Evidence for widespread changes in the structure, composition, and fire regimes of western North American forests.

Implementation of wildfire- and climate-adaptation strategies in seasonally dry forests of western North America is impeded by numerous constraints and uncertainties. After more than a century of resource and land use change, some question the need for proactive management, particularly given novel social, ecological, and climatic conditions. To address this question, we first provide a framework for assessing changes in landscape conditions and fire regimes. Using this framework, we then evaluate evidence of change in contemporary conditions relative to those maintained by active fire regimes, i.e., those uninterrupted by a century or more of human-induced fire exclusion. The cumulative results of more than a century of research document a persistent and substantial fire deficit and widespread alterations to ecological structures and functions. These changes are not necessarily apparent at all spatial scales or in all dimensions of fire regimes and forest and nonforest conditions. Nonetheless, loss of the once abundant influence of low- and moderate-severity fires suggests that even the least fire-prone ecosystems may be affected by alteration of the surrounding landscape and, consequently, ecosystem functions. Vegetation spatial patterns in fire-excluded forested landscapes no longer reflect the heterogeneity maintained by interacting fires of active fire regimes. Live and dead vegetation (surface and canopy fuels) is generally more abundant and continuous than before European colonization. As a result, current conditions are more vulnerable to the direct and indirect effects of seasonal and episodic increases in drought and fire, especially under a rapidly warming climate. Long-term fire exclusion and contemporaneous social-ecological influences continue to extensively modify seasonally dry forested landscapes. Management that realigns or adapts fire-excluded conditions to seasonal and episodic increases in drought and fire can moderate ecosystem transitions as forests and human communities adapt to changing climatic and disturbance regimes. As adaptation strategies are developed, evaluated, and implemented, objective scientific evaluation of ongoing research and monitoring can aid differentiation of warranted and unwarranted uncertainties.

Precision of bone density and micro-architectural properties at the distal radius and tibia in children: an HR-pQCT study.

Precision errors need to be known when monitoring bone micro-architecture in children with HR-pQCT. Precision errors for trabecular bone micro-architecture ranged from 1 to 8% when using the standard evaluation at the radius and tibia. Precision errors for cortical bone micro-architecture ranged from 1 to 11% when using the advanced cortical evaluation. INTRODUCTION: Our objective was to define HR-pQCT precision errors (CV%RMS) and least significant changes (LSCs) at the distal radius and tibia in children using the standard evaluation and the advanced cortical evaluation. METHODS: We scanned the distal radius (7% of ulnar length) and tibia (8% of tibia length) of 32 children (age range 8-13; mean age 11.3; SD 1.6 years) twice (1 week apart) using HR-pQCT (XtremeCT1). We calculated root-mean-squared coefficients of variation (CV%RMS) to define precision errors and LSC to identify differences required to detect change. RESULTS: Precision errors ranged between 1-8 and 1-5% for trabecular bone outcomes (obtained with standard evaluation) and between 1.5-11 and 0.5-6% for cortical bone outcomes (obtained with advanced cortical evaluation) at the distal radius and tibia, respectively. Related LSCs ranged between 3-21 and 3-14% for trabecular bone outcomes and between 4-30 and 2-16% for cortical bone outcomes at the distal radius and tibia, respectively. CONCLUSIONS: HR-pQCT precision errors were between 1 and 8% (LSC 3-21%) for trabecular bone outcomes and 1 and 11% (LSC 2-30%) for cortical bone outcomes at the radius and tibia in children. Cortical bone outcomes obtained using the advanced cortical evaluation appeared to have lower precision errors than cortical outcomes derived using the standard evaluation. These findings, combined with better-defined cortical bone contours with advanced cortical evaluation, indicate that metrics from advanced cortical evaluation should be utilized when monitoring cortical bone properties in children.

Differential effects of air conditioning type on residential endotoxin levels in a semi-arid climate.

Residential endotoxin exposure is associated with protective and pathogenic health outcomes. Evaporative coolers, an energy-efficient type of air conditioner used in dry climates, are a potential source of indoor endotoxins; however, this association is largely unstudied. We collected settled dust biannually from four locations in homes with evaporative coolers (n=18) and central air conditioners (n=22) in Utah County, Utah (USA), during winter (Jan-Apr) and summer (Aug-Sept), 2014. Dust samples (n=281) were analyzed by the Limulus amebocyte lysate test. Housing factors were measured by survey, and indoor temperature and relative humidity measures were collected during both seasons. Endotoxin concentrations (EU/mg) were significantly higher in homes with evaporative coolers from mattress and bedroom floor samples during both seasons. Endotoxin surface loads (EU/m2 ) were significantly higher in homes with evaporative coolers from mattress and bedroom floor samples during both seasons and in upholstered furniture during winter. For the nine significant season-by-location comparisons, EU/mg and EU/m2 were approximately three to six times greater in homes using evaporative coolers. A plausible explanation for these findings is that evaporative coolers serve as a reservoir and distribution system for Gram-negative bacteria or their cell wall components in homes.

Role of endocortical contouring methods on precision of HR-pQCT-derived cortical micro-architecture in postmenopausal women and young adults.

UNLABELLED: Precision errors of cortical bone micro-architecture from high-resolution peripheral quantitative computed tomography (pQCT) ranged from 1 to 16 % and did not differ between automatic or manually modified endocortical contour methods in postmenopausal women or young adults. In postmenopausal women, manually modified contours led to generally higher cortical bone properties when compared to the automated method. INTRODUCTION: First, the objective of the study was to define in vivo precision errors (coefficient of variation root mean square (CV%RMS)) and least significant change (LSC) for cortical bone micro-architecture using two endocortical contouring methods: automatic (AUTO) and manually modified (MOD) in two groups (postmenopausal women and young adults) from high-resolution pQCT (HR-pQCT) scans. Second, it was to compare precision errors and bone outcomes obtained with both methods within and between groups. METHODS: Using HR-pQCT, we scanned twice the distal radius and tibia of 34 postmenopausal women (mean age ± SD 74 ± 7 years) and 30 young adults (27 ± 9 years). Cortical micro-architecture was determined using AUTO and MOD contour methods. CV%RMS and LSC were calculated. Repeated measures and multivariate ANOVA were used to compare mean CV% and bone outcomes between the methods within and between the groups. Significance was accepted at P < 0.05. RESULTS: CV%RMS ranged from 0.9 to 16.3 %. Within-group precision did not differ between evaluation methods. Compared to young adults, postmenopausal women had better precision for radial cortical porosity (precision difference 9.3 %) and pore volume (7.5 %) with MOD. Young adults had better precision for cortical thickness (0.8 %, MOD) and tibial cortical density (0.2 %, AUTO). In postmenopausal women, MOD resulted in 0.2-54 % higher values for most cortical outcomes, as well as 6-8 % lower radial and tibial cortical BMD and 2 % lower tibial cortical thickness. CONCLUSIONS: Results suggest that AUTO and MOD endocortical contour methods provide comparable repeatability. In postmenopausal women, manual modification of endocortical contours led to generally higher cortical bone properties when compared to the automated method, while no between-method differences were observed in young adults.

Cortical Bone Porosity: What Is It, Why Is It Important, and How Can We Detect It?

There is growing recognition of the role of micro-architecture in osteoporotic bone loss and fragility. This trend has been driven by advances in imaging technology, which have enabled a transition from measures of mass to micro-architecture. Imaging trabecular bone has been a key research focus, but advances in resolution have also enabled the detection of cortical bone micro-architecture, particularly the network of vascular canals, commonly referred to as 'cortical porosity.' This review aims to provide an overview of what this level of porosity is, why it is important, and how it can be characterized by imaging. Moving beyond a 'trabeculocentric' view of bone loss holds the potential to improve diagnosis and monitoring of interventions. Furthermore, cortical porosity is intimately linked to the remodeling process, which underpins bone loss, and thus a larger potential exists to improve our fundamental understanding of bone health through imaging of both humans and animal models.

In vivo precision of three HR-pQCT-derived finite element models of the distal radius and tibia in postmenopausal women.

BACKGROUND: The distal radius is the most common osteoporotic fracture site occurring in postmenopausal women. Finite element (FE) modeling is a non-invasive mathematical technique that can estimate bone strength using inputted geometry/micro-architecture and tissue material properties from computed tomographic images. Our first objective was to define and compare in vivo precision errors for three high-resolution peripheral quantitative computed tomography (HR-pQCT, XtremeCT; Scanco) based FE models of the distal radius and tibia in postmenopausal women. Our second objective was to assess the role of scan interval, scan quality, and common region on precision errors of outcomes for each FE model. METHODS: Models included: single-tissue model (STM), cortical-trabecular dual-tissue model (DTM), and one scaled model using imaged bone mineral density (E-BMD). Using HR-pQCT, we scanned the distal radius and tibia of 34 postmenopausal women (74 ± 7 years), at two time points. Primary outcomes included: tissue stiffness, apparent modulus, average von Mises stress, and failure load. Precision errors (root-mean-squared coefficient of variation, CV%RMS) were calculated. Multivariate ANOVA was used to compare the mean of individual CV% among the 3 HR-pQCT-based FE models. Spearman correlations were used to characterize the associations between precision errors of all FE model outcomes and scan/time interval, scan quality, and common region. Significance was accepted at P < 0.05. RESULTS: At the distal radius, CV%RMS precision errors were <9 % (Range STM: 2.8-5.3 %; DTM: 2.9-5.4 %; E-BMD: 4.4-8.7 %). At the distal tibia, CV%RMS precision errors were <6 % (Range STM: 2.7-4.8 %; DTM: 2.9-3.8 %; E-BMD: 1.8-2.5 %). At the radius, Spearman correlations indicated associations between the common region and associated precision errors of the E-BMD-derived apparent modulus (ρ = -0.392; P < 0.001) and von Mises stress (ρ = -0.297; P = 0.007). CONCLUSION: Results suggest that the STM and DTM are more precise for modeling apparent modulus, average von Mises stress, and failure load at the distal radius. Precision errors were comparable for all three models at the distal tibia. Results indicate that the noted differences in precision error at the distal radius were associated with the common scan region, illustrating the importance of participant repositioning within the cast and reference line placement in the scout view during the scanning process.

Knee osteoarthritis patients with severe nocturnal pain have altered proximal tibial subchondral bone mineral density.

OBJECTIVE: Our objective was to investigate relationships between proximal tibial subchondral bone mineral density (BMD) and nocturnal pain in patients with knee osteoarthritis (OA). METHODS: The preoperative knee of 42 patients booked for knee arthroplasty was scanned using quantitative computed tomography (QCT). Pain was measured using the Western Ontario and McMaster Universities Arthritis Index (WOMAC) and participants were categorized into three groups: 'no pain', 'moderate pain', and 'severe pain' while lying down at night. We used depth-specific image processing to assess tibial subchondral BMD at normalized depths of 0-2.5 mm, 2.5-5.0 mm and 5-10 mm relative to the subchondral surface. Regional analyses of each medial and lateral plateau included total BMD and maximum BMD within a 10 mm diameter core or 'focal spot'. The association between WOMAC pain scores and BMD measurements was assessed using Spearman's rank correlation. Regional BMD was compared pairwise between pain and no pain groups using multivariate analysis of covariance using age, sex, and BMI as covariates and Bonferroni adjustment for multiple comparisons. RESULTS: Lateral focal BMD at the 2.5-5 mm depth was related to nocturnal pain (ρ = 0.388, P = 0.011). The lateral focal BMD was 33% higher in participants with 'severe pain' than participants with 'no pain' at 2.5-5 mm depth (P = 0.028) and 32% higher at 5-10 mm depth (P = 0.049). There were no BMD differences at 0-2.5 mm from the subchondral surface. CONCLUSION: This study suggests that local subchondral bone density may have a role in elucidating OA-related pain pathogenesis.

Bone strength and muscle properties in postmenopausal women with and without a recent distal radius fracture.

UNLABELLED: Distal radius (wrist) fracture (DRF) in women over age 50 years is an early sign of bone fragility. Women with a recent DRF compared to women without DRF demonstrated lower bone strength, muscle density, and strength, but no difference in dual-energy x-ray absorptiometry (DXA) measures, suggesting DXA alone may not be a sufficient predictor for DRF risk. INTRODUCTION: The objective of this study was to investigate differences in bone and muscle properties between women with and without a recent DRF. METHODS: One hundred sixty-six postmenopausal women (50-78 years) were recruited. Participants were excluded if they had taken bone-altering medications in the past 6 months or had medical conditions that severely affected daily living or the upper extremity. Seventy-seven age-matched women with a fracture in the past 6-24 months (Fx, n = 32) and without fracture (NFx, n = 45) were measured for bone and muscle properties using the nondominant (NFx) or non-fractured limb (Fx). Peripheral quantitative computed tomography (pQCT) was used to estimate bone strength in compression (BSIc) at the distal radius and tibia, bone strength in torsion (SSIp) at the shaft sites, muscle density, and area at the forearm and lower leg. Areal bone mineral density at the ultradistal forearm, spine, and femoral neck was measured by DXA. Grip strength and the 30-s chair stand test were used as estimates of upper and lower extremity muscle strength. Limb-specific between-group differences were compared using multivariate analysis of variance (MANOVA). RESULTS: There was a significant group difference (p < 0.05) for the forearm and lower leg, with the Fx group demonstrating 16 and 19% lower BSIc, 3 and 6% lower muscle density, and 20 and 21% lower muscle strength at the upper and lower extremities, respectively. There were no differences between groups for DXA measures. CONCLUSIONS: Women with recent DRF had lower pQCT-derived estimated bone strength at the distal radius and tibia and lower muscle density and strength at both extremities.

Least significant changes and monitoring time intervals for high-resolution pQCT-derived bone outcomes in postmenopausal women.

BACKGROUND: Least Significant Change (LSC) assists in determining whether observed bone change is beyond measurement precision. Monitoring Time Interval (MTI) estimates time required to reliably detect skeletal changes. MTIs have not been defined for bone outcomes provided by high resolution peripheral quantitative computed tomography (HR-pQCT). The purpose of this study was to determine the LSCs and MTIs for HR-pQCT derived bone area, density and micro-architecture with postmenopausal women. METHODS: Distal radius and tibia of 33 postmenopausal women (mean age: 77, SD: ±7 years), from the Saskatoon cohort of the Canadian Multicentre Osteoporosis Study (CaMos), were measured using HR-pQCT at baseline and 1-year later. We determined LSC from precision errors and divided them by the median annual percent changes to define MTIs for bone area, density, and micro-architecture. RESULTS: Distal radius: HR-pQCT LSCs indicated a 1-8% observed change was needed for reliable monitoring of bone area and density while a 3-18% change was needed for micro-architectural measures. The longest MTIs (>3 years) pertained to cortical and trabecular area and density measures, cortical thickness and bone volume fraction; the shortest MTIs (~2 years) pertained to bone micro-architectural measures (trabecular number, thickness, separation and heterogeneity). Distal tibia: LSCs indicated a <1-5% observed change was needed for reliable monitoring of bone area and density, while a 3-19% change was needed for micro-architectural measures. The longest MTIs (>3 years) pertained to trabecular density, bone volume fraction, number, separation and heterogeneity; the shortest MTIs (~1 year) pertained to cortical and trabecular area, cortical density and thickness. CONCLUSION: MTIs suggest that performing HR-pQCT follow-up measures in postmenopausal women every 2 years at the distal radius and every 1 year at the distal tibia to monitor true skeletal changes as indicated by the LSCs.

Characterizing microarchitectural changes at the distal radius and tibia in postmenopausal women using HR-pQCT.

UNLABELLED: Limited prospective evidence exists regarding bone microarchitectural deterioration. We report annual changes in trabecular and cortical bone microarchitecture at the distal radius and tibia in postmenopausal women. Lost trabeculae with corresponding increase in trabecular thickness at the radius and thinning tibial cortex indicated trabecularization of the cortex at both sites. INTRODUCTION: Osteoporosis is characterized by low bone mass and the deterioration of bone microarchitecture. However, limited prospective evidence exists regarding bone microarchitectural changes in postmenopausal women: a population prone to sustaining osteoporotic fractures. Our primary objective was to characterize the annual change in bone area, density, and microarchitecture at the distal radius and distal tibia in postmenopausal women. METHODS: Distal radius and tibia were measured using high-resolution peripheral quantitative computed tomography (HR-pQCT) at baseline and 1 year later in 51 women (mean age ± SD, 77 ± 7 years) randomly sampled from the Saskatoon cohort of the Canadian Multicentre Osteoporosis Study (CaMos). We used repeated measures analysis of variance (ANOVA) with Bonferroni adjustment for multiple comparisons to characterize the mean annual change in total density, cortical perimeter, trabecular and cortical bone area, density, content, and microarchitecture. Significant changes were accepted at P < 0.05. RESULTS: At the distal radius in women without bone-altering drugs, total density (-1.7%) and trabecular number (-6.4%) decreased, while trabecular thickness (+6.0%), separation (+8.6%), and heterogeneity (+12.1%) increased. At their distal tibia, cortical area (-4.5%), density (-1.9%), content (-6.3%), and thickness (-4.4%) decreased, while trabecular area (+0.4%) increased. CONCLUSIONS: The observed loss of trabeculae with concomitant increase in trabecular size at the distal radius and the declined cortical thickness, density, and content at the distal tibia indicated a site-specific trabecularization of the cortical bone in postmenopausal women.

Regional depth-specific subchondral bone density measures in osteoarthritic and normal patellae: in vivo precision and preliminary comparisons.

SUMMARY: Computed tomography-based depth-specific image processing is able to precisely identify regional differences between healthy patellae and patellae with osteoarthritis. INTRODUCTION: This study aims to assess the precision errors and potential differences in regional, depth-specific subchondral bone mineral density (BMD) in normal and osteoarthritic (OA) human patellae in vivo using CT-based density analyses. METHODS: Fourteen participants (2 men and 12 women; mean age, 51.4; SD, 11.8 years) were scanned using clinical quantitative CT (QCT) three times over 2 days. Participants were categorized as either normal (n = 7) or exhibiting radiographic OA (n = 7). Average subchondral BMD was assessed at three depths relative to the subchondral surface. Regional BMD analysis included: total lateral facet BMD, total medial facet BMD, and superior/middle/inferior BMD of lateral and medial facets at normalized depths of 0-2.5, 2.5-5, and 5-7.5 mm from the subchondral surface. We assessed precision using root mean square coefficients of variation (CV%). We evaluated differences between OA and normal BMD by (1) calculating percentage differences between the groups (in relation to normal BMD) (2) relating percentage differences to respective CV% errors and (3) determining effect sizes using Cohen's d. RESULTS: Root mean square CV% precision errors ranged from 1.1 to 5.9 %. Percentage differences between OA and normal BMD varied from -1.6 to -30.1 % (BMD lower in OA patellae). In relation to precision errors, percentage differences were, on average, 5.5× greater than CV% errors. Cohen's d effect sizes ranged from -1.7 to -0.1. Largest differences were noted at depths of 2.5-5 and 5-7.5 mm from the subchondral surface. CONCLUSIONS: Patellar subchondral BMD measures were precise (average CV%, ≤3 %). This region- and depth-specific CT-based imaging tool characterized regional standardized BMD differences between normal and OA patellae in vivo.

Linearity and sex-specificity of impact force prediction during a fall onto the outstretched hand using a single-damper-model.

OBJECTIVES: To assess the linearity and sex-specificity of damping coefficients used in a single-damper-model (SDM) when predicting impact forces during the worst-case falling scenario from fall heights up to 25 cm. METHODS: Using 3-dimensional motion tracking and an integrated force plate, impact forces and impact velocities were assessed from 10 young adults (5 males; 5 females), falling from planted knees onto outstretched arms, from a random order of drop heights: 3, 5, 7, 10, 15, 20, and 25 cm. We assessed the linearity and sex-specificity between impact forces and impact velocities across all fall heights using analysis of variance linearity test and linear regression, respectively. Significance was accepted at P<0.05. RESULTS: Association between impact forces and impact velocities up to 25 cm was linear (P=0.02). Damping coefficients appeared sex-specific (males: 627 Ns/m, R(2)=0.70; females: 421 Ns/m; R(2)=0.81; sex combined: 532 Ns/m, R(2)=0.61). CONCLUSIONS: A linear damping coefficient used in the SDM proved valid for predicting impact forces from fall heights up to 25 cm. RESULTS suggested the use of sex-specific damping coefficients when estimating impact force using the SDM and calculating the factor-of-risk for wrist fractures.

Magnetic resonance imaging of bone and muscle traits at the hip: an in vivo precision study.

OBJECTIVE: To determine the in vivo precision of MRI-based measures of bone and muscle traits at the hip. METHODS: Left proximal femoral neck and shaft of 14 participants (5M:9 F; age:21-68) were scanned 3 times using a 1.5 T MRI. Commercial and custom image processing methods were used to derive bone geometry and strength traits at the proximal femoral neck and shaft along with muscle area of various muscle groups at the shaft site. For precision, root mean square coefficients of variation (CV%rms) and standard deviations (SDrms) were calculated. RESULTS: At the femoral neck, CV%rms for area-based bone measures ranged between 1.7-5.0%; CV%rms for cortical thickness varied from 4.7 to 5.6%; and CV%rms for bending, torsional and buckling-based strength indices ranged between 4.6-7.1%. At the femoral shaft, CV%rms for bone area ranged between 1.2-3.0%; CV%rms for cortical thickness varied from 1.7 to 2.0%; and CV%rms for bending and buckling-based strength indices ranged between 1.4-3.1%. For muscle area, CV%rms ranged between 1.3-4.5%. CONCLUSIONS: MRI-based measures of bone and muscle traits at the proximal femoral neck and shaft demonstrated in vivo precision errors <7.1%. MRI is a promising 3D technique for monitoring changes in bone and muscle at the clinically important hip.

Monitoring time interval for pQCT-derived bone outcomes in postmenopausal women.

UNLABELLED: Evidence of measurement precision, annual changes and monitoring time interval is essential when designing and interpreting longitudinal studies. Despite the precise measures, small annual changes in bone properties led to monitoring time intervals (MTIs) of 2-6 years in peripheral quantitative computed tomography (pQCT)-derived radial and tibial bone area, density, and estimated strength in postmenopausal women. INTRODUCTION: The purpose of the study was to determine the precision error, annual change, and MTI in bone density, area, and strength parameters in postmenopausal women. METHODS: Postmenopausal women (n = 114) from the Saskatoon cohort of the Canadian Multicentre Osteoporosis Study had annual pQCT scans of the distal and shaft sites of the radius and tibia for 2 years. Median annualized rates of percent change and the MTI were calculated for bone density, area, and strength parameters. Root mean squared coefficients of variation (CV%) were calculated from duplicate scans in a random subgroup of 35 postmenopausal women. RESULTS: CV% ranged from 1.4 to 6.1 % at the radius and 0.7 to 2.1 % at the tibia. MTIs for the distal radius were 3 years for total bone density (ToD) and 4 years for total bone cross sectional area (ToA), trabecular area, and bone strength index. At the diaphyseal radius, MTI was 3 years for ToA, 5 years for cortical density, and 6 years for polar stress strain index (SSIp). Similarly, MTI for total and trabecular density was 3 years at the distal tibia. At the diaphyseal tibia, MTI for ToA was 3 years and SSIp 4 years. CONCLUSION: MTI for longitudinal studies in older postmenopausal women should be at least 2-6 years at the radius and tibia, with specific monitoring of the total and trabecular area, total density, and bone strength at the radius and total and trabecular density, total area, and bone strength at the tibia.

Egr1 involvement in evening gene regulation by melatonin.

Seasonal photoperiodic responses in mammals depend on the pineal hormone melatonin. The pars tuberalis (PT) region of the anterior pituitary has emerged as a principal melatonin target tissue, controlling endocrine responses. Rising melatonin levels acutely influence the expression of a small cluster of genes either positively (exemplified by cryptochrome-1, cry1) or negatively (exemplified by the type 1 melatonin receptor, mt1). The purpose of this study was to characterize the pathways through which these evening actions of melatonin are mediated. In vitro experiments showed that cAMP signaling in the PT directly influences mt1 but not cry1 expression. Analysis of nuclear extracts from sheep PT tissue collected 90 min after melatonin or saline control injections highlighted the response element for the immediate early gene egr1 (EGR1-RE) as a candidate for acute melatonin-dependent transcriptional regulation. We identified putative EGR1-RE's in the proximal promoter regions of the ovine cry1 and mt1 genes, and confirmed their functionality in luciferase reporter assays. Egr1 expression is suppressed by melatonin in PT cell cultures, and is rhythmic in the ovine PT with a nadir in the early night. We propose that melatonin-dependent effects on EGR1-RE's contribute to evening gene expression profiles in this pituitary melatonin target tissue.

Computed tomography topographic mapping of subchondral density (CT-TOMASD) in osteoarthritic and normal knees: methodological development and preliminary findings.

OBJECTIVES: To develop a precise imaging tool which measures three-dimensional (3D) subchondral bone mineral density (BMD), and investigate its ability to distinguish subchondral bone properties in osteoarthritic and normal cadaveric tibiae. METHODS: We developed a novel imaging tool [Computed tomography topographic mapping of subchondral density (CT-TOMASD)], which employs a surface projection image processing technique to map 3D subchondral BMD measured in relation to depth from the joint surface. Sixteen intact cadaver knees from 10 donors (8M:2F; age: 77.8+/-7.4) were scanned using quantitative computed tomography (QCT). Projections of average BMD to normalized depths of 2.5mm and 5.0mm were acquired, with regional analyses including: (1) medial and lateral BMD, (2) anterior/central/posterior compartmental BMD, (3) max BMD contained within a 10mm diameter 'core', and (4) medial:lateral BMD ratio. Precision was assessed using coefficients of variation (CV%). Osteoarthritis (OA) severity was assessed by examination of computed tomography (CT) and fluoroscopic radiographic images, and categorized using modified Kellgren-Lawrence (mKL) scoring. RESULTS: Precision errors for CT-TOMASD BMD measures were focused around 1.5%, reaching a maximum CV% of 3.5%. OA was identified in eight compartments of six knees. Substantial qualitative and quantitative differences were observed between the OA and normal knees, with the medial:lateral BMD ratio and peak core regional analyses demonstrating differences greater than 4.7 standard deviations (SDs) when compared with normals. Preliminary results revealed effect sizes ranging from 1.6 to 4.3 between OA and normal knees. CONCLUSIONS: CT-TOMASD offers precise 3D measures of subchondral BMD. Preliminary results demonstrate large qualitative and quantitative differences and large effect sizes between OA and normal knees. This method has the potential to identify and quantify changes in subchondral BMD associated with OA disease progression.

Strength indices from pQCT imaging predict up to 85% of variance in bone failure properties at tibial epiphysis and diaphysis.

Our primary objective was to validate the Bone Strength Index for compression (BSIC) by determining the amount of variance in failure load and stiffness that was explained by BSIC and bone properties at two distal sites in human cadaveric tibiae when tested in axial compression. Our secondary objective was to assess the variance in failure moment and flexural rigidity that was explained by bone properties, geometry and strength indices in the tibial diaphysis when tested in 4-point bending. Twenty cadaver tibiae pairs from 5 female and 5 male donors (mean age 74 yrs, SD 6 yrs) were measured at the distal epiphysis (4 and 10% sites of the tibial length from the distal end) and diaphysis (50 and 66% sites) by peripheral Quantitative Computed Tomography (pQCT; XCT 2000, Stratec). After imaging, we conducted axial compression tests on the distal tibia and 4-point bending tests on the diaphysis. Total bone mineral content and BSIC (product of total area and squared density of the cross-section) at the 4% site predicted 75% and 85% of the variance in the failure load and 52% and 57% in stiffness, respectively. At the diaphyseal sites 80% or more of the variance in failure moment and/or flexural rigidity was predicted by total and cortical area and content, geometry and strength indices corresponding to the axes of bending.

The Big Breakfast Study: Chrono-nutrition influence on energy expenditure and bodyweight.

A growing body of evidence highlights the importance of the biological clock as a modulator of energy balance and metabolism. Recent studies in humans have shown that ingested calories are apparently utilised more efficiently in the morning than in the evening and this is manifest through improved weight loss, even under iso-energetic calorie intake. The mechanisms behind this enhanced morning energy metabolism are not yet clear, although it may result from behavioural adaptations or circadian driven variations in physiology and energy metabolism. A major objective of the newly funded Big Breakfast Study therefore is to investigate the mechanistic basis of this amplified morning thermogenesis leading to enhanced weight loss, by exploring behavioural and physiological adaptations in energy expenditure alongside the underlying circadian biology. This report briefly discusses the current research linking meal timing, circadian rhythms and metabolism; highlights the research gaps; and provides an overview of the studies being undertaken as part of the Medical Research Council-funded Big Breakfast Study.

Regulation of MT melatonin receptor expression in the foetal rat pituitary.

During development, melatonin receptors are transiently expressed in multiple neuroendocrine tissues, suggesting a novel role for melatonin in developmental physiology. The best characterised model of melatonin signalling during development is the pars distalis of the rat pituitary. However, although many studies have characterised the postnatal decline of melatonin receptors in the rat pars distalis, the mechanism(s) that time the developmental onset of receptor expression during embryogenesis are unknown. Analysis of these mechanisms may yield important information regarding the putative role of melatonin in neuroendocrine development. Here, we report the expression of MT(1) melatonin receptor mRNA in the rat pituitary from embryonic day 15.5 (e15.5). Prior to e15.5, the homeodomain transcription factor Msx-1, an inhibitor of cellular differentiation, is widely expressed throughout the pituitary. In transient transfection experiments, Msx-1 potently inhibited pituitary homeobox-1 (Pitx-1)-induced MT(1) promoter activity and therefore may represent a key inhibitor of MT(1) expression in early pituitary development. During late embryogenesis, MT(1) mRNA was expressed in both the ventral and dorsal pituitary. Analysis of a 1.5-kb fragment of the rat MT(1) promoter revealed four putative cis-elements for the POU domain factor Pit-1, which is associated with mid-dorsal cell lineages. Although Pit-1 induced a strong, dose-dependent stimulation of MT(1) promoter activity in vitro, dual-labelled in situ hybridisation revealed no colocalisation of MT(1) and Pit-1 mRNAs in vivo at e19.5. By contrast, all MT(1) positive cells colocalised with alphaGSU and most with betaTSH mRNA. Our data therefore implicate the decline of Msx-1 expression as a key event that times the onset of melatonin receptor expression to the differentiation of endocrine cells types in the developing pituitary gland, and suggest that the melatonin-sensitive cells in the embryonic pituitary are primarily Pit-1-independent thyrotrophs in the rostral pituitary, with a secondary population of pars distalis gonadotrophs.