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.

Estimating total cross sections from neutron-nucleus collisions using a simple functional form

Total cross sections for neutron scattering from nuclei, with energies ranging from 10 to 600 MeV and from many nuclei spanning the mass range 6Li to 238U, have been analyzed using a simple, three-parameter, functional form. The calculated cross sections are compared with results obtained by using microscopic (g-folding) optical potentials as well as with experimental data. The functional form reproduces those total cross sections very well. When allowance is made for Ramsauer-like effects in the scattering, the parameters of the functional form required vary smoothly with energy and target mass. They too can be represented by functions of energy and mass.

Truck overloading study in developing countries and strategies to minimize its impact

Overloading truck traffic is an untenable problem around the world. The occurrence of overloaded truck traffic can be evidence of rapid development of an economy. Most of the developing countries emphasize the development of economy, thus supporting reform of infrastructure is limited. This research investigates the relationship between truck overloading and the condition of road damage. The objective of this research is to determine the amount of economic loss due to overloaded truck traffic is. Axle load will be used to calculate the total ESAL to pavement. This study intends to provide perspective on the relationship between change in axle load due to overloading and the resultant service life of pavement. It can then be used in the estimation of pavement damage in other developing countries facing the problem of truck overloading. In conclusion, economical loss was found, which include reduction of pavement life and increase in maintenance and rehabilitation (M&R) cost. As a result, net present value (NPV) of pavement investment with overloading truck traffic is higher than normal truck traffic.

Current evidence on integrated treatment for serious mental disorder and substance misuse

Substance misuse in people with serious mental disorders is common and has a wideranging negative impact. The multiplicity of problems suggests that this comorbidity is better conceptualized as a type of complex disorder than by ‘dual diagnosis’. Problems with sequential and parallel treatments have led to the development of integrated approaches, with one practitioner or team addressing both the substance use and mental disorder. These treatments are typically characterized by motivation enhancement, minimizing treatment-related stress, emphasizing harm reduction as well as abstinence, and assertive outreach. A review of published randomized trials demonstrates that superior effects to controls are rarely consistent across treatment foci and over time. While motivational interventions assist engagement, more intervention is usually required for integrated treatment programs to improve long-term outcomes more than control conditions. More intensive case management does not consistently improve impact, but extended cognitive-behavioral therapies have promise. Suggestions for maximizing treatment effects and improving research evidence are provided.

Challenges in implementing evidence-based practice into mental health services

This paper highlights challenges in implementing mental health policy at a service delivery level. It describes an attempt to foster greater application of recovery-orientated principles and practices within mental health services. Notwithstanding a highly supportive policy environment, strong support from service administrators, and an enthusiastic staff response to training, application of the training and support tools was weaker than anticipated. This paper evaluates the dissemination trial against key elements to promote sustained adoption of innovations. Organisational and procedural changes are required before mental health policies are systematically implemented in practice.

The prognostic significance of quality of life following breast cancer [Conference Abstract]

Introduction: Evidence suggests a positive association between quality of life (QOL). and overall survival(OS). among metastatic breast cancer (BC). patients, although the relationship in early-stage BC is unclear. This work examines the association between QOL and OS following a diagnosis of early-stage BC. ----- Methods: A population-based sample of Queensland women (n=287). with early-stage, invasive, unilateral BC, were prospectively observed for a median of 6.6 years. QOL was assessed at six and 18 months post-diagnosis using the Functional Assessment of Cancer Therapy, Breast FACT-B+4. questionnaire. Raw scores for the FACT-B+4 scales were computed and individuals were categorised according to whether QOL declined, remained stable or improved over time. OS was measured from the date of diagnosis to the date of death or was censored at the date of last follow-up. Risk ratios (RR) and 95% confidence intervals (CI). for the association between QOL and OS were obtained using Cox proportional hazards survival models adjusted for confounding characteristics. ----- Results: A total of 27 (9.4%). women died during the follow-up period. Three baseline QOL scales (emotional, general and overall QOL) were significantly associated with OS, with RRs ranging between 0.89 95% CI: 0.81, 0.98; P=0.01. and 0.98 (95% CI: 0.96, 0.99; P=0.03),indicating a 2%-11% reduced risk of death for every one unit increase in QOL. When QOL was categorised according to changes between six and 18 months post-diagnosis, analyses showed that for those who experienced declines in functional and physical QOL, risk of death increased by two- (95% CI: 1.43, 12.52; P<0.01) and four-fold (95% CI: 1.15, 7.19; P=0.02), respectively. Conclusions: This work indicates that specific QOL scales at six months post-diagnosis, and changes in certain QOL scales over the subsequent 12-month period (as measured by the FACT-B+4), are associated with overall survival in women with early-stage breast cancer.

Levelling expectations across different years in an undergraduate degree to support work-related learning : evidence for a multi-pronged approach.

One of the ways in which university departments and faculties can enhance the quality of learning and assessment is to develop a ‘well thought out criterion‐referenced assessment system’ (Biggs, 2003, p. 271). In designing undergraduate degrees (courses) this entails making decisions about the levelling of expectations across different years through devising objectives and their corresponding criteria and standards: a process of alignment analogous to what happens in unit (subject) design. These decisions about levelling have important repercussions in terms of supporting students’ work‐related learning, especially in relation to their ability to cope with the increasing cognitive and skill demands made on them as they progress through their studies. They also affect the accountability of teacher judgments of students’ responses to assessment tasks, achievement of unit objectives and, ultimately, whether students are awarded their degrees and are sufficiently prepared for the world of work. Research reveals that this decision‐making process is rarely underpinned by an explicit educational rationale (Morgan et al, 2002). The decision to implement criterion referenced assessment in an undergraduate microbiology degree was the impetus for developing such a rationale because of the implications for alignment, and therefore ‘levelling’ of expectations across different years of the degree. This paper provides supporting evidence for a multi‐pronged approach to levelling, through backward mapping of two revised units (foundation and exit year). This approach adheres to the principles of alignment while combining a work‐related approach (via industry input) with the blended disciplinary and learner‐centred approaches proposed by Morgan et al. (2002). It is suggested that this multi‐pronged approach has the potential for making expectations, especially work‐related ones across different year levels of degrees, more explicit to students and future employers.

The Influence of Farm Management on NSW Rural Property Income and Total Average Annual Returns

The importance of agriculture in many countries has tended to reduce as their economies move from a resource base to a manufacturing industry base. Although the level of agricultural production in first world countries has increased over the past two decades, this increase has generally been at a less significant rate compared to other sectors of the economies. Despite this increase in secondary and high technology industries, developed countries have continued to encourage and support their agricultural industries. This support has been through both tariffs and price support. Following pressure from developing economies, particularly through the World Trade Organisation (WTO), GATT Uruguay round and the Cairns Group developed countries are now in various stages of winding back or de-coupling agricultural support within their economies. A major concern of farmers in protected agricultural markets is the impact of a free market trade in agricultural commodities on farm incomes, profitability and land values. This paper will analyse both the capital and income performance of the NSW rural land market over the period 1990-1999. This analysis will be based on several rural land use classifications and will compare the total return from rural properties based on the farm income generated by both the average farmer and those farmers considered to be in the top 20% of the various land use areas. The analysis will provide a comprehensive overview of rural production in a free trade economy.

Total rural land performance in a free trade economy

The importance of agriculture in many countries has tended to reduce as their economies move from a resource base to a manufacturing industry base. Although the level of agricultural production in first world countries has increased over the past two decades, this increase has generally been at a less significant rate compared to other sectors of the economies. Despite this increase in secondary and high technology industries, developed countries have continued to encourage and support their agricultural industries. This support has been through both tariffs and price support. Following pressure from developing economies, particularly through the World Trade Organisation (WTO), GATT Uruguay round and the Cairns Group Developed countries are now in various stages of winding back or de-coupling agricultural support within their economies. A major concern of farmers in protected agricultural markets is the impact of a free market trade in agricultural commodities on farm incomes and land values. This paper will analyse the capital and income performance of the NSW rural land market over the period 1990-1999. This analysis will be based on land use and will compare the total return from rural properties based on world agricultural commodity prices.

Age-related development of a refractive index plateau in the human lens : evidence for a distinct nucleus

The human lens comprises two distinct regions in which the refractive index changes at different rates. The periphery contains a rapidly increasing refractive index gradient, which becomes steeper with age. The inner region contains a shallow gradient, which flattens with age, due to formation of a central plateau, of RI = 1.418, which reaches a maximum size of 7.0 × 3.05 mm around age 60 years. Formation of the plateau can be attributed to compression of fibre cells generated in prenatal life. Present in prenatal but not in postnatal fibre cells, γ-crystallin may play a role in limiting nuclear cell compression.

Sampling perceptions; testing reality : an evidence-based approach to measurably improve information literacy and student research skills

Do commencing students possess the level of information literacy (IL) knowledge and skills they need to succeed at university? What impact does embedding IL within the engineering and design curriculum have? This paper reports on the self-perception versus the reality of IL knowledge and skills, across a large cohort of first year built environment and engineering students. Acting on the findings of this evaluation, the authors (a team of academic librarians) developed an intensive IL skills program which was integrated into a faculty wide unit. Perceptions, knowledge and skills were re-evaluated at the end of the semester to determine if embedded IL education made a difference. Findings reveal that both the perception and reality of IL skills were significantly and measurably improved.

Clinical supervision in four mental health professions : a review of the evidence

Examines a range of theoretical issues and the empirical evidence relating to clinical supervision in 4 mental health professions: clinical psychology, occupational therapy, social work, and speech pathology. There is widespread acceptance of the value of supervision among practitioners and a large quantity of literature on the topic, but there is very little empirical evidence in this area. To date, there is insufficient evidence to demonstrate which styles of supervision are most beneficial for particular types of staff, in terms of their level of experience or learning style. The data suggest that directive forms of supervision, rather than unstructured approaches, are preferred by relatively inexperienced practitioners, and that experienced clinicians also value direct supervision methods when learning new skills or dealing with complex or crisis situations. The available evidence suggests that supervisors typically receive little training in supervision methods. However, there is little information to guide us as to the most effective ways of training supervisors. While acknowledging the urgent need for research, this paper concludes that supervision is likely to form a valuable component of professional development for mental health professionals.

Further evidence for a deficit in switching attention in schizophrenia

In this study, sustained, selective, divided, and switching attention, and reloading of working memory were investigated in schizophrenia by using a newly developed Visual Attention Battery (VAB). Twenty-four outpatients with schizophrenia and 24 control participants were studied using the VAB. Performance on VAB components was correlated with performance of standard tests. Patients with schizophrenia were significantly impaired on VAB tasks that required switching of attention and reloading of working memory but had normal performance on tasks involving sustained attention or attention to multiple stimulus features. Switching attention and reloading of working memory were highly correlated with Trails (B - A) score for patients. The decline in performance on the switching-attention task in patients with schizophrenia met criteria for a differential deficit in switching attention. Future research should examine the neurophysiological basis of the switching deficit and its sensitivity and specificity to schizophrenia.

Evidence-based decision making to strengthen local governance : nutritional health interventions in Bantul and Gunungkidul

Since 2001, district governments have had the main responsibility for providing public health care in Indonesia. One of the main public health challenges facing many district governments is improving nutritional standards, particularly among poorer segments of the population. Developing effective policies and strategies for improving nutrition requires a multi-sectoral approach encompassing agricultural development policy, access to markets, food security (storage) programs, provision of public health facilities, and promotion of public awareness of nutritional health. This implies a strong need for a coordinated approach involving multiple government agencies at the district level. Due to diverse economic, agricultural, and infrastructure conditions across the country, district governments’ ought to be better placed than central government both to identify areas of greatest need for public nutrition interventions, and devise policies that reflect local characteristics. However, in the two districts observed in this study—Bantul and Gunungkidul—it was clear that local government capacity to generate, obtain and integrate evidence about local conditions into the policy-making process was still limited. In both districts, decision-makers tended to rely more on intuition,anecdote, and precedent in formulating policy. The potential for evidence-based decision making was also severely constrained by a lack of coordination and communication between agencies, and current arrangements related to central government fiscal transfers, which compel local governments to allocate funding to centrally determined programs and priorities.

Evidence based decision making to strenghten local governance : nutritional health interventions

Since 2001, district governments have had the main responsibility for providing public health care in Indonesia. One of the main public health challenges facing many district governments is improving nutritional standards, particularly among poorer segments of the population. Developing effective policies and strategies for improving nutrition requires a multi-sectoral approach encompassing agricultural development policy, access to markets, food security (storage) programs, provision of public health facilities, and promotion of public awareness of nutritional health. This implies a strong need for a coordinated approach involving multiple government agencies at the district level. Due to diverse economic, agricultural,and infrastructure conditions across the country, district governments’ ought to be better placed than central government both to identify areas of greatest need for public nutrition interventions, and devise policies that reflect local characteristics. However, in the two districts observed in this study—Bantul and Gunungkidul—it was clear that local government capacity to generate, obtain and integrate evidence about local conditions into the policy-making process was still limited. In both districts, decision-makers tended to rely more on intuition,anecdote, and precedent in formulating policy. The potential for evidence-based decision making was also severely constrained by a lack of coordination and communication between agencies, and current arrangements related to central government fiscal transfers, which compel local governments to allocate funding to centrally determined programs and priorities.