The genetic basis of human height : the role of estrogen

Height is a complex physical trait that displays strong heritability. Adult height is related to length of the long bones, which is determined by growth at the epiphyseal growth plate. Longitudinal bone growth occurs via the process of endochondral ossification, where bone forms over the differentiating cartilage template at the growth plate. Estrogen plays a major role in regulating longitudinal bone growth and is responsible for inducing the pubertal growth spurt and fusion of the epiphyseal growth plate. However, the mechanism by which estrogen promotes epiphyseal fusion is poorly understood. It has been hypothesised that estrogen functions to regulate growth plate fusion by stimulating chondrocyte apoptosis, angiogenesis and bone cell invasion in the growth plate. Another theory has suggested that estrogen exposure exhausts the proliferative capacity of growth plate chondrocytes, which accelerates the process of chondrocyte senescence, leading to growth plate fusion. The overall objective of this study was to gain a greater understanding of the molecular mechanisms behind estrogen-mediated growth and height attainment by examining gene regulation in chondrocytes and the role of some of these genes in normal height inheritance. With the heritability of height so well established, the initial hypothesis was that genetic variation in candidate genes associated with longitudinal bone growth would be involved in normal adult height variation. The height-related genes FGFR3, CBFA1, ER and CBFA1 were screened for novel polymorphisms using denaturing HPLC and RFLP analysis. In total, 24 polymorphisms were identified. Two SNPs in ER (rs3757323 C>T and rs1801132 G>C) were strongly associated with adult male height and displayed an 8 cm and 9 cm height difference between homozygous genotypes, respectively. The TC haplotype of these SNPs was associated with a 6 cm decrease in height and remarkably, no homozygous carriers of the TC haplotype were identified in tall subjects. No significant associations with height were found for polymorphisms in the FGFR3, CBFA1 or VDR genes. In the epiphyseal growth plate, chondrocyte proliferation, matrix synthesis and chondrocyte hypertrophy are all major contributors to long bone growth. As estrogen plays such a significant role in both growth and final height attainment, another hypothesis of this study was that estrogen exerted its effects in the growth plate by influencing chondrocyte proliferation and mediating the expression of chondrocyte marker genes. The examination of genes regulated by estrogen in chondrocyte-like cells aimed to identify potential regulators of growth plate fusion, which may further elucidate mechanisms involved in the cessation of linear growth. While estrogen did not dramatically alter the proliferation of the SW1353 cell line, gene expression experiments identified several estrogen regulated genes. Sixteen chondrocyte marker genes were examined in response to estrogen concentrations ranging from 10-12 M to 10-8 M over varying time points. Of the genes analysed, IHH, FGFR3, collagen II and collagen X were not readily detectable and PTHrP, GHR, ER, BMP6, SOX9 and TGF1 mRNAs showed no significant response to estrogen treatments. However, the expression of MMP13, CBFA1, BCL-2 and BAX genes were significantly decreased. Interestingly, the majority of estrogen regulated genes in SW1353 cells are expressed in the hypertrophic zone of the growth plate. Estrogen is also known to regulate systemic GH secretion and local GH action. At the molecular level, estrogen functions to inhibit GH action by negatively regulating GH signalling. GH treated SW1353 cells displayed increases in MMP9 mRNA expression (4.4-fold) and MMP13 mRNA expression (64-fold) in SW1353 cells. Increases were also detected in their respective proteins. Treatment with AG490, an established JAK2 inhibitor, blocked the GH mediated stimulation of both MMP9 and MMP13 mRNA expression. The application of estrogen and GH to SW1353 cells attenuated GH-stimulated MMP13 levels, but did not affect MMP9 levels. Investigation of GH signalling revealed that SW1353 cells have high levels of activated JAK2 and exposure to GH, estrogen, AG490 and other signalling inhibitors did not affect JAK2 phosphorylation. Interestingly, AG490 treatment dramatically decreased ERK2 signalling, although GH did stimulate ERK2 phosphorylation above control levels. AG490 also decreased CBFA1 expression, a transcription factor known to activate MMP9 and MMP13. Finally, GH and estrogen treatment increased expression of SOCS3 mRNA, suggesting that SOCS3 may regulate JAK/STAT signalling in SW1353 cells. The modulation of GH-mediated MMP expression by estrogen in SW1353 cells represents a potentially novel mechanism by which estrogen may regulate longitudinal bone growth. However, further investigation is required in order to elucidate the precise mechanisms behind estrogen and GH regulation of MMP13 expression in SW1353 cells. This study has provided additional evidence that estrogen and the ER gene are major factors in the regulation of growth and the determination of adult height. Newly identified polymorphisms in the ER gene not only contribute to our understanding of the genetic basis of human height, but may also be useful in association studies examining other complex traits. This study also identified several estrogen regulated genes and indicated that estrogen modifies the expression of genes which are primarily expressed in the hypertrophic region of the epiphyseal growth plate. Furthermore, synergistic studies incorporating GH and estrogen have revealed the ability of estrogen to attenuate the effects of GH on MMP13 expression, revealing potential pathways by which estrogen may modulate growth plate fusion, longitudinal bone growth and even arthritis.

Incomplete pregnancy and risk of ovarian cancer : results from two Australian case-control studies and systematic review

Although full-term pregnancies reduce the risk of ovarian cancer, it has not been conclusively established whether incomplete pregnancies also influence risk. We investigated the relationship between a history of incomplete pregnancy and incident epithelial ovarian cancer among over 4,500 women who participated in two large Australian population-based case-control studies in 1990-1993 and 2002-2005. They provided responses to detailed questions about their reproductive histories and other personal factors. Summary odds ratios (OR) and confidence intervals (CI) derived from each study using the same covariates were aggregated. We found no significant associations between the number of incomplete pregnancies and ovarian cancer, for parous (OR = 0.98, 95% CI: 0.89, 1.08) or nulliparous (OR = 1.06, 95% CI: 0.75, 1.48) women, nor for the number of spontaneous or induced abortions and ovarian cancer for parous women (OR = 0.95, 95% CI 0.82, 1.09; OR = 1.08, 95% CI: 0.86, 1.36) or nulliparous women (OR = 1.2, 95% CI: 0.6, 2.4; OR = 0.8, 95% CI: 0.47, 1.38), respectively. A systematic review of 37 previous studies of the topic confirmed our findings that a history of incomplete pregnancy does not influence a woman’s risk of epithelial ovarian cancer.

Multi-vehicles interaction graph model for cooperative collision warning system

Cooperative collision warning system for road vehicles, enabled by recent advances in positioning systems and wireless communication technologies, can potentially reduce traffic accident significantly. To improve the system, we propose a graph model to represent interactions between multiple road vehicles in a specific region and at a specific time. Given a list of vehicles in vicinity, we can generate the interaction graph using several rules that consider vehicle's properties such as position, speed, heading, etc. Safety applications can use the model to improve emergency warning accuracy and optimize wireless channel usage. The model allows us to develop some congestion control strategies for an efficient multi-hop broadcast protocol.

Nursing students’ knowledge and practice of infection control precautions : an educational intervention

Aim. This paper is a report of the effectiveness of a purpose-designed education program in improving undergraduate nursing students’ understanding and practice of infection control precautions. Background. The severe acute respiratory syndrome outbreak in 2003 highlighted that healthcare workers were under-prepared for such an epidemic. While many in-service education sessions were arranged by institutions in response to the outbreak, preservice nursing education has overlooked preparation for handling such infectious disease epidemics. Method. A quasi-experimental design was used and a 16-hour, purpose-designed infection control education programme was implemented for preservice nursing students in southern Taiwan. Self-administered questionnaires were distributed at three time points during the period September 2005 to April 2006 to examine the sustainability and effectiveness of the intervention. Results. A total of 175 preservice nursing students participated in the study. Following the education programme, students in the intervention group showed a statistically significant improvement across time in their knowledge of these precautions [F(2, 180) = 13Æ53, P < 0Æ001] and confidence in resolving infectionrelated issues [F(1Æ79, 168Æ95) = 3Æ24] when compared with those in the control group. Conclusion. To improve nursing students’ capacity in responding to infectious epidemics, an educational programme that integrates the theme of infection precautions, learning theory and teaching strategies is recommended for all nursing institutes.

Application of Dynamic Hysteresis Band Height Control to Improve Output Voltage Transient in Boost and Positive Buck-Boost Converters

This paper presents dynamic hysteresis band height control to reduce the overshoot and undershoot issue on output voltage caused by load change. The converters in this study are Boost and Positive Buck-Boost (PBB) converters. PBB has been controlled to work in a step up conversion and avoid overshoot when load is changed. Simulation and experimental results have been presented to verify the proposed method.

Modernity and the 'failure' of crime control

Rather than understanding the recurrent failure of various attempts at crime control as unfortunate and undesirable aberrations, all too familiar glitches an otherwise uninterrupted teleological march to a better society, such failures are instead positioned as part of the fabric of late modernity itself. That is, society changes not according to a predetermined logic along neatly defined and clearly reasoned tracks, rather it hurtles from crisis to crisis, from failure to failure, and it is the regulation of that failure which produces new initiatives and new forms of governance. Utilising the example of the modern prison, this chapter contends that too great an emphasis upon this institution’s ‘failure’ results not only in a neglect of the many other functions that it serves in the regulation of difference, but also, and more generally, it results in an underestimation of the importance of failure in providing new impetus for social transformation.

Hard Lessons : Reflections on Governance and Crime Control in Late Modernity

The essays in this book catalogue a wide and varied range of instances where 'things go wrong' in the practice of criminal justice. The contributions document instances where laws, policies and practices have produced unintended consequences of the most deleterious kind, drawing attention to 'boot camps', detention centres and specific penal policies such as 'short, sharp shock' and 'three strikes and you're out'. Also examined are policing practices such as 'zero tolerance', 'saturation policing' and punitive laws in the area of drug use, sex offences, and prostitution. It will be demonstrated that in each of these cases, the objectives of government resulted in the creation of new and unforeseen problems requiring further reform to the justice system.

Prediction of adherence and control in diabetes

This study aims to predict adherence to diabetic treatment regimens and sustained diabetic control. During two clinic visits that were 2 months apart, 63 adult outpatients completed measures of diabetic history, current treatment, diabetic control, adherence, and self-efficacy about adherence to treatment. Results showed that self-efficacy was a significant predictor of later adherence to diabetes treatment even after past levels of adherence were taken into account. Posttest levels of adherence in turn were significantly associated with posttest %HbA1c after control for illness severity. A stepwise multiple regression to predict %HbAlc at post entered pretest measures of diabetic control, treatment type, and self-efficacy, which together predicted 50% of the variance. Results are related to self-efficacy theory and implications for practice are discussed.

In search of a hidden long-term isolated sub-chondritic 142Nd/144Nd reservoir in the deep mantle : implications for the Nd isotope systematics of the Earth

Here we search for evidence of the existence of a sub-chondritic 142Nd/144Nd reservoir that balances the Nd isotope chemistry of the Earth relative to chondrites. If present, it may reside in the source region of deeply sourced mantle plume material. We suggest that lavas from Hawai’i with coupled elevations in 186Os/188Os and 187Os/188Os, from Iceland that represent mixing of upper mantle and lower mantle components, and from Gough with sub-chondritic 143Nd/144Nd and high 207Pb/206Pb, are favorable samples that could reflect mantle sources that have interacted with an Early-Enriched Reservoir (EER) with sub-chondritic 142Nd/144Nd. High-precision Nd isotope analyses of basalts from Hawai’i, Iceland and Gough demonstrate no discernable 142Nd/144Nd deviation from terrestrial standards. These data are consistent with previous high-precision Nd isotope analysis of recent mantle-derived samples and demonstrate that no mantle-derived material to date provides evidence for the existence of an EER in the mantle. We then evaluate mass balance in the Earth with respect to both 142Nd/144Nd and 143Nd/144Nd. The Nd isotope systematics of EERs are modeled for different sizes and timing of formation relative to ε143Nd estimates of the reservoirs in the μ142Nd = 0 Earth, where μ142Nd is ((measured 142Nd/144Nd/terrestrial standard 142Nd/144Nd)−1 * 10−6) and the μ142Nd = 0 Earth is the proportion of the silicate Earth with 142Nd/144Nd indistinguishable from the terrestrial standard. The models indicate that it is not possible to balance the Earth with respect to both 142Nd/144Nd and 143Nd/144Nd unless the μ142Nd = 0 Earth has a ε143Nd within error of the present-day Depleted Mid-ocean ridge basalt Mantle source (DMM). The 4567 Myr age 142Nd–143Nd isochron for the Earth intersects μ142Nd = 0 at ε143Nd of +8 ± 2 providing a minimum ε143Nd for the μ142Nd = 0 Earth. The high ε143Nd of the μ142Nd = 0 Earth is confirmed by the Nd isotope systematics of Archean mantle-derived rocks that consistently have positive ε143Nd. If the EER formed early after solar system formation (0–70 Ma) continental crust and DMM can be complementary reservoirs with respect to Nd isotopes, with no requirement for significant additional reservoirs. If the EER formed after 70 Ma then the μ142Nd = 0 Earth must have a bulk ε143Nd more radiogenic than DMM and additional high ε143Nd material is required to balance the Nd isotope systematics of the Earth.

Multi-criteria ranking and source apportionment of fine particulate matter in Brisbane, Australia

This paper reports the application of multicriteria decision making techniques, PROMETHEE and GAIA, and receptor models, PCA/APCS and PMF, to data from an air monitoring site located on the campus of Queensland University of Technology in Brisbane, Australia and operated by Queensland Environmental Protection Agency (QEPA). The data consisted of the concentrations of 21 chemical species and meteorological data collected between 1995 and 2003. PROMETHEE/GAIA separated the samples into those collected when leaded and unleaded petrol were used to power vehicles in the region. The number and source profiles of the factors obtained from PCA/APCS and PMF analyses were compared. There are noticeable differences in the outcomes possibly because of the non-negative constraints imposed on the PMF analysis. While PCA/APCS identified 6 sources, PMF reduced the data to 9 factors. Each factor had distinctive compositions that suggested that motor vehicle emissions, controlled burning of forests, secondary sulphate, sea salt and road dust/soil were the most important sources of fine particulate matter at the site. The most plausible locations of the sources were identified by combining the results obtained from the receptor models with meteorological data. The study demonstrated the potential benefits of combining results from multi-criteria decision making analysis with those from receptor models in order to gain insights into information that could enhance the development of air pollution control measures.

Dual-process action of exercise on appetite control : increase in orexigenic drive but improvement in meal-induced satiety

Background: Exercise could contribute to weight loss by altering the sensitivity of the appetite regulatory system. Objective: The aim of this study was to assess the effects of 12 wk of mandatory exercise on appetite control. Design: Fifty-eight overweight and obese men and women [mean (±SD) body mass index (in kg/m2) = 31.8 ± 4.5, age = 39.6 ± 9.8 y, and maximal oxygen intake = 29.1 ± 5.7 mL · kg–1 · min–1] completed 12 wk of supervised exercise in the laboratory. The exercise sessions were designed to expend 2500 kcal/wk. Subjective appetite sensations and the satiating efficiency of a fixed breakfast were compared at baseline (week 0) and at week 12. An Electronic Appetite Rating System was used to measure subjective appetite sensations immediately before and after the fixed breakfast in the immediate postprandial period and across the whole day. The satiety quotient of the breakfast was determined by calculating the change in appetite scores relative to the breakfast's energy content. Results: Despite large variability, there was a significant reduction in mean body weight (3.2 ± 3.6 kg), fat mass (3.2 ± 2.2 kg), and waist circumference (5.0 ± 3.2 cm) after 12 wk. The analysis showed that a reduction in body weight and body composition was accompanied by an increase in fasting hunger and in average hunger across the day (P < 0.0001). Paradoxically, the immediate and delayed satiety quotient of the breakfast also increased significantly (P < 0.05). Conclusions: These data show that the effect of exercise on appetite regulation involves at least 2 processes: an increase in the overall (orexigenic) drive to eat and a concomitant increase in the satiating efficiency of a fixed meal.

Bifocal lens control of myopia progression in children

This research investigated underlying issues that were critical to the success of the bifocal trial and comprised of three studies. The first study evaluated if Chinese-Canadian children were suitable subjects for the bifocal trial. The high prevalence of myopia in Chinese children suggests that genetic input plays a role in myopia development, but the rapid increase in prevalence over the last few decades indicates environmental factors are also important. Since this bifocal trial was conducted in Canada, this work aimed to determine whether Chinese children who had migrated to Canada would still have high myopia prevalence and a high rate of myopia progression. The second study determined the optimal bifocal lens power for myopia treatment and the effect of incorporating base-in prism into the bifocal. In the majority of published myopia control studies, the power of the prescribed near addition was usually predetermined in the belief that the near addition would always help to improve the near focus. In fact, the effect of near addition on the accommodative error might be quite different even for individuals in which the same magnitude of accommodation lag had been measured. Therefore, this work was necessary to guide the selection of bifocal and prism powers most suitable for the subsequent bifocal trial. The third study, the ultimate goal of this research, was to conduct a longitudinal clinical trial to determine if bifocals and prismatic bifocals could control myopia progression in children.