Genetic factors contributing to late adverse musculoskeletal effects in childhood acute lymphoblastic leukemia survivors.

BACKGROUND: A substantial number of survivors of childhood acute lymphoblastic leukemia (ALL) suffer from treatment-related late adverse effects. While multiple studies have identified the effects of chemotherapeutics and radiation therapy on musculoskeletal outcomes, few have investigated their associations with genetic factors. METHODS: Here we analyzed musculoskeletal complications in relation to common and rare genetic variants derived through whole-exome sequencing of the PETALE cohort. Top-ranking associations were further assessed through stratified and multivariate analyses. RESULTS: DUOX2 variant was associated with skeletal muscle function deficit, as defined by peak muscle power Z score ≤ -2 SD (P = 4.5 × 10-5 for genotyping model). Upon risk stratification analysis, common variants in the APOL3, COL12A1, and LY75 genes were associated with Z score ≤ -2 SD at the cross-sectional area (CSA) at 4% radial length and lumbar bone mineral density (BMD) in high-risk patients (P ≤ 0.01). The modulation of the effect by risk group was driven by the interaction of the genotype with cumulative glucocorticoid dose. Identified variants remained significant throughout multivariate analyses incorporating non-genetic factors of the studied cohort. CONCLUSION: This exploratory study identified novel genetic variants associated with long-term musculoskeletal impairments in childhood ALL survivors. Replication in an independent cohort is needed to confirm the association found in this study.

Pre-implantation alcohol exposure induces lasting sex-specific DNA methylation programming errors in the developing forebrain.

BACKGROUND: Prenatal alcohol exposure is recognized for altering DNA methylation profiles of brain cells during development, and to be part of the molecular basis underpinning Fetal Alcohol Spectrum Disorder (FASD) etiology. However, we have negligible information on the effects of alcohol exposure during pre-implantation, the early embryonic window marked with dynamic DNA methylation reprogramming, and on how this may rewire the brain developmental program. RESULTS: Using a pre-clinical in vivo mouse model, we show that a binge-like alcohol exposure during pre-implantation at the 8-cell stage leads to surge in morphological brain defects and adverse developmental outcomes during fetal life. Genome-wide DNA methylation analyses of fetal forebrains uncovered sex-specific alterations, including partial loss of DNA methylation maintenance at imprinting control regions, and abnormal de novo DNA methylation profiles in various biological pathways (e.g., neural/brain development). CONCLUSION: These findings support that alcohol-induced DNA methylation programming deviations during pre-implantation could contribute to the manifestation of neurodevelopmental phenotypes associated with FASD.

Developmental genome-wide DNA methylation asymmetry between mouse placenta and embryo.

In early embryos, DNA methylation is remodelled to initiate the developmental program but for mostly unknown reasons, methylation marks are acquired unequally between embryonic and placental cells. To better understand this, we generated high-resolution DNA methylation maps of mouse mid-gestation (E10.5) embryo and placenta. We uncovered specific subtypes of differentially methylated regions (DMRs) that contribute directly to the developmental asymmetry existing between mid-gestation embryonic and placental DNA methylation patterns. We show that the asymmetry occurs rapidly during the acquisition of marks in the post-implanted conceptus (E3.5-E6.5), and that these patterns are long-lasting across subtypes of DMRs throughout prenatal development and in somatic tissues. We reveal that at the peri-implantation stages, the de novo methyltransferase activity of DNMT3B is the main driver of methylation marks on asymmetric DMRs, and that DNMT3B can largely compensate for lack of DNMT3A in the epiblast and extraembryonic ectoderm, whereas DNMT3A can only partially compensate in the absence of DNMT3B. However, as development progresses and as DNMT3A becomes the principal de novo methyltransferase, the compensatory DNA methylation mechanism of DNMT3B on DMRs becomes less effective.

Environmental, health, wellbeing, social and equity effects of urban green space interventions: A meta-narrative evidence synthesis.

BACKGROUND: As populations become increasingly urbanised, the preservation of urban green space (UGS) becomes paramount. UGS is not just dedicated recreational space such as public parks, but other types of informal green space are important, for example, street trees and roof gardens. Despite the potential from cross-sectional evidence, we know little about how to design new, or improve or promote existing UGS for health, wellbeing, social and environmental benefits, or known influencing factors such as physical activity. OBJECTIVES: To perform a meta-narrative review of the evidence regarding the health, wellbeing, social, environmental and equity effects, or known influencing factors of these outcomes, of UGS interventions. DATA SOURCES: Eight electronic databases were searched ((Medline, PsycINFO, Web of Science (Science and Social Science Citation Indices), PADDI (Planning Architecture Design Database Ireland), Zetoc, Scopus, Greenfiles, SIGLE (System for Information on Grey Literature in Europe)), and reference lists of included studies and relevant reviews were hand searched for further relevant studies. STUDY ELIGIBILITY CRITERIA, PARTICIPANTS, AND INTERVENTIONS: Eligibility criteria included: (i) evaluation of an UGS intervention; and (ii) health, wellbeing, social or environmental outcome(s), or known influencing factors of these outcomes, measured. Interventions involving any age group were included. Interventions must have involved: (a) physical change to green space in an urban-context including improvements to existing UGS or development of new UGS, or (b) combination of physical change to UGS supplemented by a specific UGS awareness, marketing or promotion programme to encourage use of UGS. STUDY APPRAISAL AND SYNTHESIS METHODS: Following a meta-narrative approach, evidence was synthesised by main intervention approach, including: (i) park-based; (ii) greenways/trails; (iii) urban greening; (iv) large green built projects for environmental purposes. Outcomes such as economic (e.g. cost effectiveness and cost-benefit analyses), adverse effects and unintended consequences were also extracted. Evidence was synthesised following the RAMESES guidelines and publication standards, the PROGRESS-plus tool was used to explore equity impact, and risk of bias/study quality was assessed. The findings from the evidence review were presented at an expert panel representing various disciplines in a workshop and these discussions framed the findings of the review and provide recommendations that are relevant to policy, practice and research. RESULTS: Of the 6997 studies identified, 38 were included. There was strong evidence to support park-based (7/7 studies) and greenway/trail (3/3 studies) interventions employing a dual-approach (i.e. a physical change to the UGS and promotion/marketing programmes) particularly for park use and physical activity; strong evidence for the greening of vacant lots (4/4 studies) for health, wellbeing (e.g. reduction in stress) and social (e.g. reduction in crime, increased perceptions of safety) outcomes; strong evidence for the provision of urban street trees (3/4 studies) and green built interventions for storm water management (6/7 studies) for environmental outcomes (e.g. increased biodiversity, reduction in illegal dumping). Park-based or greenway/trail interventions that did not employ a dual-approach were largely ineffective (7/12 studies showed no significant intervention effect). Overall, the included studies have inherent biases owing to the largely non-randomized study designs employed. There was too little evidence to draw firm conclusions regarding the impact of UGS interventions on a range of equity indicators. LIMITATIONS; CONCLUSIONS AND IMPLICATIONS OF KEY FINDINGS: UGS has an important role to play in creating a culture of health and wellbeing. Results from this study provide supportive evidence regarding the use of certain UGS interventions for health, social and environmental benefits. These findings should be interpreted in light of the heterogeneous nature of the evidence base, including diverging methods, target populations, settings and outcomes. We could draw little conclusions regarding the equity impact of UGS interventions. However, the true potential of UGS has not been realised as studies have typically under-evaluated UGS interventions by not taking account of the multifunctional nature of UGS. The findings have implications for policymakers, practitioners and researchers. For example, for policymakers the trajectory of evidence is generally towards a positive association between UGS and health, wellbeing, social and environmental outcomes, but any intervention must ensure that negative consequences of gentrification and unequal access are minimised.

Is there a relationship between vitamin D nutritional status and metabolic syndrome in childhood acute lymphoblastic leukemia survivors? A PETALE study.

BACKGROUND: Treatment of childhood acute lymphoblastic leukemia (cALL) has reached unprecedented success leading to survival rates reaching 90%. This is regrettably linked to increased risk of developing long-term health-related sequels into early adulthood. OBJECTIVE: This study aims at assessing the relationship between the vitamin D status and metabolic biomarkers in PETALE, a well-characterized cohort of cALL survivors. RESULTS: We demonstrate that 15.9% of the study participants exhibited 3 or more metabolic syndrome (MetS) risk factors. We also show a direct relationship between s25OHD3 and plasma HDL-Cholesterol concentrations in female but not male participants. CONCLUSION: Our data, from a metabolically well-described cohort, support a modest role for vitamin D in lipid metabolism in childhood leukemia survivors. The major outcome of this study is the strong association between HDL-Cholesterol concentration and s25OHD3 only in female subjects, thereby conveying vitamin D a gender-specific cardio-protective effect. cALL survivors represent a population at higher risk for secondary diseases. For this reason thorough nutritional evaluation, including vitamin D should be part of the regular follow-up.

Vitamin D nutritional status and bone turnover markers in childhood acute lymphoblastic leukemia survivors: A PETALE study.

BACKGROUND: The remarkable progress in the treatment of childhood acute lymphoblastic leukemia (cALL) has led to a survival rate reaching 90%. This success story is unfortunately linked to increased risk of impaired skeletal mass accumulation during childhood and adolescence, predisposing the patients to osteoporosis and pathological fractures at adulthood. OBJECTIVE: This study aims at characterizing the vitamin D status and bone health biomarkers in a well-characterized cohort of cALL survivors. RESULTS: Food frequency questionnaires reveal that (i) the total vitamin D intake varies greatly (44-2132 IU/d), (ii) only 16.8% of the participants consume vitamin D supplements, and (iii) 74% of survivors' intakes are below the Recommended Daily Intakes (400 IU/d). For the 42 participants taking vitamin D supplements, the median (2.5-97.5%iles) intake is 600 IU/d (21.2-1972 IU/d). Sixteen participants are vitamin D deficient (<30 nM) and 66 insufficient (≥30 - <50 nM). Serum 24,25(OH)2D3 concentrations are directly related to those of 25OHD3, and those of 3-epi-25OHD3 below the Lower Limit of Quantification in most samples. The participants' serum concentrations of cross-linked C-telopeptide of type-I collagen and intact amino-terminal pro-peptide of type-I collagen decrease steadily with age, leveling at adulthood, and are at all times higher in males. CONCLUSION: The present study shows that the prevalence of vitamin D insufficiency or deficiency is not greater in cALL survivors compared to the general Canadian population despite low vitamin D food and supplement intakes. Furthermore, there seem to be no overt imbalance in the gender- and age-adjusted serum bone turnover marker concentrations.

Nutrition education and cooking workshops for families of children with cancer: a feasibility study.

BACKGROUND: Changes in food intake are common in children with cancer and are often caused by nausea and perturbations in sense of taste. The VIE (Valorization, Implication, Education) study proposes family-based nutrition and cooking education workshops during childhood cancer treatments. Process evaluation during implementation allows to assess if the intervention was delivered as planned and to determine its barriers and facilitators. The study objective was to describe the implementation process of a nutrition education and cooking workshop program for families of children actively treated for cancer in a non-randomized non-controlled feasibility study. METHODS: Six open-to-all in-hospital workshops were offered on a weekly basis during a one-year implementation phase. We collected qualitative and quantitative data using field notes and activity reports completed by the registered dietician facilitator; surveys and questionnaires fulfilled by the workshop participants and by the families enrolled in the VIE study. Field notes were used to collect only qualitative data. Survey respondents (n = 26) were mostly mothers (n = 19, 73%). Children's mean age was 7.80 (± 4.99) years and the mean time since diagnosis was 7.98 (± 0.81) months. Qualitative data were codified using hybrid content analysis. The first deductive analysis was based on the Steckler & Linnan concepts. Subthemes were then identified inductively. Quantitative data were presented with descriptive statistics. RESULTS: Workshop attendance was low (17 participants over 1 year) and 71% of the planned workshops were cancelled due to lack of participants. The principal barriers to participation referred the child's medical condition, parental presence required at the child's bedside and challenges related to logistics and time management. The level of interest in the topics addressed was found high or very high for 92% of the participants. The themes that were perceived as the most useful by parents were related to the child's specific medical condition. CONCLUSIONS: Despite high interest, workshops delivered in a face-to-face format were poorly feasible in our sample population. This supports the need to develop educational programs in pediatric oncology using strategies and delivery formats that address the major barriers for participation encountered by families.

Impact of genetic polymorphisms determining leukocyte/neutrophil count on chemotherapy toxicity.

Neutropenia and infection are major dose-limiting side effects of chemotherapy. The risk of initial infection and subsequent complications are directly related to the depth and duration of neutropenia. Recent genome-wide association studies identified variants in DARC and CXCL2 genes, and in ORMDL3-GSDMA-CSF3 locus on chromosome 17q21 that influence white blood cell and neutrophil counts in healthy individuals. To investigate whether polymorphisms in these loci in conjunction with chemotherapy may modulate risk of treatment complications, we analyzed 21 SNPs across these genes for an association with chemotherapy-related neutropenia and infection in 286 Caucasian children with acute lymphoblastic leukemia. After correction for multiple testing, DARC polymorphism rs3027012 in 5'-UTR was associated with higher risk of low absolute phagocyte count (APC<500 and <1000 cells per microliter, P=0.001 and P<0.0005, respectively) and hospitalization due to febrile neutropenia (P=0.002). Protective effect was instead seen for DARC rs12075 A to G substitution (P=0.004). The SNP rs3859192 in the GSDMA were associated with hospitalization due to infection (P=0.004); infection was also modulated in the additive manner by the CXCL2 rs16850408 (P=0.002). This study shows for the first time that the variations in DARC, GSDMA and CXCL2 genes may play a role in the onset of chemotherapy complications.

How to interpret high levels of distress when using the Distress Thermometer in the long-term follow-up clinic? A study with Acute Lymphoblastic Leukemia survivors.

OBJECTIVES: Recent guidelines recommend to assess emotional distress in pediatric oncology during treatment and in after care. One tool used to do this is the distress thermometer (DT), a simple tool which has almost exclusively been studied in its screening abilities. Given its increased used as a measure of distress per se, it is necessary to document its concurrent validity. The goal of this study was to identify clinical domains (eg, depression, anxiety) and individual symptoms associated with pediatric cancer survivors' rating on the DT. PARTICIPANTS: To do so we used data collected from 84 young (≤18 years old), and 120 older (>18 years old) survivors who were treated for pediatric leukemia. METHODS: Participants responded to self-report questionnaires as part of a research visit. RESULTS: Results from stepwise regressions show that in the younger group, high scores on the thermometer were associated with higher negative affectivity only. In adults, high scores were associated with higher anxiety, higher negative affectivity, and lower positive affectivity. When exploring associations with individual items, we found that the main emotional tone reflected by the thermometer score was anxiety. CONCLUSIONS: Interpreting ratings on the thermometer should probably focus on anxiety in childhood cancer survivors. This widely used tool also does not measure the same domains in young versus older survivors, so that age groups should be considered separately in future work.

A 2-year dyadic longitudinal study of mothers' and fathers' marital adjustment when caring for a child with cancer.

OBJECTIVE: Studies examining interrelationships within parental couples confronted with pediatric cancer are scarce. This study explored dyadic longitudinal associations between both partners' family functioning and mood at diagnosis, and marital adjustment 2 years later. METHOD: Parents of children (n = 47 couples) with acute lymphoblastic leukemia (ALL) completed the Family Well-Being Assessment and Profile of Mood States-Bipolar Form at diagnosis, and the Locke-Wallace Marital Adjustment Test 2 years post diagnosis. Multilevel linear models using the actor-partner interdependence model (APIM) and controlling for baseline marital adjustment were conducted to evaluate within subject and dyadic longitudinal effects. RESULTS: For mothers, better marital adjustment 2 years post diagnosis was associated with perception of greater family support and less role conflict and role overload at diagnosis. For fathers, better marital adjustment 2 years post-diagnosis was associated with perception of less role conflict, greater role ambiguity, and being more tired at diagnosis, as well as their partner's perception of less role conflict at diagnosis. CONCLUSIONS: These findings highlight the importance of considering both partners' perspectives in understanding marital adjustment across treatment phases in parents of children with ALL. Early interventions for couples should be tailored to meet each partner's needs in order to foster resilience within the couple.

Adverse neuropsychological effects associated with cumulative doses of corticosteroids to treat childhood acute lymphoblastic leukemia: A literature review.

Corticosteroids (CS) are an essential component of childhood acute lymphoblastic leukemia treatments (cALL). Although there is evidence that daily doses of CS can have neuropsychological effects, few studies have investigated the role of cumulative doses of CS in short- and long-term neuropsychological effects in cALL. The aims of this review were to identify the measures used for documenting adverse neuropsychological effects (ANEs) of CS treatment and to study the association between cumulative doses of CS and the presence of ANEs. Twenty-two articles met the inclusion criteria. A variety of measures were used to evaluate outcomes in the domains of emotion, behaviour, neurocognition, and fatigue/sleep. The results suggest that we cannot conclude in favour of an association between the cumulative dosage of CS and ANEs. Yet, several factors including the heterogeneity of measures used to evaluate outcomes and reporting biases may limit the scope of the results. We offer several recommendations that could help improve the future published evidence on ANEs in relation to CS treatment in cALL.

Polymorphisms of ABCC5 and NOS3 genes influence doxorubicin cardiotoxicity in survivors of childhood acute lymphoblastic leukemia.

Anthracyclines are efficient chemotherapy agents. However, their use is limited by anthracycline-induced cardiotoxicity (CT). We investigated the influence of polymorphisms in doxorubicin metabolic and functional pathways on late-onset CT as estimated by echocardiography in 251 childhood acute lymphoblastic leukemia (cALL) patients. Association analyses revealed a modulating effect of two variants: A-1629 T in ABCC5, an ATP-binding cassette transporter, and G894T in the NOS3 endothelial nitric oxide synthase gene. Individuals with the ABCC5 TT-1629 genotype had an average of 8-12% reduction of ejection (EF) and shortening fractions (SF; EF: P<0.0001, and SF: P=0.001, respectively). A protective effect of the NOS3 TT894 genotype on EF was seen in high-risk patients (P=0.02), especially in those who did not receive dexrazoxane (P=0.002). Analysis of an additional cohort of 44 cALL patients replicated the ABCC5 association but was underpowered for NOS3. In summary, we identified two biomarkers that may contribute to cALL anthracycline CT risk stratification.

A survey of surgical draping practices in small-animal practice in the UK.

Veterinary practices in the United Kingdom were surveyed to compare their surgical draping practices with Royal College of Veterinary Surgeons (RCVS) accreditation tier and other surgery-related factors. Using descriptive statistics and logistic or ordinal regression analysis (where appropriate), the relationships between draping material and accreditation tier and other surgery-related factors were assessed. Procedures were categorised as short or long. Two hundred and sixty-nine surveys were completed. Reusable drapes were used in 66 per cent of practices. Antibiotics were administered routinely in 38 per cent of short and 93 per cent of long procedures. Practices accredited as a Veterinary Hospital (VH) were 6.3-7.2 (short and long surgeries, respectively) times more likely to use disposable drapes, when compared with non-accredited practices. Use of dedicated surgical attire, draping the whole animal/table, and routine antibiotic usage were also positively correlated with disposable drape usage. Fifty-one per cent of practices rated infection rate as most important when choosing drape material. 'Best practice' techniques are associated with lower importance given to infection rate, and higher importance given to financial cost, when choosing drape material. Disposable drape use correlates with RCVS accreditation and with other aspects of surgical technique. Importance ratings awarded correlate with best practice procedures. Clinical relevance 'Best practice' draping procedures, that are not governed by RCVS accreditation scheme, are also more frequently performed in accredited VHs.

Association between genetic variants in the HNF4A gene and childhood-onset Crohn's disease.

Hepatocyte nuclear 4 alpha (HNF4α), involved in glucose and lipid metabolism, has been linked to intestinal inflammation and abnormal mucosal permeability. Moreover, in a genome-wide association study, the HNF4A locus has been associated with ulcerative colitis. The objective of our study was to evaluate the association between HNF4α genetic variants and Crohn's disease (CD) in two distinct Canadian pediatric cohorts. The sequencing of the HNF4A gene in 40 French Canadian patients led to the identification of 27 single nucleotide polymorphism (SNP)s with a minor allele frequency >5%. To assess the impact of these SNPs on disease susceptibility, we first conducted a case-control discovery study on 358 subjects with CD and 542 controls. We then carried out a replication study in a separate cohort of 416 cases and 1208 controls. In the discovery cohort, the genotyping of the identified SNPs revealed that six were significantly associated with CD. Among them, rs1884613 was replicated in the second CD cohort (odds ratio (OR): 1.33; P<0.012) and this association remained significant when both cohorts were combined and after correction for multiple testing (OR: 1.39; P<0.004). An 8-marker P2 promoter haplotype containing rs1884613 was also found associated with CD (P<2.09 × 10(-4) for combined cohorts). This is the first report showing that the HNF4A locus may be a common genetic determinant of childhood-onset CD. These findings highlight the importance of the intestinal epithelium and oxidative protection in the pathogenesis of CD.

Polymorphism in multidrug resistance-associated protein gene 3 is associated with outcomes in childhood acute lymphoblastic leukemia.

Multidrug resistance-related proteins (MRPs) 2, 3 and 5 are involved in the efflux of drugs used in acute lymphoblastic leukemia (ALL) treatment. Polymorphisms of these genes were investigated for an association with treatment responses in 273 childhood ALL patients. The MRP3 A-189 allele of the regulatory AT polymorphism was associated with reduced event-free survival (P=0.01). The results remained significant after adjustment for multiple comparisons and in the multivariate analysis. Among patients with an event, the A-189 carriers had significantly higher methotrexate plasma levels (P=0.03). MRP3 A-189 also conferred four times higher risk of a relapse in central nervous system (P=0.01). Patients with this allele tended to have lower frequency of thrombocytopenia grade 2 (P=0.06). Gene reporter assay showed that the haplotype tagged by the A-189 had higher promoter activity (P≤0.01). In conclusion, MRP3 A-189 T polymorphism was associated with treatment responses in ALL, likely due to the change in MRP3 efflux.

Genetic characterisation of Toxoplasma gondii in wildlife from North America revealed widespread and high prevalence of the fourth clonal type.

Little is known of the genetic diversity of Toxoplasma gondii circulating in wildlife. In the present study wild animals, from the USA were examined for T. gondii infection. Tissues of naturally exposed animals were bioassayed in mice for isolation of viable parasites. Viable T. gondii was isolated from 31 animals including, to our knowledge for the first time, from a bald eagle (Haliaeetus leucocephalus), five gray wolves (Canis lupus), a woodrat (Neotoma micropus), and five Arctic foxes (Alopex lagopus). Additionally, 66 T. gondii isolates obtained previously, but not genetically characterised, were revived in mice. Toxoplasma gondii DNA isolated from these 97 samples (31+66) was characterised using 11 PCR-restriction fragment length polymorphism (RFLP) markers (SAG1, 5'- and 3'-SAG2, alt.SAG2, SAG3, BTUB, GRA6, c22-8, c29-2, L358, PK1 and Apico). A total of 95 isolates were successfully genotyped. In addition to clonal Types II, and III, 12 different genotypes were found. These genotype data were combined with 74 T. gondii isolates previously characterised from wildlife from North America and a composite data set of 169 isolates comprised 22 genotypes, including clonal Types II, III and 20 atypical genotypes. Phylogenetic network analysis showed limited diversity with dominance of a recently designated fourth clonal type (Type 12) in North America, followed by the Type II and III lineages. These three major lineages together accounted for 85% of strains in North America. The Type 12 lineage includes previously identified Type A and X strains from sea otters. This study revealed that the Type 12 lineage accounts for 46.7% (79/169) of isolates and is dominant in wildlife of North America. No clonal Type I strain was identified among these wildlife isolates. These results suggest that T. gondii strains in wildlife from North America have limited diversity, with the occurrence of only a few major clonal types.

A new atypical highly mouse virulent Toxoplasma gondii genotype isolated from a wild black bear in Alaska.

Most strains of Toxoplasma gondii isolated in North America and Europe are grouped into 3 (Types I, II, III) genotypes and are considered clonal. Recent evidence suggests that illness due to toxoplasmosis in immunocompetent persons may be related to infection with an atypical genotype; these strains are mouse virulent. In the present study, a new mouse-virulent atypical T. gondii genotype was isolated from an asymptomatic black bear ( Ursus americanus ) from Alaska. The bear had a titer of 1ratio1,600 using the modified agglutination test for T. gondii . Swiss Webster out-bred mice inoculated with bear heart homogenate died of acute toxoplasmosis, 12 days post-inoculation (PI). Cats fed tissues from chronically infected animals (day 30 PI) shed oocysts, but only 1 of 3 cats fed acutely infected mice (12, 16, 18 days PI) shed oocysts. The isolate (designated TgBbUS1) was mouse virulent; mice inoculated with 1 oocyst or 1 tachyzoite died of acute toxoplasmosis. The restricted fragment length polymorphism using 10 markers revealed that the strain possessed an atypical genotype: type I allele at loci SAG1, (5'-3')SAG2, SAG3, c22-8, c29-2, L358, and Apico; type II allele at locus alt.SAG2; and type III allele at loci BTUB, GRA6, and PK1. DNA sequencing at intron loci EF1, HP2, and UPRT1 revealed that the TgBbUS1 is a divergent T. gondii strain. These results indicate that mouse-virulent atypical T. gondii genotypes are also circulating in wildlife in North America.

The TP53 Arg72Pro and MDM2 309G>T polymorphisms are not associated with breast cancer risk in BRCA1 and BRCA2 mutation carriers.

BACKGROUND: The TP53 pathway, in which TP53 and its negative regulator MDM2 are the central elements, has an important role in carcinogenesis, particularly in BRCA1- and BRCA2-mediated carcinogenesis. A single nucleotide polymorphism (SNP) in the promoter region of MDM2 (309T>G, rs2279744) and a coding SNP of TP53 (Arg72Pro, rs1042522) have been shown to be of functional significance. METHODS: To investigate whether these SNPs modify breast cancer risk for BRCA1 and BRCA2 mutation carriers, we pooled genotype data on the TP53 Arg72Pro SNP in 7011 mutation carriers and on the MDM2 309T>G SNP in 2222 mutation carriers from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Data were analysed using a Cox proportional hazards model within a retrospective likelihood framework. RESULTS: No association was found between these SNPs and breast cancer risk for BRCA1 (TP53: per-allele hazard ratio (HR)=1.01, 95% confidence interval (CI): 0.93-1.10, P(trend)=0.77; MDM2: HR=0.96, 95%CI: 0.84-1.09, P(trend)=0.54) or for BRCA2 mutation carriers (TP53: HR=0.99, 95%CI: 0.87-1.12, P(trend)=0.83; MDM2: HR=0.98, 95%CI: 0.80-1.21, P(trend)=0.88). We also evaluated the potential combined effects of both SNPs on breast cancer risk, however, none of their combined genotypes showed any evidence of association. CONCLUSION: There was no evidence that TP53 Arg72Pro or MDM2 309T>G, either singly or in combination, influence breast cancer risk in BRCA1 or BRCA2 mutation carriers.