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Objectives The purpose of this study was to assess the use of computer-aided combined movement examination (CME) to measure change in low back movement after neurosurgical intervention for lumbar spondylosis and to use a CME normal reference range (NRR) to compare and contrast movement patterns identified from lumbar disk disease, disk protrusion, and nerve root compression cases. Methods A test-retest, cohort observational study was conducted. Computer-aided CME was used to record lumbar range of motion in 18 patients, along with pain, stiffness, disability, and health self-report questionnaires. A minimal clinically important difference of 30% was used to interpret meaningful change in self-reports. z Scores were used to compare CME. Post hoc observation included subgrouping cases into 3 discrete pathologic conditions—disk disease, disk protrusion, and nerve root compression—to report intergroup differences in CME. Results Self-report data indicated that 11, 7, and 10 patients improved by ≥30% in pain, stiffness, and function, respectively. Three patients experienced clinically significant improvement in health survey. A CME pattern reduced in all directions suggested disk disease. Unilaterally restricted movement in side-flexed or extended directions suggested posterolateral disk protrusion with or without ipsilateral nerve root compression. Bilateral restrictions in extension suggested posterior disk protrusion with or without nerve root compression. In 11 of the 18 cases, CME converged toward the NRR after surgery. Conclusion We described the use of CME to identify atypical lumbar movement relative to an NRR. Data from this short-term postoperative study provide preliminary evidence for CME movement patterns suggestive of disk disease, disk protrusion, and nerve root compression.

Objective A test-retest cohort study was conducted to assess the use of a novel computer-aided, combined movement examination (CME) to measure change in low back movement after pain management intervention in 17 cases of lumbar spondylosis. Additionally we desired to use a CME normal reference range (NRR) to compare and contrast movement patterns identified from 3 specific structural pathologic conditions: intervertebral disc, facet joint, and nerve root compression. Methods Computer-aided CME was used before and after intervention, in a cohort study design, to record lumbar range of movement along with pain, disability, and health self-report questionnaires in 17 participants who received image-guided facet, epidural, and/or rhizotomy intervention. In the majority of cases, CME was reassessed after injection together with 2 serial self-reports after an average of 2 and 14 weeks. A minimal clinically important difference of 30% was used to interpret meaningful change in self-reports. A CME NRR (n = 159) was used for comparison with the 17 cases. Post hoc observation included subgrouping cases into 3 discrete pathologic conditions, intervertebral disc, facet dysfunction, and nerve root compression, in order to report intergroup differences in CME movement. Results Seven of the 17 participants stated that a “combined” movement was their most painful CME direction. Self-report outcome data indicated that 4 participants experienced significant improvement in health survey, 5 improved by ≥30% on low back function, and 8 reported that low back pain was more bothersome than stiffness, 6 of whom achieved the minimal clinically important difference for self-reported pain. Subgrouping of cases into structure-specific groups provided insight to different CME movement patterns. Conclusion The use of CME assists in identifying atypical lumbar movement relative to an age and sex NRR. Data from this study, exemplified by representative case studies, provide preliminary evidence for distinct intervertebral disc, facet joint, and nerve root compression CME movement patterns in cases of chronic lumbar spondylosis.

Purpose Nuclear imaging is an important preclinical research tool to study infectious diseases in vivo and could be extended to investigate complex aspects of malaria infections. As such, we report for the first time successful radiolabeling of a novel antibody specific to Plasmodium-infected erythrocytes (IIIB6), its in vitro assessment and molecular imaging in nude mice. Procedures In vitro confocal microscopy was used to determine the stage-specificity of Plasmodium-infected erythrocytes recognised by IIIB6. To enable micro-positron emission tomography (PET)/X-ray computed tomography (CT) imaging, IIIB6 was conjugated to Bz-DFO-NCS and subsequently radiolabeled with zirconium-89. Healthy nude mice were injected with [89Zr]IIIB6, and pharmacokinetics and organ uptake were monitored over 24 h. This was followed by post-mortem animal dissection to determine the biodistribution of [89Zr]IIIB6. Results IIIB6 recognised all the relevant stages of Plasmodium falciparum-infected erythrocytes (trophozoites, schizonts and gametocytes) that are responsible for severe malaria pathology. [89Zr]IIIB6-radiolabeling yields were efficient at 84–89 %. Blood pool imaging analysis indicated a pharmacological half-life of 9.6 ± 2.5 h for [89Zr]IIIB6. The highest standard uptake values were determined at 2–6 h in the liver followed by the spleen, kidneys, heart, stomach and lung, respectively. Minimal activity was present in muscle and bone tissues. Conclusion In vitro characterization of IIIB6 and pharmacokinetic characterization of [89Zr]IIIB6 revealed that this antibody has potential for future use in Plasmodium-infected mouse models to study malaria in a preclinical in vivo setting with PET/CT imaging

Objectives The aim of this study is to report the development and validation of a low back computer-aided combined movement examination protocol in normal individuals and record treatment outcomes of cases with symptomatic degenerative lumbar spondylosis. Design Test–retest, following intervention. Background Self-report assessments and combined movement examination were used to record composite spinal motion, before and following neurosurgical and pain medicine interventions. Methods 151 normal individuals aged from 20 years to 69 years were assessed using combined movement examination between L1 and S1 spinal levels to establish a reference range. Cases with degenerative low back pain and sciatica were assessed before and after therapeutic interventions with combined movement examination and a battery of self-report pain and disability questionnaires. Change scores for combined movement examination and all outcome measures were derived. Findings Computer-aided combined movement examination validation and intraclass correlation coefficient with 95% confidence interval and least significant change scores indicated acceptable reliability of combined movement examination when recording lumbar movement in normal subjects. In both clinical cases lumbar spine movement restrictions corresponded with self-report scores for pain and disability. Post-intervention outcomes all showed significant improvement, particularly in the most restricted combined movement examination direction. Interpretation This study provides normative reference data for combined movement examination that may inform future clinical studies of the technique as a convenient objective surrogate for important clinical outcomes in lumbar degenerative spondylosis. It can be used with good reliability, may be well tolerated by individuals in pain and appears to change in concert with validated measures of lumbar spinal pain, functional limitation and quality of life.

New macrobicyclic cage amine or "sarcophagine" (sar) bifunctional chelators have been synthesised that form copper complexes of exceptional in vivo stability and incorporate isothiocyanate (-NCS) functional groups for conjugation to an antibody. The chelators were synthesised from the methyl-capped complex [Mg(II)(CH3)(NH2)sar](2+). Coordination of Mg(II) within the cavity of the cage amine ligand protects the secondary amine atoms from reacting with the -NCS functional groups. Two different [Mg(II)(NCS-sar)](2+) derivatives were conjugated to the HER2/neu-targeting antibody trastuzumab and the progress of the reaction monitored by electrospray mass spectrometry. The Mg(II) ion was removed from the immunoconjugates under mild conditions (0.1 M citrate buffer, pH 6). Labelling of the (CH3)(p-NCS-Ph)sar-trastuzumab conjugate with (64)Cu(II), a radioisotope suitable for positron emission tomography (PET), was fast (∼5 min) and easily performed at room temperature with high radiochemical purity (95%). Biodistribution and PET imaging studies in vivo showed that (64)Cu-labelled (CH3)(p-NCS-Ph)sar-trastuzumab maintained high stability under physiological conditions with high and selective uptake in a HER2-positive cancer cell line. The stability of the copper complex and the 12.7 h half-life of the radioisotope allows clear visualisation of tumours out to 48 h.

Approximately one quarter of patients undergoing breast conserving therapy for breast cancer will require a second operation to achieve adequate clearance of the margins. A number of techniques to assess margins intraoperatively have been reported. This systematic review examines current intraoperative methods for assessing margin status. The final pathology status, statistical measures including accuracy of tumour margin assessment, average time impact on the procedure and second operation rate, were used as criteria for comparison between studies. Although pathological methods, such as frozen section and imprint cytology performed well, they added on average 20-30 min to operation times. An ultrasound probe allows accurate examination of the margins and delivers results in a timely manner, yet it has a limited role with DCIS where calcification is present and in multifocal cancer. Further research is required in other intraoperative margin assessment techniques, such as mammography, radiofrequency spectroscopy and optical coherence tomography.

Previously we reported that the corresponding 2-dimensional (2D) structural geometry measures derived from quantitative computed tomography (QCT) and dual-energy X-ray absorptiometry (DXA) of femoral neck were different. Now, we test the hypothesis that the following 4 measures: areal bone mineral density, W, and 2 new measures, standard deviation (σ) of a normalized mineral mass projection profile distribution and the displacement between centre of mineral mass and geometric centre of mineral mass (δ) of the projection profile allow transformation from one measurement modality to the other with high precision. QCT and DXA scans and hip structural analysis (HSA) performed on 237 women were randomly allocated into cohorts of 118 (cohort A) and 119 (cohort B). Intercepts and gradients from linear regression of the 4 QCT- and DXA-derived measures were obtained from cohort A and used to convert cohort B QCT-derived structural geometry measurements into their DXA equivalent. Corresponding cohort B QCT- and DXA-derived structural geometrical measurements were compared using Bland-Altman plots and regression analysis. Apart from W, comparisons of the 7 nontransformed QCT- and DXA-derived variables were significantly different using paired t-tests. Cross-calibration with the set of 4 base measures resolved the differences in all original variables. These data provide a mechanism for cross-calibrating HSA outcomes acquired using QCT and DXA and demonstrate that a complex 2D digitized structure can be described by 4 variables.

Objective Biomarkers for Alzheimer disease (AD) can detect the disease pathology in asymptomatic subjects and individuals with mild cognitive impairment (MCI), but their cognitive prognosis remains uncertain. We aimed to determine the prognostic value of β‐amyloid imaging, alone and in combination with memory performance, hippocampal atrophy, and apolipoprotein E e4 status in nondemented, older individuals. Methods A total of 183 healthy individuals (age = 72.0 ± 7.26 years) and 87 participants with MCI (age = 73.7 ± 8.27) in the Australian Imaging, Biomarkers, and Lifestyle study of ageing were studied. Clinical reclassification was performed after 3 years, blind to biomarker findings. β‐Amyloid imaging was considered positive if the 11C‐Pittsburgh compound B cortical to reference ratio was ≥1.5. Results Thirteen percent of healthy persons progressed (15 to MCI, 8 to dementia), and 59% of the MCI cohort progressed to probable AD. Multivariate analysis showed β‐amyloid imaging as the single variable most strongly associated with progression. Of combinations, subtle memory impairment (Z score = −0.5 to −1.5) with a positive amyloid scan was most strongly associated with progression in healthy individuals (odds ratio [OR] = 16, 95% confidence interval [CI] = 3.7–68; positive predictive value [PPV] = 50%, 95% CI = 19–81; negative predictive value [NPV] = 94%, 95% CI = 88–98). Almost all amnestic MCI subjects (Z score ≤ −1.5) with a positive amyloid scan developed AD (OR = ∞; PPV = 86%, 95% CI = 72–95; NPV = 100%, 95% CI = 80–100). Hippocampal atrophy and e4 status did not add further predictive value. Interpretation Subtle memory impairment with a positive β‐amyloid scan identifies healthy individuals at high risk for MCI or AD. Clearly amnestic patients with a positive amyloid scan have prodromal AD and a poor prognosis for dementia within 3 years. Ann Neurol 2013;74:905–913

Osteoporosis research has focused on vertebral fractures and trabecular bone loss. However, non-vertebral fractures at predominantly cortical sites account for 80% of all fractures and most fracture-related morbidity and mortality in old age. We aimed to re-examine cortical bone as a source of bone loss in the appendicular skeleton.In this cross-sectional study, we used high-resolution peripheral CT to quantify and compare cortical and trabecular bone loss from the distal radius of adult women, and measured porosity using scanning electron microscopy. Exclusion criteria were diseases or prescribed drugs affecting bone metabolism. We also measured bone mineral density of post-mortem hip specimens from female cadavers using densitometry. Age-related differences in total, cortical, and trabecular bone mass, trabecular bone of cortical origin, and cortical and trabecular densities were calculated.We investigated 122 white women with a mean age of 62.8 (range 27-98) years. Between ages 50 and 80 years (n=89), 72.1 mg (95% CI 67.7-76.4) hydroxyapatite (68%) of 106.5 mg hydroxyapatite of bone lost at the distal radius was cortical and 34.3 mg (30.5-37.8) hydroxyapatite (32%) was trabecular; 17.1 mg (11.7-22.5) hydroxyapatite (16%) of total bone loss occurred between ages 50 and 64 years (n=34) and 89.4 mg (83.7-101.1) hydroxyapatite (84%) after age 65 years (n=55). Remodelling within cortex adjacent to the marrow accounted for 49.9 mg (45.4-53.7) hydroxyapatite (47%) of bone loss. Between ages 50-64 years (n=34) and 80 years and older (n=33), cortical density decreased by 127.8 mg (93.1-162.1) hydroxyapatite per cm(3) (15%, p0.0001) before porosity trabecularising the cortex was included, but 374.3 mg (318.2-429.5) hydroxyapatite per cm(3) (43%, p0.0001) after; trabecular density decreased by 18.2 mg (-1.4 to 38.2) hydroxyapatite per cm(3) (14%, p=0.06) before cortical remnants were excluded, but 68.7 mg (37.7-90.4) hydroxyapatite per cm(3) (52%, p0.0001) after.Accurate assessment of bone structure, especially porosity producing cortical remnants, could improve identification of individuals at high and low risk of fracture and therefore assist targeting of treatment.Australia National Health and Medical Research Council.

A 1-year randomized controlled trial of resistance training compared with a control group was undertaken in 143 men aged 55-80 years. Although hip bone mineral density, lean body mass, and function increased in both groups, lean body mass and function but not bone density increased more in the resistance group.Previous studies have demonstrated a positive effect of resistance training on bone mineral density (BMD) in postmenopausal women, but the effect in men is unclear. The aim was to examine the effect of a 1-year resistance training program on bone and lean body mass in 143 men aged 55-80 years, randomized to either resistance training or active control.Resistance exercises were selected to provide loading at the hips. Measurements were taken at 0, 6, and 12 months for BMD (whole body, hip, and spine), lean body mass, strength, and functional fitness.The intervention showed a significant increase in total hip BMD for both groups at 12 months (active control, 1,014-1,050 mg/cm(2); resistance, 1,045-1,054 mg/cm(2), p0.05) with no increased effect of resistance training compared to active control. However, compared to the active control group, the resistance group increased their lean body mass (active control, 0.1 +/- 2.1%; resistance, 1.5 +/- 2.7%, p0.05), fitness (active control, 4.6 +/- 11.1%; resistance, 13.0 +/- 13.4%, p0.05), and lower limb muscle strength (active control, 14.3 +/- 16.8%; resistance, 39.4 +/- 30.87%, p0.05).In contrast to previous findings in older women, in older men, a resistance training program does not increase hip bone mass more than walking 30 min three times a week.

Forearm bone mineral density (BMD) was measured by single-energy photon absorptiometry in 360 healthy females without known axial fractures, 202 of whom were postmenopausal. The three sites addressed included an ultradistal (U) region containing approximately 60% trabecular bone. The other sites, distal (D) and shaft (S), were progressively more cortical. Reproducibility was 1.7-1.9% CV. The earliest evidence of a significant correlation between BMD and years since menopause was seen in trabecular bone in subjects aged 45-55 years. Fractional decrease in BMD, relative to the premenopausal value, was significantly larger at U than at S for the decades 55-65 years and above. Fractional rates of bone loss at all sites were a maximum in the first postmenopausal decade, the rate at U being 0.035, approximately 1.5 times that at D or S. A total of 33 subjects reported 54 previous minimally traumatic nonaxial (MTNA) fractures. When BMD measurements of the entire study were divided into quintiles, the prevalence of MTNA fracture cases in the lowest quintile was eight times that of each of the upper three quintiles. Prevalence of fracture cases ranked by quintiles of BMD were not different for the three scan sites. Therefore, ultradistal measurements confer no advantages over distal or shaft BMD for discriminating past MTNA fracture cases but do show larger fractional rates of loss during the first postmenopausal decade.(ABSTRACT TRUNCATED AT 250 WORDS)

The etiology of age-related bone loss is unclear but both lack of exercise and dietary calcium deficiency have been implicated in its causation. This 2-year randomized placebo-controlled study was designed to examine the effects of increased dietary calcium and exercise in 168 women who were more than 10 years postmenopausal. The subjects were randomized into one of 4 groups: placebo, milk powder containing 1 g of calcium, calcium tablets 1 g/night, and calcium tablets 1 g/night and an exercise regimen. The exercise group aimed to undertake 4 h of extra weight-bearing exercise per week and were undertaking 10% more activity than other groups at 2 years. Bone mineral density at the lumbar spine, three hip sites, and two sites of the tibia close to the ankle joint were measured at 6 month intervals. Dietary intake was evaluated by a weighed food record, exercise was evaluated by an exercise diary, and blood and urine samples were obtained to examine effects on calcium homeostasis. Individual data points were compared using repeated measures ANOVA and least squares regression. Calcium supplementation by either the calcium tablets or the milk powder resulted in cessation of bone loss at the intertrochanteric hip site (placebo, calcium tablets, calcium and exercise, milk powder -0.81, +0.17, +0.23, and +0.07% per year, respectively; p < 0.05 for all supplementation groups compared with placebo) with similar results at the trochanteric hip site. The calcium and exercise group had less bone loss at the femoral neck site when compared with calcium supplementation alone (placebo, calcium tablets, calcium and exercise, milk powder -0.67, -0.18, +0.28, and -0.18% per year, respectively; p < 0.05 for calcium and exercise compared with calcium alone). There was a significant reduction in the rate of bone loss at the ultradistal site of the tibia (placebo, calcium tablets, calcium and exercise, milk powder -2.5, -1.6, -1.0, and -1.5% per year, respectively; p < 0.05 for all supplementation groups compared with placebo). There was no significant bone loss at the spine site in any group.(ABSTRACT TRUNCATED AT 250 WORDS)

We have compared the use of new markers of bone turnover in the assessment and treatment of Paget disease and made observations on the mechanisms of bone resorption. Urine hydroxyproline (Hyp) as a bone resorption marker and serum alkaline phosphatase (ALP) as a bone formation marker have traditionally been used to biochemically assess and monitor treatment of Paget disease. Hyp and total ALP were compared with total urine pyridinoline (Pyd) and deoxypyridinoline (Dpd), free urine Pyd and Dpd, urine type I collagen N-terminal cross-linked telopeptide (NTX), type I collagen C-terminal propeptide (PICP), serum osteocalcin, and bone ALP in Paget patients treated with pamidronate. Patients were divided into three biochemical severity-based treatment groups by their fasting urine hydroxyprolline excretion (HypE) levels (Le., group 1, HypE5.0 mumol/l of glomerular filtrate [GF]; group 2, HypE of 5.0-9.9 mumol/l of GF; group 3, HypE10 mumol/l of GF). Group 1 received one 60 mg intravenous infusion of pamidronate, and groups 2 and 3 received four and six 60 mg infusions at weekly intervals, respectively. Fasting serum and morning urine specimens were taken before and at 2, 6, 13, and 26 weeks after starting treatment. Baseline Z scores were used to compare separation of patient results from normal, and the difference in Z scores from baseline to 13 weeks was used to compare response to treatment. Baseline discrimination and response to treatment at all disease activity levels was greatest for NTX and was poor for osteocalcin, PICP, and C-terminal cross-linked telopeptide of type I collagen (ICTP). The other markers showed good discrimination and response at medium and high levels of disease activity. NTX, total Pyd and Dpd, free Pyd and Dpd, and ICTP are all pyridinoline cross-link-based markers, but discrimination and response by NTX was generally much greater than for the others. Determination of the mechanism of the difference between NTX and other cross-link measures is necessary for appropriate use of the markers and may also lead to a better understanding of the bone resorption process. It has been proposed that the greater sensitivity and discrimination of NTX is because it is more bone-specific than the other cross-link markers with significant amounts of free Pyd and Dpd coming from nonbone sources. We propose another model where the proportion of peptide-bound cross-links such as NTX may be increased in high bone turnover states partly due to a rate-limiting step in their degradation to free cross-links. Conditions with high bone resorption rates would have high levels of NTX that would decline rapidly when resorption rates fall to a level where the capacity to degrade NTX matches the rate of production.

Interspinous process implants, used to augment lumbar spine surgery, putatively induce a local segmental lumbar kyphosis yet few investigations outline the effect in vivo on thoracolumbar sagittal curvature. Changes in lumbar skeletal alignment and posture have traditionally relied upon radiographic and back surface spinal curvature measurements, respectively.Lumbar lordosis curvature in 10 healthy subjects (6F, 4M; mean age 36 years) and 10 interspinous implant lumbar surgery patients (5F, 5M; mean age 51 years) was assessed with rasterstereography at baseline and at 6 weeks. Skeletal lumbar lordosis in standing was measured from lateral erect radiography pre- and 6 weeks post-operatively in the surgical cohort, and compared to angulation obtained for surface lordosis curvature derived from rasterstereography.Repeatable measurement of standing lumbar lordosis from rasterstereographic back shape imaging in healthy volunteers and lumbar surgery cases was demonstrated. Reductions of 0.6 (NS) in healthy and 3.1 (significant, P0.001) in surgical subjects were recorded for surface lumbar lordosis angle between the 6 week time-points. Slight flattening of the segmental angle and regional lordosis after DIAM surgery was revealed by radiography. Skeletal and surface lumbar lordosis changes were uncorrelated preoperatively (rho=0.28) and postoperatively (rho=0.26).Rasterstereography is sensitive in assessing lumbar lordosis changes in healthy and lumbar surgical individuals over time. Surgery with DIAM for lumbar pathology may result in an initial mild flattening of lordosis. Serial investigations of spinal curvature after surgery with DIAM interspinous implant are warranted in order to better understand the time-course of spinal posture changes of such cases.

Two-dimensional areal bone mineral density (aBMD) of the proximal femur measured by three-dimensional quantitative computed tomography (QCT) in 91 elderly women was compared to dual-energy X-ray absorptiometry (DXA) aBMD results measured in the same patients. The measurements were highly correlated, though QCT aBMD values were marginally lower in absolute units. Transformation of the QCT aBMD values to T score values using National Health and Nutrition Examination Survey (NHANES) DXA-derived reference data improved agreement and clinical utility.World Health Organization guidelines promulgate aBMD (g cm(-2)) measurement of the proximal femur for the diagnosis of bone fragility. In recent years, there has been increasing interest in QCT to facilitate understanding of three-dimensional bone structure and strength.To assist in comparison of QCT-derived data with DXA aBMD results, a technique for deriving aBMD from QCT measurements has been developed.To test the validity of the QCT method, 91 elderly females were scanned on both DXA and CT scanners. QCT-derived DXA equivalent aBMD (QCT(DXA) aBMD) was calculated using CTXA Hip software (Mindways Software Inc., Austin, TX, USA) and compared to DXA-derived aBMD results.Test retest analysis indicated lower root mean square (RMS) errors for CTXA; F test between CTXA and DXA was significantly different at femoral neck (FN) and trochanter (TR) (p0.05). QCT underestimates DXA values by 0.02 +/- 0.05 g cm(-2) (total hip, TH), 0.01 +/- 0.04 g cm(-2) (FN), 0.03 +/- 0.07 g cm(-2) (inter-trochanter, IT), and 0.02 +/- 0.05 g cm(-2) (TR). The RMS errors (standard error of estimate) between QCT and DXA T scores for TH, FN, IT, and TR were 0.36, 0.40, 0.39, and 0.49, respectively.This study shows that results from QCT aBMD appropriately adjusted can be evaluated against NHANES reference data to diagnose osteoporosis.

Areal bone mineral density (aBMD), derived from dual-energy X-ray absorptiometry (DXA) scanners is used routinely to infer bone strength. With DXA hip scans there is growing acceptance of the advantages of also measuring bone structural geometric variables, that complement conventional aBMD to improve understanding of bone modelling, remodelling and processes of metabolic bone disease. However, phantoms for assessing structural geometric variables from DXA scans are not widely available, unlike those for aBMD. This study describes the development of such a phantom, simulating the cortical shell of the human femoral neck, using dental plaster as a material radiologically similar to cortical bone. The mass attenuation coefficient of the dental plaster differed by < 1% from cortical bone, over the relevant energy range. Performance testing was carried out with DXA, to determine accuracy and precision of the phantom structural geometry, using its dimensions and composition as 'gold standards'. Accuracy and precision of cortical structural geometry were poor when measured in a simulated 1 mm-thick osteoporotic cortex (5.5% precision and 50% accuracy errors), but improved with increasing cortical thickness. This study demonstrates the limitations of DXA-based Hip Structure Analysis when applied to femora with thin cortices, and indicates improvements in the design of a phantom to better simulate such cortical structures.

We report the engineering of poly(ethylene glycol) (PEG) hydrogel particles using a mesoporous silica (MS) templating method via tuning the PEG molecular weight, particle size, and the presence or absence of the template and investigate the cell association and biodistribution of these particles. An ex vivo assay based on human whole blood that is more sensitive and relevant than traditional cell-line based assays for predicting in vivo circulation behavior is introduced. The association of MS@PEG particles (template present) with granulocytes and monocytes is higher compared with PEG particles (template absent). Increasing the PEG molecular weight (from 10 to 40 kDa) or decreasing the PEG particle size (from 1400 to 150 nm) reduces phagocytic blood cell association of the PEG particles. Mice biodistribution studies show that the PEG particles exhibit extended circulation times (>12 h) compared with the MS@PEG particles and that the retention of smaller PEG particles (150 nm) in blood, when compared with larger PEG particles (>400 nm), is increased at least 4-fold at 12 h after injection. Our findings highlight the influence of unique aspects of polymer hydrogel particles on biological interactions. The reported PEG hydrogel particles represent a new class of polymer carriers with potential biomedical applications.

The proton beam energy of an isochronous 18MeV cyclotron was determined using a novel version of the stacked copper-foils technique. This simple method used stacked foils of natural copper forming 'thick' targets to produce Zn radioisotopes by the well-documented (p,x) monitor-reactions. Primary beam energy was calculated using the (65)Zn activity vs. depth profile in the target, with the results obtained using (62)Zn and (63)Zn (as comparators) in close agreement. Results from separate measurements using foil thicknesses of 100, 75, 50 or 25µm to form the stacks also concurred closely. Energy was determined by iterative least-squares comparison of the normalized measured activity profile in a target-stack with the equivalent calculated normalized profile, using 'energy' as the regression variable. The technique exploits the uniqueness of the shape of the activity vs. depth profile of the monitor isotope in the target stack for a specified incident energy. The energy using (65)Zn activity profiles and 50-μm foils alone was 18.03±0.02 [SD] MeV (95%CI=17.98-18.08), and 18.06±0.12MeV (95%CI=18.02-18.10; NS) when combining results from all isotopes and foil thicknesses. When the beam energy was re-measured using (65)Zn and 50-μm foils only, following a major upgrade of the ion sources and nonmagnetic beam controls the results were 18.11±0.05MeV (95%CI=18.00-18.23; NS compared with 'before'). Since measurement of only one Zn monitor isotope is required to determine the normalized activity profile this indirect yet precise technique does not require a direct beam-current measurement or a gamma-spectroscopy efficiency calibrated with standard sources, though a characteristic photopeak must be identified. It has some advantages over published methods using the ratio of cross sections of monitor reactions, including the ability to determine energies across a broader range and without need for customized beam degraders.

Hip structural analysis (HSA) is a technique for extracting strength-related structural dimensions of bone cross-sections from two-dimensional hip scan images acquired by dual energy X-ray absorptiometry (DXA) scanners. Heretofore the precision of the method has not been thoroughly tested in the clinical setting. Using paired scans from two large clinical trials involving a range of different DXA machines, this study reports the first precision analysis of HSA variables, in comparison with that of conventional bone mineral density (BMD) on the same scans. A key HSA variable, section modulus (Z), biomechanically indicative of bone strength during bending, had a short-term precision percentage coefficient of variation (CV%) in the femoral neck of 3.4-10.1%, depending on the manufacturer or model of the DXA equipment. Cross-sectional area (CSA), a determinant of bone strength during axial loading and closely aligned with conventional DXA bone mineral content, had a range of CV% from 2.8% to 7.9%. Poorer precision was associated with inadequate inclusion of the femoral shaft or femoral head in the DXA-scanned hip region. Precision of HSA-derived BMD varied between 2.4% and 6.4%. Precision of DXA manufacturer-derived BMD varied between 1.9% and 3.4%, arising from the larger analysis region of interest (ROI). The precision of HSA variables was not generally dependent on magnitude, subject height, weight, or conventional femoral neck densitometric variables. The generally poorer precision of key HSA variables in comparison with conventional DXA-derived BMD highlights the critical roles played by correct limb repositioning and choice of an adequate and appropriately positioned ROI.

We report a prospective, randomized, multicenter, open-label 2-year trial of 81 postmenopausal women aged 53-79 years with at least one minimal-trauma vertebral fracture (VF) and low (T-score below - 2) lumbar bone mineral density (BMD). Group HRT received piperazine estrone sulfate (PES) 0.625 - 1.25 mg/d +/- medroxyprogesterone acetate (MPA) 2.5 - 5 mg/d; group HRT/D received HRT plus calcitriol 0.25 microg bd. All with a baseline dietary calcium (Ca) of1 g/ d received Ca carbonate 0.6 g nocte. Final data were on 66 - 70 patients. On HRT/D, significant (P0.001) BMD increases from baseline by DXA were at total body - head, trochanter, Ward's, total hip, intertrochanter and femoral shaft (% group mean delta 4.2, 6.1, 9.3, 3.7, 3.3 and 3.3%, respectively). On HRT, at these 6 sites, significant deltaS were restricted to the trochanter and Wards. Significant advantages of HRT/D over HRT were in BMD of total body (- head), total hip and trochanter (all P = 0.01). The differences in mean delta at these sites were 1.3, 2.6 and 3.9%. At the following, both groups improved significantly -lumbar spine (AP and lateral), forearm shaft and ultradistal tibia/fibula. The weightbearing, site - specific benefits of the combination associated with significant suppression of parathyroid hormone-suggest a beneficial effect on cortical bone. Suppression of bone turnover was significantly greater on HRT/D (serum osteocalcin P = 0.024 and urinary hydroxyproline/creatinine ratio P = 0.035). There was no significant difference in the number of patients who developed fresh VFs during the trial (HRT 8/36, 22%; HRT/D 4/34, 12% - intention to treat); likewise in the number who developed incident nonvertebral fractures. This is the first study comparing the 2 treatments in a fracture population. The results indicate a significant benefit of calcitriol combined with HRT on total body BMD and on BMD at the hip, the major site of osteoporotic fracture.

Bone mineral density (BMD) was measured at three sites (forearm, spine, and hip) using dual X-ray and single-photon absorptiometry in 68 patients with Paget's disease before and after treatment with iv pamidronate. Patients were treated according to the severity of their disease; the mild category (Group I, hydroxyproline excretion (Hyp(E))5.0 micromol/L GF) received 120 mg, the moderate category (Group II, Hyp(E) 5.0-9.99 micromol/GF) 180 mg, and the severe category (Group III,or = 10.0 micromol/GF) 240 mg. Group I was followed for 1 year, and both Groups II and III for 2 years. At the lumbar spine in pagetic bone there were no differences between groups in early responses, with a profound increase 6 months after treatment 20.5 +/- 2.0% above baseline values to 1.403 +/- 0.063 g/cm(2) (mean +/- SEM)(P0.001). This increase in BMD was sustained to 2 years (1.355 +/- 0.078 g/cm(2), P0.001) and was 15.0 +/- 2.2% above baseline values. The pagetic total hip BMD increased after treatment in all groups, with a mean rise of 10.4 +/- 1.4% at 1 year to 1.505 +/- 0.083 g/cm(2) (P0.01). At the pagetic femoral neck the response was similar, with a peak significant rise at 1 year of 10.7 +/- 1.7% to 1.403 +/- 0.097 g/cm(2) (P0.01). In nonpagetic spinal bone there were no differences between the group responses, with a combined mean increase of 4.3 +/- 0.7% at 1 year to 0.999 +/- 0.027 g/cm(2) (P0.01). In both Groups II and III the increase in BMD was significantly higher than baseline values at 1 and 2 years (P0.01). In the nonpagetic total hip BMD remained unchanged over the 2-year period and likewise, there were no significant changes from baseline at the nonpagetic femoral neck site. In the nonpagetic forearm we found a significant loss in BMD at the ultradistal (mainly trabecular), midregion (80% cortical), and proximal shaft (95% cortical) sites in Group III, persisting to 2 years at the latter two sites. The increase in bone density in pagetic bone, persisting at least 2 years, provides a new modality of assessment of the response of pagetic bone to treatment and suggests a mechanism for the reduction in fracture risk in such bone after effective bisphosphonate treatment. Severity-dependent nonpagetic forearm bone loss, persisting to 2 years at cortical sites, suggests a potential drug-induced fracture risk at the forearm and possibly elsewhere in the absence of appropriate preventive cotreatment.

Combined movement examination (CME) of the lumbar spine has been recommended for clinical examination as it confers information about mechanical pain patterns. However, little quantitative study has been undertaken to validate its use in manual therapy practice. This study used computer aided CME to develop a normal reference range, and to guide provisional diagnosis and management. Two cases were assessed, before and after manual therapy using CME, a pain Visual Analogue Scale, the Roland Morris Low Back Pain and Disability Questionnaire and the Short Form (SF-12) Health Survey. Diagnosis and management were guided by comparing each CME pattern with the age and gender matched reference range. Self-reports data and CME total change scores were markedly improved for both cases, particularly for the most painful and restricted CME directions. This report describes how computer-aided CME and a normal reference range may be used objectively to inform a diagnosis and as an outcome measure in cases of mechanical LBP. Future investigations of cases with specific lumbar pathologies are required to validate this concept.

There are limited data detailing the pattern of age and gender-related changes to the thoracic vertebral bodies and intervertebral discs. A retrospective MR investigation, involving T1-weighted midsagittal images from 169 cases, was undertaken to examine age influences on the anterior wedge (anteroposterior height ratio or Ha/Hp), biconcavity (midposterior height ratio or Hm/Hp), and compression indices (posterior height/anteroposterior diameter or Hp/D) of the thoracic vertebral bodies. Disc degenerative changes in the annulus, nucleus, end-plate and disc margin were noted on T2-weighted sagittal images for the 169 cases, based on a 3-level grading system. A linear age-related decline in the Ha/Hp and Hm/Hp indices was noted. The Hp/D index increased during the first few decades of life, then decreased gradually thereafter. The prevalence of abnormal findings in the annuli, nuclei and disc margins increased with increasing age, particularly in the mid and lower thoracic discs. Greater disc degenerative changes were observed in males. These findings provide further insight into the nature of thoracic vertebral shape changes across the lifespan, and the typical patterns of degeneration of the thoracic intervertebral discs.

Objective. The aim of this study was to examine age, gender, and segmental trends in thoracic vertebral body shape, utilising thoracic spine magnetic resonance images involving an age range spanning the life span. Design. A quantitative, cross-sectional, retrospective study design involving a sample of convenience. Background. Thoracic vertebral shape data are commonly derived from radiographic resources. The non-ionising properties of magnetic resonance imaging and availability of digital data for image analysis suggest potential for MR-based morphometric studies. For the thoracic spine, there is limited vertebral shape data on males, while few studies have examined the pattern of age-related changes across the life span. Methods. Morphometry was performed on 220 mid sagittal T1-weighted MR images using image analysis software. Three indices of vertebral shape were utilised: the antero-posterior height ratio or anterior wedge index, mid-posterior height ratio or biconcavity index, and ratio of posterior vertebral height to mid antero-posterior diameter or compression index. Results. Different segmental patterns were noted for the vertebral shape indices. Significantly lower mean values were noted in males for the compression index. Age trends were significant, with a linear age-related decline demonstrated for the anterior wedge and biconcavity indices, and a quadratic trend noted for the compression index. Conclusions. Thoracic vertebral body shape may be uniquely described using specific shape indices, for examining various segmental, gender and age-associated changes. Relevance These results suggest the importance of defining specific reference criteria for thoracic vertebral body shape indices, particularly age-related data encompassing a wide age range. Magnetic resonance studies enable interpretation of vertebral shape data in relation to the wide spectrum of pathologies afflicting the thoracic spine, without the concerns of ionising radiation.

In a randomized trial involving 71 postmenopausal osteoporotic women with vertebral compression fractures, radiocalcium absorption studies using the (45)Ca single isotope method (alpha) were performed at baseline and after 8 months of treatment with either continuous combined hormone replacement therapy (HRT, as piperazine estrone sulfate 0.625-0.937 mg daily +/- medroxyprogesterone acetate 2.5 mg daily depending on uterine status) or HRT plus calcitriol 0. 25 microg twice daily. A calcium supplement of 600 mg nocte was given to only those women who had a daily calcium intake of less than 1 g per day at baseline, as assessed by recalled dietary intake. There was a significant decrease [0.74 (+/- 0.35 SD) to 0.58 (+/- 0. 22), Dalpha = -0.17 (+/- 0.26), p0.0005] in alpha at 8 months compared with baseline in the HRT-treated group, but a significant increase [0.68 (+/- 0.31) to 0.84 (+/- 0.27), Dalpha = +0.16 (+/- 0. 30), p0.003] in the HRT-plus-calcitriol treated patients, resulting in alpha being significantly higher after 8 months in the latter group than in the HRT-only group. Although 72% of the patients had been supplemented with calcium between the first and second studies, separate analyses revealed that the change in calcium intake had not affected the result. Further breakdown of the groups into baseline 'normal' absorbers (alpha/=0.55) and 'malabsorbers' (alpha0.55) revealed that alpha decreased with HRT treatment only in the normal absorbers, and remained stable in the malabsorbers. Conversely, following HRT plus calcitriol treatment, alpha increased only in the malabsorbers, the normal absorbers in this group remaining unchanged. In conclusion, our data show that HRT, of the type and dose used in this study, did not produce an increase in absorption efficiency; it was in fact associated with a fall. Increased absorption efficiency cannot be achieved unless calcitriol is used concurrently, and then only in patients with malabsorption. Calcitriol also had a significant effect in normal absorbers in that it prevented the decline in alpha seen with HRT alone, and thus should be considered in all patients with postmenopausal osteoporosis treated with HRT.

Twenty-five years after the first paper on etidronate in Paget's disease, there are few published papers that address bisphosphonate resistance as a specific clinical phenomenon. We report our data from two studies. Study 1 is a retrospective study of 20 patients with moderate to severe disease who were treated with intravenous (iv) pamidronate (221 +/- 18 mg [SEM]; range 60-360 mg), and after biochemical remission and relapse were retreated with generally larger iv dosage (293 +/- 28 mg; range 180-600 mg). The nadir bone turnover values were similar: plasma alkaline phosphatase (pAP) in 20 patients was 243 +/- 40 IU/l (mean +/- SEM) after the first course, and 267 +/- 44 IU/l after the second (reference range [RR] 35-135 IU/l). Likewise, fasting urinary hydroxyproline excretion (HypE) in 14 of the 20 patients was 4.5 +/- 1.1 micromol/LGF and 4.1 +/- 0.9 micromol/LGF, respectively (RR 0.40-1.92 micromol/LGF). However the minimum duration of biochemical remission was significantly shorter after the second course-10.9 +/- 1.7 months (first) and 5.6 +/- 0.9 months (second) (p0.03; Friedman's ANOVA n = 17). A subgroup of 10 patients who were followed for three courses showed a significantly higher pAP nadir in the third course. Study 2 is a prospective study of 40 patients, 23 previously untreated (NILPREV) and 17 previously treated with iv pamidronate (PAMPREV) and in biochemical relapse, who were randomly allocated to either oral alendronate 40 mg daily in 3 month units, or iv pamidronate 60 mg every 3 months. Treatment was continued until pAP and fasting urinary deoxypyridinoline/creatinine (Dpy/Cr) ratios (RR 5-27 micromol/mol) were both in the reference range, or a clear plateau in each marker developed. At baseline, there were no significant differences in either marker between the two NILPREV groups and between the two PAMPREV groups. Using log-transformed data, in NILPREV the pAP reductions were significant and similar over the first 6 months. However, although each Dpy/Cr reduction was also significant, the difference in responses favored alendronate (p0.015). In PAMPREV both markers showed no significant response to pamidronate; comparison showed a significantly greater response to alendronate (pAP p0.02; Dpy/Cr p0.002). Using two-way ANOVA, the pAP responses to alendronate in NILPREV and PAMPREV were similar and those to pamidronate were different (p = 0.034). The percentage of patients with both markers in the RR at 6 months or earlier were identical in NILPREV patients: alendronate 87% and pamidronate 87%. However in PAMPREV they were different: alendronate 83% and pamidronate 0% (p = 0.003). These data indicate: 1) patients treated with the same aminobisphosphonates for two courses show similar nadir values of bone turnover markers but a shorter remission time after the second course. In a third course the nadirs are significantly higher; and 2) in the alendronate/pamidronate comparison, NILPREV and PAMPREV patients showed similar pAP responses to alendronate, but significantly different responses to pamidronate. Thus, patients showing acquired partial resistance to one aminobisphosphonate (usually after two or more previous courses) are still capable of remission after exposure to another compound of the same class.

Morphometric X-ray absorptiometry (MXA) offers some potential advantages over spinal radiography for the quantitative evaluation of vertebral fractures in individuals with spinal osteoporosis. This ex vivo study examined the accuracy of MXA and quantitative morphometry (QM) for the evaluation of vertebral height, in relation to direct measurements from cadaveric vertebral columns. Spinal radiographs and MXA scans were obtained from nine cadaveric vertebral columns (mean age at death 64 years). Anterior, middle and posterior vertebral body heights of all segments from T4 to L4 were measured interactively using MXA software and QM (from the spinal radiographs), and compared with direct measurements derived using digital callipers following cadaveric dissection. Coefficients of variation for repeat QM and MXA scan analysis were less than 2%. The QM and MXA measurements were both strongly correlated (r 2= 0.99) with the direct measurements, with accuracy errors of between 2.6% and 4.3%, and 4.5% and 4.8%, for QM and MXA respectively. At the three measurement sites, analysis of measurement differences showed that QM tended to overestimate the true height and MXA tended towards under-estimation. The mean difference between the direct measurements and QM measurements ranged from 2.7% to 8.7%, and the mean difference between direct and MXA measurements ranged from –2.9% to 4.1%. There was strong linear association between the MXA and QM measurements (r 2= 0.99) with mean differences at the three measurement sites ranging from –4.1% to –5.9%. Under the optimal (ex vivo) scanning conditions used in this study, MXA is comparable to spinal radiography for the assessment of vertebral height. Further studies are required to determine the conditions under which satisfactory MXA image resolution and measurement accuracy can be achieved in a clinical population.

It has been shown previously that intravenous pamidronate treatment for severe Paget's disease is associated with appendicular bone loss. This 2 year study was designed to determine whether cotreatment with calcitriol and a calcium supplement would prevent this. Intravenous pamidronate was used to treat 49 patients with symptomatic Paget's disease. Patients were stratified into two groups of differing biochemical severity based on hydroxyproline excretion (HypE) expressed as micromoles per liter of glomerular filtrate (GF): (1) a severe group with HypE10 micromol/L GF; and (2) a moderate group with HypE 5-10 micromol/L GF. Within each group, patients were randomly allocated to receive supplements of calcium and calcitriol (supplemented) or no supplements (unsupplemented) after initiation of pamidronate therapy. The severe group received 360 mg of pamidronate as six doses of 60 mg once weekly and the moderate group received 240 mg as four weekly doses of 60 mg. Patients were followed for 24 months following treatment and had serial bone densitometry of the forearm measured as well as urine and plasma biochemistry. When the groups were combined, the unsupplemented patients showed a decrease in bone mineral density (BMD) at the ultradistal forearm site, which persisted to 24 months. Those supplemented with calcium and calcitriol showed an increase in BMD and the difference between the two groups was significant at all times posttreatment (p0.03). When the groups were analyzed separately, those with moderate disease again showed significant differences in BMD between supplemented and unsupplemented patients at all timepoints. In the severe group, the differences did not reach statistical significance due to smaller patient numbers. Similar changes in BMD were also observed at the forearm shaft site. When serial parathyroid hormone (PTH) levels (with the moderate and severe groups combined) were plotted against time since treatment the rise in PTH in the supplemented patients was less than the rise in the unsupplemented patients (p0.04). These results suggest that forearm bone loss after intravenous pamidronate treatment for moderate-to-severe Paget's disease can largely be prevented by administration of calcium and calcitriol. The mechanism may be a blunting of the secondary hyperparathyroidism that occurs after intravenous pamidronate. These findings may have wider application in moderate-to-severe Paget's disease treated with other bisphosphonates.

In 2010, the Australian Institute of Health and Welfare published a report examining the characteristics of Australian women diagnosed with ductal carcinoma in situ (DCIS). This study identified the characteristics of women who were diagnosed with DCIS in Western Australia (WA) 1996–2005, and built on a national study by determining the rate of second operation and breast cancer events (BCE) in WA. A retrospective analysis of data from the WA Cancer Registry and the Hospital Morbidity Database was undertaken. The main outcome measures were histological characteristics, second operation rate, breast cancer events. A total of 1356 cases of DCIS were diagnosed in WA between 1996 and 2005, with a minimum 5-year follow-up. The age-standardised incidence rate in 2005 was 15.4 per 100,000 women. 72 % of patients received breast-conserving therapy for primary treatment, 18 % of patients requiring a second operation to obtain adequate margins and 35 % of patients received postoperative radiotherapy. 17.3 % of cases had a subsequent BCE, with the 5- and 10-year probabilities being 4.36 and 8.27 %, respectively. A BCE was significantly associated with age (p

One of the pathological hallmarks of Alzheimer's disease is the presence of amyloid-β plaques in the brain and the major constituent of these plaques is aggregated amyloid-β peptide. New thiosemicarbazone-pyridylhydrazine based ligands that incorporate functional groups designed to bind amyloid-β plaques have been synthesized. The new ligands form stable four coordinate complexes with a positron-emitting radioactive isotope of copper, (64)Cu. Two of the new Cu(II) complexes include a functionalized styrylpyridine group and these complexes bind to amyloid-β plaques in samples of post-mortem human brain tissue. Strategies to increase brain uptake by functional group manipulation have led to a (64)Cu complex that effectively crosses the blood-brain barrier in wild-type mice. The new complexes described in this manuscript provide insight into strategies to deliver metal complexes to amyloid-β plaques.

DXA-derived bone structural geometry has been reported extensively but lacks an accuracy standard. In this study, we describe a novel anthropometric structural geometry phantom that simulates the proximal femur for use in assessing accuracy of geometry measurements by DXA or other X-ray methods. The phantom consists of seven different interchangeable neck modules with geometries that span the range of dimensions in an adult human proximal femur, including those representing osteoporosis. Ten repeated hip scans of each neck module using two current DXA scanner models were performed without repositioning. After scanner specific calibration, hip structure analysis was used to derive structural geometry. Scanner performance was similar for the two manufacturers. DXA-derived HSA geometric measurements were highly correlated with values derived directly from phantom geometry and position; R2 between DXA and phantom measures were greater than 94 % for all parameters, while precision error ranged between 0.3 and 3.9 %. Despite high R2 there were some systematic geometry errors for both scanners that were small for outer diameter, but increasing with complexity of geometrical parameter; e.g. buckling ratio. In summary, the anthropometric phantom and its fabrication concept were shown to be appropriate for evaluating proximal femoral structural geometry in two different DXA systems.

Background Spinal rotation couples with lateral flexion as a composite movement. Few data report the in vivo mechanical deformation of the nucleus pulposus following sustained rotation. MRI provides a non-invasive method of examining nucleus pulposus deformation by mapping the hydration signal distribution within the intervertebral disc. Methods T1 weighted coronal and sagittal lumbar images and T2 weighted axial images at L1–2 and L4–5 were obtained from 10 asymptomatic subjects (mean age 29, range: 24–34 years) in sustained flexed and extended positions plus combined positions of left rotation with flexion and extension. Nucleus pulposus deformation was tracked by mapping the change in hydration profiles from coronal and sagittal pixel measurements. Findings An average sagittal change in position of 44° (SD 14.5°) from flexion to extension was recorded between L1 and S1 (range: 18°– 60°) resulting in a mean anterior nucleus pulposus deformation of 16% of disc hydration profile (range: 3.5%–19%) in 19/20 discs. When rotation was combined with either flexion or extension, mean coronal deformation was 4.8% (SD—5.1%; range: 0.4%–15%). Lateral nucleus pulposus deformation direction varied in rotation (44% deformed left and 56% deformed right). Intersegmental lateral flexion direction more strongly predicted nucleus pulposus deformation direction with 75% deforming contralaterally. Interpretation Nucleus pulposus deformation direction in young subjects was more predictable following sagittal position change than in rotation combined with flexion or extension. Deformation magnitude was reduced in rotated positions. Intersegmental lateral flexion was a stronger predictor of nucleus pulposus deformation direction.

Average dietary calcium intake and energy intake of 113 18-year-old university students in Western Australia was examined. Four-day, weighted diet records, including 1 weekend day, were completed by the subjects. A large proportion of the students (68%) had an average daily calcium consumption below the 800 mg recommended by the National Health and Medical Research Council of Australia. A strong positive association was also found between dietary calcium and dietary energy intakes. Many young women on self-imposed energy reduction diets are at risk of a dietary calcium intake deficit at a time when it should be enhanced. These findings are significant for nursing practice as they indicate the need for further health education concerning the importance of dietary calcium in young women.

Segmental variations in vertebral body cancellous bone architecture throughout the thoracolumbar spine were examined using histomorphometry and microradiography, and compared to bone mass measured using dual energy X-ray absorptiometry. In six human vertebral columns (T1 to L5) bone mineral content (BMC) and bone mineral density (BMD) of each vertebral body was determined in the lateral projection. Sagittal plane cancellous bone architecture was assessed from two-dimensional surface stained images and microradiographs of two 1 mm thick sections at each vertebral level. Computer-assisted image analysis was used to measure the total bone area (TBA), mean trabecular width (MTW) and trabecular number (TbN) from the stained images, and the skeletonized network length (SNL) from the radiographic images. Consistent segmental trends were observed for all structural parameters across the six columns examined. Higher TBA and TbN values were observed in the upper thoracic segments and decreased caudally. The MTW was relatively constant in the thoracic vertebrae before increasing in the lumbar spine. Pooled correlations between TBA and the bone density measurements were poor (BMC: r = 0.17, BMD: r = 0.25), while the TBA and SNL were only moderately correlated (r = 0.42). In conclusion, histomorphometric and radiological measurements appear to provide different information about cancellous bone structure. Bone structure is poorly correlated to integral measurements of bone mass. The consistent segmental variations in bone architecture appear to reflect a skeletal response to the relative extent of habitually applied loads in different regions of the spine.

Some previously immunodeficient HIV patients responding to antiretroviral therapy display poor recovery of CD4⁺ T cells. Evaluation of the contribution of thymic function requires sensitive detection and quantitation of metabolically active thymic tissue. We describe patients with low but detectable thymopoiesis assessed as circulating CD4⁺ naive T cells expressing CD31. High-resolution computed tomography and PET scans found no residual thymic tissue even though metabolic activity was demonstrable by PET in lymph nodes.

Structural geometric parameters at neck of the proximal femur were obtained using DXA-derived hip structural analysis (APEX 3) and quantitative computed tomography-derived (BIT QCT) techniques in 237 elderly females. Linear correlations for parameters ranged from 0.45 to 0.90. The average value of the subperiosteal width, as determined by the two techniques, was the same; variables dependent on mass measurements were different. There has been increasing interest in using bone structural geometry to assess bone fragility to complement bone mineral mass. The objective of this study is to compare structural geometrical differences between “2D” DXA-derived and “3D” QCT-derived techniques in unselected clinical cases. All 237 females had both DXA and QCT assessments of femoral neck structural geometry. Variables compared were areal bone mineral density, cross-sectional area (CSA), cross-sectional moment of inertia (CSMI), section modulus (Z), averaged cortical thickness (Ct), endosteal width (ESW), subperiosteal width (W), and buckling ratio (BR). Correlation of femoral neck variables ranged from 0.45 for ESW to 0.90 for CSA. APEX 3 and BIT QCT-derived femoral neck W values were numerically similar. However CSA, CSMI, Z and Ct values measured by APEX 3 were higher and ESW and BR values were lower than corresponding BIT QCT. 2D DXA structural analysis of neck of femur is related to but different from same parameters calculated from true 3D images obtained by CT. Femoral neck size values are similar for DXA and QCT, but structural geometrical variables dependent on mass calibration standards, location of neck ROI and mathematical derivation techniques are different.

Lateral scanning with dual energy X-ray absorptiometry (DXA) was undertaken on 153 thoracic and lumbar vertebral bodies from nine individuals (mean age 67; range 34–92 years) to establish their bone mineral content (BMC). All specimens were subsequently de-fatted and ashed to compare ash weight with BMC of the Tl to L5 segments. Linear regression analysis indicated a higher correlation between BMC and measured ash weights for each vertebral column (range: r = 0.97 0.99), with error analysis for all vertebrae tested showing a standard error of 0.40 g, or 10.8%. For the L2 4 segments the accuracy error was 0.50 g or 7.9%. In both cases there was a mean trend towards underestimation of ash weight. Mean BMC values of the T1 to T5 segments were similar before a progressive increase caudally. These data affirm the utility of DXA for determining bone mineral content in the vertebral column across wide ranges of age, and segmental and bone density.

International audience; The Australian Imaging, Biomarkers and Lifestyle (AIBL) study of aging, a participant of the worldwide Alzheimer's Disease Neuroimaging Initiative (ADNI), performed (11)C-Pittsburgh Compound B (PiB) scans in 177 healthy controls (HC), 57 mild cognitive impairment (MCI) subjects, and 53 mild Alzheimer's disease (AD) patients. High PiB binding was present in 33% of HC (49% in ApoE-epsilon4 carriers vs 21% in noncarriers) and increased with age, most strongly in epsilon4 carriers. 18% of HC aged 60-69 had high PiB binding rising to 65% in those over 80 years. Subjective memory complaint was only associated with elevated PiB binding in epsilon4 carriers. There was no correlation with cognition in HC or MCI. PiB binding in AD was unrelated to age, hippocampal volume or memory. Beta-amyloid (Abeta) deposition seems almost inevitable with advanced age, amyloid burden is similar at all ages in AD, and secondary factors or downstream events appear to play a more direct role than total beta amyloid burden in hippocampal atrophy and cognitive decline.

Human lactation is associated with transient decreases in bone mineral density (BMD). Bone strength is related to both mass and structural geometry. This study investigated longitudinal changes of hip bone strength during lactation using hip structural analysis (HSA), which determines hip structural geometry (including areal BMD, BMDa) from dual-energy X-ray absorptiometry scans (DXA). Forty-eight lactating women were studied longitudinally at the proximal femur using DXA at approximately 2 weeks postpartum, peak-lactation and post-lactation. Nonpregnant, nonlactating women (NPNL, n = 23) were studied concurrently at baseline and after 1 year. Hip scans were analysed using HSA at the narrow neck, intertrochanter and proximal shaft. No significant change (> 0.05) was observed in NPNL women for any measurement. In contrast, for lactating women BMDa decreased significantly from 2 weeks postpartum to peak-lactation at narrow neck (−2.8%), intertrochanter (−3.2%) and shaft (−1.4%). Cross-sectional area (CSA) decreased at narrow neck (−3.4%) and intertrochanter (−2.7%). There were no significant changes in bone width. Section modulus decreased at intertrochanter (−2.1%). At shaft, cortical thickness decreased (−1.7%) and buckling ratio increased (2.3%). By post-lactation, measurements were not significantly different from 2 weeks postpartum except for decrements in BMDa (−1.1%) and CSA (− 1.2%) at the shaft. During the study, lactating women lost 5% of their body weight. Adjusting for weight changes decreased the magnitude and significance of HSA changes at peak-lactation and by post-lactation there were no significant differences from 2 weeks postpartum. Calcium intake was not a significant predictor of changes in HSA variables. In conclusion, lactation is associated with significant but transient changes in hip BMD and structural geometry. Changes in body weight but not calcium intake were associated with these changes. These small changes at the hip during lactation occurred mainly at internal surfaces and had minimal impact on bending or compressive strength., Research highlights ►Lactation is associated with transient changes in hip BMD and structural geometry. ►Body weight, but not calcium intake, is associated with changes in bone. ►Lactation associated changes occur mainly at endosteal surfaces of hip. ►Changes have minimal impact on hip bending and compressive strength.

Osteoporosis is a complex disorder and commonly leads to fractures in elderly persons. Genome-wide association studies (GWAS) have become an unbiased approach to identify variations in the genome that potentially affect health. However, the genetic variants identified so far only explain a small proportion of the heritability for complex traits. Due to the modest genetic effect size and inadequate power, true association signals may not be revealed based on a stringent genome-wide significance threshold. Here, we take advantage of SNP and transcript arrays and integrate GWAS and expression signature profiling relevant to the skeletal system in cellular and animal models to prioritize the discovery of novel candidate genes for osteoporosis-related traits, including bone mineral density (BMD) at the lumbar spine (LS) and femoral neck (FN), as well as geometric indices of the hip (femoral neck-shaft angle, NSA; femoral neck length, NL; and narrow-neck width, NW). A two-stage meta-analysis of GWAS from 7,633 Caucasian women and 3,657 men, revealed three novel loci associated with osteoporosis-related traits, including chromosome 1p13.2 (RAP1A, p = 3.6×10−8), 2q11.2 (TBC1D8), and 18q11.2 (OSBPL1A), and confirmed a previously reported region near TNFRSF11B/OPG gene. We also prioritized 16 suggestive genome-wide significant candidate genes based on their potential involvement in skeletal metabolism. Among them, 3 candidate genes were associated with BMD in women. Notably, 2 out of these 3 genes (GPR177, p = 2.6×10−13; SOX6, p = 6.4×10−10) associated with BMD in women have been successfully replicated in a large-scale meta-analysis of BMD, but none of the non-prioritized candidates (associated with BMD) did. Our results support the concept of our prioritization strategy. In the absence of direct biological support for identified genes, we highlighted the efficiency of subsequent functional characterization using publicly available expression profiling relevant to the skeletal system in cellular or whole animal models to prioritize candidate genes for further functional validation., Author Summary BMD and hip geometry are two major predictors of osteoporotic fractures, the most severe consequence of osteoporosis in elderly persons. We performed sex-specific genome-wide association studies (GWAS) for BMD at the lumbar spine and femor neck skeletal sites as well as hip geometric indices (NSA, NL, and NW) in the Framingham Osteoporosis Study and then replicated the top findings in two independent studies. Three novel loci were significant: in women, including chromosome 1p13.2 (RAP1A) for NW; in men, 2q11.2 (TBC1D8) for NSA and 18q11.2 (OSBPL1A) for NW. We confirmed a previously reported region on 8q24.12 (TNFRSF11B/OPG) for lumbar spine BMD in women. In addition, we integrated GWAS signals with eQTL in several tissues and publicly available expression signature profiling in cellular and whole-animal models, and prioritized 16 candidate genes/loci based on their potential involvement in skeletal metabolism. Among three prioritized loci (GPR177, SOX6, and CASR genes) associated with BMD in women, GPR177 and SOX6 have been successfully replicated later in a large-scale meta-analysis, but none of the non-prioritized candidates (associated with BMD) did. Our results support the concept of using expression profiling to support the candidacy of suggestive GWAS signals that may contain important genes of interest.

Hip structural analysis (HSA) has been developed over 20 yr, applied extensively in research, and has demonstrated useful outcomes associating bone structural geometry with bone fragility (research-HSA or r-HSA). In 2007, Hologic Inc. (Bedford, MA) incorporated HSA with some modifications as an option for Hologic dual-energy X-ray absorptiometry (DXA) scanners (clinical HSA or c-HSA). This brought HSA from the research environment into the clinical environment. This article reports a comparison of r-HSA and c-HSA implementations using DXA scans from a group of 191 females. Bland-Altman plots at the narrow-neck (NN) HSA region indicated higher r-HSA areal bone mineral density (mean difference: 0.27 g/cm(2); 21.7% [of mean]); cross-sectional area (0.63 cm(2); 18.7%); cross-sectional moment of inertia (0.26 cm(4); 11.1%), and section modulus (0.22 cm(3); 14.5%) compared with c-HSA. The converse was observed for NN subperiosteal width (-0.09 cm; 3.1%). High linear correlations (r(2) > 0.81) were found between r-HSA and c-HSA NN structural geometric outcomes, with the exception of neck shaft angle (r(2) > 0.47). As differences were significant (p < 0.001), slopes and intercepts are provided to enable linear transformations from r-HSA to corresponding c-HSA structural geometric data.

Osteoporosis among older women is a major public health problem. We studied the effects of three approaches to the prevention of osteoporosis in women with low bone density.One hundred twenty postmenopausal women (mean [+/- SD] age, 56 +/- 4) who were selected because they had low forearm bone density were enrolled in a double-blind, placebo-controlled, randomized study comparing the effects of an exercise regimen (exercise group, n = 41), exercise plus dietary calcium supplementation (exercise-calcium group, n = 39), and exercise plus continuous replacement of estrogen and progesterone (exercise-estrogen group, n = 40). Periodically during the two-year study period, we measured the women's bone density at three forearm sites, measured indexes of calcium metabolism, and recorded symptom scores. A comparison group of 42 women (mean age, 55.5 +/- 3.1) with normal bone density was also followed for two years.Significant bone loss in the distal forearm occurred in the group with normal bone density (control group) and the exercise group (change, -2.7 percent and -2.6 percent of the base-line value per year, respectively). Bone loss at the distal forearm site was significantly lower in the exercise-calcium group (-0.5 percent of the base-line value per year), and bone density increased at this site in the exercise-estrogen group (+2.7 percent of the base-line value per year). Bone loss at the median forearm site was significantly lower in the exercise-calcium group (-1.3 percent of the base-line value per year) than in the exercise group (-2.4 percent), and bone density at this site increased significantly in the exercise-estrogen group (+0.8 percent of the base-line value per year). Breast tenderness occurred in 47 percent of the women in the exercise-estrogen group but in only 20 percent in the other two treatment groups. Vaginal bleeding occurred at some time in 52 percent of the women who had not had a hysterectomy in the exercise-estrogen group, as compared with 11 percent and 12.5 percent, respectively, in the exercise and exercise-calcium groups.In postmenopausal women with low bone density, bone loss can be slowed or prevented by exercise plus calcium supplementation or estrogen-progesterone replacement. Although the exercise-estrogen regimen was more effective than exercise and calcium supplementation in increasing bone mass, it also caused more side effects.

The healthcare cost of managing osteoporotic fractures is projected to rise because of the change in population demographics. To reduce the fracture epidemic, strategies are needed to identify those at risk early to allow preventative intervention to be implemented. The aim of this study was to investigate if low-cost community-based assessments, such as calcaneal ultrasound and falls risk assessments, can discriminate a group of elderly women at risk of osteoporotic fracture from those at lower risk. Over the period of 2002-2003, 104 community-dwelling women (mean age 71.3, standard deviation 5.8) were recruited via various modes including advertisements in community newspaper and community centres. These women underwent dual-energy X-ray absorptiometry bone mineral density (BMD) and calcaneal quantitative ultrasound (QUS) measurements; spinal radiography; and performance-based assessment of strength, mobility and balance. The women were classified into a 'high risk' (osteoporotic) group, based on low BMD (T-score of/= -2.5) and/or a history of a fragility fracture, or a 'low risk' (non-osteoporotic) group. Multiple stepwise logistic regression identified decreased speed of sound (SOS), a QUS variable, and poor mobility [slower performance in the timed 'up and go' (TUG) task], as significant discriminators, adjusted for age [SOS: adjusted odds ratio (OR) = 2.96, 95% confidence interval (CI) = 1.64-5.12, P0.001; TUG: adjusted OR = 1.69, 95% CI = 1.04-2.73, P = 0.031]. This result suggests that there may be a potential role for primary healthcare practitioners to use calcaneal QUS and functional mobility assessment (TUG) to screen for post-menopausal women at risk of osteoporotic fracture in community settings.

Individuals with existing vertebral fractures may not be aware that they are at high risk of subsequent fractures. We investigated if calcaneal quantitative ultrasonometry (QUS) and assessment of thoracic kyphosis could discriminate a group of older women with prevalent vertebral fracture from those without.One hundred four women (mean age 71.3 +/- 5.8 yrs) underwent dual-energy x-ray absorptiometry (DEXA) bone mineral density (BMD; lumbar spine and hip), calcaneal QUS, and video rasterstereographic thoracic kyphosis measurements. They were dichotomized into a group with prevalent vertebral fracture (VF, n = 24) or without vertebral fracture (NVF, n = 80).Univariate variables associated with the VF group included broadband ultrasound attenuation (BUA; age-adjusted OR 1.96, 95% CI 1.12-3.42, p = 0.018); speed of sound (SOS; age-adjusted OR 2.01, 95% CI 1.09-3.70, p = 0.026); and thoracic kyphosis (age-adjusted OR 1.72, 95% CI 1.01-2.92, p = 0.049). A composite model (BUA and thoracic kyphosis) had higher area under the receiver-operating characteristic curve (AUC = 0.75) compared to lumbar spine DEXA BMD (AUC = 0.50, p = 0.0004) and total hip DEXA BMD (AUC = 0.60, p = 0.057).Reduced calcaneal QUS values and greater thoracic kyphosis were found to be significantly associated with the group of women with prevalent vertebral fractures. A composite risk score (BUA and thoracic kyphosis) had better discriminatory power than the individual risk factor of (low) DEXA BMD.

Oral (44Ca: 0.13-0.20 mmol) and intravenous (42Ca: 0.02-0.037 mmol) isotopically enriched stable calcium (Ca) tracers were given together with an oral dose of 2.5 mmol of natural Ca to normal subjects. Blood and urine samples were collected up to 24 h after the tracer doses and atom fractions (AFs) of these tracers (relative to natural Ca) were measured by high-precision thermal ionization mass spectrometry (TIMS). The time-dependent fractional rate of oral dose absorbed and true fractional intestinal Ca absorption (alpha) were derived from the Afs by mathematical deconvolution. After 6 h, the ratio AF oral tracer/AF intravenous tracer in blood equalled that in urine and did not change thereafter. Reproducibility of the combination of chemical precipitation of Ca (from a urine standard) and subsequent TIMS measurements, in nine runs over 13 months, was 1.2% (coefficient of variation). This was in accord with the within-run reproducibility. An estimate of alpha derived from a single blood or urine measurement was 6-10% higher than the reference value obtained by deconvolution. This discrepancy could be explained by a correction factor depending, in part, on the elapsed time for peak Ca intestinal absorption rate. Instrumentally induced mass fractionation, as well as contributions from radiogenic Ca, had a significant effect on the accuracy and reproducibility of the ratio of AFs of tracers in blood and urine.

The foramen ovale is usually obliterated following establishment of the adult circulation but remains patent in 25% of individuals. This potential communication between the venous and arterial circulations can allow thromboembolic material to bypass the lungs and enter the systemic circulation. We report two cases of paradoxical embolization through a patent foramen ovale following acute large pulmonary embolism (PE) and discuss the factors that predispose to paradoxical embolization following PE.

Background The nucleus pulposus deforms towards an area of least compression in response to offset loading, however, there is a lack of data reporting the deformation patterns of nuclear material in rotated positions of the lumbar spine. Our purpose was to assess a novel methodology using MRI to track nuclear deformation in response to flexion and extension positions, and the combined positions of flexion with left rotation and extension with left rotation, at L1–2 and L4–5. Methods Three asymptomatic female subjects, mean age 27 years, underwent T2 weighted MRI sequences in flexed, extended, and left rotated positions combined with flexion and extension. A pixel profile technique was employed to determine direction and magnitude of nuclear deformation. Results In 5 of 6 discs examined, deformation of the nucleus occurred anteriorly in extension and posteriorly in flexion. Left rotation resulted in migration of nuclear material to the right in 9 of 12 discs. Of the three discs that demonstrated a right nuclear migration, two occurred at L4–5 and one at L1–2. Interpretation This methodology demonstrated that nucleus pulposus deformation can be measured reliably in various positions achieved within the confines of the MRI. The consistent migration of nuclear material following sagittal plane movement and the less consistent response to rotation positions suggest other asymmetrical loading on the intervertebral disc may accompany rotation.

The effects of dietary calcium intake and physical activity on longitudinal changes in BMD over a mean of 9.4 years were examined in 62 healthy young women. Proximal femur BMD declined, lumbar spine BMD increased, and physical activity was associated with BMD change at intertrochanter and total hip sites. Introduction: Maximizing premenopausal BMD is an important strategy for the prevention of osteoporosis and resultant fractures later in life. Materials and Methods: Young women who previously participated in a placebo-controlled 2-year calcium intervention study at a mean age of 18.5 ± 0.3 years were remeasured at 27.8 ± 1.0 years of age. DXA (Hologic QDR 1000W) was used to measure changes in BMD, and lifestyle factors were ascertained by questionnaire. Results and Conclusions: Early decline in BMD at the neck of femur (−3.3%/decade) and the converse gain in BMD at the lumbar spine (+4.3%/decade) and intertrochanter (+1.9%/decade) suggest site-specific changes in BMD in young premenopausal women. No effect of previous calcium supplementation was seen on current BMD or changes in BMD (p > 0.10). Lifestyle predictors of change in BMD were determined using hierarchical regression analysis after forced correction for the covariates baseline BMD and previous calcium supplementation. Physical activity was positively associated with change in BMD at total hip and intertrochanter sites (β-coefficients, β = 0.26 and 0.26 respectively; p < 0.05). Calcium intake was negatively associated with change in BMD at the lumbar spine (β = −0.27, p < 0.05). Parity was negatively associated with change in BMD at all sites (β = −0.40 to −0.26, p < 0.05). These data show that BMD is already declining at the proximal femur in these healthy young women. Physical activity assists in maintenance of BMD at some sites and thus may contribute to lifelong fracture prevention. There was no positive association between calcium intake and change in BMD.

There are uncertainties concerning the optimal threshold value of bone mineral density (BMD) for the diagnosis of osteoporosis using dual-energy X-ray absorptiometry (DXA). The most widely accepted clinical criteria are based on T- and Z-scores, derived statistically from an age-dependent BMD reference range that includes healthy young adults. This study has compared different analyses of BMD data of healthy, nonfractured, adult white females aged 18–90 years, consisting of 953 studied with DXA in the L1–L4 spine and 1018 measured at the hip. Four regression curves were applied to each reference data set; mean peak BMD (PBMD R ) and the age-independent standard deviation (SD R ) were calculated. These data, plus derived T-score thresholds, were compared with equivalent values (PBMD YN , SD YN ) determined from BMDs of a subgroup of young normals. Choice of regression curve caused a variation of 0.044 g/cm 2 in spinal PBMD R and 0.015–0.022 g/cm 2 in the hip. The variation in calculated SD R between the regressions was minimal (maximum variation, 0.03 SD unit in the spine). A split-linear model was chosen as the best overall fit for both the spine and the hip on the basis of goodness-of-fit and biological plausibility. PBMD R and PBMD YN varied by less than 1% at the spine or hip. Although the difference between SD R and SD YN was ≤7% for the hip sites, SD R was 0.022 g/cm 2 > SD YN for the spine (17% difference). At each hip site, BMD T-score thresholds, derived from regression analysis of the entire reference range (T R ) or from young normals only (T YN ), were not significantly different; however, equivalent spinal values differed by 0.062 g/cm 2 for T=–2.5. The percentage of the Australian female population (AFP) aged 50 yr or older and classified as osteoporotic, using population census data and the split-line-based T-score threshold of T R = –2.5, was 23% for spinal BMD and 17% for the total hip. For T YN = –2.5, the values were 36% (spine) and 17% (total hip). The hip BMDs of this study were greater than those of NHANES III in the third, seventh and eighth decades by as much as 0.6 SD. This produced a difference of 0.049–0.077 g/cm 2 for T YN = –2.5 between the two reference ranges. However, this study is in broad agreement with an Eastern Australian and the U.S. DXA manufacturer's reference range. It is concluded that (i) derivation of peak BMD and its standard deviation are critical for calculation of T-scores in the spine but not in the hip; (ii) there are significant differences between the hip peak BMDs of young normals, as derived from studies of similar populations in different regions, significantly affecting the impact of the subsequent clinical application of the calculated T-score.