Analysis of existing mathematics textbooks for use in secondary schools.

Thesis (Ed.M.)--Boston University Thesis (M.A.)--Boston Universit

Vitamin D measurement, the debates continue, new analytes have emerged, developments have variable outcomes

The demand for measurement of vitamin D metabolites for clinical diagnosis and to advance our understanding of the role of vitamin D in human health has significantly increased in the last decade. New developments in technologies employed have enabled the separation and quantification of additional metabolites and interferences. Also, developments of immunoassays have changed the landscape. Programmes and materials for assay standardisation, harmonisation and the expansion of the vitamin D external quality assurance scheme (DEQAS) with the provision of target values as measured by a reference measurement procedure have improved standardisation, quality assurance and comparability of measurements. In this article, we describe developments in the measurement of the commonly analysed vitamin D metabolites in clinical and research practice. We describe current analytical approaches, discuss differences between assays, their origin, and how these may be influenced by physiological and experimental conditions. The value of measuring metabolites beyond 25 hydroxyvitamin D (25(OH)D), the marker of vitamin D status, in routine clinical practice is not yet confirmed. Here we provide an overview of the value and application of the measurement of 1,25 dihydroxyvitamin D, 24,25 dihydroxyvitamin D and free 25OHD in the diagnosis of patients with abnormalities in vitamin D metabolism and for research purposes

Reference intervals for serum 24,25-Dihydroxyvitamin D and the ratio with 25-Hydroxyvitamin established using a newly developed LC-MS/MS method

24,25(OH)2D is the product of 25(OH)D catabolism by CYP24A1.The measurement of serum 24,25(OH)2D concentration may serve as an indicator of vitamin D catabolic status and the relative ratio with 25(OH)D can be used to identify patients with inactivating mutations in CYP24A1. We describe a LC-MS/MS method to determine: 1) the relationships between serum 24,25(OH)2D and 25(OH)D; 2) serum reference intervals in healthy individuals; 3) the diagnostic accuracy of 24,25(OH)2D measurement as an indicator for vitamin D status; 4) 24,25(OH)2D cut-off value for clinically significant change between inadequate and sufficient 25(OH)D status. Serum samples of healthy participants (n=1996) from Army recruits and patients (n=294) were analysed. The LC-MS/MS assay satisfied industry standards for method validation. We found a positive, concentration-dependent relationship between serum 24,25(OH)2D and 25(OH)2D concentrations. The 25(OH)D:24,25(OH)2D ratio was significantly higher (p4.2 nmol/L was identified as a diagnostic cut-off for 25(OH)D replete status. One patient sample with an elevated 25(OH)D:24,25(OH)2D ratio of 32 and hypercalcaemia who on genetic testing confirmed to have a biallelic mutation of CYP24A1. Our study demonstrated the feasibility of a combined 24,25(OH)2D and 25(OH)D assessment profile. Our established cut-off value for 24,25(OH)2D and ratio reference ranges can be useful to clinicians in the investigation of patients with an impaired calcium/phosphate metabolism and may point towards the existence of CYP24A1 gene abnormalities

Post-exercise cold-water immersion modulates skeletal muscle PGC-1α mRNA expression in immersed and non-immersed limbs: evidence of systemic regulation

Mechanisms mediating post-exercise cold-induced increases in PGC-1α gene expression in human skeletal muscle are yet to be fully elucidated, but may involve local cooling effects on AMPK and p38 MAPK related signalling and/or increased systemic β-adrenergic stimulation. We aimed to therefore examine whether post-exercise cold-water immersion enhancement of PGC-1α mRNA is mediated through local or systemic mechanisms. Ten subjects completed acute cycling (8x5 min at ~80% peak power output) followed by seated-rest (CON) or single-leg cold-water immersion (CWI; 10 min, 8°C). Muscle biopsies were obtained pre-, post- and 3 h post-exercise from a single limb in the CON condition but from both limbs in CWI (thereby providing tissue from a CWI and non-immersed limb, NOT). Muscle temperature decreased up to 2 h post-exercise following CWI (-5°C) in the immersed limb, with lesser changes observed in CON and NOT (-3°C; P<0.05). No differences between limbs were observed in p38MAPK phosphorylation at any time point (P<0.05), whilst a significant interaction effect was present for AMPK phosphorylation (P=0.031). Exercise (CON) increased gene expression of PGC-1α 3 h post-exercise (~5-fold; P<0.001). CWI augmented PGC-1α expression above CON in both the immersed (CWI; ~9-fold; P=0.003) and NOT limbs (~12-fold; P=0.001). Plasma Normetanephrine concentration was higher in CWI vs. CON immediately post-immersion (860 vs. 665 pmol/L; P=0.034). We report for the first time that local cooling of the immersed limb evokes transcriptional control of PGC1-α in the non-immersed limb, suggesting increased systemic β-adrenergic activation of AMPK mediates, in part, post-exercise cold-induction of PGC-1α mRNA

Formalising the Continuous/Discrete Modeling Step

Formally capturing the transition from a continuous model to a discrete model is investigated using model based refinement techniques. A very simple model for stopping (eg. of a train) is developed in both the continuous and discrete domains. The difference between the two is quantified using generic results from ODE theory, and these estimates can be compared with the exact solutions. Such results do not fit well into a conventional model based refinement framework; however they can be accommodated into a model based retrenchment. The retrenchment is described, and the way it can interface to refinement development on both the continuous and discrete sides is outlined. The approach is compared to what can be achieved using hybrid systems techniques.Comment: In Proceedings Refine 2011, arXiv:1106.348

Comparative study of healthy older and younger adults shows they have the same skin concentration of vitamin D3 precursor, 7-dehydrocholesterol, and similar response to UVR

Vitamin D3 synthesis in human skin is initiated by solar ultraviolet radiation (UVR) exposure of precursor 7-dehydrocholesterol (7DHC), but influence of age on the early stage of vitamin D3 metabolism is uncertain. We performed a prospective standardised study in healthy ambulant adults aged ≥65 and ≤40 years examining (1) if baseline skin 7DHC concentration differs between younger and older adults and (2) the impact of older age on serum vitamin D3 response to solar simulated UVR. Eleven younger (18–40 years) and 10 older (65–89 years) adults, phototype I–III, received low-dose UVR (95% UVA, 5% UVB, 1.3 SED) to ~35% of the body surface area. Biopsies were taken for 7DHC assay from unexposed skin, skin immediately and 24 h post-UVR, and blood sampled at baseline, 24 h and 7 d post-UVR for vitamin D3 assay. Samples were analysed by HPLC-MS/MS. Baseline skin 7DHC (mean ± SD) was 0.22 ± 0.07 and 0.25 ± 0.08 µg/mg in younger versus older adults (no significant difference). Baseline serum vitamin D3 concentration was 1.5 ± 1.5 and 1.5 ± 1.7 nmol/L in younger versus older adults, respectively, and showed a significant increase in both groups post-UVR (no significant differences between age groups). Thus, skin 7DHC concentration was not a limiting factor for vitamin D3 production in older relative to younger adults. This information assists public health guidance on sun exposure/vitamin D nutrition, with particular relevance to the growing populations of healthy ambulant adults ≥65 years

Models and metaphors: complexity theory and through-life management in the built environment

Complexity thinking may have both modelling and metaphorical applications in the through-life management of the built environment. These two distinct approaches are examined and compared. In the first instance, some of the sources of complexity in the design, construction and maintenance of the built environment are identified. The metaphorical use of complexity in management thinking and its application in the built environment are briefly examined. This is followed by an exploration of modelling techniques relevant to built environment concerns. Non-linear and complex mathematical techniques such as fuzzy logic, cellular automata and attractors, may be applicable to their analysis. Existing software tools are identified and examples of successful built environment applications of complexity modelling are given. Some issues that arise include the definition of phenomena in a mathematically usable way, the functionality of available software and the possibility of going beyond representational modelling. Further questions arising from the application of complexity thinking are discussed, including the possibilities for confusion that arise from the use of metaphor. The metaphor of a 'commentary machine' is suggested as a possible way forward and it is suggested that an appropriate linguistic analysis can in certain situations reduce perceived complexity

Characterization of Shewanella oneidensis MtrC: a cell-surface decaheme cytochrome involved in respiratory electron transport to extracellular electron acceptors

MtrC is a decaheme c-type cytochrome associated with the outer cell membrane of Fe(III)-respiring species of the Shewanella genus. It is proposed to play a role in anaerobic respiration by mediating electron transfer to extracellular mineral oxides that can serve as terminal electron acceptors. The present work presents the first spectropotentiometric and voltammetric characterization of MtrC, using protein purified from Shewanella oneidensis MR-1. Potentiometric titrations, monitored by UV–vis absorption and electron paramagnetic resonance (EPR) spectroscopy, reveal that the hemes within MtrC titrate over a broad potential range spanning between approximately +100 and approximately -500 mV (vs. the standard hydrogen electrode). Across this potential window the UV–vis absorption spectra are characteristic of low-spin c-type hemes and the EPR spectra reveal broad, complex features that suggest the presence of magnetically spin-coupled low-spin c-hemes. Non-catalytic protein film voltammetry of MtrC demonstrates reversible electrochemistry over a potential window similar to that disclosed spectroscopically. The voltammetry also allows definition of kinetic properties of MtrC in direct electron exchange with a solid electrode surface and during reduction of a model Fe(III) substrate. Taken together, the data provide quantitative information on the potential domain in which MtrC can operate

Small-volume potentiometric titrations: EPR investigations of Fe-S cluster N2 in mitochondrial complex

EPR-based potentiometric titrations are a well-established method for determining the reduction potentials of cofactors in large and complex proteins with at least one EPR-active state. However, such titrations require large amounts of protein. Here, we report a new method that requires an order of magnitude less protein than previously described methods, and that provides EPR samples suitable for measurements at both X- and Q-band microwave frequencies. We demonstrate our method by determining the reduction potential of the terminal [4Fe-4S] cluster (N2) in the intramolecular electron-transfer relay in mammalian respiratory complex I. The value determined by our method, Em7 = − 158 mV, is precise, reproducible, and consistent with previously reported values. Our small-volume potentiometric titration method will facilitate detailed investigations of EPR-active centres in non-abundant and refractory proteins that can only be prepared in small quantities

Assessing a 12-month course of oral alendronate for adults with avascular necrosis of the hip: MANTIS RCT with internal pilot

Background People with avascular necrosis of the hip have very limited treatment options currently available to stop the progression of this disease; this often results in the need for a hip replacement. There is some weak evidence that a class of drugs called bisphosphonates may delay the course of the disease, and this trial was commissioned and set up to provide robust evidence regarding the use of bisphosphonates in adults aged ≥ 18 years with this condition. Objectives The aim of the Managing Avascular Necrosis Treatments: an Interventional Study (MANTIS) trial was to evaluate the clinical effectiveness and cost-effectiveness of a 12-month course of alendronate in the treatment of avascular necrosis. Design This was a 66-month, definitive, multisite, two-arm, parallel-group, placebo-controlled, double-blind, randomised controlled trial, with an internal pilot phase. Setting Eight secondary care NHS hospitals across the UK. Participants Planned trial size – 280 adult patients with avascular necrosis. Intervention Participants in the intervention group received 70 mg of alendronate (an oral bisphosphonate) weekly for 12 months. Main outcomes The main outcomes were Oxford Hip Score at 12 months (short-term outcome) and the time to decision that a hip replacement is required at 36 months (long-term outcome). Results Twenty-one patients were recruited and randomised to receive either the intervention drug, alendronate, or a placebo-matched tablet. Limitations This trial was principally limited by low disease prevalence. Other limitations included the late disease stage at which participants were identified and the rapid progression of the disease. Future work This trial was limited by a low recruitment rate. Avascular necrosis of the hip should be treated as a rare disease. Future trials would need to recruit many more sites and recruit over a longer time period, and, for this reason, a registry may provide a more effective means of collecting data pertaining to this disease. Conclusions The MANTIS trial was terminated at the end of the pilot phase, because it did not meet its go/no-go criteria. The main issue was a poor recruitment rate, owing to a lower than expected disease prevalence and difficulties in identifying the condition at a sufficiently early stage. Those patients who were identified and screened either were too advanced in their disease progression or were already taking medication. We would not recommend that a short-term interventional study is conducted on this condition until its prevalence, geographic foci and natural history and better understood. The difficulty of acquiring this understanding is likely to be a barrier in most health-care markets. One means of developing this understanding would be the introduction of a database/registry for patients suffering from avascular necrosis of the hip. Trial registration The trial is registered as ISRCTN14015902. Funding This project was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 26, No. 43. See the NIHR Journals Library website for further project information