The association between adolescent psychopathology and subsequent physical activity in young adulthood: a 21-year birth cohort study.

BACKGROUND: The beneficial effects of physical activity (PA) for both physical and mental wellbeing are well established. Given that adolescence presents a critical developmental period during which life-long patterns of PA become established, the exploration of the longitudinal impact of adolescent psychopathology on adult PA status is of interest. METHODS: We analysed prospective data from 3663 young adults who participated in the Mater-University of Queensland Study of Pregnancy. Psychopathology was measured using the Youth Self-Report (YSR) at age 14. Participants' engagement in three types of PA (vigorous exercise, moderate exercise and walking) at age 21 were dichotomised into either 'none' or 'any'. For our main analysis, we examined the association between the YSR score and subsequent PA engagement using logistic regression. We also conducted sensitivity analyses of longitudinal associations between the YSR internalising and externalising symptoms score at age 14 and PA engagement at age 21. RESULTS: We found no longitudinal association between the total YSR score at age 14 and PA engagement at age 21. In addition, there was no longitudinal association between the YSR internalising or externalising symptoms and PA engagement. CONCLUSION: Our findings suggest that there is no longitudinal association between adolescent psychopathology and PA in young adulthood.

A double-click approach to the protecting group free synthesis of glycoconjugates.

The use of a bi-functional linker, containing an alkyne and an alkene, allows the protecting group free conjugation of reducing sugars to thiols via a double click process. Firstly the linker is attached to the sugar via one-pot glycosyl azide formation and Cu-catalysed azide-alkyne cycloaddition. Photochemical thiol-ene click reaction then allows conjugation to a range of thiols, including cysteine residues of peptides.

Chimeric Allografts Induced by Short-Term Treatment With Stem Cell-Mobilizing Agents Result in Long-Term Kidney Transplant Survival Without Immunosuppression: A Study in Rats.

Transplant tolerance allowing the elimination of lifelong immunosuppression has been the goal of research for 60 years. The induction of mixed chimerism has shown promise and has been extended successfully to large animals and to the clinic; however, it remains cumbersome and requires heavy early immunosuppression. In this study, we reported that four injections of AMD3100, a CXCR4 antagonist, plus eight injections of low-dose FK506 (0.05 mg/kg per day) in the first week after kidney transplantation extended survival, but death from renal failure occurred at 30-90 days. Repeating the same course of AMD3100 and FK506 at 1, 2 and 3 mo after transplant resulted in 92% allograft acceptance (n = 12) at 7 mo, normal kidney function and histology with no further treatment. Transplant acceptance was associated with the influx of host stem cells, resulting in a hybrid kidney and a modulated host immune response. Confirmation of these results could initiate a paradigm shift in posttransplant therapy.

Chimeric Allografts Induced by Short-Term Treatment With Stem Cell Mobilizing Agents Result in Long-Term Kidney Transplant Survival Without Immunosuppression: II, Study in Miniature Swine.

Transplantation is now lifesaving therapy for patients with end-stage organ failure but requires lifelong immunosuppression with resultant morbidity. Current immunosuppressive strategies inhibit T cell activation and prevent donor-recipient engagement. Therefore, it is not surprising that few host cells are demonstrated in donor grafts. However, our recent small animal studies found large numbers of recipient stem cells present after transplantation and pharmacological mobilization, resulting in a chimeric, repopulated organ. We now confirm these findings in a well-characterized large animal preclinical model. Here, we show that AMD3100 and FK506 mobilization of endogenous stem cells immediately post kidney transplantation combined with repeat therapy at 1, 2, and 3 months led to drug-free long-term survival in maximally immunologically mismatched swine. Three long-term recipients have stable chimeric transplants, preserved antidonor skin graft responses, and normal serum creatinine levels despite withdrawal of all medication for 3 years.

Generational increase in obesity among young women: a prospective analysis of mother-daughter dyads.

BACKGROUND/OBJECTIVES: Increases in obesity in young adults over recent decades are shown by national survey data but have yet to be replicated using prospective data. We aim to quantify the increase in obesity and overweight over two generations of young adult women using prospective measures of body mass index (BMI). SUBJECTS/METHODS: Data are from the Mater University Study of Pregnancy (MUSP), a prospective pre-birth cohort study started in 1981 in Brisbane, Australia. Analyses were restricted to 992 mother-daughter dyads who were at similar ages at the time they were assessed and for whom measures of BMI were available. We also conducted an additional analysis to test whether there was a similar increase amongst father-son dyads. We used multinomial logistic regression for clustered data to compare the same prospective measures of BMI categories between mother and daughters. RESULTS: Controlling for a number of sociodemographic and lifestyle factors in the female sample, daughters had 5.04 (3.03, 8.85) times the odds of being obese and 2.54 (1.86, 3.54) times the odds of being overweight compared with their mothers. A large increase in obesity was also observed in the male sample. CONCLUSIONS: Using a longitudinal design to partly account for familial confounding of obesity risk factors, this study confirms a large and concerning increases in obesity rates over two generations of young adults and suggests increases in obesity over the past 20 years may be greater than previously anticipated.

Successful transplantation of kidney allografts in sensitized rats after syngeneic hematopoietic stem cell transplantation and fludarabine.

Current methods to remove donor-specific HLA antibody (DSA) from sensitized patients remain imperfect. We tested novel approaches to desensitization using an animal model of allogeneic sensitization with skin grafts from dark agouti (DA) to Lewis rats. At the peak IgG alloantibody response we transplanted DA kidneys into nephrectomized Lewis recipients (n = 6) and all died within 10 days from antibody-mediated rejection (AMR). Allogeneic hematopoietic stem cell transplants (HSCT) from DA donors failed to engraft after lethal or sub-lethal irradiation. Sensitized rats given lethal irradiation plus syngeneic green fluorescent protein (GFP) + HSCT had repopulation of blood, spleen, thymus and lymph nodes by GFP+ cells. At 2 months after HSCT, serum DSA levels were reduced 60-70% and DSA (IgG) production in cultured splenocytes was also significantly decreased. However, there was only a modest improvement in graft survival from an average of 6.5 to 13.9 (n = 9) days. Adding seven daily doses of fludarabine to the preconditioning regimen resulted in long-term survival (>90 days) in 7 out of 10 rat kidney allografts. We conclude that syngeneic HSCT performed after preconditioning with irradiation and fludarabine can reduce DSA, prevent DSA rebound and AMR, enabling successful transplantation in animals with strong antibody reactivity to the donor MHC.

Adolescents bullying and young adults body mass index and obesity: a longitudinal study.

OBJECTIVE: To examine whether adolescent males and females who were victims of bullying were at greater risk of a higher body mass index (BMI) and obesity by young adulthood. DESIGN: Secondary analysis of data from a community-based cohort study. SUBJECTS: A sub-sample of 1694 offspring (50% males) who were participants in the Mater-University of Queensland Study of Pregnancy (MUSP), Brisbane, and who provided bullying information at 14 years and physical assessment at 21 years. MAIN OUTCOME MEASURES: BMI and its categories as normal, overweight or obese at 21 years. RESULTS: One in two adolescent males and one in three adolescent females reported that they had been bullied at school by others. We found that adolescent males and females who were bullied were at a significantly greater risk of a higher BMI and obesity by young adulthood. Fourteen-year-old males who were occasionally/often bullied at school had 0.64 (95% confidence interval (CI): 0.02, 1.27) kg m(2) greater mean BMI by 21 years compared with males who were never bullied by 14 years. This mean difference in BMI was 1.52, (95% CI: 0.75, 2.29) kg m(2) for females. Similarly, the odds of being obese were 2.54 (95% CI: 1.58, 4.09) times at 21 years for those males who were bullied occasionally/often compared with adolescent males who were never bullied. For females, this was 2.18 (95% CI: 1.40, 3.39). Overweight adolescents who experienced bullying had the greatest increase in BMI by young adulthood. Adjusting for potential confounding or mediating factors, the associations remain strong for males but are attenuated for females. CONCLUSIONS: The findings of this study suggest that both male and female adolescents who were bullied often/sometimes by their peer group at 14 years were at greater risk of higher BMI and obesity by young adulthood.

The heritability of delusional-like experiences.

OBJECTIVE: Delusional-like experiences (DLE) are common in the general community and are associated with a family history of mental illness. The aim of this study was to estimate the heritability of DLE. METHOD: The Peter's Delusional Inventory (PDI) was administered to a population-based cohort of mothers (n = 2861, aged 35-67 years) and their adult offspring (n = 3079, aged 18-23 years). Heritability of DLE was estimated from the sum scores of the 21 item PDI under the assumption that the covariance between mother-offspring scores is attributable to shared additive genetic factors. RESULTS: The means (medians and standard deviations) for the total PDI scores for the mothers and their offspring were 3.6 (3.0, 3.0) and 5.0 (4.0, 3.5), respectively. The Pearson correlation coefficient between mother and offspring PDI scores was 0.17 (P < 0.001). The heritability was estimated to be 0.35 (standard error 0.04). CONCLUSION: Heritable factors contribute to over a third of the variance of PDI scores in this population. In light of the association between a family history of a wide range of mental disorders and DLE, these experiences may represent a useful quantitative endophenotype for genetic studies of common mental disorders in population settings.

Smoking behaviour in pregnancy and its impact on smoking cessation at various intervals during follow-up over 21 years: a prospective cohort study.

OBJECTIVE: To determine whether mothers who quit or reduce their level of smoking in pregnancy comprise a group of health-conscious women who are disproportionally likely to adopt a healthier smoking lifestyle in the medium to longer term, compared with women who continue to smoke during pregnancy. DESIGN: A prospective cohort study. SETTING: A public hospital in Australia. POPULATION: A cohort of 6703 individual mothers who completed both initial phases of data collection in 1981-1983; mothers who smoked daily (2992) before pregnancy were included in this study. METHODS: Mothers were interviewed at 3-5 days post-delivery, 6 months, 5 years, 14 years and 21 years to determine their smoking status. An inverse probability-weighted Poisson regression with a robust error variance was fitted to the data using a log-link function and a binary response variable for smoking outcome, and adjusting for several possible confounding factors. MAIN OUTCOME MEASURE: Smoking cessation at several follow-up points, for up to 21 years. RESULTS: Of the mothers who smoked daily before pregnancy, 12, 23, 37 and 41% reported having ceased smoking at 6 months and at 5, 14 and 21 years, respectively. The decision to quit smoking during pregnancy was found to be independently associated with a higher rate ratio (RR) of smoking cessation at 6 months (RR 30.60, 95% CI 20.50-45.69), 5 years (RR 4.36; 95% CI 3.61-5.27), 14 years (RR 2.42, 95% CI 2.12-2.75) and 21 years (RR 1.86; 95% CI 1.60-2.15), after adjusting for several possible confounding factors. CONCLUSIONS: Pregnancy appears to be an opportunity for successfully quitting smoking, regardless of socio-economic circumstances or demographic background.

Successful transplantation of reduced-sized rat alcoholic fatty livers made possible by mobilization of host stem cells.

Livers from Lewis rats fed with 7% alcohol for 5 weeks were used for transplantation. Reduced sized (50%) livers or whole livers were transplanted into normal DA recipients, which, in this strain combination, survive indefinitely when the donor has not been fed alcohol. However, none of the rats survived a whole fatty liver transplant while six of seven recipients of reduced sized alcoholic liver grafts survived long term. SDF-1 and HGF were significantly increased in reduced size liver grafts compared to whole liver grafts. Lineage-negative Thy-1+CXCR4+CD133+ stem cells were significantly increased in the peripheral blood and in allografts after reduced size fatty liver transplantation. In contrast, there were meager increases in cells reactive with anti Thy-1, CXCR4 and CD133 in peripheral blood and allografts in whole alcoholic liver recipients. The provision of plerixafor, a stem cell mobilizer, salvaged 5 of 10 whole fatty liver grafts. Conversely, blocking SDF-1 activity with neutralizing antibodies diminished stem cell recruitment and four of five reduced sized fatty liver recipients died. Thus chemokine insufficiency was associated with transplant failure of whole grafts, which was overcome by the increased regenerative requirements promoted by the small grafts and mediated by SDF-1 resulting in stem cell influx.

Mobilization of host stem cells enables long-term liver transplant acceptance in a strongly rejecting rat strain combination.

Careful examination of liver, kidney and heart transplants in human recipients has revealed small numbers of host bone marrow derived stem cells in the graft. If the limited recipient repopulation of a donor graft that is currently observed could be facilitated, it is possible that conversion to a predominantly host phenotype would permit long-term graft function without immunosuppression. We proposed to "engineer" repopulation after transplant in a strain combination (dark agouti [DA] to Lewis green fluorescent protein+[LEW GFP+]) which rejects liver grafts strongly, a model that more closely resembles the situation in humans. Treatment on days 0, 1, 2, 3 and 7 after transplantation with low-dose (0.1 mg/kg) tacrolimus (T) designed to blunt rejection combined with plerixafor (P) to mobilize host stem cells resulted in greater than 180 days graft survival with extensive albeit spotty conversion of a small (50%) DA graft to the recipient LEW GFP+ genotype. Subsequent skin grafting revealed donor-specific graft prolongation. The T plus P treatment resulted in higher levels of Lin-Thy1+CD34+CD133+ stem cells and Foxp3+ regulatory T cells in the blood and liver at day 7. Thus, pharmacological mobilization of host stem cells sustains liver allografts by two mechanisms: repopulation of injured donor cells and regulation of the immune response.

Inner dynein arm defects causing primary ciliary dyskinesia: repeat testing required.

Primary ciliary dyskinesia (PCD) results in chronic nasal symptoms and chest disease leading to bronchiectasis. We noted a number of patients referred for diagnostic testing whose initial results suggested PCD due to an inner dynein arm or radial spoke defect but in whom no abnormality was found on retesting. The present study was an audit of all patients referred for PCD diagnostic testing over a 3-yr period whose initial electron microscopy (EM) and beat pattern analysis suggested an inner dynein arm or radial spoke defect. 21 patients referred for diagnostic testing for PCD suspected of an inner dynein arm defect and six suspected of a radial spoke defect on initial EM and beat pattern analysis had repeat testing performed. On repeat testing, five patients initially suspected of an inner dynein arm defect and one with a radial spoke defect had normal EM and beat pattern, leading to the initial diagnosis being questioned. Patients suspected of PCD due to an inner dynein arm defect or radial spoke defect should have the diagnosis reassessed if it has been based on only one diagnostic sample.

DNA damage in fetal liver cells of turkey and chicken eggs dosed with aflatoxin B1.

The present study was undertaken to investigate the potential of the potent hepatocarcinogen aflatoxin B(1) (AFB) to produce DNA damage in turkey and chicken fetal livers in ovo. Effects of a single injection of two different doses (0.062 and 6.2 µg) of AFB were examined under both short-term (4 h) and longer-term (4 day) dosing of eggs from turkeys at 24 days and chickens at 18 days of development. Liver cells prepared from the fetuses were used to assess the extent of DNA damage by the alkaline single-cell gel electrophoresis (comet) assay. The results demonstrate that AFB produces dose-related DNA damage in the fetal livers of both turkeys and chicken at 4 h, which was reduced by 4 days. Turkey embryos appeared to be slightly more susceptible to AFB damage, although no difference in the survival between chicken and turkey fetuses was observed.

A review of mammalian carcinogenicity study design and potential effects of alternate test procedures on the safety evaluation of food ingredients.

Extensive experience in conducting long term cancer bioassays has been gained over the past 50 years of animal testing on drugs, pesticides, industrial chemicals, food additives and consumer products. Testing protocols for the conduct of carcinogenicity studies in rodents have been developed in Guidelines promulgated by regulatory agencies, including the US EPA (Environmental Protection Agency), the US FDA (Food and Drug Administration), the OECD (Organization for Economic Co-operation and Development) for the EU member states and the MAFF (Ministries of Agriculture, Forestries and Fisheries) and MHW (Ministry of Health and Welfare) in Japan. The basis of critical elements of the study design that lead to an accepted identification of the carcinogenic hazard of substances in food and beverages is the focus of this review. The approaches used by entities well-known for carcinogenicity testing and/or guideline development are discussed. Particular focus is placed on comparison of testing programs used by the US National Toxicology Program (NTP) and advocated in OECD guidelines to the testing programs of the European Ramazzini Foundation (ERF), an organization with numerous published carcinogenicity studies. This focus allows for a good comparison of differences in approaches to carcinogenicity testing and allows for a critical consideration of elements important to appropriate carcinogenicity study designs and practices. OECD protocols serve as good standard models for carcinogenicity testing protocol design. Additionally, the detailed design of any protocol should include attention to the rationale for inclusion of particular elements, including the impact of those elements on study interpretations. Appropriate interpretation of study results is dependent on rigorous evaluation of the study design and conduct, including differences from standard practices. Important considerations are differences in the strain of animal used, diet and housing practices, rigorousness of test procedures, dose selection, histopathology procedures, application of historical control data, statistical evaluations and whether statistical extrapolations are supported by, or are beyond the limits of, the data generated. Without due consideration, there can be result conflicting data interpretations and uncertainty about the relevance of a study's results to human risk. This paper discusses the critical elements of rodent (rat) carcinogenicity studies, particularly with respect to the study of food ingredients. It also highlights study practices and procedures that can detract from the appropriate evaluation of human relevance of results, indicating the importance of adherence to international consensus protocols, such as those detailed by OECD.

Ontogeny of the immune response. II. Correlations between the development of the afferent and efferent limbs.

The development of the ability of young rats to generate a prompt primary antibody response to polymerized flagellin, with IgM to IgG transition, is correlated in time with the development of structures in the cortex of lymph nodes that localize antigen to spherical areas which subsequently become primary lymphoid follicles. Throughout development the increased magnitude of the antibody response parallels the increased ability of lymphoid structures to retain antigen. During the first week of life primitive lymphoid tissue appears capable of undergoing the initial steps in differentiation toward antibody production in response to neonatal injections of polymerized flagellin. However, further maturation appears to be blocked resulting in a complex immunological state at the age of 2 weeks characterized by increased IgM and decreased IgG antibody response to antigenic challenge at this time. The possible relationship between the block in cellular differentiation toward antibody formation and the ease of tolerance induction is discussed.

Ontogeny of the immune response. I. The development of the follicular antigen-trapping mechanism.

Polymerized flagellin from Salmonella adelaide was labeled with I(125) and injected into rats varying in age from 0 to 42 days. Lymphoid organs were removed at various intervals and the progressive development of antigen-capturing structures was studied using autoradiography. The chief findings were as follows: 1. Newborn rats lack the follicular and medullary antigen-trapping structures characteristic of adult animals. 2. At the age of 10 to 14 days, the first signs of specific cortical antigen localization appear in lymph nodes. This initially takes the form of a continuous "cortical rim" of antigen localization. 3. Within a further 4 to 6 days, the Anlagen of true follicular antigen-capturing structures appear, the continuous rim being only a transitional mechanism. 4. The antigen-capturing part of the follicle appears before the lymphoid component; follicle Anlagen can be defined only on autoradiographs and cannot be seen on ordinary histological sections. 5. The system of medullary macrophages develops gradually over the period 2 to 6 weeks of age. 6. The ability of lymph nodes to retain antigen increases progressively, there being a fivefold increase in the amount of antigen retained per unit weight of lymphoid tissue between 2 and 6 wk of age.

The antecedents of non-affective psychosis in a birth-cohort, with a focus on measures related to cognitive ability, attentional dysfunction and speech problems.

OBJECTIVE: Adults with non-affective psychosis show subtle deviations in a range of developmental trajectories as children and adolescents. METHOD: Based on a birth-cohort (n = 3801), we examined the Peabody Picture Vocabulary Test (PPTV) at age 5, and Raven's Standard Progressive Matrices (RSPM) and Wide Range Achievement Test reading scale (WRAT-R) at age 14. Items related to speech problems and attentional dysfunction were available from maternal- or self-report. At age 21, we identified 60 cohort members who were screen-positive for non-affective psychosis (SP-NAP). RESULTS: Impaired performance on the PPVT and RSPM (but not WRAT-R) predicted SP-NAP for males only. Male cohort members in the highest quartile for attentional dysfunction at ages 5 and 14 were about 5-8 times more likely to develop SP-NAP. SP-NAP in males was significantly associated with speech problems at age 14. CONCLUSION: Males who develop non-affective psychoses have subtle impairments in cognitive capacity prior to the development of their psychotic disorder.

Longitudinal correlates of the persistence of irregular eating from age 5 to 14 years.

AIM: To report the stability of parent-perceived child irregular eating from 6 months to 14 years of age and to investigate a predictive model inclusive of child and parent factors. METHODS: Of the 7223 singleton children in a birth cohort, 5122 children were re-interviewed at 5 years and 4554 for the 14-year analysis. Information was obtained from structured interviews including questions answered by parents of the child at birth, 6 months, 5 years and 14 years; and by teenagers at age 14 years and from physical measures of the child. The mother's perception that the child was an irregular eater at age 14 years was the major outcome variable of interest. RESULTS: Approximately 40% of irregular eaters at age 5 will still be irregular eaters at age 14 years. This was not related to maternal education or socio-economic class. Significant at multivariate analysis were infant feeding problems and the children's ability to regulate their sleep and mood. Significant maternal factors were greater age, not feeling positive about the baby and persistent maternal anxiety during the child's early years. CONCLUSION: Irregular eating behaviour displays considerable continuity from childhood to mid-adolescence. Independent contributions to this behavioural phenotype include child biological and psychological factors and maternal anxiety during the child's early years.

Spatial and Climatic Factors Influence Ambrosia Beetle (Coleoptera: Curculionidae) Abundance in Intensively Managed Plantations of Eastern Black Walnut.

Invasive ambrosia beetles are among the most economically important pests of forest and plantation trees world-wide. The development of effective management guidelines for these pests in plantations of high-value hardwood species is hindered by a lack of baseline information regarding their seasonal abundance and dispersal behavior. By analyzing long-term monitoring data from intensively-managed plantations of eastern black walnut (Juglans nigra L.) in north-central Indiana, we identified key spatial and climatic variables that could improve the timing and precision of management actions to reduce ambrosia beetle populations. We also used geospatial analyses to compare species-specific spatial patterns of population density and evaluate the sensitivity of the trap density deployed in our long-term monitoring efforts. Xyleborinus saxesenii Ratzeburg and Xylosandrus crassiusculus Matschulsky (Coleoptera: Curculionidae) were more abundant during the spring in years preceded by a hot, dry growing season, and cold winter. Both species were positively associated with plantation edges during the fall flight period. However, X. saxesenii was less abundant in plantations close to forest corridors, whereas X. crassiusculus was more abundant in plantations closer to woodlots and other walnut plantations. Geospatial analysis revealed X. crassiusculus is active in larger, more spatially continuous patches than X. saxesenii, and that 200-m trap spacing is likely to be sufficient to detect both species in the spring flight period but may be insufficient to detect X. saxesenii during the fall flight period. Our findings underscore the power and utility of long-term monitoring to improve management strategies.

Maternal smoking during and after pregnancy and lung function in early adulthood: a prospective study.

BACKGROUND AND AIMS: There is a paucity of evidence about whether exposure to antenatal smoking impacts on offspring's lung function in early adulthood. This study aimed to examine whether (1) in utero exposure to maternal smoking is related to poorer respiratory functioning in early adulthood; (2) the impact of prenatal smoking is independent of postnatal maternal smoking; and (3) the link between prenatal smoking and a young adult's lung function is explained by the child's birth weight, smoking or history of asthma. METHODS: Data were from a 21-year follow-up of mothers and their children recruited into the Mater-University of Queensland Study of Pregnancy, a longitudinal prebirth cohort. The study is based on 2409 young adults (1185 males and 1224 females) who had prospective data available on respiratory function at 21 years and maternal smoking during and after pregnancy. A Spirobank G spirometer system was used to measure forced vital capacity (FVC), forced expiratory volume in 1 s (FEV(1)) and forced expiratory flow between 25% and 75% of FVC (FEF(25-75)). RESULTS: In utero exposure to maternal smoking was associated with a reduction in FEV(1) and FEF(25-75) in males (regression coefficient, -0.16; 95% CI, -0.30 to -0.02), after accounting for maternal smoking after pregnancy. At least part of the effect of in utero smoking on young adults' lung function was explained by the child's birth weight and subsequent asthma. CONCLUSIONS: Adverse effects of antenatal smoking on development of airway growth may persist into early adulthood. Gender differences noted in this longitudinal cohort need to be explored further.