a 3-month winter period in three general practice clinics in an urban population in southern Israel to identify the etiological agents of respiratory tract infections (RTI) in adults. RTI was defined as an acute febrile illness with cough, coryza, sore throat or hoarseness. Serum samples were taken from all patients in both the acute and convalescent phases of their illness. Tests were conducted for detection of 17 microorganisms known to cause RTI, including serological tests for 16 known pathogens. An etiological diagnosis was established in 80 (66%) of the 122 patients who participated in the study. The distribution of the etiological agents was as follows: influenza B virus in 27 (22%) patients. Chlamydia pneumoniae in 22 (18%), Legionella spp. in 15 (12%), Mycoplasma pneumoniae in 13 (11%), influenza A virus in 11 (9%), Bordetella pertussis in 9 (7%), adenovirus in 4, Epstein Barr virus in 4, Haemophilus influenzae in 3, beta-hemolytic streptococci in 3, Streptococcus pneumoniae in 2, respiratory syncytial virus in 2, parainfluenza 1 virus in 2 and parainfluenza 2 virus in 1. No patients were found to be infected with Coxiella burnetii, Moraxella catarrhalis or parainfluenza 3 virus. More than one pathogen was identified in 27 (34%) patients in whom an etiological diagnosis was established. It is concluded that RTI is caused by a broad spectrum of etiological agents, a considerable number of patients having evidence of infection with more than one pathogen. The therapeutic significance of these findings should be elucidated in further studies.

The antigen-specific serological response to Chlamydia pneumoniae was studied in 24 patients with sarcoidosis and compared to that seen in acute C. pneumoniae respiratory infection. By the micro-immunofluorescence test, five sarcoidosis patients had acute antibody, 15 had chronic antibody and four had no antibody against C. pneumoniae . By enzyme immunoassay, 20 sarcoidosis patients had antibody against ReLPS that cross-reacts with chlamydial LPS. Immunoblot analysis of sera using purified C. pneumoniae elementary bodies showed that recognition of the 40 kDa C. pneumoniae major outer membrane protein was rare (20%). Reactivities with proteins with M w of 42 K (70%), 60 K (65%), 98 K (55%) and 52 K (50%) were often noted. To study reactivity of chlamydial HSP 60 in sarcoidosis sera, sarkosyl-soluble (contains the 60 kDa HSP) and sarkosyl-insoluble (contains the 60 kDa structural protein) fractions of C. pneumoniae elementary bodies were prepared. The 60 kDa structural protein was recognized with equal frequency by sera from patients with sarcoidosis and acute respiratory infection, while the HSP 60 was more frequently recognized by sera with acute respiratory infection than sarcoidosis. Recombinant fusion proteins expressed from pGEX-2T containing overlapping DNA fragments of the C. pneumoniae 60 kDa HSP gene were purified. Different recognition patterns were identified for sera from sarcoidosis patients and from patients with acute C. pneumoniae respiratory infection.

Owing to molecular mimicry, periodontal pathogen carriage may result in a systemic cross-reactive immune response with the host. The analyses were performed to investigate if serum antibody levels to human heat shock protein 60 (HSP60) are associated with the antibody levels and salivary carriage of two periodontal pathogens, Aggregatibacter actinomycetemcomitans and Porphyromonas gingivalis, as well as with the dental status in patients with acute coronary syndrome (ACS). ACS patients (n = 141) were monitored at baseline when entering to hospital, and after 1 week, 3 months and 1 year. Periodontal status was recorded by dental radiographs, and A. actinomycetemcomitans and P. gingivalis were detected by PCR from saliva at baseline. Serum IgG and IgA antibody levels were determined at all time points. All antibody levels remained quite stable during the follow-up. Serum IgG-class antibody levels to A. actinomycetemcomitans and HSP60 had a strong positive correlation with each other at all time points (r∼0.4, P0.05). Mean serum IgG antibody levels to HSP60 were significantly higher in the A. actinomycetemcomitans IgG- and IgA-seropositive than in the seronegative patients, but did not differ between the pathogen carriers compared to the non-carriers. HSP60 antibody levels did not differ significantly between the edentulous, non-periodontitis and periodontitis patients. Despite the observed cross-reactivity in the systemic IgG-class antibody response to HSP60 and A. actinomycetemcomitans, the pathogen carriage in saliva or the periodontal status did not affect the HSP60 antibody levels in ACS patients.

A promoter polymorphism -174 G/C in the inflammatory cytokine interleukin-6 (IL-6) gene has been associated with differences in serum IL-6 levels and a risk for inflammatory conditions, such as cardiovascular diseases. We investigated whether this polymorphism is associated with Chlamydia pneumoniae, a common causative agent of respiratory infection with tendency for persistent infections, in 867 Finnish military recruits. IgG seropositivity in arrival and departure serum samples during 6-12 months of military service was considered as persistence of antibodies and a possible prolonged or chronic infection. The -174C allele was significantly associated with IgG seropositivity (P = 0.0002) and the persistence of IgG antibodies (P = 0.0002) as well as with slightly elevated C-reactive protein (CRP) levels (P = 0.003). In addition, the association was stronger when persistent C. pneumoniae antibodies were present together with elevated CRP than when either of them was positive alone (OR; 95% CI: 3.45; 2.00-5.98 and 1.41; 1.00-1.99, respectively). Our data suggest that IL-6 -174 G/C polymorphism is associated with persistence of C. pneumoniae antibodies and may be linked to the chronic or prolonged infection with systemic low-grade inflammation.

The diagnostic efficacy of two methods--demonstration of seroconversion in paired sera and detection of antigen in clinical specimens--was evaluated in 183 children with respiratory syncytial, parainfluenza or adenoviral, or pneumococcal respiratory tract infection. Viral infection was diagnosed in 46 (37%) of the 125 cases by antigen assay alone, in 36 (29%) by antibody assay alone and in 43 (34%) by both methods. In respiratory syncytial viral infections, antigen assays were more often positive than antibody assays; 80% of the cases were antigen positive and 63% solely antigen positive. In parainfluenza and adenoviral infections, antigen assays were not as useful; a positive result was seen in 59% and 44% of cases, respectively. Pneumococcal infection was diagnosed in 25 (30%) of the 84 cases by antigen assay alone, in 54 (64%) by antibody assay alone and in only 5 (6%) by both methods. Thus nearly all pneumococcal infections were diagnosed by only one method. The efficacy of antigen and antibody assay was clearly dependent on the age of the patients. In infants less than six months of age, nearly all (27 (90%)) of the 30 infections were diagnosed by antigen detection; 25 solely by antigen detection. In older patients, antigen and antibody assays supplemented each other. We conclude that antigen detection should be used as the primary method for the diagnosis of viral or pneumococcal respiratory tract infection. In infants, antigen detection is the only reliable method of microbial diagnosis. In addition, antigen detection is the method of rapid microbial diagnosis. In pneumococcal infections, the sensitivities of antigen detection methods are not sufficient; this is an important area for further research.

Matrix metalloproteinases are responsible for degradation and remodelling of extracellular matrix and exert important roles in initiation and progression of inflammatory diseases. We aimed to examine the role of Matrix metalloproteinases (MMPs) and their regulators in degenerative arterial diseases. Serum samples were collected from patients with arterial disease (n = 126), who underwent surgery because of symptomatic aorto-occlusive disease (AOD, n = 18), carotid artery stenosis (n = 67) or abdominal arotic aneurysm (n = 41). Serum MMP-1, MMP-8, MMP-13, TIMP-1, myeloperoxidase (MPO) and neutrophil elastase (HNE) concentrations were determined by ELISA, and the molar ratio of MMP-8 and TIMP-1 was calculated. To get reference values, the determinations were done on samples of healthy blood donors (n = 100). In univariate analyses, the patients had higher MMP-8 (P0.001), TIMP-1 (P = 0.045), and MMP-8/TIMP-1 (P0.001), and lower MPO (P0.001) when compared with the blood donors. All three subgroups had higher MMP-8 (P0.001) and MMP-8/TIMP-1 (P0.001), and lower MPO (P0.01, except AOD) levels when compared with the references. In multiple logistic regression analyses, the male gender (P0.01), age (P0.001), elevated MMP-8 (P0.001) and decreased MPO (P0.001) concentrations associated significantly with the risk for arterial disease, and provided an area under curve (AUC) of 0.97 in the Receiver operating characteristics analyses. In multiple linear regression analyses, HNE correlated with both MMP-8 (P0.001) and MPO (P = 0.008) concentrations. Combination of high MMP-8 and low MPO level in serum eventually reflecting selectively modified neutrophil degranulation may indicate increased risk for arterial disease.

A prospective eight-month study was carried out in 50 children admitted to hospital for radiologically confirmed community-acquired pneumonia. A potential causative agent of infection was identified in 44 (88%) cases. Using virus isolation, virus antigen detection and enzyme immunoassay serology, respiratory virus infection was diagnosed in 30 (60%) patients. Antibody assays for seven bacteria and antigen detection from serum and urine for Streptococcus pneumoniae produced evidence of bacterial infection in 31 (62%) cases. Streptococcus pneumoniae (38%), respiratory syncytial virus (30%) and Mycoplasma pneumoniae (20%) were the most common causative agents. A mixed infection was diagnosed in 25 (50%) episodes. Nine patients failed to respond to antibiotics within 24 h after onset of treatment. Three of them had a pure viral infection, three a mixed viral-bacterial infection, two a Mycoplasma pneumoniae infection mixed with other bacteria and one a pure Mycoplasma pneumoniae infection. All three Mycoplasma pneumoniae infections were initially treated with penicillin.

Standard adjuvant chemotherapy regimens for patients with moderate-to-high-risk early breast cancer typically contain a taxane, an anthracycline, and cyclophosphamide. We aimed to investigate whether integration of capecitabine into such a regimen enhances outcome.In this open-label trial, we randomly assigned (centrally by computer; stratified by node status, HER2 status, and centre) 1500 women with axillary node-positive or high-risk node-negative breast cancer to either three cycles of capecitabine and docetaxel followed by three cycles of cyclophosphamide, epirubicin, and capecitabine (capecitabine group, n=753), or to three cycles of docetaxel followed by three cycles of cyclophosphamide, epirubicin, and fluorouracil (control group, n=747). The primary endpoint was recurrence-free survival. A planned interim analysis was done after 3 years' median follow-up. Efficacy analyses were by modified intention to treat. The study is registered with ClinicalTrials.gov, number NCT00114816.Two patients in each group were excluded from efficacy analyses because of withdrawal of consent or distant metastases. After a median follow-up of 35 months (IQR 25.5-43.6), recurrence-free survival at 3 years was better with the capecitabine regimen than with control (93%vs 89%; hazard ratio 0.66, 95% CI 0.47-0.94; p=0.020). The capecitabine regimen was associated with more cases of grade 3 or 4 diarrhoea (46/740 [6%] vs 25/741 [3%]) and hand-foot syndrome (83/741 [11%] vs 2/741 [1%]) and the control regimen with more occurrences of grade 3 or 4 neutropenia (368/375 [98%] vs 325/378 [86%]) and febrile neutropenia (65/741 [9%] vs 33/742 [4%]). More patients discontinued planned treatment in the capecitabine group than in the control group (178/744 [24%] vs 23/741 [3%]). Four patients in the capecitabine group and two in the control group died from potentially treatment-related causes.The capecitabine-containing chemotherapy regimen reduced breast cancer recurrence compared with a control schedule of standard agents. Capecitabine administration was frequently discontinued because of adverse effects.Roche, Sanofi-Aventis, AstraZeneca, Cancer Society of Finland.

We analysed data from three clinical trials in Parkinson's disease (PD) patients with wearing-off to determine whether early enhancement of levodopa therapy with entacapone can lead to better long-term outcomes than delayed entacapone treatment.Post-hoc analysis of pooled data from three randomized, double-blind, placebo-controlled studies and their long-term, open-label extension phases. In all three studies, patients on levodopa/dopa-decarboxylase inhibitor (DDCI) were first randomized to entacapone ('early-start' group) or placebo ('delayed-start' group) for the initial 6-month double-blind phase, after which all patients received open-label levodopa/DDCI and entacapone treatment for up to 5 years.A total of 488 PD patients with wearing-off were included in the analysis. A statistically significant benefit of early initiation of levodopa/DDCI and entacapone was found, with an improvement in Unified Parkinson's Disease Rating Scale Part III (motor) score of -1.66 (95% confidence intervals [-3.01, -0.31]) points compared with the delayed-start treatment group (P0.05). Levodopa/DDCI and entacapone therapy was well tolerated. There was no excess of dyskinesia in the early-start group.These data suggest that early rather than delayed addition of entacapone to levodopa/DDCI in PD patients with wearing-off provides a modest clinical benefit over levodopa/DDCI that is maintained for up to 5 years.

Background: A history of pre-eclampsia has been shown to be associated with an increased risk of subsequent coronary artery disease. The intima-media thickness of carotid arteries and the detection of plaques are useful measures as regards preclinical atherosclerosis. The aim of this study was to examine whether women with a history of pre-eclampsia more often show signs of atherosclerosis compared with 2 control groups. Methods: We used data from a large Finnish cross-sectional health examination survey. We had women with previous pre-eclampsia (n = 35) or pregnancy-induced hypertension (n = 61) and 2 control groups. Laboratory tests and physical examination were performed. Information on reproductive and medical history was obtained at the home interview. Carotid atherosclerosis was assessed by ultrasonography. Results: The women with previous pre-eclampsia had significantly (p = 0.008) more atherosclerotic plaques than the healthy parous controls. The intima-media thickness in the women with previous pre-eclampsia also tended to be higher than in the other groups, although the differences did not reach statistical significance. In logistic regression analysis, advanced age (OR: 1.08; 95% CI: 1.04–1.13; p < 0.001) and pre-eclampsia (OR: 3.63; 95% CI: 1.50–8.79; p = 0.004) were independent risk factors as regards plaque, and in linear regression analysis advanced age (estimate: 0.012; 95% CI: 0.010–0.014; p < 0.001), HDL cholesterol (estimate: –0.049; 95% CI: –0.088 to –0.010; p = 0.013), systolic blood pressure, BMI (estimate: 0.005; 95% CI: 0.000–0.009; p = 0.043) and high-sensitivity C-reactive protein (estimate: –0.003; 95% CI: –0.007 to –0.000; p = 0.048) were independent risk factors with respect to intima-media thickness. Conclusions: Our data suggest that pre-eclampsia is an independent risk factor as regards developing plaque later in life.

The effect of superheat on grain sedimentation and macrosegregation has been investigated using experimental castings of a low-alloyed steel grade. With a high superheat of ~ 40 °C, the central equiaxed parts of the slabs consisted of randomly oriented fine dendrites but with a low superheat of ~ 10 °C, coarse globular structures formed. The mean carbon content measured with optical emission spectroscopy was of the order of 15% smaller with coarse globular structures than in fine equiaxed dendritic structures. Electron probe microanalysis of other alloying elements indicates that the negative segregation in the slab central zones is caused by sedimentation of globulites. With superheat in the range ~ 20 - 40 °C, the equiaxed zone is bordered by a columnar to equiaxed transition (CET) zone. In this region a positive macrosegregation of carbon and other alloying elements was observed. These phenomena are important when considering the through-thickness properties of the slabs and final products.

Outcome and prognostic factors were prospectively studied in 277 adult patients (average age 62 yrs) with community-acquired pneumonia requiring hospitalization. The aetiology was established in 68%, with S. pneumoniae as the predominating agent. Mortality was 4% (12 of 277), and all but one who died were greater than or equal to 60 yrs of age. Features associated with high mortality included greater age, absence of chills and chest pain, high respiratory rate (greater than 30 breaths.min-1) and low serum albumin on admission, and the occurrence of airway colonization and secondary infection during hospital stay. Multivariate analysis showed that low serum albumin and the occurrence of secondary infection, but also absence of chills and airway colonization, were correlated to a higher mortality. In patients who survived, the median length of hospital stay was seven days, and at follow-up, about eight weeks after admission, 81% had recovered and chest X-ray was normal in 84%. In conclusion, we believe that the outcome of community-acquired pneumonia can be influenced by prophylactic measures against pneumococcal infection, and an increased surveillance of risk patients.

Background Cryopyrin-Associated Periodic Syndromes (CAPS) include a group of rare inherited autoinflammatory diseases consisting of Familial Cold Autoinflammatory Syndrome (FCAS), Muckle-Wells Syndrome and the most severe form, Neonatal Onset Multisystem Inflammatory Disease (NOMID). Anakinra is an IL-1-receptor antagonist that has proven effective and safe in the treatment of severe CAPS1 with reported sustainable reduction of chronic inflammation, organ specific inflammation, steroid use and a growth catch-up after long-term use2. The beneficial effect of anakinra on bone mineral density (BMD) has been reported in a small cohort of patients with rheumatoid arthritis3 but BMD data in patients with severe CAPS have not yet been investigated. Objectives To evaluate the changes in BMD in patients with severe CAPS during anakinra treatment up to 60 months. Methods A prospective, open-label, single arm study of anakinra including 43 patients was conducted at the National Institutes of Health1. The study included yearly assessment of BMD using dual energy X-ray absorptiometry (DEXA) scans (g/cm2) with a Hologic Densitometer. The BMD was assessed at the total hip, intertrochanteric, femoral neck and L1-L4 (anterior posterior) and evaluated using age-, gender-, and race-matched Z-scores based on DEXA assessments (normal Z-score: -2 to +2) at baseline and up to 60 months. The changes from baseline were estimated in the intention-to-treat population using a mixed model for repeated measures (MMRM) and the proportions of patients with abnormally low values (

Background Cryopyrin-Associated Periodic Syndromes (CAPS) include a group of rare inherited autoinflammatory diseases consisting of Familial Cold Autoinflammatory Syndrome (FCAS), Muckle-Wells Syndrome and the most severe form, Neonatal-Onset Multisystem Inflammatory Disease (NOMID). One goal of anakinra therapy is to reduce the concomitant use of steroids. Side effects involving the cardiovascular system and infections are the most frequently reported adverse events (AEs) in steroid-treated patients with rheumatic diseases 1 . An analysis of a previous data cut of this study indicated a substantial decrease in the mean daily prednisone-equivalent dose in 16 patients with severe CAPS treated with anakinra for up to 60 months 2 . Objectives The objective of the present analysis is to further evaluate the steroid-sparing potential and its consequences in an expanded cohort of patients with severe CAPS treated with anakinra. Methods A prospective, open-label, single arm study of anakinra including 43 patients was conducted at the National Institutes of Health 3 . The primary efficacy endpoint, Diary Symptom Sum Score (DSSS), collected daily up to 60 months, included 5 symptoms (fever, rash, joint pain, vomiting, headache), each scored from 0 (no symptoms) to 4 (severe symptoms). Use of steroid medication was obtained from the patient diary. The prednisone dose was to be decreased by 20% at each study visit in which the subject9s disease activity was “moderately” or “significantly” improved. Different types of steroids were converted into prednisone-equivalent doses to enable comparisons. The AEs were analyzed with the infection rate (number of infections per patient years of treatment). Results The proportion of steroid-treated patients in the ITT population decreased from 47.1% at baseline to 33.3% at Month 60. Among the patients using steroids at baseline the mean (SEM) prednisone-equivalent dose was 0.76 (0.31) mg/kg at baseline, but doses were promptly tapered during the first 6 months to 0.15 (0.03) mg/kg. At Month 36 and Month 60 there was a further decline in the prednisone-equivalent dose to 0.08 (0.02) and 0.05 (0.02) mg/kg, respectively. DSSS decreased rapidly both in patients not using steroids and in patients reducing the steroid dose. The decrease was maintained up to Month 60 (p Conclusions The steroid dose among patients using steroids at baseline decreased from 0.76 mg/kg/day to 0.05 mg/kg/day after 60 months of anakinra treatment and the positive anakinra treatment effect was independent of reduced steroid use. The infection rate decreased in patients who reduced or stopped steroid use during the study. Overall, it can be concluded that steroids could be tapered and in some cases stopped without affecting the positive effect of anakinra treatment and that the reduced steroid use coincided with a decreased risk for infections. References Hoes et al. Ann Rheum Dis. 2007;66:1560-67. Sibley et al. Arthritis Rheum. 2012;64:2375-86. Goldbach-Mansky et al. NEJM. 2006;355:581-92. Acknowledgements The authors would like to thank Dr. Goldbach-Mansky and the NIH team. Disclosure of Interest T. Kullenberg Employee of: Sobi, B. Hallen Shareholder of: Sobi, H. Olivecrona Employee of: Sobi, M. Leinonen Consultant for: Sobi

We compared docetaxel with vinorelbine for the adjuvant treatment of early breast cancer. Women with tumors that overexpressed HER2/neu were also assigned to receive concomitant treatment with trastuzumab or no such treatment.We randomly assigned 1010 women with axillary-node-positive or high-risk node-negative cancer to receive three cycles of docetaxel or vinorelbine, followed by (in both groups) three cycles of fluorouracil, epirubicin, and cyclophosphamide. The 232 women whose tumors had an amplified HER2/neu gene were further assigned to receive or not to receive nine weekly trastuzumab infusions. The primary end point was recurrence-free survival.Recurrence-free survival at three years was better with docetaxel than with vinorelbine (91 percent vs. 86 percent; hazard ratio for recurrence or death, 0.58; 95 percent confidence interval, 0.40 to 0.85; P=0.005), but overall survival did not differ between the groups (P=0.15). Within the subgroup of patients who had HER2/neu-positive cancer, those who received trastuzumab had better three-year recurrence-free survival than those who did not receive the antibody (89 percent vs. 78 percent; hazard ratio for recurrence or death, 0.42; 95 percent confidence interval, 0.21 to 0.83; P=0.01). Docetaxel was associated with more adverse effects than was vinorelbine. Trastuzumab was not associated with decreased left ventricular ejection fraction or cardiac failure.Adjuvant treatment with docetaxel, as compared with vinorelbine, improves recurrence-free survival in women with early breast cancer. A short course of trastuzumab administered concomitantly with docetaxel or vinorelbine is effective in women with breast cancer who have an amplified HER2/neu gene. (International Standard Randomised Controlled Trial number, ISRCTN76560285.).

To assess the association between antibodies to Chlamydia trachomatis heat shock proteins 60 and 10 (Hsp60 and Hsp10) and subfertility in a general population sample.A nested case (n = 146)-control (n = 278) study in a population-based birth cohort. Serum immunoglobulin (Ig)G and IgA antibodies against C. trachomatis Hsp60 and Hsp10, explanatory factors, were measured by enzyme immunoassay, using recombinant proteins as antigens. The main outcome variable was subfertility (time to pregnancyor =12 months).The prevalence and medians of serum IgA antibodies to Hsp60 and Hsp10 were significantly higher in the female partners of subfertile couple than in their fertile controls. On the contrary, among male partners of subfertile couple, especially among smokers serum antibody levels to Hsp antigens were lower than in the controls.The results indicate a serological association of antibodies to chlamydial Hsp antigens with female subfertility in a population-based sample.

Chlamydia pneumoniae infection and immune response to the C. pneumoniae heat shock protein 60 (CpHsp60) have been suggested to be associated with asthma.To study whether a slightly elevated C-reactive protein (CRP) level as a marker of low-grade systemic inflammation has a role in this association, we collected serum and sputum samples from 103 asthma patients with disease severity ranging from mild to moderate and from 30 healthy volunteers.IgA and IgG antibodies to C. pneumoniae elementary bodies (CpEB) and CpHsp60 were measured by enzyme immunoassay. Serum CRP levels were measured with a rapid two-site ultra-sensitive assay based on time-resolved immunofluorometry.The asthma patients, especially those with moderate asthma, had higher serum IgA antibody levels to CpHsp60 than the healthy controls (test for trend, p = 0.05), whereas antibody levels to CpEB antigen did not differ between the study groups. CRP levels were higher in both asthma groups compared to the control group and moreover, the patients with moderate asthma had higher CRP levels than those with mild asthma (test for trend, p0.01). The subjects with a slightly elevated CRP level, defined asor =1.8 mg/l, had higher CpEB IgA (p = 0.001), CpEB IgG (p = 0.008) and CpHsp60 IgA (p = 0.023) antibody levels in serum compared to the subjects with lower CRP levels.Slightly elevated CRP levels as a marker of low-grade systemic inflammation may be associated with C. pneumoniae infection in asthma patients.

The long-term safety and efficacy of the catechol-O-methyltransferase (COMT) inhibitor entacapone was investigated in a 3-year open-label extension of the 6-month double-blind placebo-controlled Nordic (NOMECOMT) study. After a wash-out following this study, 132 patients with Parkinson's disease (PD) experiencing motor fluctuations treated with levodopa/dopa decarboxylase (DDC) inhibitor received additional therapy with entacapone 200 mg, administered with each dose of levodopa. The most common adverse events (AEs) were insomnia (30%), dizziness (20%), nausea (20%), aggravated parkinsonism (17%) and hallucinations (14%). Only 19 (14%) patients discontinued because of AEs. Most dopaminergic AEs occurred shortly after initiation of entacapone, and these could be managed by levodopa down-adjustment. The mean duration of benefit of a single dose of levodopa increased significantly from 2.1 to 2.8 h (P0.01) at 3 months and remained prolonged for the whole study. At the end of the study, the mean daily dose of levodopa was significantly decreased from baseline (from 737 to 696 mg; P0.05). The patients' global assessment indicated that 69% of patients improved when given entacapone and this proportion was maintained until the end of the study (64%). There was a significant worsening of disability upon withdrawal of entacapone. In conclusion, entacapone given in combination with levodopa, has a good long-term safety profile and a sustained beneficial effect in patients with PD with motor fluctuations.

The link and system level performance of a cellular hierarchical cell structure (HCS) network utilising DS-CDMA and multi-user detection is evaluated. The adjacent channel interference (ACI) attenuation masks for the system level simulations were generated by using the characteristics of a measured power amplifier IC. The capacity of hierarchical cell structure network is evaluated. In this paper, both uplink and downlink are considered.

BackgroundStructural brain abnormalities are prevalent in patients with schizophrenia and affective disorders.AimsTo study how regional brain volumes and their ratios differ between patients with schizophrenia, psychotic depression, severe non-psychotic depression and healthy controls.MethodMagnetic resonance imaging scans of the brain on first-episode patients and on healthy controls.ResultsPatients with schizophrenia had a smaller left frontal grey matter volume than the other three groups. Patients with psychotic depression had larger ventricular and posterior sulcal cerebrospinal fluid (CSF) volumes than controls. Patients with depression had larger white matter volumes than the other patients.ConclusionsLeft frontal lobe, especially its grey matter volume, seems to be specifically reduced in first-episode schizophrenia. Enlarged cerebral ventricles and sulcal CSF volumes are prevalent in psychotic depression. Preserved or expanded white matter is typical of non-psychotic depression.

Chlamydia pneumoniae is an obligate intracellular pathogen with a tendency to cause persistent infections that has been associated with many chronic conditions such as asthma and coronary artery disease. However, its immunopathogenic mechanisms are poorly understood. When aiming to study the impact of C. pneumoniae infection on host cell apoptosis, we found that epithelial infected (HL) cells and macrophages (U937-line) were resistant to staurosporine and tumour necrosis factor (TNF)-alpha-induced physiological apoptosis 48, 72 or 120 h post-infection, as determined by flow cytometry, DNA fragmentation assay and fluorescence microscopy. The antiapoptotic influence was observed even at a late stage of the chlamydial life cycle and was dependent on the chlamydial protein synthesis. The mechanisms involved blockage of mitochondrial cytochrome c release and caspase 3 activation. We also found that during a persistent C. pneumoniae infection induced in vitro by penicillin treatment of cell cultures, the inhibition of apoptosis was extended for up to 120 h of follow-up post-infection and was restricted to the cells carrying chlamydial inclusions. Our findings suggest that inhibition of apoptosis may be one of the pathogenetic mechanisms by which C. pneumoniae infection can mediate the development of chronic diseases.

To determine the efficacy and safety of the catechol-O-methyltransferase (COMT) inhibitor entacapone, used as an adjunct to levodopa, in Parkinson's disease (PD) patients.In this parallel group, randomized, double-blind study, 301 PD patients, the majority with motor fluctuations, received entacapone (200 mg) or placebo with each daily dose of standard or controlled-release (CR) levodopa. The 24-week treatment period was followed by 2 weeks of entacapone withdrawal. Efficacy was determined by home diaries ('on' and 'off' times), Unified Parkinson's Disease Rating Scale (UPDRS) and changes in levodopa dosage, and safety by adverse-event inquiry, vital signs, electro cardiography (ECG) and laboratory tests.In the total population, the UPDRS activities of daily living and motor scores were significantly improved (P0.05) by entacapone vs placebo. In fluctuating patients, 'on' time increased (1.7 h) and 'off' time decreased (1.5 h) significantly more with entacapone than with placebo (0.5 and 0.6 h, respectively; P0.05), and the daily levodopa dose was reduced by 54 mg with entacapone and increased by 27 mg with placebo (P0.05). Entacapone benefit was lost on withdrawal. Entacapone efficacy was comparable between patients using CR and standard levodopa preparations. Increased dyskinesias (entacapone 34%, placebo 26%) and nausea (10 and 5%, respectively), mostly occurring shortly after treatment initiation, were generally managed by reducing the levodopa dose. Diarrhoea (entacapone 8%, placebo 4%) was seldom severe. There were no differences in vital signs, ECG or laboratory results.Entacapone is an effective and safe levodopa extender and enhancer, improving the symptomatic efficacy of levodopa in PD and adding to the patients' benefit.

CAPS is a rare monogenic autoinflammatory syndrome consisting of a spectrum of three conditions: Familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), and the most severe form, NOMID/CINCA. Progressive hearing loss is a characteristic of severe CAPS [1]. Previous analyses showed that long-term anakinra treatment stabilized the progression of hearing loss [2,3]. CAPS patients with different NLRP3 mutations have distinctly different trajectories of hearing loss, suggesting a mutation-specific risk that should be considered when making treatment decisions [4].

The safety of entacapone combined with levodopa and a dopadecarboxylase (DDC) inhibitor was tested in a 12-month double-blind study of 326 patients with idiopathic Parkinson's disease (PD). The study population represented 'typical' PD outpatients, including patients with varying disease severity and with various concomitant medications. Two-thirds of the patients were randomized to receive 200 mg of entacapone with each of 2--10 daily levodopa doses, and one-third to receive placebo. All entacapone patients were included in the safety evaluation of adverse events (AEs), vital signs, ECG, and laboratory parameters. Entacapone was well tolerated with a discontinuation rate due to AEs of 14% compared with 11% with placebo (NS). As expected, due to dopaminergic enhancement, dyskinesia was more frequent as an AE with entacapone than with placebo. Dryness of mouth, urine discoloration and diarrhoea were more frequent non-dopaminergic AEs with entacapone than with placebo. Entacapone had no adverse effects on hepatic enzyme activity, ECG or haemodynamic parameters, and there was no evidence of any toxicity. As an indication of levodopa enhancement with entacapone, patients taking 5--10 doses of levodopa, most likely representing predominantly fluctuating patients, showed a significant decrease in their mean daily levodopa dose of 94 mg in the entacapone group compared with a decrease of 39 mg in the placebo group (P < 0.01). The interval between the first two morning doses of levodopa increased by 17% with entacapone, whereas with placebo no extension was observed (P < 0.05). Despite levodopa dose reduction, efficacy of entacapone was maintained. As further evidence of efficacy, Parkinsonian symptoms markedly worsened in all patients after withdrawal of entacapone. We conclude that entacapone is safe in optimizing levodopa in long-term treatment of idiopathic Parkinson's disease. Monitoring of liver or other safety parameters during entacapone treatment is not required.

Nickel(II) acetylacetonate bound to polybenzimidazole has been shown to be an efficient catalyst for the aerobic epoxidation of alkenes with an aldehyde as co-reactant. Rates of reaction and yields of epoxide are higher with this system than with dissolved Ni(II) acetylacetonate under otherwise identical conditions. The polymer-bound complex acts as a heterogeneous catalyst and can be recovered from the reaction mixture. Some loss of activity is observed upon re-use of the catalyst due to leaching of the metal complexes.

This randomised, crossover study compared the efficacy, safety, acceptability and patient preference of two multidose powder inhalers (MDPIs)--beclomethasone dipropionate Easyhaler (BDP-EH) and budesonide Turbohaler (BUD-TH)--in 79 stable asthmatics who used inhaled steroids but had no experience of MDPIs. After eight weeks' treatment a mean increase in morning PEF of 16 l/min from a baseline of 356 +/- 112 l/min was observed for each treatment. Similar improvements occurred in evening PEF, FEV1, FVC and asthma symptoms. Both treatments had only minimal effect on morning serum cortisol levels. Compliance with both treatments was high (97%) but almost twice as many patients favoured the EH (59%) compared with the TH (33%); 7% rated the devices equally. Scores of device acceptability were significantly in favour of the EH (p = 0.001). BDP-EH and BUD-TH showed comparable efficacy and safety in the treatment of asthma. Each MDPI had a high rate of compliance, but patients registered greater preference for the EH than the TH.

Background and Objectives: An equivalence study was conducted in which the efficacy and safety of a daily dose of 800 μg of beclomethasone diproprionate administered via a multidose powder inhaler, Easyhaler, and via a metered-dose inhaler (MDI) with a large-volume spacer were compared in adult, newly diagnosed, steroid-naive asthmatic patients. Acceptability of the medications was also compared. Methods: One hundred and forty-four patients were recruited into the double-blind, double-dummy, randomised, parallel-group multicentre study. The study treatment period was 8 weeks. It was preceded by a 2-week run-in period. Morning and evening peak expiratory flow (PEF), numbers of inhalations of a sympathomimetic and asthma symptoms were recorded daily. Spirometry and histamine challenge were performed, and health-related quality of life and morning serum cortisol levels measured during control visits. Results: Criteria indicating treatment equivalence were met. The mean of the primary outcome variable, morning PEF, increased significantly, from 426 to 461 litres/min in the Easyhaler group and from 436 to 467 litres/min in the MDI+spacer group. Similar improvements between groups were also seen in relation to all secondary variables. Changes in serum cortisol levels were minor. In 6 out of 10 questions about device acceptability, the majority of patients rated Easyhaler as better than the MDI+spacer combination. Conclusion: It was concluded that the devices tested were equivalent in terms of efficacy and safety.

The efficacy of pneumococcal vaccines in protecting against pneumococcal pneumonia can feasibly be measured only with a diagnostic technique that has a high specificity (0.98 to 1.00) and a sensitivity greatly exceeding that of blood cultures (>0.2 to 0.3). In this context immune-complex enzyme immunoassays (EIAs) offer a novel, convenient diagnostic method, and we have investigated three such assays with appropriate study populations in Kenya. Sera from 129 Kenyan adults with pneumococcal pneumonia and 97 ill controls from the same clinics, but without pneumococcal disease syndromes, were assayed with immune-complex EIAs for pneumolysin, C-polysaccharide, and mixed capsular polysaccharides (Pneumovax II). At an optical density (OD) threshold yielding a specificity of 0.95, the sensitivities (95% confidence intervals) of the assays were 0.22 (0.15 to 0.30), 0.26 (0.19 to 0.34), and 0.22 (0.15 to 0.29), respectively. For pneumolysin immune complexes, human immunodeficiency virus (HIV)-positive patients had a higher mean OD than HIV-negative patients (639 versus 321; P < 0.0001), but stratification by HIV infection status did not alter the performance of this test. Combining the results of all three EIAs did not enhance the diagnostic performances of the individual assays. In Kenyan adults the sensitivities of the immune-complex EIAs could exceed that of blood cultures only at levels of specificity that were insufficient for the performance of vaccine efficacy studies.

Causative diagnosis of pneumonia is problematic. The lack of a reliable gold standard for diagnosis has also made the development of new diagnostic methods for different microbes causing pneumonia difficult. Serologic methods are continuously used in the diagnosis of pneumonia caused by viruses and atypical bacteria. However, rapid diagnostic methods are urgently needed to guide clinicians to choose proper antibiotic treatment because resistant bacteria are emerging in different parts of the world.

Factors involved in the development of inflammation and asthma in nonatopic subjects have remained largely obscure, although there is some evidence to suggest that certain infections may play a role.We investigated the association between serological evidence of Chlamydia pneumoniae infection and asthma in adults, and the possible modifying effect of the patients' atopic status on this association.Four hundred and thirty consecutive patients who attended the hospital between 1992 and 1993 with symptoms suggestive of asthma, rhinitis or allergy were enrolled. Diagnostic procedures including lung function measurements and skin-prick tests were performed in all patients. The patients with established asthma (n = 332) were divided into those with recent asthma (n = 224, onset 1985 onward) and longstanding asthma (n = 108, onset before 1985). The controls (n = 98) comprised all subjects who did not meet the criteria of asthma. Serum immunoglobulin (Ig)G, IgA and IgM antibodies to C. pneumoniae were measured by the microimmunofluorescence test.In women, the prevalences of elevated IgG (a titre of/= 128) and IgA (/= 32) antibody levels and the age-adjusted geometric mean titres (GMT) of IgG and IgA antibodies were invariably highest among subjects with nonatopic longstanding asthma. Elevated IgG titres in women occurred in 11% of controls, in 28% of nonatopic recent onset asthmatics, and in 43% of asthmatics with nonatopic longstanding disease; for men the respective figures were 33, 50 and 64%. Logistic regression analysis controlling for age, sex and smoking showed that asthma was significantly associated with elevated IgG antibody levels to C. pneumoniae (odds ratio 3.3, 1.6-6.8 for longstanding asthma, 2.3, 1. 2-4.4 for recent asthma, and among women only 4.2, 1.6-10.9 for longstanding asthma, and 3.0, 1.3-7.2 for recent asthma). When the atopics and nonatopics were analysed separately, an even stronger relationship in the nonatopics was obtained for longstanding asthma (6.0,2.1-17.1). In contrast, the relationship between atopic asthma, either recent or longstanding, and elevated IgG titres was not significant, indicating that asthma per se does not predispose to C. pneumoniae infection.Asthma was significantly associated with elevated IgG antibody levels to C. pneumoniae, and this association was strongest for nonatopic longstanding asthma.

Chronic Chlamydia pneumoniae infection has been associated with atherosclerosis by seroepidemiological studies. Further, acute bacterial infections are known to influence lipid metabolism. To clarify the possible pathogenetic mechanisms of this association, we studied serum lipids and the C. pneumoniae IgG antibody titers of 1,053 males who participated in the reindeer herders health survey in Northern Finland in 1986-1989. The mean age of the study group was 47 years (range 20-87). When comparing nonsmoking C. pneumoniae antibody-positive (IgGor = 32) subjects to those with no antibodies, the age-adjusted mean concentration of triglycerides was increased (1.34 vs. 1.04 mmol/l; p = 0.03) and high-density lipoprotein (HDL) was decreased (1.24 vs. 1.35 mmol/l; p0.001). HDL:total cholesterol ratio was also decreased (0.20 vs. 0.23; p = 0.01). In smokers changes were very similar, but not statistically significant. Thus, C. pneumoniae antibodies seem to correlate with an altered serum lipid profile considered to increase the risk of atherosclerosis. This finding supports the proposal that infections, in this case C. pneumoniae infection, may play a role in the pathogenesis of atherosclerosis.

Chronic infections may predispose to malignant growth. Recently, serological markers of chronic Chlamydia pneumoniae infection have been associated with lung cancer. Our aim was to study the possible association between chronic chlamydial infections and malignant lymphomas. The present case-control study involved 72 patients with lymphoma (31 females and 41 males) and matched controls. 53 patients had non-Hodgkin's lymphoma (NHL) and 19 had Hodgkin's disease. The sera, collected at the time of diagnosis, were tested for IgG antibodies and immune complexes to C. pneumoniae and C. trachomatis by a microimmunofluorescence method and ELISA and for IgG antibodies and immune complexes to Helicobacter pylori by ELISA. The serological markers suggesting chronic chlamydial infection were associated with malignant lymphoma. The association was most evident for the presence of C. pneumoniae-specific immune complexes in NHL (OR = 7.3, 95% CI 2.2-25) and appeared to be limited to men. No association between H. pylori antibodies or immune complexes and malignant lymphomas could be demonstrated. Our study provides seroepidemiological evidence of an association between chronic chlamydial infections and lymphomas.

The etiology of acute lower respiratory tract infections (mostly pneumonia) in children is well characterized, but these are only some of the community-acquired infections warranting parenteral antimicrobial therapy. We prospectively evaluated all such infections among children aged 3 months to 15 years by use of blood cultures, examination of nasopharyngeal aspirates, and serologies for 15 viral, 7 bacterial, and 1 protozoal agent. Immunocompromised patients and those with urinary tract infection, meningitis, or osteoarticular infection were excluded. In all, 170 children were included. The pathogenic agent was identified in 62% of the cases. Bacteria were detected in 54%, and a pneumococcus was found in 59% of the cases identified. Viruses were found in 15% overall. Sole bacterial or viral infections were detected in 47.1% and 8.1%, respectively. Since thorough screening established the etiology in less than two-thirds of patients ill enough to be hospitalized and treated parenterally, better diagnostics are needed, especially to identify those who would truly benefit from antimicrobial therapy.

We assessed the effectiveness of a 23-valent pneumococcal vaccine in the prevention of pneumococcal pneumonia and of pneumonia overall in non-immunocompromised middle-aged and elderly people.The prospective, multicentre, double-blind, randomised, placebo-controlled trial was carried out across departments of infectious diseases at six tertiary-care or university hospitals in Sweden. 691 non-immunocompromised patients aged 50-85 years who had been treated as inpatients for community-acquired pneumonia (CAP) were randomly assigned either 23-valent pneumococcal capsular polysaccharide vaccine or placebo (sodium chloride). We used Cox regression models to estimate the relative risks of pneumonia overall and pneumococcal pneumonia for the placebo group compared with the vaccine group.63 (19%) of 339 patients in the vaccine group and 57 (16%) of 352 patients in the placebo group developed a new pneumonia, corresponding to a relative risk over time for the placebo group compared with the vaccine group of 0.83 (95% CI 0.58-1.12, p=0.31). Pneumococcal pneumonia was diagnosed in 16 (4.5%) patients in the placebo group and in 19 (5.6%) in the vaccine group, corresponding to a relative risk for the placebo group of 0.78 (95% CI 0.40-1.51, p=0.45). We found no difference in the death rate between the two study groups.The 23-valent pneumococcal polysaccharide vaccine did not prevent pneumonia overall or pneumococcal pneumonia in middle-aged and elderly individuals.

Background/Purpose: Cryopyrin-Associated Periodic Syndromes (CAPS) are a group of rare inherited autoinflammatory diseases consisting of a spectrum of three conditions: FCAS, Muckle-Wells Syndrome and the most severe form, NOMID. Anakinra was recently approved in the US for treatment of NOMID and in the European Union for treatment of CAPS. The objective of the present analysis is to assess the response rate to anakinra treatment and time to changes in symptom severity after initiation, withdrawal and re-institution of the treatment in patients with severe CAPS. Methods: A prospective, open-label withdrawal design study of anakinra treatment with long-term extension including 43 patients was conducted at the National Institutes of Health (Goldbach-Mansky et al 2006, Sibley et al 2012). The primary efficacy endpoint, the Diary Symptom Sum Score (DSSS) collected daily up to 60 months included 5 symptoms (fever, rash, joint pain, vomiting, headache); each scored from 0 (no symptoms) to 4 (severe symptoms). Earlier data demonstrated that rash and conjunctivitis disappeared in 3 days in all patients, the DSSS was decreased at 3 months and all patients except one met the criteria of a flare during the 7-day withdrawal phase (Goldbach-Mansky et al 2006). In the present analysis, we defined the response as at least 50% improvement from baseline in the weekly average DSSS. The mean changes in DSSS were estimated with Mixed Model for Repeated Measures (MMRM). Results: Twenty nine out of the 43 enrolled patients provided valid DSSS data for the analysis. A majority of the patients were children (17% 80% of the patients met the response criteria. Eleven consecutive patients participated in the withdrawal phase at 3 months of treatment. After treatment withdrawal the average DSSS increased from 0.6 to 5.2 (p

To study the efficacy of pneumococcal capsular polysaccharide vaccine among the elderly by use of a population-based intervention in one township, Varkaus, Eastern Finland.A randomized, controlled trial in which elderly inhabitants (aged 60 years or older) of the catchment area were randomized to receive either pneumococcal and influenza vaccines (PI group = vaccinated) or influenza vaccine alone (I group = controls) and offered participation. The response rate was 67.4%. The PI group consisted of 1,364 persons and the I group of 1,473 persons. The vaccinations were performed in the municipal health center in the fall of 1982, and all elderly inhabitants were followed for 3 years for the development of radiologically confirmed pneumonia. Pneumococcal etiology was identified by serological methods.The incidence of pneumonia was 18.8 per 1,000 person-years in the PI group (73 pneumonia episodes) and 16.6 per 1,000 person-years in the I group (69 episodes). Pneumococcal etiology was found in 27 episodes in the PI group (incidence 7.0 per 1,000 person-years) and in 36 episodes in the I group (incidence 8.6 per 1,000 person-years). In controls (I group) the incidence of pneumococcal pneumonia was significantly higher among persons with increased risk for contracting pneumonia (19 per 1,000 person-years) than among controls with low risk status (4 per 1,000 person-years). No significant protection from pneumococcal pneumonia was found in the study group as a whole (vaccine efficacy 15%, 95% CI -43% to 50%). However, in persons with medical risk factors for contracting pneumonia, there was a statistically significant protective efficacy of 59% (95% CI, 6% to 82%).Pneumococcal vaccination significantly reduced the incidence of pneumococcal pneumonia in elderly persons at increased risk for contracting pneumonia. This increased/high-risk category comprised 34% of the population aged 60 years or older. Because targeted vaccination of this large group may be difficult to organize in an efficient manner, vaccinating all elderly persons may be the best strategy to prevent this rather common and often fatal disease.

The Sámi people in northernmost Finland have lower mortality from cardiovascular diseases than the main population of Finland. Chronic infections caused by Chlamydia pneumoniae and Helicobacter pylori, both quite recently discovered gram-negative bacteria, have been associated with atherosclerosis. We studied the prevalence of these infections in Sámi and Finnish men by analysing the C. pneumoniae and H. pylori specific serum IgG and IgA antibodies using microimmune fluorescence and enzyme linked immunosorbent assay methods, respectively. The frequency of C. pneumoniae IgG antibodies and the age adjusted geometric mean titres differed significantly between these groups. The Finns were more often sero-positive than the Sámi (76% vs. 67%, respectively), the age adjusted geometric mean titre being 71.6 in the Finns and 38.3 in the Sámi; p = 0.001. No significant difference was found in the H. pylori IgG and IgA antibody prevalences, nor in the geometric mean titres between these groups. The difference in cardiovascular mortality between the Sámi and Finns may be partly explained by the lower incidence of chlamydial infections in the Sámi.

Background. Pneumococcal infections are a common cause of morbidity and mortality among elderly people. Protection against pneumococcal infections is mediated by serotype-specific antibodies to capsular polysaccharides. To obtain an estimate of anti-pneumococcal immunity, prevalence and levels of pneumococcal antibodies were studied in an unvaccinated elderly population. Methods. IgG antibodies to pneumococcal serotypes 3, 6A, and 8 and to cell wall polysaccharide (C-PS, a common antigen to all pneumococci) were measured by enzyme immuno-assay in 480 subjects aged 64-97 years (206 men, 274 women) who were a random sample (41%) of elderly inhabitants in a semirural community in Finland. Results. An average of 10% of the elderly lacked antibodies to serotypes 3, 6A, and 8, and 62% of the elderly had them in low titres only. Anti-C-PS antibodies were found in 99% of the elderly, and in significantly higher titres than anti-capsular antibodies. Antibody titres to C-PS and to type 6A decreased with age. Elderly women had significantly lower antibody levels than men. Among the men, current smokers had higher antibody titres than non-smokers; in the women, this analysis was not possible because of infrequent history of smoking. The effect of smoking on antibody titres was reversible after cessation of smoking. Conclusions. A considerable proportion of the elderly lacked protective antibodies to commonly infecting pneumococcal serotypes 3, 6A, and 8. Smoking increased the prevalence and levels of pneumococcal antibodies probably as a consequence of numerous respiratory infections. These observations emphasize the importance of administration of the pneumococcal vaccine among the elderly.

Epidemiological evidence suggests that airway obstruction is an independent risk factor for lung cancer and that this cannot be explained by active or passive smoking alone. Chlamydia pneumoniae infection has been associated with chronic bronchitis and its exacerbates. Our aim was to evaluate the association between chronic C. pneumoniae infection and risk of lung cancer among male smokers. Smoking males with lung cancer (n = 230) and their age- and locality-matched controls were selected among participants of the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study. The presence of C. pneumoniae infection was assessed by analyzing specific antibodies and immune complexes in 2 serum samples collected with a 3-year interval before the lung cancer diagnosis. The diagnosis of chronic infection was based on stable levels of positive specific IgA antibody (titeror = 16) and immune complex (titeror = 4). Relative risks were estimated by odds ratios (OR) adjusted for age, locality and smoking history by a conditional logistic regression model. Markers suggesting chronic C. pneumoniae infection were present in 52% of cases and 45% of controls and hence were positively associated with the incidence of lung cancer (OR 1.6; 95% confidence interval [CI] 1.0-2.3). The incidence was especially increased in men younger than 60 years (OR 2.9; 95% CI 1.5-5.4) but not in the older age group (OR 0.9; 95% CI 0.5-1.6). Before concluding that C. pneumoniae infection is a new independent risk factor for lung cancer, corroboration from other studies with larger number of cases and longer follow-up is needed.

There is accumulating evidence that persistent Chlamydia pneumoniae infections occur in vivo. Animal studies are necessary in order to evaluate the effects of different treatment regimens for eradication of such infections. A mouse model was found to be efficacious for the study of the effects of cortisone and antimicrobial agents on C. pneumoniae infection.

Anakinra is a recombinant, non-glycosylated form of the human IL-1 receptor antagonist, which recently was approved in US for neonatal onset multisystem inflammatory disease (NOMID), the most severe form of the Cryopyrin-Associated Periodic Syndromes (CAPS). This autoinflammatory disease can be effectively controlled by daily subcutaneous administrations of Kineret[1-3]. The recommended initial dose is 1-2 mg/kg/day and the average maintenance dose is 3-4 mg/kg/day.

Background In severe forms of the rare monogenic autoinflammatory syndrome CAPS (NOMID, also denoted CINCA), persistent systemic and organ specific inflammation includes rash, central nervous system, and eye and cochlear inflammation leading to progressive hearing and vision loss. CAPS is caused by an uncontrolled IL-1β release, demonstrated by the often complete response after treatment with the IL-1 blocker anakinra (Kineret®) in all three entities of CAPS 1,2,3 Objectives To characterize the long-term efficacy and safety of Kineret® in patients with severe CAPS. Methods A prospective, open-label withdrawal design study with long-term extension including 43 patients (7 adult and 36 pediatric) was conducted at the NIH (study 03-AR-0298). Diary disease sum scores (DSSS), inflammatory serum markers, CNS inflammation, hearing, vision, joint status, quality of life, and safety were evaluated for up to 5 years, and the pharmacokinetics and dosing of Kineret® in CAPS patients were evaluated. Results The median follow up time for the 43 patients was 4.9 years (range Conclusions Kineret® treatment for up to 5 years in severe CAPS patients was safe and resulted in the control of disease symptoms, inflammatory markers, CNS inflammation, and stabilized organ function. Careful monitoring with rapid individual dosing adjustments is important to achieve optimal control of organ inflammation. References Hawkins PN et al. N Engl J Med 2003;348:2583–4 Hoffman HM et al. Lancet 2004;364:1779–85. Goldbach-Mansky et al.N Engl J Med 2006;355:581–92. Sibley CH et al. Arthritis Rheum 2012;64:2375–2386. Disclosure of Interest H. Olivecrona Employee of: Swedish Orphan Biovitrum AB, M. Alden Raboisson Employee of: Swedish Orphan Biovitrum AB, K. Soderberg Employee of: Swedish Orphan Biovitrum AB, B. Hallen Employee of: Swedish Orphan Biovitrum AB, M. Leinonen Consultant for: Swedish Orphan Biovitrum AB, C. Sibley: None Declared, N. Plass: None Declared, C. Brewer: None Declared, K. King: None Declared, C. Zalewski: None Declared, J. Kim: None Declared, R. Bishop: None Declared, S. Hill: None Declared, S. Paul: None Declared, D. Stone: None Declared, D. Chapelle: None Declared, J. Butman: None Declared, R. Goldbach-Mansky Grant/research support from: Swedish Orphan Biovitrum AB, Regeneron, and Novartis

Background CAPS is a rare monogenic autoinflammatory syndrome consisting of a spectrum of three conditions: FCAS, Muckle-Wells syndrome (MWS), and the most severe form, NOMID/CINCA. Progressive hearing loss is a characteristic of severe CAPS1. Previous analyses showed that long-term Kineret treatment stabilized the progression of hearing loss2. Objectives To evaluate whether long-term Kineret treatment stabilizes hearing loss among pediatric patients, with focus on the subset of infants/toddlers. Methods A prospective open-label study with long-term extension including 43 patients was conducted at the National Institutes of Health (NIH study 03-AR-0298)1,2. The patients were classified as children (age Results The baseline 4F-PTA correlated with age at treatment start so that older patients presented with more hearing loss. The MMRM analysis of 4F-PTA included 12 children (median follow-up (FU) 60 months) and 9 adolescents/adults (median FU 54 months). The mean (SD) baseline 4F-PTA in the best ear based on air conduction was 27.6 (19.6) dB HL in children and 53.5 (32.2) dB HL in adolescents/adults. No significant changes were seen in mean 4F-PTA at any time point up to 5 years in either children or adolescents/adults; thus, hearing remained stable. The estimated change from baseline to 5 years was -1.0 dB HL (95% CI -8.6 to 6.6) in children and 2.7 dB HL (95% CI -2.1 to 7.5) in adolescents/adults. Comparable findings were seen in the worst ear and for both ears based on bone conduction assessments. In the subset of 5 infants/toddlers (median FU 48 months), the audiogram monitoring was started after 1-3 years of treatment. The hearing in the best ear remained normal (4F-PTA ≤20 dB HL) in all infants/toddlers at all visits except one transient elevation to 21 dB HL. One of the 5 infants/toddlers presented with a moderate conductive hearing loss (4F-PTA 65 dB HL) in the worst ear associated with middle ear effusion. The audiogram results were supported by non-increased proportion of cochlear enhancement. Conclusions Correlation between the audiogram and age at treatment start is consistent with progressive hearing loss observed in untreated NOMID patients. Kineret treatment for up to 5 years stabilized the progression of hearing loss in both pediatric and adolescent/adult patients as well as in infants/toddlers. Efforts should be made for early diagnosis of the disease and early treatment initiation. References Goldbach-Mansky et al. N Engl J Med 2006;355:581–92. Sibley et al. Arthritis Rheum 2012;2375–86 Disclosure of Interest M. Leinonen Consultant for: Swedish Orphan Biovitrum AB, K. Soderberg Employee of: Swedish Orphan Biovitrum AB, H. Olivecrona Employee of: Swedish Orphan Biovitrum AB, M. Alden Raboisson Employee of: Swedish Orphan Biovitrum AB, C. Sibley: None Declared, C. Brewer: None Declared, N. Plass: None Declared, K. King: None Declared, C. Zalewski: None Declared, J. Kim: None Declared, D. Stone: None Declared, D. Chapelle: None Declared, R. Goldbach-Mansky Grant/research support from: Swedish Orphan Biovitrum AB, Regeneron, and Novartis