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In patients with syphilis, central nervous system (CNS) involvement is often difficult to determine. In patients who also are infected with human immunodeficiency virus (HIV), this is even more challenging, as cerebrospinal fluid (CSF) pleocytosis can be attributed to HIV, syphilis, or both. Hence, this study investigated (i) CSF chemokine (C-X-C motif) ligand 13 (CXCL13) as a potential marker to diagnose neurosyphilis in HIV-infected individuals and (ii) the added value of CSF CXCL13 to conventional CSF biomarkers, such as the rapid plasma reagin test (RPR), in diagnosing neurosyphilis. We included 103 syphilis patients from two centers in The Netherlands: 47 non-HIV-infected patients and 56 HIV-infected patients. A positive CSF-RPR was regarded as the gold standard for neurosyphilis. CSF CXCL13 levels were significantly higher in neurosyphilis patients when neurosyphilis was diagnosed by CSF-RPR ( P = 0.0002) than in the syphilis control group. The sensitivity and specificity of CSF CXCL13 (cutoff of 76.3 pg/ml) to diagnose neurosyphilis by using positive CSF-RPR as the gold standard were 50% and 90%, respectively. CSF CXCL13 had an added value to CSF-RPR positivity in 70% of HIV-positive patients and in 33% of HIV-negative patients. Our data show that CSF CXCL13 might be a potential additional marker in neurosyphilis when other markers are not conclusive. The added value of CSF CXCL13 measurement to the current neurosyphilis gold standard appears to benefit HIV-positive patients more than HIV-negative patients.

The aim of this study was to compare humoral and cellular immune responses to influenza vaccination in cancer survivors with and without severe symptoms of fatigue. Severely fatigued (n = 15) and non-fatigued (n = 12) disease-free cancer survivors were vaccinated against seasonal influenza. Humoral immunity was evaluated at baseline and post-vaccination by a hemagglutination inhibition assay. Cellular immunity was evaluated at baseline and post-vaccination by lymphocyte proliferation and activation assays. Regulatory T cells were measured at baseline by flow cytometry and heat-shock protein 90 alpha levels by ELISA. Comparable humoral immune responses were observed in fatigued and non-fatigued patients, both pre- and post-vaccination. At baseline, fatigued patients showed a significantly diminished cellular proliferation upon virus stimulation with strain H3N2 (1414 ± 1201 counts), and a trend in a similar direction with strain H1N1 (3025 ± 2339 counts), compared to non-fatigued patients (3099 ± 2401 and 5877 ± 4604 counts, respectively). The percentage of regulatory T lymphocytes was significantly increased (4.4 ± 2.1% versus 2.4 ± 0.8%) and significantly lower amounts of interleukin 2 were detected prior to vaccination in fatigued compared to non-fatigued patients (36.3 ± 44.3 pg/ml vs. 94.0 ± 45.4 pg/ml with strain H3N2 and 28.4 ± 44.0 pg/ml versus 74.5 ± 56.1 pg/ml with strain H1N1). Pre-vaccination heat-shock protein 90 alpha concentrations, post-vaccination cellular proliferation, and post-vaccination cytokine concentrations did not differ between both groups. In conclusion, influenza vaccination is favorable for severely fatigued cancer survivors and should be recommended when indicated. However, compared to non-fatigued cancer survivors, fatigued cancer survivors showed several significant differences in immunological reactivity at baseline, which warrants further investigation.

To the Editor: The susceptibility to asthma development in childhood is influenced by genetic as well as environmental factors, and interactions between these factors [1–3]. However, at present, their exact role is still largely undetermined. Genetic variations in the innate immune system may lead to different adaptive immune responses to bacteria and may therefore vary the development of asthma [2, 4, 5]. We performed a prospective longitudinal study in preschool children, in which we determined polymorphisms in Toll-like receptors ( TLR s) and CD14 , the presence of bacteria, and the proportion of regulatory T-cells (Treg) all in relation to an asthma diagnosis at 6 years of age. We hypothesise that specific genetic variants in genes that affect the innate immune system influence the response to bacteria and the recruitment of Treg in preschool children, leading to an increased likelihood of asthma at 6 years of age. The Asthma DEtection and Monitoring (ADEM) study is a long-term prospective case–control study. A detailed protocol of this study has previously been published [6]. A total of 202 children who had experienced at least two wheezing episodes during their lifetime (International Study of Asthma and Allergies in Childhood (ISAAC) questionnaire) [7] and 50 children without wheezing episodes were included at 2–4 years of age. The children were randomly selected from a random population sample in Limburg, the Netherlands, based on the presence or absence of recurrent wheeze [6]. During the initial visit, saliva or buccal cells (DNA), nasal and throat swabs (bacterial cultures), and blood (Treg) were collected. Participants were genotyped for six single nucleotide polymorphisms in TLR2 , TLR4 , TLR9 and CD14 (Sequenom …

We measured the vaccination response to the new H1N1 virus in relation to the lymphocyte count prior to vaccination in pediatric cancer patients. The absolute lymphocyte count above the lower normal limits (LNL) for age prior to vaccination predicts the response to influenza vaccination in pediatric cancer patients treated with chemotherapy.

Contains fulltext : 169827.pdf (Publisher’s version ) (Closed access) HIV in the central nervous system (CNS) mainly infects microglial cells which are known to express toll-like receptors (TLRs). This paper aimed to study the role of soluble TLR2 (sTLR2), sTLR4, and other inflammatory markers in cerebrospinal fluid (CSF) in HIV/Simian immunodeficiency virus (SIV)-related neurological sequelae. We determined sTLR2 and sTLR4 levels in CSF and serum/plasma of SIV-infected rhesus macaques with and without neurological sequelae, as well as in HIV-infected patients with and without cognitive impairments and Alzheimer's disease (AD) patients and matched controls. CSF cytokines and chemokines levels were analyzed in macaques as markers of neuroinflammation, while neopterin and S100B CSF concentrations were measured in HIV-infected patients as microglial and astrocyte marker, respectively. We found detectable levels of sTLR2 and sTLR4 in CSF of macaques and humans. Furthermore, CSF sTLR2 and sTLR4 concentrations were higher in SIV-infected macaques with neurological sequelae compared to those without neurological complications (p = 0.0003 and p = 0.0006, respectively). CSF IL-8 and monocyte chemoattractant protein-1 (MCP-1) levels were elevated in macaques with neurological sequelae, and a positive correlation was found between CSF levels of sTLR2/4 and IL-8 and MCP-1. Also in humans, elevated CSF sTLR4 levels were found in HIV-infected patients with cognitive impairments compared to HIV-infected patients with normal cognition (p = 0.019). Unlike CSF S100B levels, neopterin correlated positively with sTLR2 and sTLR4. No difference was found in plasma and CSF sTLR2 and sTLR4 levels between AD patients and control subjects (p = 0.26). In conclusion, CSF sTLR2 and sTLR4 may play a role in HIV/SIV-related neuroinflammation and subsequent neuropathology.

Background: Interpretation of serological assays in Lyme borreliosis requires an understanding of the clinical indications and the limitations of the currently available tests. We therefore systematically reviewed the accuracy of serological tests for the diagnosis of Lyme borreliosis in Europe. Methods: We searched EMBASE en MEDLINE and contacted experts. Studies evaluating the diagnostic accuracy of serological assays for Lyme borreliosis in Europe were eligible. Study selection and data-extraction were done by two authors independently. We assessed study quality using the QUADAS-2 checklist. We used a hierarchical summary ROC meta-regression method for the meta-analyses. Potential sources of heterogeneity were test-type, commercial or in-house, Ig-type, antigen type and study quality. These were added as covariates to the model, to assess their effect on test accuracy. Results: Seventy-eight studies evaluating an Enzyme-Linked ImmunoSorbent assay (ELISA) or an immunoblot assay against a reference standard of clinical criteria were included. None of the studies had low risk of bias for all QUADAS-2 domains. Sensitivity was highly heterogeneous, with summary estimates: erythema migrans 50 % (95 % CI 40 % to 61 %); neuroborreliosis 77 % (95 % CI 67 % to 85 %); acrodermatitis chronica atrophicans 97 % (95 % CI 94 % to 99 %); unspecified Lyme borreliosis 73 % (95 % CI 53 % to 87 %). Specificity was around 95 % in studies with healthy controls, but around 80 % in cross-sectional studies. Two-tiered algorithms or antibody indices did not outperform single test approaches. Conclusions: The observed heterogeneity and risk of bias complicate the extrapolation of our results to clinical practice. The usefulness of the serological tests for Lyme disease depends on the pre-test probability and subsequent predictive values in the setting where the tests are being used. Future diagnostic accuracy studies should be prospectively planned cross-sectional studies, done in settings where the test will be used in practice.

To investigate if infections in pregnancy and very early in life present a risk for wheezing, eczema, or atopic sensitization in later infancy. A total of 2319 children enrolled before birth in the KOALA Birth Cohort Study were followed during their first 2 yr of life using repeated questionnaires. Information was obtained on common colds, fever, and diarrhea with fever as well as on wheeze and eczema at ages 3 and 7 months and 1 and 2 yr, respectively. Blood samples were collected from 786 children at age 2 yr for specific immunoglobulin E analyses. Children with a common cold [adjusted odds ratio (aOR) 2.03 95% CI 1.21-3.41] or fever episode (aOR 1.81 95% CI 1.10-2.96) in the first 3 months of life had a higher risk of new onset wheeze in the second year of life compared to children who had not. For children with diarrhea with fever in the first 3 months of life, the aOR for new onset wheeze in the second year of life was 3.94 (95% CI 1.36-11.40) compared to children without diarrhea. Infections becoming clinically manifest during the first 3 months of life may be a general marker for a wheezy phenotype.

P>Background:The toll-like receptor (TLR)-related pathway is important in host defence and may be crucial in the development of asthma and atopy. Numerous studies have shown associations of TLR-related pathway genes with asthma and atopy phenotypes. So far it has not been investigated whether gene-gene interactions in this pathway contribute to atopy and asthma development.Methods:One hundred and sixty-nine haplotype tagging single nucleotide polymorphisms (SNPs) of 29 genes (i.e. membrane and intracellular receptors, TLR4 or lipopolysaccharide-binding/facilitating proteins, adaptors, interleukin-1 receptor associated kinases, kinases, chaperone molecules, transcription factors and inhibitors) were analysed for single- and multilocus associations with atopy [total and specific immunglobulin E (IgE) at 1-2 and 6-8 years] and asthma (6-8 years). A total of 3062 Dutch children from the birth cohorts PIAMA, PREVASC and KOALA (Allergenic study) were investigated. Chi-squared test, logistic regression and the data mining approach multifactor dimensionality reduction method (MDR) were used in analysis.Results:Several genes in the TLR-related pathway were associated with atopy and/or asthma [e.g. IL1RL1, BPI, NOD1, NOD2 and MAP3K7IP1]. Multiple, single associations were found with the phenotypes under study. MDR analysis showed novel, significant gene-gene interactions in association with atopy and asthma phenotypes (e.g. IL1RL1 and TLR4 with sIgE to indoor allergens and IRAK1, NOD1 and MAP3K7IP1 with asthma). Interestingly, gene-gene interactions were identified with SNPs that did not have an effect on their own.Conclusion:Our unbiased approach provided suggestive evidence for interaction between several TLR-related pathway genes important in atopy and/or asthma development and pointed to novel genes.

Different CD14 polymorphisms have been associated with atopic phenotypes in infants. In addition, CD14 genotypes of breastfeeding mothers have been associated with soluble CD14 (sCD14) levels in breast milk. The role of CD14 genotypes of infant and mother and their interaction with sCD14 levels in breast milk in atopy development remain to be established. We aimed to study the associations of CD14 single nucleotide polymorphisms (SNPs), and their interaction with breast milk sCD14, with atopy development until age two. In addition, we assessed whether levels of sCD14 in breast milk associated with SNPs in CD14. Four SNPs in CD14 gene were investigated in 698 infants and 188 mothers. Associations between these SNPs, sCD14 and atopy development were analyzed in multiple logistic or linear regression models. The CD14/-1619 SNP was associated with eczema. CC homozygotes showed a lower risk of eczema vs. TT homozygotes (adjusted odds ratio = 0.56, 95% confidence interval 0.33-0.96) in a co-dominant model. Breast milk sCD14 levels did not significantly modify the effect of the child's CD14 genotype on atopy development (p interaction > or =0.10). Maternal CD14 SNPs were not significantly associated with sCD14 levels in breast milk (anova, p > or = 0.48). We found only an association between CC homozygozity of SNP CD14/-1619 and eczema. Our data did not support a modifying role of breast milk sCD14 levels on the relationship between CD14 genotype and atopy development until age 2 yr.

Item does not contain fulltext BACKGROUND: The increase in incidence of atopic diseases (ADs) in the developed world over the past decades has been associated with reduced exposure of childhood infections. OBJECTIVE: To investigate the relation between early intestinal viral infections in relation to the development of atopic symptoms (eczema, wheeze and atopic sensitization) in the first and second year(s) of life. METHODS: In the KOALA Birth Cohort Study, we assessed IgG seropositivity for rota- and norovirus (GGI.1 and GGII.4) at 1 year of age. This was related to allergic sensitization [specific immunoglobulin E (IgE)] at 1 and 2 years, and parent reported eczema and wheeze in the first 2 years, using logistic regression analysis adjusted for confounders. RESULTS: Rotavirus seropositivity (39%) was associated with an unexpected higher risk of recurrent wheeze in the first and second year of life [adjusted odds ratio (OR) 3.1 and 95% confidence intervals (CI) 1.1-9.1] and persistent and new recurrent wheeze (adjusted OR 2.7 and 95% CI 1.1-6.2). No further associations were found between intestinal viral seropositivity and atopic manifestations. CONCLUSION: Our data did not show a clear protection by enteric viral infections in young children on development of IgE response to allergens, but rotavirus infection in the first year was a risk factor for wheeze. However, this needs to be followed up to older ages in order to establish the true importance of intestinal viral infections and especially cumulative effects in AD aetiology. Exposure to rotavirus may offer a new and interesting focus on infant wheeze and later asthma development.

Cytomegalovirus (CMV) and Parvovirus B19 infections acquired during pregnancy may result in developmental disabilities of the foetus. This study evaluates the occupational risk of these infections in female day care personnel. IgG seroprevalence was determined in 310 Dutch day care workers and 158 nursing school students. CMV seroprevalence was age-related, starting at 21% in those20 years and reaching 65% in those35 years. Between the ages of 20 and 24 years the CMV prevalence was higher in day care personnel than in controls, 50% versus 31% (p = 0.03). In the first 2 years of employment the risk of attracting CMV was significantly increased (OR(adj) = 3.80; p0.001) and the occupational risk was also increased (OR(adj) 2.19; p0.001). Parvovirus seropositivity (71-77%) was not related to age or working at a day care centre. In conclusion, an occupational risk was observed for CMV, but not for Parvovirus infection in female day care personnel.

Studying gene-environment interactions may elucidate the complex origins of atopic diseases but requires large study populations. Pooling data from several cohort studies may help but may also obscure findings. Gene-environment interactions in atopy development were studied and the benefits of pooling data were evaluated.Haplotype-tagging polymorphisms in the genes interleukin (IL)13 and CD14 were genotyped in 3,062 children from the following birth cohorts: the Prevention and Incidence of Asthma and Mite Allergy (PIAMA) study; the Prevention of Asthma in Children (PREVASC) study; and the Child, Parent, Health, Focus on Lifestyle and Predisposition (KOALA) study, and tested for association with total and specific immunoglobulin (Ig)E and interaction with tobacco smoke and pet exposure at ages 1, 2, 4 and 8 yrs by analysis of variance, Chi-squared tests and regression analyses.At all ages, in IL13, minor alleles of rs1295685 and rs20541 were significantly associated with elevated IgE levels in pooled analyses. In CD14, the rs2569190-TT and rs2569191-CC genotypes associated with lower IgE and decreased risk of sensitisation at 4 and 8 yrs in children exposed to pets, with an opposite effect in nonexposed children. Findings for IL13 and CD14 were comparable in separate cohorts.The present study indicates that atopy is importantly influenced by interleukin 13 at age 1-8 yrs and by CD14 in interaction with pet exposure at ages 4 and 8 yrs. Additionally, pooled data improved effect estimates and genetic effects could be detected in interaction with important environmental factors.

We prospectively investigated whether organic food consumption by infants was associated with developing atopic manifestations in the first 2 years of life. The KOALA Birth Cohort Study in the Netherlands (n 2764) measured organic food consumption, eczema and wheeze in infants until age 2 years using repeated questionnaires. Diet was defined as conventional ( 90 % organic). Venous blood samples taken from 815 infants at 2 years of age were analysed for total and specific IgE. Multivariate logistic regression models were fitted to control for potential confounding factors. Eczema was present in 32 % of infants, recurrent wheeze in 11 % and prolonged wheezing in 5 %. At 2 years of age, 27 % of children were sensitised against at least one allergen. Of all the children, 10 % had consumed a moderately organic diet and 6 % a strictly organic diet. Consumption of organic dairy products was associated with lower eczema risk (OR 0·64 (95 % CI 0·44, 0·93)), but there was no association of organic meat, fruit, vegetables or eggs, or the proportion of organic products within the total diet with the development of eczema, wheeze or atopic sensitisation. Further studies to substantiate these results are warranted.

OBJECTIVES. Among potential etiologic factors for atopic manifestations, infant vaccinations have recently been discussed. We evaluated in a prospective design whether infants who were unvaccinated or vaccinated according to incomplete vaccination schedules in the first 6 months of age were at decreased risk for eczema and recurrent wheeze in the first year of life. METHODS. Information on vaccinations against diphtheria, pertussis, poliomyelitis, tetanus; Haemophilus influenzae type b vaccine; and eczema and recurrent wheeze was collected by repeated questionnaires in 2764 families participating in the KOALA Birth Cohort Study in the Netherlands. A standard vaccination schedule referred to 3 diphtheria, pertussis, poliomyelitis, tetanus, and Haemophilus influenzae type b vaccinations in the first 6 months with the first given in months 1 to 3; an incomplete vaccination schedule was defined as any other vaccination schedule. Exclusion criteria were prematurity (gestational age RESULTS. During the first year of life, the incidence of eczema was 23% (584 of 2537 infants) and of recurrent wheeze, the incidence was 8.5% (203 of 2402 infants). At age 6 months, 1969 (77%) of 2545 infants had been vaccinated according to a standard schedule, 393 (15%) vaccinated according to an incomplete schedule, and 182 (7%) never vaccinated. Compared with infants with standard vaccination schedules, infants with incomplete schedules did not differ significantly in eczema risk or recurrent wheeze. This was also true for infants who had never been vaccinated. CONCLUSION. This study shows that the risk of eczema or recurrent wheeze at 1 year of age does not differ between infants with different vaccination status at the age of 6 months.

OBJECTIVES. Antibiotic exposure in early life may be associated with atopic disease development either by interfering with bacterial commensal flora or by modifying the course of bacterial infections. We evaluated early life exposure to antibiotics and the subsequent development of eczema, wheeze, and allergic sensitization in infancy. METHODS. Information on antibiotic use in the first 6 months and eczema and wheeze until age 2 was collected by repeated questionnaires in 2764 families participating in the KOALA (Child, Parent and Health: Lifestyle and Genetic Constitution [in Dutch]) Birth Cohort Study in the Netherlands. Antibiotic intake was evaluated both as maternal antibiotic use during breastfeeding and infant oral medication. Venous blood samples taken from 815 infants at 2 years of age were analyzed for total and specific immunoglobulin E against common food and inhalant allergens using a radioallergosorbent test. Multivariate logistic regression analysis was used to adjust for confounding factors. RESULTS. During the first 2 years, eczema was present in 32% of all infants, recurrent wheeze in 11%, and prolonged wheezing in 5%. At 2 years old, 27% of children were sensitized against ≥1 allergen. At 6 months old, 11% had been exposed to antibiotics through breast milk and 20% directly through medication. The risk for recurrent wheeze, and prolonged wheeze was higher in infants directly exposed to antibiotics through medication, also after excluding from the analyses children who wheezed in the same period as an antibiotic had been used (avoiding reverse causation). Antibiotic use through breastfeeding was associated with recurrent wheeze, but prolonged wheeze was not. Eczema and sensitization were not associated with antibiotic exposure. CONCLUSIONS.We demonstrated that early antibiotic use preceded the manifestation of wheeze but not eczema or allergic sensitization during the first 2 years of life. Different biological mechanisms may underlie the etiology of wheeze compared with eczema or sensitization. Antibiotic exposure through breastfeeding enhanced the risk for recurrent wheeze, but this needs further confirmation.

Objective To investigate the potential effect of modification by maternal allergic status on the relationship between breast-feeding duration and infant atopic manifestations in the first 2 years of life. Study design Data from 2705 infants of the KOALA Birth Cohort Study (The Netherlands) were analyzed. The data were collected by repeated questionnaires at 34 weeks of gestation and 3, 7, 12, and 24 months postpartum. Total and specific immunoglobulin E measurements were performed on venous blood samples collected during ionic visits at age 2 years. Relationships were analyzed using logistic regression analyses. Results Longer duration of breast-feeding was associated with a lower risk for eczema in infants of mothers without allergy or asthma (P-trend = .01) and slightly lower risk in those of mothers with allergy but noasthma(P-trend =.14). There was no such association for asthmatic mothers (P-trend =.87). Longer breast-feeding duration decreased the risk of recurrent wheeze independent of maternal allergy (P-trend =.02) or asthma status See editorial, p 331 and (P-trend =.06). related articles, p 352 Conclusions Our findings show that the relationship between breast-feeding and and p 359 infant eczema in the first 2 years of life is modified by maternal allergic status. The protective effect of breast-feeding on recurrent wheeze may be associated with protection against respiratory infections

OBJECTIVE: The aim of this study was to examine the contribution of a broad range of external influences to the gut microbiotic composition in early infancy. METHODS: Fecal samples from 1032 infants at 1 month of age, who were recruited from the KOALA Birth Cohort Study in the Netherlands, were subjected to quantitative real-time polymerase chain reaction assays for the enumeration of bifidobacteria, Escherichia coli, Clostridium difficile, Bacteroides fragilis group, lactobacilli, and total bacterial counts. Information on potential determinants of the gut microbiotic composition was collected with repeated questionnaires. The associations between these factors and the selected gut bacteria were analyzed with univariate and multivariate analyses. RESULTS: Infants born through cesarean section had lower numbers of bifidobacteria and Bacteroides, whereas they were more often colonized with C difficile, compared with vaginally born infants. Exclusively formula-fed infants were more often colonized with E coli, C difficile, Bacteroides, and lactobacilli, compared with breastfed infants. Hospitalization and prematurity were associated with higher prevalence and counts of C difficile. Antibiotic use by the infant was associated with decreased numbers of bifidobacteria and Bacteroides. Infants with older siblings had slightly higher numbers of bifidobacteria, compared with infants without siblings. CONCLUSIONS: The most important determinants of the gut microbiotic composition in infants were the mode of delivery, type of infant feeding, gestational age, infant hospitalization, and antibiotic use by the infant. Term infants who were born vaginally at home and were breastfed exclusively seemed to have the most "beneficial" gut microbiota (highest numbers of bifidobacteria and lowest numbers of C difficile and E coli). AD - Department of Epidemiology, Nutrition and Toxicology Research Institute Maastricht, Maastricht University, PO Box 616, 6200 MD Maastricht, Netherlands. j.penders@epid.unimaas.nl

Objective Methodological standards for clinical pharmacogenetic studies should be developed to improve reporting of studies and facilitate their inclusion in systematic reviews. The essence of these studies lies within the concept of effect modification. Study Design and Setting A narrative review discussing methodological issues in the design and reporting of pharmacogenetic studies. Results Studying effect modification within a trial leads to the comparison of subgroups based on genotype. Differences in effect based on genotype should preferably be expressed in absolute terms (risk differences) to facilitate clinical decisions on treatment. Information on the distribution of potential effect modifiers or prognostic factors should be available to prevent a biased comparison of differences in effect between genotypes. The distribution of genotypes should also be presented and compared to Hardy–Weinberg equilibrium to check for selection bias. Additional points of interest include the possibility of selective nonavailability of biomaterial and the choice of a statistical model to study effect modification. Conclusion Additional methodological issues should be taken into account when designing and reporting pharmacogenetic studies, to ensure high study quality. We present several important issues for future studies investigating drug–gene interactions that can serve as a basis for further discussion on methodology in pharmacogenetics.

Summary The aim of the study was to examine the association between stress and pregnancy outcome after adjustment for possible confounding and mediating variables. A prospective cohort study of 5511 pregnancies was conducted in 2001–03 in the Netherlands. A standardised questionnaire collecting demographics and mental health data was administered at 14 and 30 weeks of pregnancy. Medical data on the pregnancy and delivery were obtained from obstetricians and midwives. The results showed that a high level of perceived stress at 14 weeks of pregnancy increased the risk for delivery of an infant that was small-for-gestational-age (OR = 1.26 [95% CI 1.01, 1.56]), but the association was reduced after adjustment for the possible confounding effects of demographic variables (OR = 1.16 [95% CI 0.92, 1.47]). The results do not support a direct relationship between perceived stress and adverse pregnancy outcome. Demographic variables may explain the association between psychosocial stress and pregnancy outcome to a significant degree.

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BACKGROUND Cytomegalovirus(CMV) infections have a significant effect on morbidity and mortality in kidney transplants. We conducted a study to ascertain the association of natural killer cell killer immunoglobulin-like receptors and human leukocyte antigen (HLA) genotype with risk of CMV disease. METHODS The 90 CMV-negative patients receiving a first renal transplantation from a CMV-positive donor in this study received triple immunosuppressive therapy and prophylactic CMV treatment for up to 3 months after transplantation. RESULTS We observed a 43.3% incidence rate of CMV disease within the first year after transplantation. Twenty-seven recipients experienced a rejection episode, 14 of which had CMV disease, mostly after rejection, suggesting that in this group, CMV disease is not a risk factor for rejection. KIR gene or genotype distribution were similar between the CMV diseased and CMV disease-free group. Twenty-seven recipients (30%) carried KIR-AA genotype, of which nine (33%) had CMV disease. Of the remaining 63 (70%) recipients with KIR-BX genotype, 30 (48%) had CMV disease. There was no significant difference between the two genotype groups with regard to occurrence of CMV disease, although there was a trend toward a lower incidence of CMV disease in recipients carrying the KIR-AA genotype. For CMV disease, we found no significant risk associated with the number of activating or inhibitory KIRs. Neither was missing KIR ligands for the inhibitory KIRs (HLA-C1/C2/Bw4) in recipients associated with lower rates of CMV disease. CONCLUSION In CMV-negative recipients, genotypic analysis of KIR repertoire and HLA ligands does not provide risk factors for primary CMV disease after renal transplantation.

Inhabitants of Ndombo (n = 614), a village in an area recently infected with Schistosoma mansoni in Northern Senegal, were examined clinically, parasitologically, and ultrasonographically to investigate the presence and degree of S. mansoni-related hepatosplenic morbidity after a few years of exposure to schistosomal infection of regional canals. Despite previous praziquantel treatment of 56% of the inhabitants prior to our investigation, the prevalence of S. mansoni infection in 1993 was 90%, and 42% of the villagers excreted more than 1,000 eggs per gram of stool. Previously untreated individuals were found to have significantly higher egg counts than treated ones. Despite the high intensities of infection, ultrasonographically detected severe periportal thickening of the liver was infrequent. Grading according to body length-dependent normal values of cross-section diameter of peripheral portal vein branches of a European control group correlated with intensities of infection. Of the total group of patients, 30% (n = 182) had more severe thickening of portal vein branch diameters above the 97th percentile and 70% of these had a splenomegaly. The highest egg counts and the most frequent development of periportal thickening were found in 11-20 year-old individuals. Periportal thickening was less frequent in praziquantel-treated adolescents than in untreated ones. This suggests that early antischistosomal medication may be useful to limit schistosomiasis-induced hepatic morbidity especially in children, even though reinfection seems inevitable.

Item does not contain fulltext Wheeze is a common symptom in preschool children. The role of bacteria, regulatory T (T(reg)) cells and their association with airway inflammation in preschool wheeze is largely unknown. We evaluated inflammatory markers in exhaled breath condensate (EBC), bacterial colonization and circulating T(reg) cells in preschool children with and without recurrent wheeze. We recruited 252 children (aged two to four years) with (N = 202) and without (N = 50) recurrent wheeze. EBC was collected using an efficient closed glass condenser. Inflammatory markers in EBC (Interleukin(IL)-2, IL-4, IL-8, IL-10, IL-13) were assessed using multiplex immunoassay. Nasal and throat swabs were analysed for presence of Streptococcus pneumoniae, Haemophilus (para)influenzae and Staphylococcus aureus. Proportions of T(reg) cells (CD4(+)CD25(high)CD127(-)) were quantified by flow cytometry. Recurrent wheezing children had elevated EBC levels of IL-2, IL-4, IL-10 and IL-13 compared to non-wheezers (odds ratio (95% confidence interval): 1.67 (1.23-2.27): 1.58 (1.15-2.18): 1.47 (1.14-1.90): 1.55 (1.16-2.06), p

Contains fulltext : 108175.pdf (Publisher’s version ) (Open Access) ABSTRACT: BACKGROUND: Chronic fatigue syndrome (CFS) is a clinical condition characterized by severe and disabling fatigue that is medically unexplained and lasts longer than 6 months. Although it is possible to effectively treat CFS, the nature of the underlying physiology remains unclear. Various studies have sought evidence for an underlying disturbance in immunity. The aim of this study was to compare the humoral and cellular immune responses upon influenza vaccination in CFS patients and healthy controls. RESULTS: Identical antibody titers were observed in CFS patients and healthy controls. Patients and controls demonstrated similar seroprotection rates against all three virus-strains of the influenza vaccine, both pre- and post-vaccination. Functional T cell reactivity was observed in both CFS patients and healthy controls. CFS patients showed a non-significant, numerically lower cellular proliferation at baseline compared to controls. Vaccination induced a significant increase in cellular proliferation in CFS patients, but not in healthy controls. Cytokine production and the number of regulatory T cells were comparable in patients and controls. CONCLUSIONS: The humoral and cellular immune responses upon influenza vaccination were comparable in CFS patients and healthy controls. Putative aberrations in immune responses in CFS patients were not evident for immunity towards influenza. Standard seasonal influenza vaccination is thus justified and, when indicated, should be recommended for patients suffering from CFS.

BACKGROUND AND AIMS: Perturbations in the intestinal microbiota composition, as a result of changed lifestyles, may be involved in the development of atopic diseases. We examined the gut microbiota composition in early infancy and the subsequent development of atopic manifestations and sensitisation. PATIENTS AND METHODS: Faeces of 957 one-month-old infants, participating in the KOALA Birth Cohort Study, were analyzed using quantitative real-time PCR. Information on the manifestation of atopic symptoms (eczema, wheeze) and potential confounders was retrieved through repeated questionnaires. Total and specific IgE were measured in venous blood samples collected during home visits at the infant's age of 2 years. During these home visits also a clinical diagnosis of atopic dermatitis was made according to the UK Working- Party criteria. RESULTS: The presence of E. coli was associated with a higher risk of developing eczema (ORadjusted = 1.87; 95%CI 1.15-3.04), this risk being increased with increasing numbers of E. coli (Pfor trend = 0.016). Infants colonised with C. difficile were at higher risk of developing eczema (ORadjusted = 1.40; 95%CI 1.02- 1.91), recurrent wheeze (ORadjusted = 1.73; 95%CI 1.08- 2.77) and allergic sensitisation (ORadjusted = 1.54; 95% CI 1.02-2.31). Furthermore, the presence of C. difficile was also associated with a higher risk of a diagnosis of atopic dermatitis during the home visit (ORadjusted = 1.73; 95%CI 1.08-2.78). CONCLUSION: This study demonstrates that differences in the gut microbiota composition precede the manifestation of atopy. Since E. coli was only associated with eczema, whereas C. difficile was associated with all atopic outcomes, the underlying mechanims explaining these association may be different.

Summary Background Atopic parents may adopt lifestyle characteristics that allegedly protect against atopic disease. If this is true, infants from atopic parents will be characterized by low-risk behaviour. Consequently, aetiologic studies on lifestyle factors and allergic disease in childhood may be biased by confounding by indication. Objective We explored whether the prevalence of ‘prudent’ lifestyle characteristics differs between atopic and non-atopic families. Methods Information about a family history of atopic manifestations and lifestyle characteristics was collected by repeated questionnaires in the Dutch KOALA Birth Cohort Study in 2469 infants from families with divergent lifestyle practices (conventional vs. alternative). Results In conventional lifestyle families, infants were less often exposed to environmental tobacco smoke when parents were atopic than when they were non-atopic (10.0% vs. 14.7%, P=0.001). In alternative lifestyle families, exposure to smoking was very rare in both groups (1.7% vs. 2.6%). Pets were less often present in families with than without parental atopy (38.8% vs. 51.1%, P=0.008 for conventional lifestyle families; 43.0% vs. 48.4%, P=0.014 for alternative lifestyle families). Infants with atopic siblings had less often been vaccinated according to the standard scheme than infants with non-atopic siblings in conventional lifestyle families (76.6% vs. 85.5%, P

Background For the moment, scientific evaluation of programs on treatment of pregnancy-related pelvic girdle and/or low back pain after delivery is hardly available with only one study with a positive result, suggesting uncertainty about the optimal approach. Investigators draw particular attention to biomedical factors but there is growing evidence that biopsychosocial factors appear to be even more important as a basis of an intervention program. Methods We studied the effectiveness of a tailor-made program with respect to biopsychosocial factors (intervention group) in women with pregnancy-related pelvic girdle and/ or low back pain versus usual care based on a pain contingent basis (control group) shortly after delivery in a randomized controlled trial. Women with severe complaints shortly after delivery were selected from a longitudinal prospective cohort study (n = 7526), aimed at pregnancy-related pelvic girdle and/or low back pain in the Netherlands. A concealed block randomization was performed after collecting baseline data. Researchers were blinded to treatment assignment. Outcomes were evaluated within the domains of the biopsychosocial approach. Primary outcome concerned limitations in activities (RDQ). Follow-up measurements were performed 12 weeks after delivery. Results Since May 2001 until July 2003, 869 women out of the cohort made a request for treatment by a physiotherapist, 10 days after delivery. Because of a quick recovery in two weeks time, we included only 126 women three weeks after delivery. There was a statistically significant and clinically relevant difference in improvement on the primary outcome (RDQ) between the two groups in favor of the experimental intervention. Conclusion The results favored the hypotheses. Women's worries about their condition were major targets in the experimental intervention. The prognosis after delivery, especially in de first weeks, turned out to be favorable.

PG - 679-84 AB - The aim of the KOALA Birth Cohort Study in the Netherlands is to identify factors that influence the clinical expression of atopic disease with a main focus on lifestyle (e.g., anthroposophy, vaccinations, antibiotics, dietary habits, breastfeeding and breast milk composition, intestinal microflora composition, infections during the first year of life, and gene-environment interaction). The recruitment of pregnant women started in October 2000. First, participants with 'conventional lifestyles' (n = 2343) were retrieved from an ongoing prospective cohort study (n = 7020) on pregnancy-related pelvic girdle pain. In addition, pregnant women (n = 491) with 'alternative lifestyles' with regard to child rearing practices, dietary habits (organic, vegetarian), vaccination schemes and/or use of antibiotics, were recruited through organic food shops, anthroposophic doctors and midwives, Steiner schools, and dedicated magazines. All participants were enrolled between 14 and 18 wk of gestation and completed an intake questionnaire on family history of atopy and infant care intentions. Documentation of other relevant variables started in the pregnant mother and covered the first and third trimester as well as early childhood by repeated questionnaires at 14-18, 30, and 34 wk of gestation and 3, 7, 12, and 24 months post-partum. A subgroup of participants, including both conventional and alternative lifestyles, was asked to consent to maternal blood sampling, breast milk and a faecal sample of the infant at 1 month post-partum, capillary blood at age 1 yr, venous blood and observation of manifestation of atopic dermatitis during home visits at the age of 2 yr (using the UK working party criteria and the severity scoring of atopic dermatitis index), and buccal swabs for DNA isolation from child-parent trios. From the start, ethical approval and informed consent procedures included gene-environment interaction studies. Follow-up at 3 and 7 months post-partum was completed with high response rates (respectively 90% and 88% in the conventional group, and 97% and 97% in the alternative group). The home visits at 2 yr of age will be completed in 2005. Preliminary results show that we have succeeded in recruiting a large population with various lifestyle choices with a fairly large contrast with regard to dietary habits (including organic foods, vegetarian diet), vaccination schemes and/or use of antibiotics. We have also been able to collect a large number of faecal samples (n = 1176) and capillary blood samples at age 1 yr (n = 956). Furthermore, a large proportion of the participants have consented with genetic studies. Mid 2006 we expect to report our first results on the relationship between the various exposures in early life and childhood atopy. An outline of the focus and design of the KOALA Birth Cohort Study is presented. AD - Department of Epidemiology, Care and Public Health Research Institute (Caphri), Maastricht University, Maastricht, The Netherlands. ischa.kummeling@epid.unimaas.nl

To the Editor: Since the outbreak of influenza A (H1N1) virus pandemic, almost 300 cases of infection with an oseltamivir-resistant influenza virus have been reported to the World Health Organization as of June 2010.1 These strains typically contain a single histidine-to-tyrosine substitution at position 275 (H275Y) of the viral neuraminidase, but they remain susceptible to zanamivir. Successful clearance of an oseltamivir-resistant virus with zanamivir, the other approved neuraminidase inhibitor, has been reported.2 We report the emergence of a pandemic influenza virus in a patient treated with neuraminidase inhibitors, with a novel resistance pattern that conferred resistance to oseltamivir, zanamivir, and . . .

9070 Background: Postcancer fatigue (PCF) is a frequently occurring problem, impairing quality of life. Patients with chronic fatigue syndrome (CFS) also suffer from severe fatigue symptoms. We hypothesized that in fatigued patients (PCF and CFS) alterations in immune response could explain fatigue symptoms. Therefore, we examined whether the humoral and/or cellular immune response after influenza vaccination differed between fatigued patients and non-fatigued individuals and between PCF and CFS patients. Methods: PCF (n=15) and CFS patients (n=22) were vaccinated against influenza. Age and gender matched non-fatigued cancer survivors (n=12) and healthy controls (n=23) were included for comparison. Antibody responses were measured at baseline and at day 21 by a hemagglutination inhibition test. T cell responses were measured at baseline and at day 7 by a lymphocyte proliferation and activation assay. Results: Both patient groups developed seroprotection rates comparable to the accompanying control groups. Functional T cell reactivity was observed in all groups. Proliferation at baseline was significantly lower in fatigued patients compared to non-fatigued individuals. A significant increase in proliferation from baseline to day 7 was observed in fatigued patients, but not in controls. At day 7, proliferation was not significantly different between fatigued patients and non-fatigued individuals. CD4+CD127-FoxP3+ expression was significantly higher in PCF patients compared to non-fatigued cancer survivors. Conclusions: We observed a lower T cell proliferation at baseline in fatigued patients compared to non-fatigued individuals, suggesting a difference in the baseline state of the immune system between fatigued patients and non-fatigued individuals. Furthermore, the difference in CD4+CD127-FoxP3+ expression between PCF and CFS patients suggests subtle differences in immune state between these two fatigued patient groups. However, since humoral and cellular immune responses after vaccination did not differ significantly between fatigued patients and non-fatigued individuals, vaccination of fatigued patients (PCF and CFS) can be effective.

9087 Background: The efficacy of vaccination in (pediatric) cancer patients is still a topic of debate. We aimed to study the immunologic determinants of influenza vaccination response in pediatric...

Background Conflicting evidence exists concerning the protective role of breastfeeding in allergy and atopic disease aetiology. Breast milk contains biologically active molecules influencing the innate immune system of newborns. Objective We aim to assess whether cytokines (TGF-beta1, IL-10 and IL-12) and soluble CD14 (sCD14) in breast milk are influenced by maternal atopic constitution and modify the development of atopic manifestations in infants. Methods Milk samples were collected at 1 month post-partum of 315 lactating mothers participating in the ongoing KOALA Birth Cohort Study. The cytokines and sCD14 were analysed by ELISA in the aqueous fraction. We compared the concentrations of cytokines and sCD14 in breast milk between mothers with and without an allergic history and also with and without allergic sensitization (specific IgE). Associations of cytokines and sCD14 with the development of eczema, wheezing in the first 2 years of life and allergic sensitization of infants at the age of 2 years were analysed by multivariate logistic regression analyses to correct for confounders. Results We found higher sCD14 levels in mothers with a positive vs. negative allergic history (7.6 vs. 7.0 microg/mL; P = 0.04) and in mothers who were sensitized vs. non-sensitized (7.8 vs. 7.1 microg/mL; P = 0.03). None of the studied immune factors were associated with infant's atopic outcomes. IL-10 was not detected above the detection limit of 0.2 pg/mL. Conclusion Taking together the results of the present and previous studies, we conclude that there is no convincing evidence for a relation between TGF-beta1, sCD14, IL-10 or IL-12 in breast milk and atopic manifestations in infants.