Hypomorphic RAG deficiency: impact of disease burden on survival and thymic recovery argues for early diagnosis and HSCT.

Patients with hypomorphic mutations in the RAG1 or RAG2 gene present with either Omenn syndrome or atypical combined immunodeficiency with a wide phenotypic range. Hematopoietic stem cell transplantation (HSCT) is potentially curative, but data are scarce. We report on a worldwide cohort of 60 patients with hypomorphic RAG variants who underwent HSCT, 78% of whom experienced infections (29% active at HSCT), 72% had autoimmunity, and 18% had granulomas pretransplant. These complications are frequently associated with organ damage. Eight individuals (13%) were diagnosed by newborn screening or family history. HSCT was performed at a median of 3.4 years (range 0.3-42.9 years) from matched unrelated donors, matched sibling or matched family donors, or mismatched donors in 48%, 22%, and 30% of the patients, respectively. Grafts were T-cell depleted in 15 cases (25%). Overall survival at 1 and 4 years was 77.5% and 67.5% (median follow-up of 39 months). Infection was the main cause of death. In univariable analysis, active infection, organ damage pre-HSCT, T-cell depletion of the graft, and transplant from a mismatched family donor were predictive of worse outcome, whereas organ damage and T-cell depletion remained significant in multivariable analysis (hazard ratio [HR] = 6.01, HR = 8.46, respectively). All patients diagnosed by newborn screening or family history survived. Cumulative incidences of acute and chronic graft-versus-host disease were 35% and 22%, respectively. Cumulative incidences of new-onset autoimmunity was 15%. Immune reconstitution, particularly recovery of naïve CD4+ T cells, was faster and more robust in patients transplanted before 3.5 years of age, and without organ damage. These findings support the indication for early transplantation.

Skin cancer risk and shade: comparing the risk of foresters with other outdoor workers.

BACKGROUND: Keratinocyte carcinoma (KC) is an increasingly important public health problem with an especially high prevalence in outdoor workers. In contrast to other occupations, foresters spend most of their outdoor time under the shade of trees. OBJECTIVES: We aimed to compare the unique sun exposure patterns and sun protection behaviour of foresters with those of other outdoor workers and their relation to the KC risk. METHODS: In July 2018, a cross-sectional study was conducted at an international forestry fair using a questionnaire about health awareness and skin cancer screening by dermatologists to assess the prevalence of KC. RESULTS: A total of 591 participants (78.7% male; mean age 46.8 ± 16.2 years) including 193 foresters were enrolled. Of all foresters, 72% experienced sunburns (solar erythema) within the past year and 50% of them experienced the worst sunburn during work. Foresters were most likely to often/always wear protective clothes (29.0%) but were least likely to often/always avoid midday sun (23.8%) and stay in the shade (31.1%). Having an outdoor profession or spending hours outside for leisure was negatively associated with sun protection. Skin examination revealed an overall KC prevalence of 16.7%, with 16.5% of foresters being affected. CONCLUSION: Despite being protected by trees, the risk of KC for foresters is comparable to that of other professional groups. Shade alone may not provide sufficient protection. Additional sun protection measures are necessary.

An approach to the asthma-protective farm effect by geocoding: Good farms and better farms.

BACKGROUND: The highly consistent association of growing up on a farm with a reduced asthma risk has so far been attributed to direct farm exposure. In contrast, geographic determinants of the larger environment have never been assessed. In this study, the effects of proximity to farms and environmental variables in relation to the residential address on asthma and atopy were assessed. METHODS: Addresses of 2265 children of the Bavarian arm of the GABRIELA study were converted into geocodes. Proximity to the nearest cow farm was calculated, and environmental characteristics were derived from satellite data or terrestrial monitoring. Bacterial diversity in mattress dust samples was assessed in 501 children by sequencing of the 16S rRNA amplicons. Logistic regression models were used to calculate associations between outcomes and exposure variables. RESULTS: Asthma and atopy were inversely associated with the presence of a farm within a radius of maximum 100 m. The environmental variables greenness, tree cover, soil sealing, altitude, air pollution differed not only between farm and non-farm children but also between farm children with and without another farm nearby. The latter distinction revealed strong associations with characteristics of traditional farms including a broader diversity of microbial exposure, which mainly contributed to the protective effect on asthma. In non-farm children, the protective effect of a farm nearby was completely explained by consumption of farm milk. CONCLUSIONS: Clustering of farms within a neighborhood of 100 m is strongly associated with the protective effect on asthma and may represent a more traditional style of farming with broader microbial exposure.

Scientific Overview on CSCI-CITAC Annual General Meeting and 2016 Young Investigators' Forum.

The 2016 Annual General Meeting of the Canadian Society of Clinician Investigators (CSCI) and Clinician Investigator Trainee Association of Canada/Association des Cliniciens-Chercheurs en Formation du Canada (CITAC/ACCFC) was a national conference held in Toronto November 21-23, 2016, in conjunction with The University of Toronto Clinician Investigator Program Research Day. The theme for this year's meeting was "Mapping Your Career as a Clinician-Scientist"; emphasizing essential skills for developing a fruitful career as clinician-scientist. The meeting featured an opening presentation by Dr. Alan Underhill, Dr. Nicola Jones and Alexandra Kuzyk. The keynote speakers were Dr. Nada Jabado (McGill University), who discussed the association between cancer and histones, Dr. Norman Rosenblum (University of Toronto), who addressed the career path and the "calling" of the Clinician Scientist, Dr. Martin Schmeing (McGill University), who was the 2016 Joe Doupe Award recipient, and Dr. Linda Rabeneck (Cancer Care Ontario and University of Toronto), who received the Friends of CIHR lectureship. The workshops, focusing on career development for clinician scientists, were hosted by Drs. Alan Underhill, Nicola Jones, Lynn Raymond, Michael Schlossmacher and Norman Rosenblum, as well as University of Toronto communication specialists, Caitlin Johannesson and Suzanne Gold. In addition, the Young Investigators' Forum included presentations from clinician investigator trainees from across the country. The research topics were diverse and comprehensive: from basic sciences to clinical practice; from epidemiology to medical engineering. All scientific abstracts are summarized in this review. Over 70 abstracts were showcased at this year's meeting during two poster sessions, with six outstanding abstracts selected for oral presentations during the President's Forum.

Environmental and mucosal microbiota and their role in childhood asthma.

BACKGROUND: High microbial diversity in the environment has been associated with lower asthma risk, particularly in children exposed to farming. It remains unclear whether this effect operates through an altered microbiome of the mucosal surfaces of the airways. METHODS: DNA from mattress dust and nasal samples of 86 school age children was analyzed by 454 pyrosequencing of the 16S rRNA gene fragments. Based on operational taxonomic units (OTUs), bacterial diversity and composition were related to farm exposure and asthma status. RESULTS: Farm exposure was positively associated with bacterial diversity in mattress dust samples as determined by richness (P = 8.1 × 10-6 ) and Shannon index (P = 1.3 × 10-5 ). Despite considerable agreement of richness between mattress and nasal samples, the association of richness with farming in nasal samples was restricted to a high gradient of farm exposure, that is, exposure to cows and straw vs no exposure at all. In mattress dust, the genera Clostridium, Facklamia, an unclassified genus within the family of Ruminococcaceae, and six OTUs were positively associated with farming. Asthma was inversely associated with richness [aOR = 0.48 (0.22-1.02)] and Shannon index [aOR = 0.41 (0.21-0.83)] in mattress dust and to a lower extent in nasal samples [richness aOR 0.63 = (0.38-1.06), Shannon index aOR = 0.66 (0.39-1.12)]. CONCLUSION: The stronger inverse association of asthma with bacterial diversity in mattress dust as compared to nasal samples suggests microbial involvement beyond mere colonization of the upper airways. Whether inhalation of metabolites of environmental bacteria contributes to this phenomenon should be the focus of future research.

Genome-wide association study of body mass index in 23 000 individuals with and without asthma.

BACKGROUND: Both asthma and obesity are complex disorders that are influenced by environmental and genetic factors. Shared genetic factors between asthma and obesity have been proposed to partly explain epidemiological findings of co-morbidity between these conditions. OBJECTIVE: To identify genetic variants that are associated with body mass index (BMI) in asthmatic children and adults, and to evaluate if there are differences between the genetics of BMI in asthmatics and healthy individuals. METHODS: In total, 19 studies contributed with genome-wide analysis study (GWAS) data from more than 23 000 individuals with predominantly European descent, of whom 8165 are asthmatics. RESULTS: We report associations between several DENND1B variants (P = 2.2 × 10(-7) for rs4915551) on chromosome 1q31 and BMI from a meta-analysis of GWAS data using 2691 asthmatic children (screening data). The top DENND1B single nucleotide polymorphisms(SNPs) were next evaluated in seven independent replication data sets comprising 2014 asthmatics, and rs4915551 was nominally replicated (P < 0.05) in two of the seven studies and of borderline significance in one (P = 0.059). However, strong evidence of effect heterogeneity was observed and overall, the association between rs4915551 and BMI was not significant in the total replication data set, P = 0.71. Using a random effects model, BMI was overall estimated to increase by 0.30 kg/m(2) (P = 0.01 for combined screening and replication data sets, N = 4705) per additional G allele of this DENND1BSNP. FTO was confirmed as an important gene for adult and childhood BMI regardless of asthma status. CONCLUSIONS AND CLINICAL RELEVANCE: DENND1B was recently identified as an asthma susceptibility gene in a GWAS on children, and here, we find evidence that DENND1B variants may also be associated with BMI in asthmatic children. However, the association was overall not replicated in the independent data sets and the heterogeneous effect of DENND1B points to complex associations with the studied diseases that deserve further study.

Farm-derived Gram-positive bacterium Staphylococcus sciuri W620 prevents asthma phenotype in HDM- and OVA-exposed mice.

BACKGROUND: Farm-derived dust samples have been screened for bacteria with potential allergo-protective properties. Among those was Staphylococcus sciuri W620 (S. sciuri W620), which we tested with regard to its protective capacities in murine models of allergic airway inflammation. METHODS: We employed two protocols of acute airway inflammation in mice administering either ovalbumin (OVA) or house dust mite extract (HDM) for sensitization. Mechanistic studies on the activation of innate immune responses to S. sciuri W620 were carried out using human primary monocytic dendritic cells (moDC) and co-culture with autologous T cells. RESULTS: The allergo-protective properties of S. sciuri W620 were proven in a T(H)2-driven OVA model as well as in a mixed T(H)1/T(H)2 phenotype HDM model as demonstrated by abrogation of eosinophils and neutrophils in the airways after intranasal treatment. In the HDM model, lymph node cell T(H)1/T(H)2 signature cytokines were decreased in parallel. Studies on human moDC revealed an activation of TLR2 and NOD2 receptors and initiation of DC maturation following incubation with S. sciuri W620. Cytokine expression analyses after exposure to S. sciuri W620 showed a lack of IL-12 production in moDC due to missing transcription of the IL-12p35 mRNA. However, such DC selectively supported T(H)1 cytokine release by co-cultured T cells. CONCLUSION AND CLINICAL RELEVANCE: Our proof-of-concept experiments verify the screening system of farm-derived dust samples as suitable to elucidate new candidates for allergo-protection. S. sciuri W620 was shown to possess preventive properties on airway inflammation providing the basis for further mechanistic studies and potential clinical implication.

Platelet distribution width and saphenous vein disease in patients after CABG. Association with graft occlusion.

OBJECTIVE: Platelets are involved in the pathogenesis of atherosclerosis. The inflammatory process in atherosclerosis may cause an increase in red blood cell distribution width (RDW) and platelet distribution width (PDW) values. Therefore, in this study we aimed to investigate whether PDW and RDW are associated with the patency of saphenous vein graft in patients at least 1 year after coronary artery bypass graft (CABG) surgery. METHODS: Patients who had undergone CABG surgery at least 1 year previously with at least one saphenous vein graft were included in the study population. Patients were referred to cardiac catheterization for stable anginal symptoms or positive stress test results. Before coronary angiography, all patients referred had routine blood tests including RDW and PDW values. RESULTS: Saphenous vein grafts were found to be patent in 69 patients and occluded in 40 patients. Although RDW levels were similar between patients with patent and occluded grafts (13.1 ± 1.1% and 13.2 ± 0.7% respectively, p = 0.37), PDW levels were significantly different between the two groups (13.1 ± 1.3% and 14.1 ± 1.1 respectively, p = 0.03). Although time after CABG operation differs significantly between the two groups (p < 0.001), multiple logistic regression analyses showed that PDW levels were found to be significantly associated with the patency of vein graft (ß = 1.682, 95% CI 1.117-2.532, p = 0.013). CONCLUSION: Our results showed that PDW levels were higher in patients with an occluded saphenous vein graft. However no association was found between the saphenous vein graft disease and RDW values. To verify this relationship between PDW values and saphenous vein graft patency, further investigations are needed.

The acute effect of percutaneous mitral balloon valvuloplasty on atrial electromechanical delay and P-wave dispersion in patients with mitral stenosis.

BACKGROUND AND AIM OF THE STUDY: The predisposition to atrial fibrillation (AF) in mitral stenosis (MS) has been demonstrated with several electrocardiographic (increased P-wave dispersion) and echocardiographic parameters (atrial electromechanical delay). Despite the improvement in P-wave dispersion after percutaneous mitral balloon valvuloplasty (PMBV), the changes in echocardiographic parameters related to AF risk are unknown. In this study we aimed to investigate the acute effect of PMBV on atrial electromechanical delay (EMD) assessed by tissue Doppler echocardiography in addition to electrocardiographic parameters. MATERIALS AND METHODS: This single-center study consisted of 30 patients with moderate or severe MS (23 females and seven males, aged 36.5 ± 8.5 years, with a mean MVA of 1.1 ± 0.2 cm) who underwent successful PMBV without complication at our clinic and 20 healthy volunteers from hospital staff as a control group (16 females and four males, aged 35.4 ± 6 years). We compared the two groups in regard to clinical, electrocardiographic and echocardiographic features. The patients with MS were also evaluated after PMBV within 72 h of the procedure. The P-wave dispersion was calculated from12-lead ECG. Interatrial and intra-atrial EMDs were measured by tissue Doppler echocardiography. These ECG and echocardiographic parameters after PMBV were compared with previous values. RESULTS: The maximum P-wave duration (138 ± 15 vs. 101 ± 6 ms, p < 0.01), PWD (58 ± 18 vs 23 ± 4, p < 0.01), the interatrial (55 ± 16 vs 36 ± 11 ms, p < 0.01) and left-sided intra-atrial EMD (40 ± 11 vs 24 ± 12 ms, p < 0.01) were higher in patients with MS than in healthy subjects. The left atrial (LA) diameter, LA volume and LA volume index had positive association with the interatrial (r = 0.5, p < 0.01; r = 0.5, p < 0.01 and r = 0.5, p < 0.01, respectively) and left-sided intra-atrial EMD (r = 0.5, p < 0.01; r = 0.4, p < 0.01; r = 0.4, p < 0.01 respectively). After PMBV, the interatrial (55 ± 16 vs. 40 ± 11 ms, p < 0.01) and left-sided intra-atrial EMD (40 ± 11 vs 31 ± 10, p < 0.01) showed significant improvement compared to previous values. There was also a statistically significant difference in maximum P-wave duration and PWD between pre-and post-PMBV (138 ± 15 vs 130 ± 14, p < 0.01, and 58 ± 18 vs 49 ± 16, p < 0.01, respectively). CONCLUSIONS: Our study shows that PMBV has a favorable effect on the electrocardiographic and echocardiographic parameters related with AF risk in patients with MS.

Environmental bacteria and childhood asthma.

BACKGROUND: We have previously found an inverse association of bacterial diversity with childhood asthma. It remains unclear whether certain bacteria account for the protective effect. METHODS: The high variability of the bacterial 16S rRNA gene allows assessing diversity and specificity of bacterial communities by single-strand configuration polymorphism (SSCP). DNA was extracted from mattress dust samples of 489 school-age children from rural and suburban regions in Germany. A fragment of the bacteria-specific 16S rRNA gene was amplified by PCR, digested to single-strand DNA, and subjected to electrophoresis. The resulting band patterns reflect the underlying DNA sequences. The individual bands were tested for associations with asthma, hay fever, and atopy in quantitative and qualitative multivariable analyses. Significantly associated bands were isolated and sequenced. The sequences were compared to a database, and distinct bacteria were identified. RESULTS: Seven of 76 independent bands were found to be inversely associated with asthma, atopic sensitization, and hay fever with odds ratios ranging from 0.17 to 0.73. The bands contained the sequences of Acinetobacter sp., Lactobacillus spp., Neisseria spp., Staphylococcus sciuri, Jeotgalicoccus sp., Corynebacterium spp., and others. CONCLUSIONS: In a diverse microbial environment, certain bacteria may account for the protective effect on the development of asthma and atopy.

Development and genetic influence of the rectal bacterial flora of newborn calves.

The aim of the study was to investigate a dynamic change in the rectal flora of calves as well as to study a genetic influence on the intestinal microflora of calves. The bacterial community of fecal samples from calves was examined by PCR single strand conformation polymorphism (PCR-SSCP) in two independent studies. In study one 14 newborn calves of the same farm were examined. Sampling was conducted directly after delivery (meconium) and after 6 h, 12 h, 24 h, 48 h, 3 d, 7 d, 14 d and 42 d of life. In study two 6 twin calves and their coresident of the same age and farm were analysed in order to study for the first time whether genetic predisposition of the host may influence the fecal microflora. All calves were weaned directly after delivery and received pumped colostrum without direct contact to other farm animals. After delivery and during the first 12h of life the SSCP profiles were simple, but became more complex since the bacterial diversity increased with time in all calves. It became obvious that the intra-individual band-pattern similarity decreased over time and inter-individual similarity was low. The analysis of fecal samples from twin calves revealed higher similarity in SSCP profiles for twins compared to their coresident indicating that the individual microflora might be genetically or epigenetically influenced. The insight that there are several conformities between intestinal microfloras of healthy calves and that there might be genetic influence on the fecal flora could help to prevent diarrhoeal diseases in the future.

Acute heart failure with accompanying chronic obstructive pulmonary disease: should we focus on beta blockers?

BACKGROUND: Acute heart failure (AHF) with systolic dysfunction is associated with increased morbidity and mortality, and optimal therapy is not well established, despite the findings of evidence-based medicine. Beta blockers provide a mortality and morbidity benefit in patients with chronic systolic HF, and are currently indicated in all stages of patients with systolic HF. We evaluated therapies before discharge, in particular beta blockers, in patients hospitalized with AHF with and without accompanying chronic obstructive pulmonary disease (COPD). METHODS: The hospital discharge records of 959 consecutive de novo AHF patients, hospitalized and treated for systolic HF (ejection fraction < 45%), were retrospectively reviewed in three cardiovascular institutions. RESULTS: The presence of accompanying COPD was associated with significantly lower prescription of beta blockers before discharge (p < 0.001). Furthermore, with regard to the type of beta blocker, patients with accompanying COPD were less frequently prescribed nonselective beta blockers (29% vs. 48%, p < 0.001). The presence of accompanying COPD among AHF patients increased the risk of omitting (not prescribing) beta blockers before discharge by a factor of 1.785. CONCLUSION: Beta blockers, a proven life-saving therapy in the setting of chronic systolic HF, were found to be less frequently prescribed before discharge in the presence of de novo AHF with accompanying COPD.

Feasibility of 2 × 24-h dietary recalls combined with a food-recording booklet, using EPIC-Soft, among schoolchildren.

BACKGROUND/OBJECTIVES: The aim of this study was to evaluate the feasibility of the suggested trans-European methodology for undertaking representative dietary surveys among schoolchildren: 2 × 24-h dietary recalls (24-HDRs) combined with a food-recording booklet, using EPIC-Soft (the software developed to conduct 24-HDRs in the European Prospective Investigation into Cancer and Nutrition (EPIC) Study) pc-program. SUBJECTS/METHODS: A total of 75 children aged 7-8 years and 70 children aged 12-13 years old were recruited through the Civil Registration System in Denmark, and 57 children aged 7-8 years and 47 children aged 12-13 years were recruited through schools in Spain. Each child with one parent completed two face-to-face 24-HDRs, combined with optional use of a food-recording booklet (FRB) to be filled in by the child, a parent or other proxy persons for preparing the recalls. Feasibility was evaluated by questionnaires completed by parents, children and interviewers, and by selected data from the 24-HDRs. RESULTS: The face-to-face interviews with the child and a parent together are confirmed as feasible. The children participated actively in the interviews, the oldest children being most active. The children, parents and interviewers agreed that children needed help from the parents, and that parents were of help to the child. In both countries, other proxy persons, such as teachers or the school cafeteria staff, were involved before the interview, and the majority of the parents and children reported that the FRB had been a help for the child during the interview. Further results point at specific needed improvements of the tools. CONCLUSIONS: The evaluated method is shown feasible in two culturally diverse European populations. However, the feasibility study also points to specific improvements of tools and data collection protocol that are strongly recommended before implementation of the method in each country of a pan-European dietary survey.

Evaluation of 2 × 24-h dietary recalls combined with a food-recording booklet, against a 7-day food-record method among schoolchildren.

BACKGROUND/OBJECTIVES: The aim of this study was to evaluate the estimated energy, nutrient and food intake from the suggested trans-European methodology for undertaking representative dietary surveys among schoolchildren: 2 × 24-h dietary recalls (24-HDRs) combined with a food-recording booklet (FRB), using EPIC-Soft pc-program (the software developed to conduct 24-HDRs in the European Prospective Investigation into Cancer and Nutrition (EPIC) Study), against a 7-day food-record (7-dFR) method among Danish schoolchildren. SUBJECTS/METHODS: A total of 74 children aged 7-8 years and 70 children aged 12-13 years were recruited through the Civil Registration System in Denmark. Each child and one of their parents completed two face-to-face 24-HDRs, combined with optional use of a FRB, followed by a 7-day-estimated FR. RESULTS: Energy intake was significantly higher with the 24-HDR method than with the 7-dFR method for both age groups. Mean energy intake was 6% higher for the youngest (P = 0.02) and 11% for the oldest children (P = 0.01); underreporting of energy occurs among the oldest children, being less present with the 24-HDR method. The intakes of carbohydrate and dietary fiber (absolute and related to energy) were significantly higher with the 24-HDR than with the 7-dFR for both age groups (P < 0.001). No significant differences between the two methods were observed for absolute intake of fat and added sugar between both age groups, and for intake of protein among the 7- to 8-year olds. The percentage of energy intake from fat from the 24-HDR, however, was significantly lower for both age groups and for energy intake from added sugar for the 12- to 13-year olds. CONCLUSIONS: The 2 × 24-HDR method compared with the 7-dFR yields relatively good values on the group level for many macronutrients and foods. However, some differences in estimated intakes of macronutrients suggest the need to carefully adapt the tools to be age and country specific. There is a tendency for parents and schoolchildren to report a healthier diet with the 24-HDR than with the FRs; this results in some concern about the method and has to be studied further.

Feasibility of repeated 24-h dietary recalls combined with a food-recording booklet, using EPIC-Soft, among preschoolers.

BACKGROUND/OBJECTIVES: This study evaluates the feasibility among preschoolers of the 2 × 24-h dietary recalls (24-HDRs) method combined with a food-recording booklet (FRB), using EPIC-Soft pc-program for the 24-HDR (the software developed to conduct 24-HDRs in the European Prospective Investigation into Cancer and Nutrition (EPIC) Study). SUBJECTS/METHODS: A total of 20 and 25 (4- to 5-year-old) children were recruited, as a convenience sample, through worksites or day or healthcare in Denmark and Spain, respectively. One parent (or both parents together) completed two face-to-face 24-HDR, combined with an optional use of a FRB. Feasibility was evaluated by evaluation questionnaires completed by parents and interviewers. RESULTS: The face-to-face interviews were primarily conducted with the mothers. The FRB was used by 90% of the participants, and proxy persons, other than the parent, were also involved; involvement of proxy persons seems necessary in a majority of the recalls in both the countries. CONCLUSIONS: The results suggest that 2 × 24-HDR with one parent combined with a FRB is feasible for registering preschoolers' diet. An FRB and/or information from proxy persons, other than the parent, is needed for a majority of the parents. In future studies, it may be beneficial to develop the FRB more like a structured food record (FR), which might, in principle, change the method to a one-day FR method from more than a 24-HDR method. It is recommended then to further investigate the use of EPIC-Soft as a data-entry tool.

Maternal vitamin D intake during pregnancy increases gene expression of ILT3 and ILT4 in cord blood.

BACKGROUND: Recent studies indicate that prenatal vitamin D intake may protect against the development of atopic diseases in young children. Vitamin D has been shown to induce tolerogenic antigen-presenting cells such as dendritic cells. Whether the allergy-protective potential of prenatal vitamin D is mediated through such mechanisms is, however, unknown. OBJECTIVE: To evaluate the association between prenatal vitamin D supplementation and tolerogenic antigen-presenting cells in cord blood (CB) as determined by mRNA measurement of immunoglobulin-like transcripts (ILT)3 and ILT4. METHODS: A prospective multi-centre birth cohort was established in rural areas of five European countries. Information on maternal exposures including vitamin D intake was collected by questionnaires during pregnancy. The gene expression of ILT3 and ILT4 was analysed by real-time PCR in the CB of 927 children. Maternal vitamin D supplementation was assessed in Finland and France (n=349). RESULTS: Maternal vitamin D supplementation during pregnancy was associated with an increase in the gene expression of ILT3 (P=0.012) and ILT4 (P<0.001). This association remained significant for ILT4 (P=0.020) and showed a positive trend for the gene expression of ILT3 (P=0.059) after multivariate analysis controlling for various confounders. CONCLUSIONS: Vitamin D supplementation during pregnancy may increase the mRNA levels of ILT3 and ILT4 in CB. This finding may point towards an early induction of tolerogenic immune responses by maternal vitamin D intake.

Coincidence of recurrent hemiparesis and detection of ALL in a 4-year-old girl: one or two diseases?

Stroke like symptoms in children such as hemiparesis are often associated with infection, cranial trauma, cardiac anomalies or sickle cell disease. In childhood leukemia, stroke like symptoms at presentation are rare and normally caused by cerebral bleedings. Here we report a patient who presented with classical stroke symptoms and hemiparesis prior to the diagnosis of acute lymphoblastic leukemia without proven CNS infiltration by leukemic cells. In general, acute leukemia or cerebral lymphoma do not lead to extensive defects of brain tissue. This unusual case suggests that acute lymphoblastic leukemia may present with stroke like CNS symptoms including hemiparesis.