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The protection of Earth's stratospheric ozone (O3) is an ongoing process under the auspices of the universally ratified Montreal Protocol and its Amendments and adjustments. A critical part of this process is the assessment of the environmental issues related to changes in O3. The United Nations Environment Programme's Environmental Effects Assessment Panel provides annual scientific evaluations of some of the key issues arising in the recent collective knowledge base. This current update includes a comprehensive assessment of the incidence rates of skin cancer, cataract and other skin and eye diseases observed worldwide; the effects of UV radiation on tropospheric oxidants, and air and water quality; trends in breakdown products of fluorinated chemicals and recent information of their toxicity; and recent technological innovations of building materials for greater resistance to UV radiation. These issues span a wide range of topics, including both harmful and beneficial effects of exposure to UV radiation, and complex interactions with climate change. While the Montreal Protocol has succeeded in preventing large reductions in stratospheric O3, future changes may occur due to a number of natural and anthropogenic factors. Thus, frequent assessments of potential environmental impacts are essential to ensure that policies remain based on the best available scientific knowledge. [ABSTRACT FROM AUTHOR]

Purpose: The purpose of the study was to determine which of the ankle, knee or hip joint is the most important contributor to horizontal velocity during maximal sprint running. Furthermore, it was undertaken to quantify the fraction of propulsive power and work produced at each of the three joints. Methods: Seven athletes of national class served as subjects for the study. One running cycle of each subject was recorded by four video cameras (240 f/s) and a recessed force platform. Inverse dynamics in 3D was calculated as well as an angle between joint moment and angular velocity to express propulsive power and propulsive joint work. Results: Previous studies indicating the hip joint being the most important joint could not be confirmed by the present results due to large inter-individual differences for the hip joint. Averaged across all subjects, 64% of the normalized positive ankle joint work and 71% of the knee joint work were propulsive, while for the hip joint, four athletes showed 0%, one athlete 8%, and two athletes 96% and 97% propulsive work, respectively. For the whole leg, the propulsive fraction was 70% of the total positive work (range 40–87%). Normalized propulsive work was significantly correlated with maximal running velocity. Conclusion: The whole leg should be considered as one functional unit in which one or more of the joints may dominate generation of propulsive joint work. [ABSTRACT FROM AUTHOR]

Chronic kidney diseases imply an ongoing need to remove toxins, with hemodialysis as the preferred treatment modality. We derive analytical expressions for phosphate clearance during dialysis, the single pass (SP) model corresponding to a standard clinical hemodialysis and the multi pass (MP) model, where dialysate is recycled and therefore makes a smaller clinical setting possible such as a transportable dialysis suitcase. For both cases we show that the convective contribution to the dialysate is negligible for the phosphate kinetics and derive simpler expressions. The SP and MP models are calibrated to clinical data of ten patients showing consistency between the models and provide estimates of the kinetic parameters. Immediately after dialysis a rebound effect is observed. We derive a simple formula describing this effect which is valid both posterior to SP or MP dialysis. The analytical formulas provide explanations to observations of previous clinical studies. [ABSTRACT FROM AUTHOR]

Ultraviolet (UV) radiation drives the net production of tropospheric ozone (O3) and a large fraction of particulate matter (PM) including sulfate, nitrate, and secondary organic aerosols. Ground-level O3 and PM are detrimental to human health, leading to several million premature deaths per year globally, and have adverse effects on plants and the yields of crops. The Montreal Protocol has prevented large increases in UV radiation that would have had major impacts on air quality. Future scenarios in which stratospheric O3 returns to 1980 values or even exceeds them (the so-called super-recovery) will tend to ameliorate urban ground-level O3 slightly but worsen it in rural areas. Furthermore, recovery of stratospheric O3 is expected to increase the amount of O3 transported into the troposphere by meteorological processes that are sensitive to climate change. UV radiation also generates hydroxyl radicals (OH) that control the amounts of many environmentally important chemicals in the atmosphere including some greenhouse gases, e.g., methane (CH4), and some short-lived ozone-depleting substances (ODSs). Recent modeling studies have shown that the increases in UV radiation associated with the depletion of stratospheric ozone over 1980–2020 have contributed a small increase (~ 3%) to the globally averaged concentrations of OH. Replacements for ODSs include chemicals that react with OH radicals, hence preventing the transport of these chemicals to the stratosphere. Some of these chemicals, e.g., hydrofluorocarbons that are currently being phased out, and hydrofluoroolefins now used increasingly, decompose into products whose fate in the environment warrants further investigation. One such product, trifluoroacetic acid (TFA), has no obvious pathway of degradation and might accumulate in some water bodies, but is unlikely to cause adverse effects out to 2100. [ABSTRACT FROM AUTHOR]

The hydraulic conductivity of rock joints is an important parameter controlling fluid flow in various rock engineering applications. The shearing and normal loading have significant effects on hydraulic conductivity of rock joints, the property of which is mainly controlled by hydraulic aperture. Despite the importance of hydro-mechanical behaviour of rock joints, the fundamental micro-scale processes leading to macro-scale observations remain unexplored partly due to difficulties with in situ measurement of hydraulic aperture and its complex relation to roughness and contact area. Therefore, in this study, a series of experiments coupling fluid flow with normal deformability and direct shear are performed on joints with varying controlled roughness at different normal stresses. Along with measuring stress and flow rate, the time-lapse X-ray micro-computed tomography is carried out to explore the evolution of joint aperture and contact area during the experiments. The results of the normal deformability experiments show that the joint conductivity is well correlated to the mean hydraulic aperture of joint profiles. Such correlation, however, is not apparent for the shearing experiment where under high normal stresses, the flow rate decreases continually indicating that damaged asperities hinder the fluid flow. Despite the trend in the average mechanical aperture not following the flow rate in some cases, the trend in the contact area follows the flow rate very closely throughout the shearing process. In addition, the results reveal that despite an increase in contact area with increase in normal stress, it is not physically possible to reach full contact even for the artificially well-mated samples at a high normal stress of 10 MPa. Finally, a new correlation is proposed to relate the hydraulic aperture to joint average mechanical aperture, contact area and roughness. The correlation estimates the experimental flow rates at both normal and shear loading conditions with good accuracy. Highlights: A series of coupled fluid flow—normal deformability and direct shear—experiments are performed on two rock joints with different roughness. The time-lapse X-ray micro-computed tomography is carried out to explore the evolution of joint aperture and contact area during the experiments. A new correlation is proposed to relate the hydraulic aperture to joint average mechanical aperture, contact area and roughness. The proposed correlation estimates the experimental flow rates at both normal and shearing loading conditions with good accuracy. [ABSTRACT FROM AUTHOR]

Aim: Responses to health anxiety include avoidance and reassurance-seeking behaviors. We tested the hypothesis that avoidance would be associated with less healthcare use and reassurance seeking with more healthcare use. Subjects and methods: Participants' (n = 395) complete measures of health anxiety behaviors, healthcare use in the previous 12 months (outpatient visits, emergency room visits, urgent care visits, number of doctors, number of scans, number of blood tests), and health anxiety intensity as a covariate. Results: Our hypothesis was partially supported, as reassurance seeking was associated with more healthcare use (p-values < 0.04), except that general reassurance seeking was not associated with number of scans (p = 0.327). Avoidance was not associated with healthcare use (p-values > 0.05), except for general avoidance with fewer scans (p = 0.010) and blood tests (p < 0.001). Conclusions: Future research on health anxiety should consider coping responses such as avoidance and reassurance seeking, and should extend this research to clinical care and similar concepts, like cancer worry. [ABSTRACT FROM AUTHOR]

Purpose: Maternal prenatal stress and postnatal depression are reported to increase the risk for early offspring psychological problems. We examined whether these two stressors predicted toddler emotional or behavioral problems based on the mother and teacher reports, respectively.Methods: A longitudinal study within the Odense Child Cohort (OCC). Prenatal stress was assessed (gestation week 28) using Cohen's Perceived Stress Scale (PSS). Depressive symptoms were assessed (3 months after birth) using the Edinburgh Postnatal Depression Scale (EPDS). Behavioral and emotional problems were assessed by mothers using the preschool version of Child Behaviour Checklist (CBCL) and by teachers using the caregiver-teacher report form (CTR-F).Results: N = 1302 mother-child dyads were included. CBCL (N = 1302) was collected at 29 months (SD 5.3) and C-TRF (N = 989) at 32.6 months (SD 6.9). N = 70 mothers (5.4%) were at high risk for postnatal depression (EPDS score > 12). Generalized additive models showed that prenatal stress (increase of + 1 on PSS-10 total score) predicted an increase in CBCL (+ 0.011) and C-TRF (+ 0.015) total scores. Postnatal depressive symptoms (increase of + 1 on EPDS total score) only predicted an increase in CBCL total score (+ 0.026).Conclusion: Prenatal maternal stress was a significant predictor of both mother and teacher reported toddler emotional and behavioral problems, although effect sizes were small. Postnatal depressive symptoms were associated with increased maternal (but not teacher) reporting of toddler problems. Mothers reported more toddler psychological problems than teachers, and the mother-teacher discrepancy was positively correlated to maternal postnatal depressive symptoms. [ABSTRACT FROM AUTHOR]

Advances in the biological sciences have led to an ongoing paradigm shift in toxicity testing based on expanded application of high-throughput in vitro screening and in silico methods to assess potential health risks of environmental agents. This review examines progress on the vision for toxicity testing elaborated by the US National Research Council (NRC) during the decade that has passed since the 2007 NRC report on Toxicity Testing in the 21st Century (TT21C). Concomitant advances in exposure assessment, including computational approaches and high-throughput exposomics, are also documented. A vision for the next generation of risk science, incorporating risk assessment methodologies suitable for the analysis of new toxicological and exposure data, resulting in human exposure guidelines is described. Case study prototypes indicating how these new approaches to toxicity testing, exposure measurement, and risk assessment are beginning to be applied in practice are presented. Overall, progress on the 20-year transition plan laid out by the US NRC in 2007 has been substantial. Importantly, government agencies within the United States and internationally are beginning to incorporate the new approach methodologies envisaged in the original TT21C vision into regulatory practice. Future perspectives on the continued evolution of toxicity testing to strengthen regulatory risk assessment are provided. [ABSTRACT FROM AUTHOR]

Purpose: Quality of life (QOL) is an important concept in the field of health and medicine. QOL is a complex concept that is interpreted and defined differently within and between disciplines, including the fields of health and medicine. The aims of this study were to systematically review the literature on QOL in medicine and health research and to describe the country of origin, target groups, instruments, design, and conceptual issues.Methods: A systematic review was conducted to identify research studies on QOL and health-related quality of life (HRQOL). The databases Scopus, which includes Embase and MEDLINE, CINAHL, and PsycINFO were searched for articles published during one random week in November 2016. The ten predefined criteria of Gill and Feinstein were used to evaluate the conceptual and methodological rigor.Results: QOL research is international and involves a variety of target groups, research designs, and QOL measures. According to the criteria of Gill and Feinstein, the results show that only 13% provided a definition of QOL, 6% distinguished QOL from HRQOL. The most frequently fulfilled criteria were: (i) stating the domains of QOL to be measured; (ii) giving a reason for choosing the instruments used; and (iii) aggregating the results from multiple items.Conclusion: QOL is an important endpoint in medical and health research, and QOL research involves a variety of patient groups and different research designs. Based on the current evaluation of the methodological and conceptual clarity of QOL research, we conclude that the majority QOL studies in health and medicine have conceptual and methodological challenges. [ABSTRACT FROM AUTHOR]

Purpose: The purpose of this study is to determine if there are any demographic and reporting differences between patients who respond and those who refuse to respond to postal questionnaires from the Danish national spine database, DaneSpine.Methods: DaneSpine collects patient-reported data, completed before surgery and at 3 months, and at 1, 2, 5, and 10 years postoperatively. The database was launched at the Center for Spine Surgery and Research at Lillebaelt Hospital on June 1st, 2010. We performed a 1-year follow-up on non-responders during a 6-month period between the 1st of August 2013 until the 31st of January 2014 using a structured phone interview to collect patient-reported outcomes, some health information and reasons for non-response.Results: Of the 506 patients who were 1-year post-operative, three did not have baseline data and six had died before the 1-year follow-up. Twenty-four patients had a second spine surgery and were re-enrolled in the database. These cases had not reached the 1-year follow-up period for the second spine surgery and were excluded from the analysis. Thus, 473 patients had reached 1-year follow-up. Of these, 57 (12 %) did not respond to postal questionnaires. A structured phone interview was performed on these 57 non-responders. Non-responders were in general, a decade younger than responders, a greater proportion were males and smokers. Apart from EQ-5D, there was no difference in patient satisfaction, improvement in back pain or leg pain between the responders and non-responders.Conclusions: Missing data from 12 % of patients do not seem to bias conclusions that can be drawn from the DaneSpine database at the Center for Spine Surgery and Research at Lillebaelt Hospital. [ABSTRACT FROM AUTHOR]

Frameshift mutations of the nucleophosmin gene (NPM1) were recently reported as a frequently occurring abnormality in patients with de novo acute myeloid leukemia (AML). To evaluate the frequency of NPM1 mutations in patients with therapy-related myelodysplasia (t-MDS) and therapy-related AML (t-AML), and their possible association to type of previous therapy and to other gene mutations, 140 patients with t-MDS or t-AML were analyzed for mutations of NPM1. NPM1 mutations were observed in 7 of 51 patients presenting as overt t-AML, as compared to only 3 of 89 patients presenting as t-MDS (P=0.037). The mutations were not related to any specific type of previous therapy, but they were significantly associated with a normal karyotype and mutations of FLT3 (P=0.0002 for both comparisons). Only 1 of 10 patients with NPM1 mutations presented chromosome aberrations characteristic of therapy-related disease, and 7q−/−7, the most frequent abnormalities of t-MDS/t-AML, were not observed (P=0.002). This raises the question whether some of the cases presenting NPM1 mutations were in fact cases of de novo leukemia. The close association to class I mutations and the inverse association to class II mutations suggest mutations of NPM1 as representing a class II mutation-like abnormality in AML.Leukemia (2008) 22, 951–955; doi:10.1038/leu.2008.17; published online 14 February 2008 [ABSTRACT FROM AUTHOR]

Myelodysplasia (MDS) and acute myeloid leukemia (AML) are heterogeneous, closely associated diseases arising de novo or following chemotherapy with alkylating agents, topoisomerase II inhibitors, or after radiotherapy. Whereas de novo MDS and AML are almost always subclassified according to cytogenetic characteristics, therapy-related MDS (t-MDS) and therapy-related AML (t-AML) are often considered as separate entities and are not subdivided. Alternative genetic pathways were previously proposed in t-MDS and t-AML based on cytogenetic characteristics. An increasing number of gene mutations are now observed to cluster differently in these pathways with an identical pattern in de novo and in t-MDS and t-AML. An association is observed between activating mutations of genes in the tyrosine kinase RAS–BRAF signal-transduction pathway (Class I mutations) and inactivating mutations of genes encoding hematopoietic transcription factors (Class II mutations). Point mutations of AML1 and RAS seem to cooperate and predispose to progression from t-MDS to t-AML. Recently, critical genetic effects underlying 5q−/−5 and 7q−/−7 have been proposed. Their association and cooperation with point mutations of p53 and AML1, respectively, extend the scenario of cooperating genetic abnormalities in MDS and AML. As de novo and t-MDS and t-AML are biologically identical diseases, they ought to be subclassified and treated similarly.Leukemia (2008) 22, 240–248. doi:10.1038/sj.leu.2405078; published online 17 January 2008 [ABSTRACT FROM AUTHOR]

Human interleukin 15 (IL-15) circulates in blood as a stable molecular complex with the soluble IL-15 receptor alpha (sIL-15Rα). This heterodimeric IL-15:sIL-15Rα complex (hetIL-15) shows therapeutic potential by promoting the growth, mobilization and activation of lymphocytes and is currently evaluated in clinical trials. Favorable pharmacokinetic properties are associated with the heterodimeric formation and the glycosylation of hetIL-15, which, however, remains largely uncharacterized. We report the site-specific N- and O-glycosylation of two clinically relevant large-scale preparations of HEK293-derived recombinant human hetIL-15. Intact IL-15 and sIL-15Rα and derived glycans and glycopeptides were separately profiled using multiple LC-MS/MS strategies. IL-15 Asn79 and sIL-15Rα Asn107 carried the same repertoire of biosynthetically-related N-glycans covering mostly α1-6-core-fucosylated and β-GlcNAc-terminating complex-type structures. The two potential IL-15 N-glycosylation sites (Asn71 and Asn112) located at the IL-2 receptor interface were unoccupied. Mass analysis of intact IL-15 confirmed its N-glycosylation and suggested that Asn79-glycosylation partially prevents Asn77-deamidation. IL-15 contained no O-glycans, whereas sIL-15Rα was heavily O-glycosylated with partially sialylated core 1 and 2-type mono- to hexasaccharides on Thr2, Thr81, Thr86, Thr156, Ser158, and Ser160. The sialoglycans displayed α2-3- and α2-6-NeuAc-type sialylation. Non-human, potentially immunogenic glycoepitopes ( e.g. N-glycolylneuraminic acid and α-galactosylation) were not displayed by hetIL-15. Highly reproducible glycosylation of IL-15 and sIL-15Rα of two batches of hetIL-15 demonstrated consistent manufacturing and purification. In conclusion, we document the heterogeneous and reproducible N- and O-glycosylation of large-scale preparations of the therapeutic candidate hetIL-15. Site-specific mapping of these molecular features is important to evaluate the consistent large-scale production and clinical efficacy of hetIL-15. [ABSTRACT FROM AUTHOR]

The article discusses a study about the variegation among patients with acute myeloid leukemia (AML) having prognostic chromosomal driver aberrations. Topics covered include the cellular composition of the patients' hematopoietic stem cell and progenitor cells (HSC/HSP), the driver aberrations' cellular origin, and comparisons between normal and aberrant transcriptional programs. The need for therapeutic strategies targeting oncogenic pathways is also mentioned.

Early detection of landfill leachate plumes may minimise aquifer degradation and financial expenditure for the landfill operator. Current methods of landfill leachate monitoring typically include analysis of groundwater field parameters such as electrical conductivity (EC), coupled with laboratory analysis of a selection of major cations and anions. In many instances, background influences can mask the impact of leachate, which only becomes apparent once a significant impact has occurred. Here, we investigate the potential for changes in fluorescent dissolved organic material (FDOM) concentration to be used as an indicator of leachate impact. The research was undertaken in a fractured rock aquifer located downgradient of a local government-operated putrescible landfill in Central West NSW, Australia. Field measurement of groundwater FDOM was undertaken using an in situ fluorometer (FDOM probe) which provides a relative measurement of FDOM. To quantify the FDOM values, a bench fluorescence spectrophotometer was used to collect excitation/emission spectra. A plume of elevated FDOM and EC levels within the fractured rock system up to 600 m downgradient of the landfill was identified, whereas analysis of major cations and anions from boreholes within the plume did not detect leachate impacts above background. Excitation/emission matrices of groundwater from these locations confirmed that similar fluorescence signatures to those collected from the landfill were present. Photodegradation experiments were conducted to determine if fluorescent whitening agents (FWAs) were a component of the fluorescence signal. Observed photodegradation of 40 % compared to background (8 %) suggests that a component of the fluorescence signal can be attributed to FWAs. FDOM in groundwater therefore provides an indicator of low-level (up to 98 % dilution) leachate influence, and the identification of FWAs within groundwater can be considered confirmation of a leachate signal. [ABSTRACT FROM AUTHOR]

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Summary: The prevalence of sarcopenia increases with age. The diagnosis of sarcopenia relies in part on normative data on muscle mass, but these data are lacking. This study provides population-based reference data on muscle mass in young men, and these results may be used clinically for the diagnosis of sarcopenia in men. Introduction: The ageing population increases the prevalence of sarcopenia. Estimation of normative data on muscle mass in young men during the peak of anabolic hormones is necessary for the diagnosis of sarcopenia in ageing males. The purposes of this study were to provide population-based reference data on lean body mass (LBM) in young men during the time of peak levels of GH/IGF-1 and testosterone and further to apply the reference data on a population-based sample of men aged 60-74 years to estimate the prevalence of sarcopenia. Methods: This is a cross-sectional, population-based single-centre study. Our participants are from random selection of 783 men, aged 20-29 years, and 600 men, aged 60-74 years. LBM was assessed by dual-energy X-ray absorptiometry (DXA). LBM T-scores were calculated on the basis of LBM in the young participants. Muscle function in the lower extremities was measured using a leg extension power (LEP) rig in the ageing participants. Results: Total lean body mass (TLB) was (mean (SD)) 64.7 kg (6.8) in the young and 60.4 kg (6.4) in the ageing men ( p < 0.001). Lower extremity lean mass (LELB) was 22.0 kg (2.6) in the young and 19.2 kg (2.4) in the ageing men ( p < 0.001). In the ageing men, TLB and LELB T-scores were −0.64 (0.94) and −1.09 (0.94). A total of 4.8 and 8.5 % had a TLB or LELB T-score of less than −2 and a LEP in the lowest quartile. Conclusions: This study provides population-based reference data on LBM in men, and these data may be used clinically for the diagnosis of sarcopenia. [ABSTRACT FROM AUTHOR]

Extreme, abrupt Northern Hemisphere climate oscillations during the last glacial cycle (140,000 years ago to present) were modulated by changes in ocean circulation and atmospheric forcing. However, the variability of the Atlantic meridional overturning circulation (AMOC), which has a role in controlling heat transport from low to high latitudes and in ocean CO2 storage, is still poorly constrained beyond the Last Glacial Maximum. Here we show that a deep and vigorous overturning circulation mode has persisted for most of the last glacial cycle, dominating ocean circulation in the Atlantic, whereas a shallower glacial mode with southern-sourced waters filling the deep western North Atlantic prevailed during glacial maxima. Our results are based on a reconstruction of both the strength and the direction of the AMOC during the last glacial cycle from a highly resolved marine sedimentary record in the deep western North Atlantic. Parallel measurements of two independent chemical water tracers (the isotope ratios of 231Pa/230Th and 143Nd/144Nd), which are not directly affected by changes in the global cycle, reveal consistent responses of the AMOC during the last two glacial terminations. Any significant deviations from this configuration, resulting in slowdowns of the AMOC, were restricted to centennial-scale excursions during catastrophic iceberg discharges of the Heinrich stadials. Severe and multicentennial weakening of North Atlantic Deep Water formation occurred only during Heinrich stadials close to glacial maxima with increased ice coverage, probably as a result of increased fresh-water input. In contrast, the AMOC was relatively insensitive to submillennial meltwater pulses during warmer climate states, and an active AMOC prevailed during Dansgaard-Oeschger interstadials (Greenland warm periods). [ABSTRACT FROM AUTHOR]

A pattern recognition algorithm has been developed to discriminate between artefacts and contractions in interdigestive motility recorded by a pressure catheter with four channels from the human duodenum. A learning and a test set, both containing natural and induced artefacts, such as respiration and body movement, are obtained from five volunteers. The event classes were phase I, II and III contractions of the interdigestive motility complex and artefacts from respiration, cough, calibration signals and movements. Length, area, amplitude, inter-event interval, up- and downstroke, and correlation to other pressure channels and to respiration, are applied to classify the events. The sensitivity of the computer scoring increases with the number of applied features. When all the features are applied, the sensitivity of the Bayes' classifier against the visually scored contractions and artefacts is 0.96 with a specificity of 0.69. [ABSTRACT FROM AUTHOR]

In recent years, the prevalence of adult female acne has increased, but the reason for this increase remains unclear. Acne is one of the most common skin disorders. It can be triggered or worsened by endogenous and exogenous factors, including genetic predisposition, hormone concentrations, diet, smoke and stress; although the interaction with this last factor is not well understood. Modern life presents many stresses including urban noises, socioeconomic pressures and light stimuli. Women are especially affected by stress during daily routine. The recent insertion in the labor market is added to the duties of the mother and wife. Women also have a higher risk of developing psychiatric disorders such as depression and anxiety. Sleep restriction is added to these factors, with several negative consequences on health, including on hormonal secretion and the immune system. This is further complicated by the natural variation in sleep architecture across the menstrual cycle. Recent studies have brought new data about the mechanisms and possible factors involved. This review aims to establish a connection between stress, sleep deprivation and adult female acne. [ABSTRACT FROM AUTHOR]

The adaptive immune system has the capacity to recognize and kill leukemic cells. However, immune tolerance mechanisms that normally protect healthy tissues from autoimmune effects prevent the development of effective antitumor immunity. Tumors use several different immunosuppressive mechanisms to evade otherwise effective T-cell responses. A growing number of immune evasion mechanisms have been characterized mainly in solid tumors. In hematological malignancies, less is known about how different immune escape mechanisms influence tumor immune evasion and the extent of their impact on ongoing immune responses. The present review highlights the potential role of three well-defined immunosuppressive mechanisms in hematological malignancies: (i) inhibitory T-cell pathways (especially programmed death ligand 1/programmed death 1 (PD-L1/PD-1)), (ii) regulatory immune cells, and (iii) metabolic enzymes such as indoeamine-2,3-dioxygenase (IDO). The possible therapeutic targeting of these pathways is also discussed. Exciting new strategies that might affect future antileukemia immunotherapy include monoclonal antibodies that block inhibitory T-cell pathways (PD-1/PD-L1) and the prevention of tryptophan depletion by IDO inhibitors. Furthermore, the clinical effect of several chemotherapeutic drugs may arise from the targeting of immunosuppressive cells. Evidence for a new feedback mechanism to suppress the function of regulatory immune cells was recently provided by the identification and characterization of spontaneous cytotoxic T lymphocyte (CTL) responses against regulatory immune cells. Such specific CTLs may be immensely useful in anticancer immunotherapy (for example, by anticancer vaccination). The targeting of one or more immunosuppressive pathways may be especially interesting in combination with antileukemic immunotherapy in cases in which immunosuppressive mechanisms antagonize the desired effects of the therapy. [ABSTRACT FROM AUTHOR]

This study describes the first use of concurrent high-precision temperature and drip rate monitoring to explore what controls the temperature of speleothem forming drip water. Two contrasting sites, one with fast transient and one with slow constant dripping, in a temperate semi-arid location (Wellington, NSW, Australia), exhibit drip water temperatures which deviate significantly from the cave air temperature. We confirm the hypothesis that evaporative cooling is the dominant, but so far unattributed, control causing significant disequilibrium between drip water and host rock/air temperatures. The amount of cooling is dependent on the drip rate, relative humidity and ventilation. Our results have implications for the interpretation of temperature-sensitive, speleothem climate proxies such as δ18O, cave microecology and the use of heat as a tracer in karst. Understanding the processes controlling the temperature of speleothem-forming cave drip waters is vital for assessing the reliability of such deposits as archives of climate change. [ABSTRACT FROM AUTHOR]

We aimed to study the occurrence of acute-onset symptoms at initial presentation in a national Danish cohort of patients with childhood- or adult-onset craniopharyngioma, and to investigate potential risk factors for acute presentation. Medical records of 189 consecutive patients (39 children, 150 adults) presenting with craniopharyngioma during the period 1985–2004 were reviewed, and data regarding initial symptoms, neuroimaging results, vision and pituitary function were systematically collected. Acute symptoms preceding hospital admission were noted. Subgroup analyses were based on age, gender and calendar year period. Potential risk factors for acute presentation were analysed through uni- and multivariate analyses. Acute symptoms were reported in 24 (13 %) patients. Acute visual symptoms, headache, nausea or vomiting were most frequently reported, and acute symptoms were more frequent among children (28 %) than among adults (9 %) ( P < 0.01). There were no differences according to sex or calendar year period. Hydrocephalus was present in half of childhood cases and one-fifth of adult patients ( P < 0.001). Intra-tumour haemorrhage was seen in two cases. Acute symptoms were more frequent among patients with tumours occupying the third ventricle ( P < 0.01), radiologic signs of calcification ( P < 0.05) or hydrocephalus ( P < 0.01). In multivariate analysis, however, only childhood onset ( P < 0.05) and calcification ( P < 0.05) were independent risk factors for acute presentation. Craniopharyngioma presented with acute symptoms in 13 % of patients. Childhood onset and radiologic signs of calcification were independent risk factors for acute presentation. Intra-tumour haemorrhage was rare. [ABSTRACT FROM AUTHOR]

Tumor-infiltrating CD4+CD25+ regulatory T cells (Tregs) are associated with an impaired prognosis in several cancers. The transcription factor forkhead box P3 (Foxp3) is generally expressed in Tregs. Here, we identify and characterize spontaneous cytotoxic immune responses to Foxp3-expressing cells in peripheral blood of healthy volunteers and cancer patients. These immune responses were directed against a HLA-A2-restricted peptide epitope derived from Foxp3. Foxp3-reactive T cells were characterized as cytotoxic CD8+ T cells. These cells recognized dendritic cells incubated with recombinant Foxp3 protein indicating that this protein was indeed internalized, processed and cross-presented in the context of HLA-A2. More importantly, however, Foxp3-specific T cells were able to specifically recognize Tregs. Similarly, Foxp3+ malignant T cells established from a Cutaneous T-cell lymphomas (CTCL) patient were readily killed by the Foxp3-specific cytotoxic T lymphocytes. The spontaneous presence of Foxp3-specific cytotoxic T-cell responses suggest a general role of such T cells in the complex network of immune regulation as such responses may eliminate Tregs, that is, suppression of the suppressors. Consequently, induction of Foxp3-specific cytotoxic T-cell responses appears as an attractive tool to boost spontaneous or therapeutically provoked immune responses, for example, for the therapy of cancer. [ABSTRACT FROM AUTHOR]

The interaction between muscle and bone is complex. The aim of this study was to investigate if variations in the muscle genes myostatin ( MSTN), its receptor ( ACVR2B), myogenin ( MYOG), and myoD1 ( MYOD1) were associated with fracture risk, bone mineral density (BMD), bone mineral content (BMC), and lean body mass. We analyzed two independent cohorts: the Danish Osteoporosis Prevention Study (DOPS), comprising 2,016 perimenopausal women treated with hormone therapy or not and followed for 10 years, and the Odense Androgen Study (OAS), a cross-sectional, population-based study on 783 men aged 20-29 years. Nine tag SNPs in the four genes were investigated. In the DOPS, individuals homozygous for the variant allele of the MSTN SNP rs7570532 had an increased risk of any osteoporotic fracture, with an HR of 1.82 (95 % CI 1.15-2.90, p = 0.01), and of nonvertebral osteoporotic fracture, with an HR of 2.02 (95 % CI 1.20-3.41, p = 0.01). The same allele was associated with increased bone loss (BMC) at the total hip of 4.1 versus 0.5 % in individuals either heterozygous or homozygous for the common allele ( p = 0.006), a reduced 10-year growth in bone area at the total hip of 0.4 versus 2.2 and 2.3 % in individuals heterozygous or homozygous for the common allele, respectively ( p = 0.01), and a nonsignificantly increased 10-year loss of total-hip BMD of 4.4 versus 2.7 and 2.9 % in individuals heterozygous or homozygous for the common allele, respectively ( p = 0.08). This study is the first to demonstrate an association between a variant in MSTN and fracture risk and bone loss. Further studies are needed to confirm the findings. [ABSTRACT FROM AUTHOR]

Aims/hypothesis: We investigated the long-term impact of diabetic ketoacidosis (DKA) at onset on metabolic regulation and residual beta cell function in a Danish population with type 1 diabetes. Methods: The study is based on data from DanDiabKids, a Danish national diabetes register for children. The register provides clinical and biochemical data on patients with type 1 diabetes diagnosed in 1996-2009 and then followed-up until 1 January 2012. Repeated-measurement models were used as statistical methods. Results: The study population comprised 2,964 children <18 years. The prevalence of DKA at diagnosis was 17.9%. Of the total subjects, 8.3% had mild, 7.9% had moderate and 1.7% had severe DKA. DKA (moderate and severe) was associated with increased HbA (%) levels (0.24; 95% CI 0.11, 0.36; p = 0.0003) and increased insulin dose-adjusted HbA (IDAA, 0.51; 95% CI 0.31, 0.70; p < 0.0001) during follow-up, after adjustment for covariates. Children without a family history of diabetes were more likely to present with DKA (19.2% vs 8.8%, p < 0.0001); however, these children had a lower HbA (%) level over time (−0.35; 95% CI −0.46, −0.24; p < 0.0001). Continuous subcutaneous insulin infusion (CSII) was associated with a long-term reduction in HbA, changing the effect of DKA, after adjustment for covariates ( p < 0.0001). Conclusions/interpretation: DKA at diagnosis was associated with poor long-term metabolic regulation and residual beta cell function as assessed by HbA and IDAA respectively; however, CSII treatment was associated with improvement in glycaemic regulation and residual beta cell function, changing the effect of DKA at onset in our population. [ABSTRACT FROM AUTHOR]

This article discusses a study which investigated nine t(9;22)-high hyperdiploidy (HeH) and two MLL-HeH acute lymphoblastic leukemia (ALL) patients. Researchers utilized single nucleotide polymorphism (SNP) array analysis to examine the patients. The study findings revealed a total of 23 intrachromosomal aberrations in 12 cases analyzed by SNP array.

Background:The Fat mass and obesity-associated gene (FTO) was the first gene reliably associated with body mass index in genome-wide association studies on a population level. At present, the genetic variations within the FTO gene are still the common variants that have the largest influence on body mass index.Methods:In the current study, we amplified the entire FTO gene, in total 412 Kbp, in over 200 long-range PCR fragments from each individual, from 524 severely obese and 527 lean Swedish children, and sequenced the products as two DNA pools using massive parallel sequencing (SOLiD).Results:The sequencing achieved very high coverage (median 18 000 reads) and we detected and estimated allele frequencies for 705 single nucleotide polymorphisms (SNPs) (19 novel) and 40 indels (24 novel) using a sophisticated statistical approach to remove false-positive SNPs. We identified 19 obesity-associated SNPs within intron one of the FTO gene, and validated our findings with genotyping. Ten of the validated obesity-associated SNPs have a stronger obesity association (P<0.007) than the commonly studied rs9939609 SNP (P<0.012).Conclusions:This study provides a comprehensive obesity-associated variation map of FTO, identifies novel lead SNPs and evaluates putative causative variants. We conclude that intron one is the only region within the FTO gene associated with obesity, and finally, we establish next generation sequencing of pooled DNA as a powerful method to investigate genetic association with complex diseases and traits. [ABSTRACT FROM AUTHOR]

BACKGROUND:Circulating angiotensin-converting enzyme (ACE) was identified as a predictor of weight loss maintenance in overweight/obese women of the Diogenes project.OBJECTIVE:To investigate whether ACE acted also as a predictor in men of the Diogenes study and to compare it with that in women.DESIGN:Subjects, who lost 8% of body weight induced by low-caloric diet in an 8-week weight loss period, were assigned to weight loss maintenance with dietary intervention for 6 months.SUBJECTS:125 overweight/obese healthy men from eight European countries who completed whole intervention.MEASUREMENTS:Concentrations and activity of serum ACE at baseline and after the 8-week weight loss, in addition to anthropometric and physiological parameters.RESULTS:Serum ACE concentration decreased by 11.3±10.6% during the weight loss period in men. A greater reduction is associated with less body weight regain during the maintenance period (r=0.227, P=0.012). ACE change was able to predict a weight regain 20% after 6 months, with an odds ratio of 1.59 (95% confidence interval (CI): 1.09-2.33, P=0.016) for every 10% reduction, which was independent of body mass index and weight loss. The prediction power was weaker in men than in women, but without a significant sex difference (P=0.137). In pooled subjects (N=218), the odds ratio was 1.96 (95% CI: 1.46-2.64, P<0.001).CONCLUSIONS:A greater reduction of ACE during weight loss is favorable for weight maintenance in both men and women. This can offer useful information for personalized advice to improve weight loss maintenance. It also confirms the role of ACE in the metabolic pathways of weight regulation. [ABSTRACT FROM AUTHOR]

ORIGIN is a proposal for the M3 mission call of ESA aimed at the study of metal creation from the epoch of cosmic dawn. Using high-spectral resolution in the soft X-ray band, ORIGIN will be able to identify the physical conditions of all abundant elements between C and Ni to red-shifts of z = 10, and beyond. The mission will answer questions such as: When were the first metals created? How does the cosmic metal content evolve? Where do most of the metals reside in the Universe? What is the role of metals in structure formation and evolution? To reach out to the early Universe ORIGIN will use Gamma-Ray Bursts (GRBs) to study their local environments in their host galaxies. This requires the capability to slew the satellite in less than a minute to the GRB location. By studying the chemical composition and properties of clusters of galaxies we can extend the range of exploration to lower redshifts ( z ∼0.2). For this task we need a high-resolution spectral imaging instrument with a large field of view. Using the same instrument, we can also study the so far only partially detected baryons in the Warm-Hot Intergalactic Medium (WHIM). The less dense part of the WHIM will be studied using absorption lines at low redshift in the spectra for GRBs. The ORIGIN mission includes a Transient Event Detector (coded mask with a sensitivity of 0.4 photon/cm/s in 10 s in the 5-150 keV band) to identify and localize 2000 GRBs over a five year mission, of which ∼65 GRBs have a redshift >7. The Cryogenic Imaging Spectrometer, with a spectral resolution of 2.5 eV, a field of view of 30 arcmin and large effective area below 1 keV has the sensitivity to study clusters up to a significant fraction of the virial radius and to map the denser parts of the WHIM (factor 30 higher than achievable with current instruments). The payload is complemented by a Burst InfraRed Telescope to enable onboard red-shift determination of GRBs (hence securing proper follow up of high-z bursts) and also probes the mildly ionized state of the gas. Fast repointing is achieved by a dedicated Controlled Momentum Gyro and a low background is achieved by the selected low Earth orbit. [ABSTRACT FROM AUTHOR]

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Objective:Recently a genome-wide association analysis from five European populations identified a polymorphism located downstream of the mannosyl-(α-1,3)-glycoprotein-β-1,2-N-acetylglucosaminyltransferase (MGAT1) gene that was associated with body-weight. In the present study, associations between MGAT1 variants combined with obesity and insulin measurements were investigated in three cohorts. Levels of fatty acids and estimated measures of Δ desaturases were also investigated among adult men.Design:Six polymorphisms downstream of MGAT1 were genotyped in a cross-sectional cohort of 1152 Swedish men. Three polymorphisms were further analyzed in a case-control study of 1076 Swedish children and in a cross-sectional study of 2249 Greek children.Results:Three polymorphisms, rs12186500 (odds ratio (OR): 1.892, 95% confidence interval (CI): 1.237-2.895, P=0.003), rs1021001 (OR: 2.102, 95% CI: 1.280-3.455, P=0.003) and rs4285184 (OR: 1.587, 95% CI: 1.024-2.459, P=0.038) were associated with a higher prevalence of obesity among the adult men and a trend for obesity was observed for rs4285184 among the Swedish (OR: 1.205, 95% CI: 0.987-1.471, P=0.067) and Greek children (OR: 1.192, 95%CI: 0.978-1.454, P=0.081). Association with body weight was observed for rs12186500 (P=0.017) and rs4285184 (P=0.024) among the men. The rs1021001 and rs4285184 were also associated with body mass index (BMI) in the two Swedish cohorts and similar trends were observed among the Greek children. The combined effect size for rs1021001 and rs4285184 on BMI z-score from a meta-analysis was 0.233 (95% CI:0.093-0.373, P=0.001) and 0.147 (95% CI:0.057-0.236, P=0.001), respectively. We further observed associations between the genetic variants and fatty acids (P<0.039) and estimated measures of Δ desaturases (P<0.040), as well as interactions for rs12186500 (P<0.019) with an effect on BMI. No association was found with homeostatic model assessment-insulin resistance in any cohort but increased insulin levels, insulin response and decreased insulin sensitivity were observed among the children (P<0.038).Conclusion:Genetic variants downstream MGAT1 seem to influence susceptibility to obesity. Moreover, these genetic variants affect the levels of serum unsaturated fatty acids and Δ desaturase indices, variables previously shown to correlate with obesity. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented regarding the presence of immunophenotypically heterogenous leukemic cell populations in B-cell precursor (BCP) acute lymphoblastic leukemia (ALL) in children.

We studied the incidence of craniopharyngioma in Denmark during the period 1985-2004 and estimated worldwide incidence rates (IR) of craniopharyngioma based on a literature review. Craniopharyngioma patients diagnosed during the period 1985-2004 were identified from the Danish National Patient Registry, the Danish Cancer Registry and regional registries. Medical records were reviewed. Danish population data were obtained from Statistics Denmark. European and World population data were obtained from EU and WHO homepages. Prior studies providing data on craniopharyngioma IRs were identified via PubMed and, if appropriate, were included in a weighted analysis estimating overall and children's IRs of craniopharyngioma. IRs are given as new cases per million per year. We identified 189 patients with new verified (162) or probable craniopharyngioma. The overall WHO World-standardised incidence rate was 1.86 (1.60-2.14) for all ages and 2.14 (1.53-2.92) for children (age <15 years). Peak incidence rates were observed in age groups 5-9 and 40-44 years. Fifteen prior studies (including 1,232 craniopharyngioma cases) were identified. Seven and 11 studies, respectively, were eligible for weighted all-ages and childhood population IR analyses, yielding summary IRs of 1.34 (1.24-1.46) (all ages) and 1.44 (1.33-1.56) (children). We have provided a detailed survey of the incidence of craniopharyngioma in Denmark during a recent 20-year period. Overall IR of craniopharyngioma in Denmark was 1.86 (1.60-2.14) as compared to 2.14 (1.53-2.92) among children. Weighted estimates of craniopharyngioma world IRs were 1.34 (1.24-1.46) in all ages and 1.44 (1.33-1.56) among children. [ABSTRACT FROM AUTHOR]

Quantitative PCR (qPCR) for detection of fusion transcripts and overexpressed genes is a promising tool for following minimal residual disease (MRD) in patients with hematological malignancies. Its widespread clinical use has to some extent been hampered by differences in data analysis and presentation that complicate multicenter clinical trials. To address these issues, we designed a highly flexible MRD-reporting software program, in which data from various qPCR platforms can be imported, processed, and presented in a uniform manner to generate intuitively understandable reports. The software was tested in a two-step quality control (QC) study; the first step involved eight centers, whose previous experience with the software ranged from none to extensive. The participants received cDNA from consecutive samples from a BCR-ABL+ chronic myeloid leukemia (CML) patient and an acute myeloid leukemia (AML) patient with both CBFβ-MYH11 and WT1 target genes, they conducted qPCR on their respective hardware platforms and generated a series of reports with pre-defined features. In step two, five centers used the software to report BCR-ABL+ MRD in a harmonized manner, applying their recently obtained CML international scale conversion factors. The QC study demonstrated that this MRD-reporting software is suitable for efficient handling of qPCR data, generation of MRD reports and harmonization of MRD data. [ABSTRACT FROM AUTHOR]

Neutral atoms stored in optical traps are strong candidates for a physical realization of a quantum logic device. Far off-resonance optical traps provide conservative potentials and excellent isolation from the environment, and they may be arranged to produce arbitrary arrays of traps, where each trap is occupied by a single atom that can be individually addressed. At present, significant effort is being expended on developing two-qubit gates based on coupling individual Rydberg atoms in adjacent optical microtraps. A major challenge associated with this approach is the reliable generation of single-atom occupancy in each trap, as the loading efficiency in the past experiments has been limited to 50% (refs 4, 7, 8, 10, 11, 12). Here we report a loading efficiency of 82.7% in an optical microtrap. We achieve this by manipulating the collisions between pairs of trapped atoms through tailored optical fields and directly observing the resulting single atoms in the trap. [ABSTRACT FROM AUTHOR]

Adiponectin, a protein classically known to be secreted by adipocytes, is also secreted by bone-forming cells. Results of previous studies have been contradictory as to whether serum adiponectin and bone mineral density (BMD) are associated. The aim of this study was to investigate a possible association between serum adiponectin and BMD in young, healthy men at a time of peak bone mass. BMD in the femoral neck, total hip, and lumbar spine were measured in this population-based cross-sectional study of 700 men aged 20–29 years participating in the Odense Androgen Study. Magnetic resonance imaging of femoral cortical thickness and bone marrow size was performed in a subsample of 363 participants. The associations between serum adiponectin and various bone measures were investigated by means of regression analyses with adjustment for potential confounding variables. An inverse association was found between serum adiponectin and total hip BMD and a direct between adiponectin and femoral bone marrow size ( r = −0.092; P = 0.036 and r = 0.164; P = 0.003, respectively). Femoral muscle size may, at least in part, explain the association between adiponectin and total hip BMD. Serum adiponectin was inversely associated with total hip BMD in men at the time of peak bone mass, but this association may be explained by factors related to muscle size and function. The observed association between adiponectin and femoral bone marrow size was retained even after adjustment for potential covariates. [ABSTRACT FROM AUTHOR]

Although childhood high hyperdiploid acute lymphoblastic leukemia is associated with a favorable outcome, 20% of patients still relapse. It is important to identify these patients already at diagnosis to ensure proper risk stratification. We have investigated 11 paired diagnostic and relapse samples with single nucleotide polymorphism array and mutation analyses of FLT3, KRAS, NRAS and PTPN11 in order to identify changes associated with relapse and to ascertain the genetic evolution patterns. Structural changes, mainly cryptic hemizygous deletions, were significantly more common at relapse (P<0.05). No single aberration was linked to relapse, but four deletions, involving IKZF1, PAX5, CDKN2A/B or AK3, were recurrent. On the basis of the genetic relationship between the paired samples, three groups were delineated: (1) identical genetic changes at diagnosis and relapse (2 of 11 cases), (2) clonal evolution with all changes at diagnosis being present at relapse (2 of 11) and (3) clonal evolution with some changes conserved, lost or gained (7 of 11), suggesting the presence of a preleukemic clone. This ancestral clone was characterized by numerical changes only, with structural changes and RTK-RAS mutations being secondary to the high hyperdiploid pattern. [ABSTRACT FROM AUTHOR]

The article presents a study related to the treatment of hematological malignancies. It is stated that an important mechanism of action of allogeneic hematopoietic cell transplantation (HCT) is the graft versus leukemia (GVL) effect. As stated, minor histocompatibility antigen (mHag) may be encoded on the Y chromosome or be derived from single nucleotide polymorphisms (SNP).

Aim The aim of this study was to evaluate if Urine Cytology (UC) is an appropriate screening procedure for detecting urinary tract neoplasia at an early stage in persons at risk in Hereditary Non-Polyposis Colorectal Cancer families. Method In the National Danish HNPCC-register persons at risk were identified in three categories of HNPCC-families (1) families harbouring a disease causing mutation in a Mismatch repair gene (MMR), (2) families fulfilling the Amsterdam I or II criteria and (3) families suspected of HNPCC. In total 3,411 persons were identified and traced in Patobank—the National Danish Pathology database. All UC and UTC (Urinary Tract Tumours) were listed and evaluated. Results 977 persons had a total of 1,868 screening procedures performed. Two of these procedures (0.1%) lead to diagnosis of an asymptomatic urothelial tumour. In ten times as many procedures (22 persons) UC lead to a false positive screening diagnosis. During the study period fourteen persons (1.4%) developed a UTC and five of these were interval tumours. The sensitivity of UC in diagnosing asymptomatic UTC in HNPCC patients was 29%. Twelve of the tumours were found in persons from families with a proven MMR-mutation and eleven out of these were MSH2 mutations (92%, 95% cl 62–100%). Discussion UC is not a proper method of screening for UTC in HNPCC. However, the study can not reveal if screening for UTC in special families ought to be recommended. Consequently, further studies needs to be performed in order to evaluate an appropriate screening programme. [ABSTRACT FROM AUTHOR]

Quantitative assessment of the JAK2 V617F allele burden during disease evolution and ongoing myelosuppressive treatment is likely to be implemented in the future clinical setting. Interferon alpha has demonstrated efficacy in treatment of both chronic myeloid leukemia and the Philadelphia chromosome negative chronic myeloproliferative disorders. Reductions in the JAK2 V617F allele burden in patients treated with pegylated interferon alpha-2a (Peg-IFN-2a) have been demonstrated, although follow-up was relatively short. We report here the first profound and sustained molecular responses with a JAK2 V617F allele burden below 1.0% in two patients with polycythemia vera treated with interferon alpha-2b (IFN-2b). Discontinuation of IFN-2b in one of the patients was followed by a sustained long-lasting (12 months of follow-up) major molecular response. [ABSTRACT FROM AUTHOR]

The article discusses the role of allogeneic hematopoietic cell transplantation (HCT) in treating hematologic malignancies. It says that HCT represents a potentially curative treatment for several hematologic malignancies. Meanwhile, the curative principle in allogeneic HCT with NMA conditioning is solely related to the graft-versus-leukemia (GVL) effect, and several lines of evidence strongly suggest that donor T cells are the main effectors.

Purpose: To investigate the impact of the Ala1330Val (rs3736228, exon 18) and Val667Met (rs4988321, exon 9) polymorphisms of the low-density lipoprotein receptor-related protein 5 (LRP5) gene on peak bone mass in young men.Methods: The Odense Androgen Study (OAS) is a population-based study comprising 783 Caucasian men aged 20-30 years. Genotyping was performed using real-time polymerase chain reaction (PCR) or fluorescence polarization. Bone mineral density (BMD) measurements were performed using dual-energy X-ray absorptiometry.Results: The CC, CT, and TT genotypes in Ala1330Val were found in 75.6%, 21.8%, and 2.6% of the participants, respectively. Similarly, the GG, GA, and AA genotypes of Val667Met were found in 89.7%, 9.8%, and 0.5%, respectively. For the Ala1330Val polymorphism, no significant differences between the genotypes were found regarding BMD in the overall study population. However, when analysis was restricted to non-sedentary men (n = 589), a significant association between the number of T-alleles and BMD in the spine and whole body were found. Each copy of the T-allele changed the Z-score of the spine by (median and 95% confidence interval) -0.21 [95% CI: -0.40; -0.03] (p < 0.02). Analysis suggested an association between the AA genotype in the Val667Met polymorphism and increased body height and decreased BMD of the femoral neck; however, no significant gene-dose effect of the A-allele could be demonstrated in the whole population. When the analysis was restricted to non-sedentary subjects, however, each number of A-alleles was associated with a change in Z-score of -0.26 [95% CI: -0.51; -0.01] (p = 0.04). No further significant results emerged with haplotype analysis.Conclusion: The Ala1330Val and Val667Met polymorphisms in the LRP5 gene are significantly associated with peak bone mass in physically active men. [ABSTRACT FROM AUTHOR]