Background: The rate of caesarean deliveries has increased 10-fold worldwide during the past decades. Objective: To evaluate differences in the establishment of gut microbiota in infants born by vaginal or caesarean delivery and its impact on mucosal immunity. Methods: Altogether, 165 consecutive children, prospectively followed from birth at our clinic in Turku, Finland, were gathered; 141 (85%) were born by vaginal delivery and 24 (15%) by caesarean section. Blood was drawn at physician visits for indirect evaluation of mucosal immunity by ELISPOT assay. Faecal samples were obtained for determination of the gut microbiota by fluorescence in situ hybridization of bacterial cells. Results: Infants delivered by caesarean section harboured fewer bifidobacteria at an early age and were shown to mount a stronger humoral immune response. At 1 month of age, the total gut bacterial cell counts per 1 g faeces were higher in vaginally delivered infants (9.9 × 10⁹, 95% CI 7.9 × 10⁹–1.2 × 10¹⁰) as compared to caesarean section delivered (3.1 × 10⁹, 95% CI 1.1 × 10⁹–8.6 × 10⁹) (p = 0.001). This distinction was mainly due to the greater number of bifidobacteria in vaginally delivered infants (1.9 × 10⁹, 95% CI 6.3 × 10⁸–5.6 × 10⁹ vs. 1.5 × 10⁶, 95% CI 4.1 × 10²–5.7 × 10⁹, respectively) (p = 0.001). During the first year of life, the total number of IgA-, IgG- and IgM-secreting cells was lower (p = 0.03, p = 0.02, p = 0.11, respectively) in infants born by vaginal delivery than in those born by caesarean section, possibly reflecting excessive antigen exposure across the vulnerable gut barrier. Conclusions: Our findings demonstrate that the mode of delivery may have, possibly via gut microbiota development, significant effects on immunological functions in the infant (http://www.clinicaltrials.gov/ct/gui/show/NCT00167700).

Infants of atopic mothers, specifically when breastfed exclusively over 2.5 months or totally over 6 months, had a higher risk of sensitization at the age of 12 months. This risk could be reduced by the use of probiotics during pregnancy and lactation, partly by resulting in a beneficial composition of the breast milk.

Prevalence of sensitization to airborne allergens, unlike that to dietary allergens, has increased over a long period of time. Our results support the concept of the immune function being programmed by external factors early in life. They also call for caution when interpretations of the pace and possible causes of the allergy epidemic are made on the basis of short-term studies.

This study calls for co-operation between scientists, governmental policy makers and healthcare professionals to ensure a continuous chain of information, applicable to nutrition counselling, from scientific data to everyday practice.

Osteonecrosis (ON) is a recognized complication of childhood ALL, but its optimal management remains unestablished. This study evaluated the effect of bisphosphonate (BP) treatment on evolution of ON lesions in childhood ALL.We included a national cohort of ALL patients diagnosed with symptomatic ON before 18 years of age and treated with BPs (N=10; five males). Patients were followed both clinically and with serial MRIs. ON lesions were graded according to the Niinimäki classification.The 10 patients had a total of 55 ON lesions. The median age was 13.3 years at ALL diagnosis and 14.8 years at ON diagnosis. Four patients had received HSCT before the ON diagnosis. BPs used were pamidronate (N=7), alendronate (N=2) and ibandronate (N=1). The duration of BP treatment varied between 4 months and 4 years. In 4/10 patients, BP treatment was given during the chemotherapy. BPs were well tolerated, with no severe complications or changes in kidney function. At the end of follow up 13/55 (24%) ON lesions were completely healed both clinically and radiographically; all these lesions were originally graded 3 or less. In contrast, ON lesions originally classified as grade 5 (joint destruction; N=4) remained at grade 5. All grade 5 hip joint lesions needed surgical treatment. During BP treatment, pain was relieved in 7/10 patients. At the end of follow up, none of the patients reported severe or frequent pain.BP treatment was safe and seemed effective in relieving ON-induced pain in childhood ALL. After articular collapse (Grade 5) lesions did not improve with BP treatment.Randomized controlled studies are needed to further elucidate the role of BPs in childhood ALL-associated ON.

Background: Many of the late effects of cancer treatment in childhood may occur even decades after the treatment, and only a minority of the survivors remain as healthy as their peers. Providing appropriate long-term care for childhood cancer survivors after transition to primary health care is a challenge. Both survivors and primary care providers need information on potential late effects. The lack of a systematic late effect follow-up plan may lead to excessive use of health care services or delayed intervention. While manual compilation of individual follow-up plans is time consuming for experienced clinicians, electronic algorithms may be feasible. Procedure: In Finland, international guidelines for determining the risk of late effects have been implemented. Nationally, Turku University Hospital was asked with developing an automatized system for calculating the risk of late effects, based on electronic patient records saved in the hospital data lake. An electronic algorithm that uses details from exposure-based health screening guidelines published by the Children's Oncology Group was created. The results were compared with those manually extracted by an experienced clinician. Results: Significant concordance between the manual and algorithm-based risk classification was found. A total of 355 patients received a classification using the algorithm, and 325 of those matched with the manual categorization, producing a Cohen's coefficient of 0.91 (95% confidence interval 0.88-0.95). Conclusion: Automated algorithms can be used to categorize childhood cancer survivors efficiently and reliably into late effect risk groups. This further enables automatized compilation of appropriate individual late effect follow-up plan for all survivors. K E Y W O R D S algorithm, childhood cancer survivor, electronic tool, late effect, long-term follow up 1 INTRODUCTION Childhood cancer survivors (CCSs) with late effects comprise a significant new patient group in the health care system, and the num-Abbreviations: CCS, childhood cancer survivor; CED, cyclophosphamide equivalent doses; CRP, C-reactive protein; HSCT, hematopoietic stem cell transplantation; ICD, International Classification of Diseases ber of CCSs is constantly increasing. The current overall survival rate for childhood malignancies is approximately 80%. 1,2 However, studies show that virtually all survivors develop at least one chronic health condition by the age of 45 years. 3-5 In many countries, individualized follow-up plans for CCSs are still not implemented. However, many patients could benefit from anticipatory guidance regarding health promotion and disease prevention aimed at minimizing the risk of

With great interest, we have read the article by Huurre et al. [1] reporting on the impact of maternal atopy and probiotic supplementation during pregnancy on infant sensitization. We would like to comment on some of the results of this trial.First, the authors found an increased risk of sensitization in infants with allergic mothers breastfeeding over 6 months or exclusively breastfeeding over 2.5 months. Therefore, they conclude that breastfeeding in atopic mothers is a risk factor for sensitization in infants. However, these results may be biased, because of reversed causation [2]. The authors give no information regarding the prevalence of allergic disease, specifically atopic dermatitis, in the participating infants. It seems likely that the presence of allergic symptoms caused mothers to continue breastfeeding for a longer period of time, which could explain the observed relation between breastfeeding and increased sensitization.Second, considerable attention is given to the observation that TGF-b2 was higher in the probiotic than in the placebo group. However, this difference did not reach significance (CI, 0.96-2.34; P = 0.073). Moreover, this moderate effect was seen only in the colostrum sample and had totally disappeared after 1 month, despite that the probiotic supplementation was still continued at that time. Therefore, it is questionable if probiotic supplementation actually changed the breast milk cytokine pattern.Finally, we regret that no faecal samples of the mothers were analysed to confirm actual colonization with the given probiotic strains. This would have given important information on compliance. References 1 Huurre A, Laitinen K, Rautava S, Korkeamaki M, Isolauri E. Impact of maternal atopy and probiotic supplementation during pregnancy on infant sensitization: a double-blind placebo-controlled study. Clin Exp Allergy 2008; 38:1342-48. 2 Laubereau B, Brockow I, Zirngibl A et al. Effect of breast-feeding on the development of atopic dermatitis during the first 3 years of life-results from the GINI-birth cohort study. J Pediatr 2004; 144:602-7.Response by Anu Huurre, on behalf of the NAMI (Nutrition, Allergy, Mucosal Immunology and Intestinal Microbiota) research groupWe thank van der Aa et al. for their interest in our study, Impact of maternal atopy and probiotic supplementation during pregnancy on infant sensitization: A double-blind placebo-controlled study, evaluating possible factors explaining the protective effect of probiotics. The questions van der Aa et al. have brought up concerns the secondary outcomes, not the main outcome of the study, i.e. that the protective potential of the combination of Lactobacillus rhamnosus strain GG and Bifidobacterium lactis Bb12 was best seen in high risk group of infants.We agree with van der Aa et al. that the secondary outcomes may have received disproportionate attention in the final version; in the version originally submitted they were not equally emphasized. The reason why the reviewers wanted to stress these findings may be the fact that th...

Cancer survivors show increased risk for non-communicable diseases and chronic lowgrade inflammation characterizes the development of such diseases. We investigated inflammatory plasma protein profiles of survivors of childhood acute lymphoblastic leukemia (ALL) in comparison to healthy controls and after an intervention with a home-based exercise program. Survivors of childhood ALL aged 16-30 years (n = 21) with a median age at diagnosis 4.9 (1.6-12.9) years and a median time of 15.9 years from diagnosis, and sex-and age-matched healthy controls (n = 21) were studied. Stored plasma samples were analyzed with Olink's 92-protein-wide Inflammation panel in 21 ALL long-term survivors at baseline, after a previous 16-week home-based exercise intervention (n = 17) and in 21 age-and sex-matched controls at baseline. Protein expression levels were compared between the groups. Inflammatory protein levels did not differ between the survivors and controls at baseline. Significantly reduced levels after the intervention were found in 11 proteins related to either vascular inflammation, insulin resistance, or both: tumor necrosis factor superfamily member 14 (TNFSF14), oncostatin M (OSM), monocyte chemoattractant protein 1 (MCP-1), MCP-2, fibroblast growth factor 21 (FGF-21), chemokine (C-C motif) ligand 4 (CCL4), transforming growth factor alpha (TGF-α), tumor necrosis factor-related apoptosisinducing ligand 10 (TRAIL), adenosine deaminase (ADA), chemokine (C-X-C motif) ligand 6 (CXCL6), and latency-associated peptide transforming growth factor beta 1