Novel requirements for HAP2-mediated gamete fusion in Tetrahymena.

The ancestral gamete fusion protein, HAP2, catalyzes sperm-egg fusion in a broad range of taxa dating to the last eukaryotic common ancestor. Remarkably, HAP2 orthologs are structurally related to the class II fusogens of modern-day viruses, and recent studies make clear that these proteins utilize similar mechanisms to achieve membrane merger. To identify factors that may regulate HAP2 activity, we screened mutants of the ciliate Tetrahymena thermophila for behaviors that mimic Δhap2 knockout phenotypes in this species. Using this approach, we identified two new genes, GFU1 and GFU2, whose products are necessary for the formation of membrane pores during fertilization and show that the product of a third gene, namely ZFR1, may be involved in pore maintenance and/or expansion. Finally, we propose a model that explains cooperativity between the fusion machinery on apposed membranes of mating cells and accounts for successful fertilization in T. thermophila's multiple mating type system.

Using 3D image registration to maximize the reproducibility of longitudinal bone strength assessment by HR-pQCT and finite element analysis.

We developed and validated a finite element (FE) approach for longitudinal high-resolution peripheral quantitative computed tomography (HR-pQCT) studies using 3D image registration to account for misalignment between images. This reduced variability in longitudinal FE estimates and improved our ability to measure in vivo changes in HR-pQCT studies of bone strength. INTRODUCTION: We developed and validated a finite element (FE) approach for longitudinal high-resolution peripheral quantitative computed tomography (HR-pQCT) studies using 3D rigid-body registration (3DR) to maximize reproducibility by accounting for misalignment between images. METHODS: In our proposed approach, we used the full common bone volume defined by 3DR to estimate standard FE parameters. Using standard HR-pQCT imaging protocols, we validated the 3DR approach with ex vivo samples of the distal radius (n = 10, four repeat scans) by assessing whether 3DR can reduce measurement variability from repositioning error. We used in vivo data (n = 40, five longitudinal scans) to assess the sensitivity of 3DR to detect changes in bone strength at the distal radius by the standard deviation of the rate of change (σ), where the ideal value of σ is minimized to define true change. FE estimates by 3DR were compared to estimates by no registration (NR) and slice-matching (SM). RESULTS: Group-wise comparisons of ex vivo variation (CVRMS, %) found that FE measurement precision was improved by SM (CVRMS < 0.80%) and 3DR (CVRMS < 0.62%) compared to NR (CVRMS~2%), and 3DR was advantageous as repositioning error increased. Longitudinal in vivo reproducibility was minimized by 3DR for failure load estimates (σ = 0.008 kN/month). CONCLUSION: Although 3D registration cannot negate motion artifacts, it plays an important role in detecting and reducing variability in FE estimates for longitudinal HR-pQCT data and is well suited for estimating effects of interventions in in vivo longitudinal studies of bone strength.

Differences in fracture prevalence and in bone mineral density between Chinese and White Canadians: the Canadian Multicentre Osteoporosis Study (CaMos).

Fracture determinants differ between Canadians of Chinese and White descent, the former constituting the second largest visible minority group in Canada. The results of this study support the importance of characterizing bone health predictors in Canadians of different ethnicity to improve population-specific fracture prevention and treatment strategies. PURPOSE: We aimed to compare clinical risk factors, bone mineral density, prevalence of osteoporosis, and fractures between Chinese and White Canadians to identify ethnicity-specific risks. METHODS: We studied 236 Chinese and 8945 White Canadians aged 25+ years from the Canadian Multicentre Osteoporosis Study (CaMos). The prevalence of osteoporosis using ethnicity-specific peak bone mass (PBM), and of prior and incident low trauma fractures were assessed and compared between groups. Linear regressions, adjusting for age and anthropometric measures, were used to examine the association between baseline and 5-year changes in BMD and ethnicity. RESULTS: Chinese participants had shorter stature, lower BMI, and lower rate of falls than White participants. Adjusted models showed no significant differences in baseline BMD between ethnic groups except in younger men where total hip BMD was 0.059 g/cm2 (0.009; 0.108) lower in Chinese. Adjusted 5-year BMD change at lumbar spine was higher in older Chinese women and men compared with Whites. When using Chinese-specific PBM, the prevalence of osteoporosis in Chinese women was 2-fold lower than when using that of White women The prevalence of fractures was higher in White women compared with Chinese with differences up to 14.5% (95% CI 9.2; 19.7) and 10.5% (95% CI 4.5-16.4) in older White men. Incident fractures were rare in young Chinese compared with White participants and not different in the older groups. CONCLUSION: Our results support the importance of characterizing bone strength predictors in Chinese Canadians and the development of ethnicity-specific fracture prediction and prevention strategies.

Effect of high-dose vitamin D supplementation on peripheral arterial calcification: secondary analysis of a randomized controlled trial.

Although high-dose vitamin D supplementation is common, effects on arterial calcification remain unexplored. Tibial artery calcification was identified and quantified over 3 years in participants randomized to 400, 4000, or 10,000 IU vitamin D3 daily. High-dose vitamin D supplementation did not affect the development or progression of arterial calcification. INTRODUCTION: To determine whether vitamin D supplementation has a dose-dependent effect on development and progression of arterial calcification. METHODS: This was a secondary analysis of the Calgary Vitamin D Study, a 3-year, double-blind, randomized controlled trial conducted at a single-center in Calgary, Canada. Participants were community-dwelling adults aged 55-70 years with serum 25-hydroxyvitamin D 30-125 nmol/L. Participants were randomized 1:1:1 to receive vitamin D3 400, 4000, or 10,000 IU/day for 3 years. Tibial artery calcification was identified and quantified (in milligrams of hydroxyapatite, mgHA) using high-resolution peripheral quantitative computed tomography (HR-pQCT) at baseline and 6, 12, 24, and 36 months. Changes in calcification over time and treatment group interaction were evaluated using a constrained linear mixed effects model. RESULTS: Of 311 randomized participants, 302 (400: 105, 4000: 96, 10,000: 101) were eligible for analysis of arterial calcification (54% male, mean (SD) age 62 (4) years, mean (SD) 25-hydroxyvitamin D 78.9 (19.9) nmol/L). At baseline, 85 (28%) had tibial artery calcification, and mean (95% CI) calcification quantity was 2.8 mgHA (95% CI 1.7-3.9). In these 85 participants, calcification quantity increased linearly by 0.020 mgHA/month (95% CI 0.012-0.029) throughout the study, with no evidence of a treatment-group effect (p = 0.645 for interaction). No participants developed new arterial calcifications during the study. CONCLUSIONS: In this population of community-dwelling adults who were vitamin D replete at baseline, supplementation with vitamin D 400, 4000, or 10,000 IU/day did not have differential effects on the development or progression of arterial calcification over 3 years. TRIAL REGISTRATION: clinicaltrials.gov (NCT01900860).

Longitudinal bone microarchitectural changes are best detected using image registration.

Longitudinal studies of bone using high-resolution medical imaging may result in non-physiological measurements of longitudinal changes. In this study, we determined that three-dimensional image processing techniques best capture realistic longitudinal changes in bone density and should therefore be used with high-resolution imaging when studying bone changes over time. INTRODUCTION: The purpose of this study was to determine which longitudinal analysis technique (no registration (NR), slice-match (SM) registration, or three-dimensional registration (3DR)) produced the most realistic longitudinal changes in a 3-year study of bone density and structure using high-resolution peripheral quantitative computed tomography (HR-pQCT). METHODS: We assessed HR-pQCT scans of the distal radius and tibia for men and women (N = 40) aged 55-70 years at baseline and 6, 12, 24, and 36 months. To evaluate which longitudinal analysis technique (NR, SM, or 3DR) best captured physiologically reasonable 3-year changes, we calculated the standard deviation of the absolute rate of change in each bone parameter. The data were compared between longitudinal analysis techniques using repeated measures ANOVA and post hoc analysis. RESULTS: As expected, both SM and 3DR better captured physiological longitudinal changes than NR. At the tibia, there were no differences between SM and 3DR; however, at the radius where precision was lower, 3DR produced better results for total bone mineral density. CONCLUSIONS: At least SM or 3DR should be implemented in longitudinal studies using HR-pQCT. 3DR is preferable, particularly at the radius, to ensure that physiological changes in bone density are observed.

Testing a theoretical model of imminent fracture risk in elderly women: an observational cohort analysis of the Canadian Multicentre Osteoporosis Study.

We examined the underlying relationship between fracture risk factors and their imminent risk. Results suggested that having past year fracture, worse past year general health, worse past year physical functioning, and lower past year BMD T-score directly predicted higher imminent fracture risk. Past year falls indirectly predicted imminent risk through physical functioning and general health. INTRODUCTION: This study aimed to examine direct and indirect effects of several factors on imminent (1 year) fracture risk. METHODS: Data from women age 65 and older from population-based Canadian Multicentre Osteoporosis Study were used. Predictors were identified from study years 5 and 10, and imminent fracture data (1-year fracture) came from years 6 and 11 (year 5 predicts year 6, year 10 predicts year 11). A structural equation model (SEM) was used to test the theoretical construct. General health and physical functioning were measured as latent variables using items from the 36-Item Short Form Health Survey (SF-36) and bone mineral density (BMD) T-score was a latent variable based on observed site-specific BMD data (spine L1-L4, femoral neck, total hip). Observed variables were fractures and falls. Model fit was evaluated using root mean square error of approximation (RMSEA), Tucker Lewis index (TLI), and comparative fit index (CFI). RESULTS: The analysis included 3298 women. Model fit tests showed that the SEM fit the data well; χ2(172) = 1122.10 < .001, RMSEA = .03, TLI = .99, CFI = .99. Results suggested that having past year fracture, worse past year general health, worse past year physical functioning, and lower past year BMD T-score directly predicted higher risk of fracture in the subsequent year (p < .001). Past year falls had a statistically significant but indirect effect on imminent fracture risk through physical functioning and general health (p < .001). CONCLUSIONS: We found several direct and indirect pathways that predicted imminent fracture risk in elderly women. Future studies should extend this work by developing risk scoring methods and defining imminent risk thresholds.

Longitudinal assessment of health-related quality of life in osteoporosis: data from the population-based Canadian Multicentre Osteoporosis Study.

Little is known about the association between health-related quality of life (HRQOL) and osteoporosis in the absence of fracture, and how HRQOL may change over time. This study provides evidence of substantially reduced HRQOL in women and men with self-reported and/or BMD-confirmed osteoporosis, even in the absence of fragility fracture. INTRODUCTION: Fragility fractures have a detrimental effect on the health-related quality of life (HRQOL) of those with osteoporosis. Less is known about the association between HRQOL and osteoporosis in the absence of fracture. METHODS: Canadian Multicentre Osteoporosis Study participants completed the SF-36, a detailed health questionnaire and measures of bone mineral density (BMD) at baseline and follow-up. We report the results of participants ≥ 50 years with 10-year follow-up. Self-reported osteoporosis at baseline and BMD-based osteoporosis at follow-up were ascertained. Multivariable linear regression models were developed for baseline SF-36 domains, component summaries, and change over time, adjusting for relevant baseline information. RESULTS: Baseline data were available for 5266 women and 2112 men. Women in the osteoporosis group had substantially lower SF-36 baseline scores, particularly in the physically oriented domains, than those without osteoporosis. A similar but attenuated pattern was evident for the men. After 10-year follow-up (2797 women and 1023 men), most domain scores dropped for women and men regardless of osteoporosis status, with the exception of mentally-oriented ones. In general, a fragility fracture was associated with lower SF-36 scores and larger declines over time. CONCLUSIONS: This study provides evidence of substantially reduced HRQOL in women and men with self-reported and/or BMD-confirmed osteoporosis, even in the absence of fragility fracture. HRQOL should be thoroughly investigated even prior to fracture, to develop appropriate interventions for all stages of the disease.

Mortality risk reduction differs according to bisphosphonate class: a 15-year observational study.

In this prospective cohort of 6120 participants aged 50+, nitrogen-bisphosphonates but not non-nitrogen bisphosphonates were associated with a significant 34% mortality risk reduction compared to non-treated propensity score matched controls. These findings open new avenues for research into mechanistic pathways. INTRODUCTION: Emerging evidence suggests that bisphosphonates (BP), first-line treatment of osteoporosis, are associated with reduced risks for all-cause mortality. This study aimed to determine the association between different BP types and mortality risk in participants with or without a fracture. METHODS: A prospective cohort study of users of different BPs matched to non-users by propensity score (age, gender, co-morbidities, fragility fracture status) and time to starting the BP medication from the population-based Canadian Multicentre Osteoporosis Study from nine Canadian centres followed from 1995 to 2013. Mortality risk for bisphosphonate users vs matched non-users was assessed using pairwise multivariable Cox proportional hazards models. RESULTS: There were 2048 women and 308 men on BP and 1970 women and 1794 men who did not receive medication for osteoporosis. The relationship between BP and mortality risk was explored in three separate 1:1 propensity score-matched cohorts of BP users and no treatment (etidronate, n = 599, alendronate, n = 498, and risedronate n = 213). Nitrogen BP (n-BP) (alendronate and risedronate) was associated with lower mortality risks [pairwise HR, 0.66 (95% CI, 0.48-0.91)] while the less potent non-n-BP, etidronate, was not [pairwise HR: 0.89 (95% CI, 0.66-1.20)]. A direct comparison between n-BP and etidronate (n = 340 pairs) also suggested a better survival for n-BP [paired HR, 0.47 (95%CI, (95% CI, 031-0.70)] for n-BP vs. etidronate]. CONCLUSION: Compared to no treatment, nitrogen but not non-nitrogen bisphosphonates appear to be associated with better survival.

The German trial on Aciclovir and Corticosteroids in Herpes-simplex-virus-Encephalitis (GACHE): a multicenter, randomized, double-blind, placebo-controlled trial.

INTRODUCTION: Comprehensive treatment of Herpes-simplex-virus-encephalitis (HSVE) remains a major clinical challenge. The current therapy gold standard is aciclovir, a drug that inhibits viral replication. Despite antiviral treatment, mortality remains around 20% and a majority of survivors suffer from severe disability. Experimental research and recent retrospective clinical observations suggest a favourable therapy response to adjuvant dexamethasone. Currently there is no randomized clinical trial evidence, however, to support the routine use of adjuvant corticosteroid treatment in HSVE. METHODS: The German trial of Aciclovir and Corticosteroids in Herpes-simplex-virus-Encephalitis (GACHE) studied the effect of adjuvant dexamethasone versus placebo on top of standard aciclovir treatment in adult patients aged 18 up to 85 years with proven HSVE in German academic centers of Neurology in a randomized and double blind fashion. The trial was open from November 2007 to December 2012. The initially planned sample size was 372 patients with the option to increase to up to 450 patients after the second interim analysis. The primary endpoint was a binary functional outcome after 6 months assessed using the modified Rankin scale (mRS 0-2 vs. 3-6). Secondary endpoints included mortality after 6 and 12 months, functional outcome after 6 months measured with the Glasgow outcome scale (GOS), functional outcome after 12 months measured with mRS and GOS, quality of life as measured with the EuroQol 5D instrument after 6 and 12 months, neuropsychological testing after 6 months, cranial magnetic resonance imaging findings after 6 months, seizures up to day of discharge or at the latest at day 30, and after 6 and 12 months. RESULTS: The trial was stopped prematurely for slow recruitment after 41 patients had been randomized, 21 of them treated with dexamethasone and 20 with placebo. No difference was observed in the primary endpoint. In the full analysis set (n = 19 in each group), 12 patients in each treatment arm achieved a mRS of 0-2. Similarly, we did not observe significant differences in the secondary endpoints (GOS, mRS, quality of life, neuropsychological testing). CONCLUSION: GACHE being prematurely terminated demonstrated challenges encountered performing randomized, placebo-controlled trials in rare life threatening neurological diseases. Based upon our trial results the use of adjuvant steroids in addition to antiviral treatment remains experimental and is at the decision of the individual treating physician. Unfortunately, the small number of study participants does not allow firm conclusions. TRIAL REGISTRATION: EudraCT-Nr. 2005-003201-81.

Economic evaluation of a population-based osteoporosis intervention for outpatients with non-traumatic non-hip fractures: the "Catch a Break" 1i [type C] FLS.

Fracture liaison services (FLS) are advocated to improve osteoporosis treatment after fragility fracture, but there are few economic analyses of different models. A population-based 1i [=type C] FLS for non-hip fractures was implemented and it costs $44 per patient and it was very cost-effective ($9200 per QALY gained). Small operational changes would convert it from cost-effective to cost-saving. INTRODUCTION: After fragility fracture, <20% of patients receive osteoporosis treatment. FLS are recommended to address this deficit but there are very few economic analyses of different FLS models. Therefore, we conducted an economic analysis of a 1i (=type C) FLS called "Catch a Break (CaB)." METHODS: CaB is a population-based FLS in Alberta, Canada, that case-finds older outpatients with non-traumatic upper extremity, spine, pelvis, or "other" non-hip fractures and provides telephonic outreach and printed educational materials to patients and their physicians. Cost-effectiveness was assessed using Markov decision-analytic models. Costs were expressed in 2014 Canadian dollars and effectiveness based on model simulations of recurrent fractures and quality-adjusted life years (QALYs). Perspective was healthcare payer; horizon was lifetime; and costs and benefits were discounted 3%. RESULTS: Over 1 year, CaB enrolled 7323 outpatients (mean age 67 years, 75% female, 69% upper extremity) at average cost of $44 per patient. Compared with usual care, CaB increased rates of bisphosphonate treatment by 4.3 to 17.5% (p < 0.001). Over their lifetime, for every 10,000 patients enrolled in CaB, 4 hip fractures (14 fractures total) would be avoided and 12 QALYs gained. Compared with usual care, incremental cost-effectiveness of CaB was estimated at $9200 per QALY. CaB was cost-effective in 85% of 10,000 probabilistic simulations. Sensitivity analyses showed if "other" fractures were excluded and intervention costs reduced 25% that CaB would become cost-saving. CONCLUSIONS: A relatively inexpensive population-based 1i (=type C) FLS was implemented in Alberta and it was very cost-effective. If CaB excluded "other" fractures and decreased intervention costs by 25%, it would be cost-saving, as would any FLS that was more effective and less expensive.

Cortical porosity exhibits accelerated rate of change in peri- compared with post-menopausal women.

The rate of change in bone density was not different between peri- and post-menopausal women. Differences in rate of change were observed in bone microarchitecture, specifically cortical porosity (Ct.Po), where peri-menopausal women increased +9% per year compared with the +6% per year for post-menopausal women. INTRODUCTION: The purpose of this study was to compare changes in bone density and microarchitecture in peri- and post-menopausal women over 6 years. METHODS: Peri- (n = 26) and post- (n = 65) menopausal women were selected from the Canadian Multicenter Osteoporosis Study. Caucasian women were scanned on dual x-ray absorptiometry (DXA) and high-resolution peripheral quantitative computed tomography (HR-pQCT) at baseline and follow-up, an average 6 years later. To compare repeat scans, automated 3D image registration was conducted. At the radius and tibia, total volumetric BMD (Tt.BMD), total bone area (Tt.Ar) and cortical porosity (Ct.Po) were assessed, and finite element analysis estimated apparent bone strength. RESULTS: At the tibia, the rate of change for Ct.Po and Tt.Ar was different between groups. Peri-menopausal women had a + 9% per year increase in Ct.Po, but this increase was slower for post-menopausal women at +6% per year (p = 0.049). In addition, post-menopausal women had an increase in Tt.Ar of +0.13% per year compared with a slower increase of +0.06% per year for peri-menopausal women (p = 0.017). The rate of change of density between groups was not significantly different and was approximately -1% per year at the hip by DXA, and -1% per year at the radius and -0.5% per year tibia by HR-pQCT. CONCLUSION: This is a 6-year prospective HR-pQCT study exploring rate of change in Caucasian peri- and post-menopausal women. The microarchitectural features represented by Ct.Po and Tt.Ar changed at a significantly different rate between groups, but group differences were not detected by density measures.

Pollinator adaptation and the evolution of floral nectar sugar composition.

A long-standing debate concerns whether nectar sugar composition evolves as an adaptation to pollinator dietary requirements or whether it is 'phylogenetically constrained'. Here, we use a modelling approach to evaluate the hypothesis that nectar sucrose proportion (NSP) is an adaptation to pollinators. We analyse ~ 2100 species of asterids, spanning several plant families and pollinator groups (PGs), and show that the hypothesis of adaptation cannot be rejected: NSP evolves towards two optimal values, high NSP for specialist-pollinated and low NSP for generalist-pollinated plants. However, the inferred adaptive process is weak, suggesting that adaptation to PG only provides a partial explanation for how nectar evolves. Additional factors are therefore needed to fully explain nectar evolution, and we suggest that future studies might incorporate floral shape and size and the abiotic environment into the analytical framework. Further, we show that NSP and PG evolution are correlated - in a manner dictated by pollinator behaviour. This contrasts with the view that a plant necessarily has to adapt its nectar composition to ensure pollination but rather suggests that pollinators adapt their foraging behaviour or dietary requirements to the nectar sugar composition presented by the plants. Finally, we document unexpectedly sucrose-poor nectar in some specialized nectarivorous bird-pollinated plants from the Old World, which might represent an overlooked form of pollinator deception. Thus, our broad study provides several new insights into how nectar evolves and we conclude by discussing why maintaining the conceptual dichotomy between adaptation and constraint might be unhelpful for advancing this field.

Primary hyperparathyroidism: review and recommendations on evaluation, diagnosis, and management. A Canadian and international consensus.

The purpose of this review is to assess the most recent evidence in the management of primary hyperparathyroidism (PHPT) and provide updated recommendations for its evaluation, diagnosis and treatment. A Medline search of "Hyperparathyroidism. Primary" was conducted and the literature with the highest levels of evidence were reviewed and used to formulate recommendations. PHPT is a common endocrine disorder usually discovered by routine biochemical screening. PHPT is defined as hypercalcemia with increased or inappropriately normal plasma parathyroid hormone (PTH). It is most commonly seen after the age of 50 years, with women predominating by three to fourfold. In countries with routine multichannel screening, PHPT is identified earlier and may be asymptomatic. Where biochemical testing is not routine, PHPT is more likely to present with skeletal complications, or nephrolithiasis. Parathyroidectomy (PTx) is indicated for those with symptomatic disease. For asymptomatic patients, recent guidelines have recommended criteria for surgery, however PTx can also be considered in those who do not meet criteria, and prefer surgery. Non-surgical therapies are available when surgery is not appropriate. This review presents the current state of the art in the diagnosis and management of PHPT and updates the Canadian Position paper on PHPT. An overview of the impact of PHPT on the skeleton and other target organs is presented with international consensus. Differences in the international presentation of this condition are also summarized.

Vertebral Fractures: Clinical Importance and Management.

Vertebral fractures are common and can result in acute and chronic pain, decreases in quality of life, and diminished lifespan. The identification of vertebral fractures is important because they are robust predictors of future fractures. The majority of vertebral fractures do not come to clinical attention. Numerous modalities exist for visualizing suspected vertebral fracture. Although differing definitions of vertebral fracture may present challenges in comparing data between different investigations, at least 1 in 5 men and women aged >50 years have one or more vertebral fractures. There is clinical guidance to target spine imaging to individuals with a high probability of vertebral fracture. Radiology reports of vertebral fracture need to clearly state that the patient has a "fracture," with further pertinent details such as the number, recency, and severity of vertebral fracture, each of which is associated with risk of future fractures. Patients with vertebral fracture should be considered for antifracture therapy. Physical and pharmacologic modalities of pain control and exercises or physiotherapy to maintain spinal movement and strength are important components in the care of vertebral fracture patients.

Associations of Protein Intake and Protein Source with Bone Mineral Density and Fracture Risk: A Population-Based Cohort Study.

UNLABELLED: High dietary protein has been hypothesized to cause lower bone mineral density (BMD) and greater fracture risk. Previous results are conflicting and few studies have assessed potential differences related to differing protein sources. OBJECTIVE: To determine associations between total protein intake, and protein intake by source (dairy, non-dairy animal, plant) with BMD, BMD change, and incident osteoporotic fracture. DESIGN/SETTING: Prospective cohort study (Canadian Multicentre Osteoporosis Study). Participants/Measures: Protein intake was assessed as percent of total energy intake (TEI) at Year 2 (1997-99) using a food frequency questionnaire (N=6510). Participants were contacted annually to ascertain incident fracture. Total hip and lumbar spine BMD was measured at baseline and Year 5. Analyses were stratified by group (men 25-49 y, men 50+ y, premenopausal women 25-49 y, and postmenopausal women 50+ y) and adjusted for major confounders. Fracture analyses were limited to those 50+ y. RESULTS: Intakes of dairy protein (with adjustment for BMI) were positively associated with total hip BMD among men and women aged 50+ y, and in men aged 25-49. Among adults aged 50+ y, those with protein intakes of <12% TEI (women) and <11% TEI (men) had increased fracture risk compared to those with intakes of 15% TEI. Fracture risk did not significantly change as intake increased above 15% TEI, and was not significantly associated with protein source. CONCLUSIONS: In contrast to hypothesized risk of high protein, we found that for adults 50+ y, low protein intake (below 15% TEI) may lead to increased fracture risk. Source of protein was a determinant of BMD, but not fracture risk.

Early Quantification of Hematoma Hounsfield Units on Noncontrast CT in Acute Intraventricular Hemorrhage Predicts Ventricular Clearance after Intraventricular Thrombolysis.

BACKGROUND AND PURPOSE: Thrombolytic efficacy of intraventricular rtPA for acute intraventricular hemorrhage may depend on hematoma composition. We assessed whether hematoma Hounsfield unit quantification informs intraventricular hemorrhage clearance after intraventricular rtPA. MATERIALS AND METHODS: Serial NCCT was performed on 52 patients who received intraventricular rtPA as part of the Clot Lysis Evaluation of Accelerated Resolution of Intraventricular Hemorrhage trial and 12 controls with intraventricular hemorrhage, but no rtPA treatment. A blinded investigator calculated Hounsfield unit values for intraventricular hemorrhage volumes on admission (t0), days 3-4 (t1), and days 6-9 (t2). Controls were matched uniquely to 12 rtPA-treated patients for comparison. RESULTS: Median intraventricular hemorrhage volume on admission for patients treated with intraventricular rtPA was 31.9 mL (interquartile range, 34.1 mL), and it decreased to 4.9 mL (interquartile range, 14.5 mL) (t2). Mean (±standard error of the mean) Hounsfield unit for intraventricular hemorrhage was 52.1 (0.59) at t0 and decreased significantly to 50.1 (0.63) (t1), and to 45.1 (0.71) (t2). Total intraventricular hemorrhage Hounsfield unit count was significantly correlated with intraventricular hemorrhage volume at all time points (t0: P = .002; t1: P < .001; t2: P < .001). On serologic and CSF analysis at t0, only higher CSF protein was positively correlated with intraventricular hemorrhage Hounsfield units (P = .03). In 24 matched patients treated with rtPA and controls, total intraventricular hemorrhage Hounsfield units were significantly lower in patients treated with rtPA at t2 (P = .02). Higher Hounsfield unit quantification of fourth ventricle hematomas independently predicted slower clearance of this ventricle (95% CI, 0.02-0.14; P = .02), along with higher intraventricular hemorrhage volume (95% CI, 0.02-0.41; P = .03) and lower CSF protein levels (95% CI, -0.003 to -0.002; P < .001). CONCLUSIONS: Intraventricular hemorrhage Hounsfield unit counts decrease significantly in the acute phase and to a greater extent with intraventricular rtPA treatment. Intraventricular hemorrhage Hounsfield units are correlated significantly with CSF protein and not with serum erythrocyte or platelet concentrations. Hounsfield unit counts may reflect intraventricular hemorrhage clot composition and rtPA sensitivity.

The relationship between serum 25(OH)D and bone density and microarchitecture as measured by HR-pQCT.

UNLABELLED: The relation between serum 25-hydroxy vitamin D [25(OH)D] and bone quality is not well understood, particularly for high levels. We measured bone microarchitecture in three groups of people stratified by their serum 25(OH)D. There was a weak association of serum 25(OH)D and microarchitecture for this cross-sectional population, suggesting possible benefits to bone quality. INTRODUCTION: Vitamin D plays an important role in bone and mineral metabolism, but the relation between serum 25(OH)D and bone quality is not well understood. Here, we present a cross-sectional study that investigated a convenience group of participants from an ongoing health initiative in Alberta, Canada, who have been receiving daily vitamin D supplementation. METHODS: A total of 105 participants were organized into three groups based on their serum 25(OH)D levels: low (<75 nmol/L), medium (75-175 nmol/L), and high (>175 nmol/L). They were also assessed with 25(OH)D as a continuous variable. Average daily supplementation was 7670 ± 438 IU, and the change in 25(OH)D ranged from 22 to 33 % during the period of receiving supplements. We used high-resolution peripheral quantitative computed tomography measurements at the radius and tibia to assess bone microarchitecture. RESULTS: Microarchitectural parameters were not strongly associated with serum 25(OH)D. In the tibia, there were fewer trabeculae (TbN; p = 0.015) and a non-significant trend toward thicker trabeculae (p = 0.067) of the high group. Body mass index (BMI) was negatively associated with serum 25(OH)D levels (p < 0.001) and PTH levels (p < 0.001). There was no clinically significant relationship detected between high serum 25(OH)D and high serum calcium. CONCLUSION: These data suggest a weak relationship between serum 25(OH)D and bone microarchitecture in this population of mostly vitamin-D-sufficient participants, and there were no indications of negative effects related to the high supplementation levels. These data provided a basis to design and implement our 3-year dose-dependent randomized controlled trial investigating the effects of vitamin D supplementation on bone health outcomes.

Bone quality in osteopenic postmenopausal women is not improved after 12 months of whole-body vibration training.

UNLABELLED: Whole-body vibration training may improve bone quality through structural adaptation. We tested if 12 months of training affects bone structure in osteopenic postmenopausal women by using advanced 3-dimensional high-resolution imaging techniques. We found that whole-body vibration training did not improve bone structure compared to inactive controls. INTRODUCTION: Whole-body vibration training (WBVT) has been suggested as a preventive measure against bone loss. Contradicting results of previous studies may be confounded by insufficiently sensitive bone density measures to detect relevant bone changes. WBVT may improve bone quality through structural adaptations, without increasing bone mineral density (BMD). We hypothesized that 12 months of WBVT will improve or maintain bone microarchitecture and bone strength in osteopenic postmenopausal women. METHODS: Twenty-two women received WBVT for 2-3 sessions/week and were compared with 20 controls. Bone outcomes were measured by high-resolution peripheral quantitative CT (HR-pQCT, XtremeCT, Scanco Medical) and finite element estimated bone strength. Balance and jump performance and maximum voluntary contraction (MVC) of knee flexor and extensor muscles were recorded. All measurements were taken at baseline, 4, 8, and 12 months and a reduced data set at 4 and 8 months follow-up and compared using a mixed model repeated measures ANOVA. RESULTS: Thirty-one women completed the study with 90 % compliance (WBVT: n = 17, control n = 14). Total BMD (p < 0.001), cortical area*(p = 0.004), cortical thickness (p = 0.011), and cortical porosity (p = 0.024) all significantly decreased over time in both groups; WBVT did not affect the response. All other bone outcomes were not affected by WBVT or time. No difference in measures of balance, jump height, and MVC due to WBVT were detected. CONCLUSION: In our cohort, WBVT did not lead to improved bone quality in postmenopausal osteopenic women after 12 months of training compared to controls, and there were no detected benefits related to balance and muscle strength outcomes.

Characteristics of hyperparathyroid states in the Canadian multicentre osteoporosis study (CaMos) and relationship to skeletal markers.

CONTEXT: PTH is an essential regulator of mineral metabolism; PTH hypersecretion may result in hyperparathyroidism including normocalcaemic, primary and secondary hyperparathyroidism. OBJECTIVE: To examine the characteristics of participants with hyperparathyroid states and the relationship to bone mineral density (BMD). DESIGN AND PARTICIPANTS: A cross-sectional study of 1872 community-dwelling men and women aged 35+ years (mostly Caucasian) with available serum PTH from Year 10 Canadian Multicentre Osteoporosis Study follow-up (2005-07). PTH was determined using a second-generation chemiluminescence immunoassay. OUTCOME MEASURES: L1-L4, femoral neck and total hip BMD. RESULTS: We established a PTH reference range (2·7-10·2 pmol/l) based on healthy participants (i.e. normal serum calcium, serum 25-hydroxyvitamin D, kidney function and body mass index, who were nonusers of antiresorptives, glucocorticoids and diuretics and not diagnosed with diabetes or thyroid disease). Participants with PTH levels in the upper reference range (5·6-10·2 pmol/l), representing a prevalence of 10·7%, had lower femoral neck and total hip BMD, by 0·030 g/cm(2) [95% confidence interval: 0·009; 0·051] and 0·025 g/cm(2) (0·001; 0·049), respectively, than those with levels 2·7-5·6 pmol/l. Participants with normocalcaemic and secondary hyperparathyroidism also had lower total hip BMD than those with levels 2·7-5·6 pmol/l, and CaMos prevalences of normocalcaemic, primary and secondary hyperparathyroidism were 3·3%, 1·4% and 5·2%, respectively. CONCLUSION: We found reduced BMD in participants with accepted hyperparathyroid states but also a notable proportion of other participants that might benefit from having lower PTH levels.