Prediction of hip fracture risk by quantitative ultrasound in more than 7000 Swiss women > or =70 years of age: comparison of three technologically different bone ultrasound devices in the SEMOF study

To compare the prediction of hip fracture risk of several bone ultrasounds (QUS), 7062 Swiss women > or =70 years of age were measured with three QUSs (two of the heel, one of the phalanges). Heel QUSs were both predictive of hip fracture risk, whereas the phalanges QUS was not. INTRODUCTION: As the number of hip fracture is expected to increase during these next decades, it is important to develop strategies to detect subjects at risk. Quantitative bone ultrasound (QUS), an ionizing radiation-free method, which is transportable, could be interesting for this purpose. MATERIALS AND METHODS: The Swiss Evaluation of the Methods of Measurement of Osteoporotic Fracture Risk (SEMOF) study is a multicenter cohort study, which compared three QUSs for the assessment of hip fracture risk in a sample of 7609 elderly ambulatory women > or =70 years of age. Two QUSs measured the heel (Achilles+; GE-Lunar and Sahara; Hologic), and one measured the heel (DBM Sonic 1200; IGEA). The Cox proportional hazards regression was used to estimate the hazard of the first hip fracture, adjusted for age, BMI, and center, and the area under the ROC curves were calculated to compare the devices and their parameters. RESULTS: From the 7609 women who were included in the study, 7062 women 75.2 +/- 3.1 (SD) years of age were prospectively followed for 2.9 +/- 0.8 years. Eighty women reported a hip fracture. A decrease by 1 SD of the QUS variables corresponded to an increase of the hip fracture risk from 2.3 (95% CI, 1.7, 3.1) to 2.6 (95% CI, 1.9, 3.4) for the three variables of Achilles+ and from 2.2 (95% CI, 1.7, 3.0) to 2.4 (95% CI, 1.8, 3.2) for the three variables of Sahara. Risk gradients did not differ significantly among the variables of the two heel QUS devices. On the other hand, the phalanges QUS (DBM Sonic 1200) was not predictive of hip fracture risk, with an adjusted hazard risk of 1.2 (95% CI, 0.9, 1.5), even after reanalysis of the digitalized data and using different cut-off levels (1700 or 1570 m/s). CONCLUSIONS: In this elderly women population, heel QUS devices were both predictive of hip fracture risk, whereas the phalanges QUS device was not.

Statistical shape analysis via principal factor analysis

Statistical shape analysis techniques commonly employed in the medical imaging community, such as active shape models or active appearance models, rely on principal component analysis (PCA) to decompose shape variability into a reduced set of interpretable components. In this paper we propose principal factor analysis (PFA) as an alternative and complementary tool to PCA providing a decomposition into modes of variation that can be more easily interpretable, while still being a linear efficient technique that performs dimensionality reduction (as opposed to independent component analysis, ICA). The key difference between PFA and PCA is that PFA models covariance between variables, rather than the total variance in the data. The added value of PFA is illustrated on 2D landmark data of corpora callosa outlines. Then, a study of the 3D shape variability of the human left femur is performed. Finally, we report results on vector-valued 3D deformation fields resulting from non-rigid registration of ventricles in MRI of the brain.

Evaluation of 41calcium as a new approach to assess changes in bone metabolism: effect of a bisphosphonate intervention in postmenopausal women with low bone mass

A new technique was evaluated to identify changes in bone metabolism directly at high sensitivity through isotopic labeling of bone Ca. Six women with low BMD were labeled with 41Ca up to 700 days and treated for 6 mo with risedronate. Effect of treatment on bone could be identified using 41Ca after 4-8 wk in each individual. INTRODUCTION: Isotopic labeling of bone using 41Ca, a long-living radiotracer, has been proposed as an alternative approach for measuring changes in bone metabolism to overcome current limitations of available techniques. After isotopic labeling of bone, changes in urinary 41Ca excretion reflect changes in bone Ca balance. The aim of this study was to validate this new technique against established measures. Changes in bone Ca balance were induced by giving a bisphosphonate. MATERIALS AND METHODS: Six postmenopausal women with diagnosed osteopenia/osteoporosis received a single oral dose of 100 nCi 41Ca for skeleton labeling. Urinary 41Ca/40Ca isotope ratios were monitored by accelerator mass spectrometry up to 700 days after the labeling process. Subjects received 35 mg risedronate per week for 6 mo. Effect of treatment was monitored using the 41Ca signal in urine and parallel measurements of BMD by DXA and biochemical markers of bone metabolism in urine and blood. RESULTS: Positive response to treatment was confirmed by BMD measurements, which increased for spine by +3.0% (p = 0.01) but not for hip. Bone formation markers decreased by -36% for bone alkaline phosphatase (BALP; p = 0.002) and -59% for procollagen type I propeptides (PINP; p = 0.001). Urinary deoxypyridinoline (DPD) and pyridinoline (PYD) were reduced by -21% (p = 0.019) and -23% (p = 0.009), respectively, whereas serum and urinary carboxy-terminal teleopeptides (CTXs) were reduced by -60% (p = 0.001) and -57.0% (p = 0.001), respectively. Changes in urinary 41Ca excretion paralleled findings for conventional techniques. The urinary 41Ca/40Ca isotope ratio was shifted by -47 +/- 10% by the intervention. Population pharmacokinetic analysis (NONMEM) of the 41Ca data using a linear three-compartment model showed that bisphosphonate treatment reduced Ca transfer rates between the slowly exchanging compartment (bone) and the intermediate fast exchanging compartment by 56% (95% CI: 45-58%). CONCLUSIONS: Isotopic labeling of bone using 41Ca can facilitate human trials in bone research by shortening of intervention periods, lowering subject numbers, and having easier conduct of cross-over studies compared with conventional techniques.

Measures of endothelial dysfunction in plasma of patients with posttraumatic stress disorder

Posttraumatic stress disorder (PTSD) confers an increased cardiovascular risk. In 14 otherwise healthy patients with PTSD and in 14 age- and gender-matched non-PTSD controls, we investigated whether the categorical diagnosis of PTSD and severity of PTSD symptom clusters (i.e. re-experiencing, avoidance, arousal, and overall score) would be associated with plasma concentrations of three markers of endothelial dysfunction [soluble tissue factor (sTF), von Willebrand factor (VWF), and soluble intercellular adhesion molecule (sICAM)-1]. Compared with controls, patients had significantly higher sTF; this difference became nonsignificant when controlling for psychological distress. VWF and sICAM-1 levels were not significantly different between patients and controls. In the entire sample virtually all PTSD symptom clusters correlated significantly and positively with sTF and VWF but not with sICAM-1. The correlation between symptoms of re-experiencing and sTF was significantly different between patients and controls. Controlling for symptoms of anxiety and depression (i.e. psychological distress) rendered most associations between PTSD symptom clusters and sTF nonsignificant, whereas controlling for age retained significance of associations with VWF. Posttraumatic stress showed a continuous relationship with sTF and VWF, with the former relationship being partly affected by psychological distress. This suggests one mechanism by which posttraumatic stress could contribute to atherosclerosis.

Enhanced antitumorigenic effects in glioblastoma on double targeting of pleiotrophin and its receptor ALK

In adults, glioblastomas are the most lethal and most frequent malignant brain tumors, and the poor prognosis despite aggressive treatment indicates the need to establish novel targets for molecular intervention. The secreted growth factor pleiotrophin (PTN, HB-GAM, HBNF, OSF-1) shows mitogenic, chemotactic, and transforming activity. Whereas PTN expression is tightly regulated during embryogenesis and is very limited in normal adult tissues, a marked PTN up-regulation is seen in tumors including glioblastomas. Likewise, the PTN receptor anaplastic lymphoma kinase (ALK) has been shown previously to be upregulated and functionally relevant in glioblastoma. In this study, we explore the antitumorigenic effects of the simultaneous ribozyme-mediated knockdown of both receptor and ligand. Various glioblastoma cell lines are analyzed for PTN and ALK expression. Beyond the individual efficacies of several specific ribozymes against PTN or ALK, respectively, antiproliferative and proapoptotic effects of a single gene targeting approach are strongly enhanced on double knockdown of both genes in vitro. More importantly, this results in the abolishment of tumor growth in an in vivo subcutaneous tumor xenograft model. Finally, the analysis of various downstream signaling pathways by antibody arrays reveals a distinct pattern of changes in the activation of signal transduction molecules on PTN/ALK double knockdown. Beyond the already known ones, it identifies additional pathways relevant for PTN/ALK signaling. We conclude that double targeting of PTN and ALK leads to enhanced antitumorigenic effects over single knockdown approaches, which offers novel therapeutic options owing to increased efficacy also after prolonged knockdown.

Mapping H5N1 highly pathogenic avian influenza risk in Southeast Asia

The highly pathogenic avian influenza (HPAI) H5N1 virus that emerged in southern China in the mid-1990s has in recent years evolved into the first HPAI panzootic. In many countries where the virus was detected, the virus was successfully controlled, whereas other countries face periodic reoccurrence despite significant control efforts. A central question is to understand the factors favoring the continuing reoccurrence of the virus. The abundance of domestic ducks, in particular free-grazing ducks feeding in intensive rice cropping areas, has been identified as one such risk factor based on separate studies carried out in Thailand and Vietnam. In addition, recent extensive progress was made in the spatial prediction of rice cropping intensity obtained through satellite imagery processing. This article analyses the statistical association between the recorded HPAI H5N1 virus presence and a set of five key environmental variables comprising elevation, human population, chicken numbers, duck numbers, and rice cropping intensity for three synchronous epidemic waves in Thailand and Vietnam. A consistent pattern emerges suggesting risk to be associated with duck abundance, human population, and rice cropping intensity in contrast to a relatively low association with chicken numbers. A statistical risk model based on the second epidemic wave data in Thailand is found to maintain its predictive power when extrapolated to Vietnam, which supports its application to other countries with similar agro-ecological conditions such as Laos or Cambodia. The model’s potential application to mapping HPAI H5N1 disease risk in Indonesia is discussed.

Prevention of bone loss in paraplegics over 2 years with alendronate

To assess the effects of long-term treatment of bone loss with alendronate in a group of paraplegic men, 55 patients were evaluated in a prospective randomized controlled open label study that was 2 years in duration comparing alendronate and calcium with calcium alone. Bone loss was stopped at all cortical and trabecular infralesional sites (distal tibial epiphysis, tibial diaphysis, total hip) with alendronate 10 mg daily.

Long-term changes in bone metabolism, bone mineral density, quantitative ultrasound parameters, and fracture incidence after spinal cord injury: a cross-sectional observational study in 100 paraplegic men

To study the time course of demineralization and fracture incidence after spinal cord injury (SCI), 100 paraplegic men with complete motor loss were investigated in a cross-sectional study 3 months to 30 years after their traumatic SCI. Fracture history was assessed and verified using patients' files and X-rays. BMD of the lumbar spine (LS), femoral neck (FN), distal forearm (ultradistal part = UDR, 1/3 distal part = 1/3R), distal tibial diaphysis (TDIA), and distal tibial epiphysis (TEPI) was measured using DXA. Stiffness of the calcaneus (QUI.CALC), speed of sound of the tibia (SOS.TIB), and amplitude-dependent SOS across the proximal phalanges (adSOS.PHAL) were measured using QUS. Z-Scores of BMD and quantitative ultrasound (QUS) were plotted against time-since-injury and compared among four groups of paraplegics stratified according to time-since-injury (<1 year, stratum I; 1-9 years, stratum II; 10-19 years, stratum III; 20-29 years, stratum IV). Biochemical markers of bone turnover (deoxypyridinoline/creatinine (D-pyr/Cr), osteocalcin, alkaline phosphatase) and the main parameters of calcium phosphate metabolism were measured. Fifteen out of 98 paraplegics had sustained a total of 39 fragility fractures within 1,010 years of observation. All recorded fractures were fractures of the lower limbs, mean time to first fracture being 8.9 +/- 1.4 years. Fracture incidence increased with time-after-SCI, from 1% in the first 12 months to 4.6%/year in paraplegics since >20 years ( p<.01). The overall fracture incidence was 2.2%/year. Compared with nonfractured paraplegics, those with a fracture history had been injured for a longer time ( p<.01). Furthermore, they had lower Z-scores at FN, TEPI, and TDIA ( p<.01 to <.0001), the largest difference being observed at TDIA, compared with the nonfractured. At the lower limbs, BMD decreased with time at all sites ( r=.49 to.78, all p<.0001). At FN and TEPI, bone loss followed a log curve which leveled off between 1 to 3 years after injury. In contrast, Z-scores of TDIA continuously decreased even beyond 10 years after injury. LS BMD Z-score increased with time-since-SCI ( p<.05). Similarly to DXA, QUS allowed differentiation of early and rapid trabecular bone loss (QUI.CALC) vs slow and continuous cortical bone loss (SOS.TIB). Biochemical markers reflected a disproportion between highly elevated bone resorption and almost normal bone formation early after injury. Turnover declined following a log curve with time-after-SCI, however, D-pyr/Cr remained elevated in 30% of paraplegics injured >10 years. In paraplegic men early (trabecular) and persistent (cortical) bone loss occurs at the lower limbs and leads to an increasing fracture incidence with time-after-SCI.