Monitoring strontium ranelate therapy in patients with osteoporosis.

PURPOSE: The purpose of this study was to review the monitoring of strontium ranelate osteoporosis therapy. METHODS: The method used in this study was comprehensive literature review with clinical perspectives. RESULTS: Changes in bone turnover markers (BTM) or bone mineral density (BMD) have been documented in osteoporosis clinical trials. However, neither BMD nor BTM changes fully explain the observed fracture risk reduction in treated patients. If changes in BMD or BTM on therapy would be easily discernable in individual patients, and were strongly associated with fracture risk reduction, monitoring individuals would be more useful. BMD changes in patients on strontium ranelate are of a greater magnitude and hence can be easily determined in an individual patient. In addition, there exists a better correlation between fracture risk reduction and increases in BMD. CONCLUSIONS: The strong correlation between measured BMD increases and fracture risk reduction in patients on strontium ranelate therapy will be of clinical benefit to physicians wishing to evaluate both treatment persistence and fracture risk reduction.

Relationship between change in femoral neck bone mineral density and hip fracture incidence during treatment with strontium ranelate.

OBJECTIVE: Strontium ranelate (SR) increases bone mineral density (BMD) in postmenopausal osteoporotic women and reduces vertebral and non-vertebral fracture incidence. Hip fracture reduction has also been observed during 3-year treatment with SR in osteoporotic women at high risk of hip fracture. The objective of this study is to analyse the association between BMD changes and hip fracture incidence during treatment with SR. MATERIAL AND METHODS: In this post-hoc analysis, 465 women aged over 74 years with low BMD at the femoral neck (T-score < or = -2.4 according to NHANES normative values) were selected from the population of a recently published study (the Treatment of Peripheral Osteoporosis Study - TROPOS). BMD was assessed at the femoral neck at baseline and after a follow-up of 3 years. Hip fractures were reported by study investigators. RESULTS: After adjusting for age, body mass index, femoral neck BMD at baseline and number of prevalent vertebral fractures, we found that for each 1% increase in femoral neck BMD observed after 3 years, the risk to experience a hip fracture after 3 years decreased by 7% (95% CI: 1-14%) (p = 0.04). In patients experiencing a hip fracture over 3 years of treatment with SR, femoral neck BMD increased by (mean [SE]) 3.41 (1.02)% compared to 7.23 (0.81)% in patients without hip fracture (p = 0.02). CONCLUSION: In this post-hoc analysis of women undergoing 3 years of SR treatment, an increase in femoral neck BMD is associated with a decrease in hip fracture incidence.

Appropriateness of internal digital phantoms for monitoring the stability of the UBIS 5000 quantitative ultrasound device in clinical trials.

In bone status assessment, proper quality assurance/quality control is crucial since changes due to disease or therapeutic treatment are very small, in the order of 2-5%. Unlike for dual X-ray absorptiometry, quality control procedures have not been extensively developed and validated for quantitative ultrasound technology, limiting its use in longitudinal monitoring. While the challenge of developing an ideal anthropometric phantom is still open, some manufacturers use the concept of the internal digital phantom mimicking human characteristics to check the stability of their device. The objective of the study was to develop a sensitive model of quality control suitable for the correction of QUS patient data. In order to achieve this goal, we simulated a longitudinal device lifetime with both correct and malfunctioning behaviors. Then, we verified the efficiency of digital phantoms in detecting those changes and subsequently established the in vitro/in vivo relationship. This is the first time that an attempt to validate an internal digital phantom has made, and that this type of validation approach is used. The digital phantom (DP) was designed to mimic normal bone (BUAP2) and osteoporotic bone (BUAP1) properties. The DP was studied using the UBIS 5000 ultrasound device (DMS, France). Diverse malfunctions of the UBIS-5000 were simulated. Several series of measurements were performed on both BUAP1 and 2 and on 12 volunteers at each grade of malfunction. The effect of each simulated malfunction on in vivo and in vitro results was presented graphically by plotting the average BUA values against the percentage change from baseline. The change from baseline in BUA was modeled using linear regression, and the in vivo/in vitro ratio was obtained from the model. All experimentations influenced the measure of BUAP1 and 2 as well as the measure of our 12 volunteers. However, the degree of significance varied as a function of the severity of the malfunction, and the results also differed substantially in magnitude between in vivo and in vitro. Indeed, the DP was about 10 times more sensitive to variations of the transfer function than was the in vivo measurement, which is very reassuring. The sensitivity of the digital phantoms was reliable in the determination of simulated malfunctions of the UBIS-5000. The digital phantoms provided an accurate evaluation of the acoustic performance of the scanner, including the fidelity of transducers. In light of these results, the QC approach of the UBIS-5000 will be extremely simple to implement compared with other devices. Indeed, since the digital phantom was automatically measured during every patient measurement, the QC approach could be built on an individual level basis rather than on an average basis.

Negative neurofunctional effects of frequency, depth and environment in recreational scuba diving: the Geneva "memory dive" study.

OBJECTIVES: To explore relationships between scuba diving activity, brain, and behaviour, and more specifically between global cerebral blood flow (CBF) or cognitive performance and total, annual, or last 6 months' frequencies, for standard dives or dives performed below 40 m, in cold water or warm sea geographical environments. METHODS: A prospective cohort study was used to examine divers from diving clubs around Lac Léman and Geneva University Hospital. The subjects were 215 healthy recreational divers (diving with self-contained underwater breathing apparatus). Main outcome measures were: measurement of global CBF by (133)Xe SPECT (single photon emission computed tomography); psychometric and neuropsychological tests to assess perceptual-motor abilities, spatial discrimination, attentional resources, executive functioning, and memory; evaluation of scuba diving activity by questionnaire focusing on number and maximum depth of dives and geographical site of the diving activity (cold water v warm water); and body composition analyses (BMI). RESULTS: (1) A negative influence of depth of dives on CBF and its combined effect with BMI and age was found. (2) A specific diving environment (more than 80% of dives in lakes) had a negative effect on CBF. (3) Depth and number of dives had a negative influence on cognitive performance (speed, flexibility and inhibition processing in attentional tasks). (4) A negative effect of a specific diving environment on cognitive performance (flexibility and inhibition components) was found. CONCLUSIONS: Scuba diving may have long-term negative neurofunctional effects when performed in extreme conditions, namely cold water, with more than 100 dives per year, and maximal depth below 40 m.

Longitudinal quality control methodology for the quantitative ultrasound Achilles+ in clinical trial settings.

Appropriate quality assurance (QA) and quality control (QC) procedures have been well developed and validated for dual X-ray absorptiometry (DXA), and are widely applied in multicenter clinical trials to monitor device stability used to check the treatment effects on bone mineral density. This is not yet the case for quantitative ultrasound (QUS) technology, for which no QC approaches have yet been fully tested. The first Achilles (GE-Lunar Corporation, Madison, WI, USA) has been on the market for 10 years (1991). The goal of this study was to develop the QC methodology for the QUS Achilles+ device using its past/current experience (log and maintenance files.) as well as by integrating the progress made over the last years in the ultrasound domain so as to better understand the influence of temperature on ultrasound parameters. Because of the lack of confidence in the external black rubber phantom used in daily QC with the Achilles+, to monitor the device stability, we selected several QC parameters known to be influenced by potential malfunctions as experienced by the maintenance department of GE-Lunar company as well as the physical approach. These are phantom temperature-adjusted speed of sound (PSOS-TC) and broadband ultrasound attenuation (PBUA-TC), water speed of sound error (WSE), water spectrum slope (WSS) and water gain (WG). We used four Achilles+ devices perfectly stable during their entire QC range, to calculate the optimum thresholds (based mostly on 95% confidence interval) for each of these parameters as well as the precision for the in vitro SOS and BUA. An additional not fully stable Achilles device has been used to run a QC procedure example. The precision expressed as the CV was 0.22% and 0.65% for the PSOS-TC and PBUA-TC, respectively. The alarm thresholds used for QC process are +/- 0.6%, +/- 1.9%, +/- 6.8 m/s, +/- 5.3% and +/- 7.3% for the PSOS-TC, PBUA-TC, WSE, WSS and WG, respectively. Applying a logical approach on the impact of each parameter on each other as well as their respective reactivity to malfunctions, we build a QC process flowchart meant to detect real malfunction in the daily QC. We found that in case of real malfunctions, the in vivo SOS should be decreased by 1.33 m/s for each 1 m/s increase in WSE. Unfortunately, in vivo BUA can not be adjusted when real malfunction occurs. Nevertheless, the BUA can be qualified as bad quality data and excluded from the medical interpretation. Using the currently available phantom and parameters, the best possible QC procedures to detect long-term drift in the daily QC of the Achilles+ was developed. To fully validate our approach and gain confidence in the defined limits it is our plan to apply this QC processing to a higher number of QUS devices.

Is time since hip fracture influencing the discrimination between fractured and nonfractured subjects as assessed at the calcaneum by three technologically different quantitative ultrasound devices?

Because quantitative ultrasound (QUS) instruments from different manufacturers have significant technical differences, it is difficult to assess whether all of them can discriminate similarly between osteoporotic fractures and age-matched controls. Thus, to avoid any bias, reliable comparative assessment of the QUS devices should be carried out on the same population. Few studies have fulfilled this condition. Another source of variability in cross-sectional studies in which fractured and nonfractured subjects are compared is the time since osteoporotic fracture. Our study evaluated the ability of three calcaneal QUS devices to discriminate patients with osteoporotic hip fracture from control subjects, using the same population. In addition, a subset of patients was re-measured about 9 months after the hip replacement surgery to check how the time since fracture affects the discriminatory ability of the different QUS devices. Fifty postmenopausal hip-fractured patients and 46 postmenopausal age-matched controls were included in this study and measured on three QUS devices, as well as 50 young healthy controls to calculate the T-score. Odds ratio results showed that a decrease in UBIS trade mark BUA of 1 SD was associated with a significant increase in fracture risk (odds ratio adjusted = 2.30) comparable with Sahara broadband ultrasound attenuation (BUA) (OR adj. = 2.30), and Achilles BUA (OR adj. = 3.5). However, given the large overlap between the 95% intervals of each OR and for the areas under ROC curves, no significant difference was found between them. In the subset of 15 hip-fractured subjects, no significant differences were found between ultrasound parameters of the first visit and 9 months after except for the heel width (soft tissue variation). Odds ratio and areas under the curve (AUC) tend to increase from visit 1 to 2 for the BUA and decrease substantially for the SOS for all but the Lunar Achilles+. Nonsignificant correlation was found between the absolute difference of the ultrasound parameters measured at the two visits and the time since fracture, except for the Sahara SOS (r = 0.45; P < 0.04). In conclusion, no significant differences between QUS technologies were observed in their positive and significant ability to discriminate hip-fractured patient from controls. However, this statement is shadowed when taking into account the time since fracture which seems to negatively influence results obtained on dry versus wet QUS systems. As a result, it is advisable that such parameters would be taken into account when designing a study aimed to demonstrate the discriminatory ability of heel ultrasound between normal and hip-fractured patients.

Monitored impact loading of the hip: initial testing of a home-use device.

Many studies have been done involving exercise, impact loading, and the effect on BMD. In some of these studies, particularly those involving outpatient activity, compliance and the specific parameters of an individual's impact loading have been difficult to monitor effectively. In this study, an individual, home-use platform was used to record daily, specific, and reproducible impact forces generated during a heel drop exercise. At three centers over 24 months, we conducted a randomized, prospective study of 157 osteoporotic and osteopenic women, aged 60-85 years. A total of 99 patients used the home Osteocare device (OrthoGenesis Incorporated, Northborough, Massachusetts USA) to generate a reproducible and specific daily impact program (active group). Controls (32) performed a similar motion on the unit but without trying to trigger an impact force (sham group), and 26 patients did no prescribed heel drop exercise (control group). All groups had the same calcium and vitamin D supplementation. Hip DXA was performed at baseline and every 6 months during the entire study duration. Compliance with the 3-5 min routine was high, and patients were able to consistently achieve the specific targeted impact range. Pooled BMD results showed no significant differences between groups in overall BMD measurements. However, a classification model that looked at individual site-specific BMD changes showed that more than 75% of the active group responded (versus 62% for both the sham and the control groups) by maintaining or increasing site-specific hip BMD over the 2-year trial. In fact, at the end of the study, 45% of the actives were gainers versus 12% and 22% in the sham and control groups, respectively. This study suggests that hip BMD may be maintained through a brief, safe, at-home, monitored impact loading program.

Fuzzy clustering-based segmented attenuation correction in whole-body PET imaging.

Segmented attenuation correction is now a widely accepted technique to reduce noise propagation from transmission scanning in positron emission tomography (PET). In this paper, we present a new method for segmenting transmission images in whole-body scanning. This reduces the noise in the correction maps while still correcting for differing attenuation coefficients of specific tissues. Based on the fuzzy C-means (FCM) algorithm, the method segments the PET transmission images into a given number of clusters to extract specific areas of differing attenuation such as air, the lungs and soft tissue, preceded by a median filtering procedure. The reconstructed transmission image voxels are, therefore, segmented into populations of uniform attenuation based on knowledge of the human anatomy. The clustering procedure starts with an overspecified number of clusters followed by a merging process to group clusters with similar properties (redundant clusters) and removal of some undesired substructures using anatomical knowledge. The method is unsupervised, adaptive and allows the classification of both pre- or post-injection transmission images obtained using either coincident 68Ge or single-photon 137Cs sources into main tissue components in terms of attenuation coefficients. A high-quality transmission image of the scanner bed is obtained from a high statistics scan and added to the transmission image. The segmented transmission images are then forward projected to generate attenuation correction factors to be used for the reconstruction of the corresponding emission scan. The technique has been tested on a chest phantom simulating the lungs, heart cavity and the spine, the Rando-Alderson phantom, and whole-body clinical PET studies showing a remarkable improvement in image quality, a clear reduction of noise propagation from transmission into emission data allowing for reduction of transmission scan duration. There was very good correlation (R2 = 0.96) between maximum standardized uptake values (SUVs) in lung nodules measured on images reconstructed with measured and segmented attenuation correction with a statistically significant decrease in SUV (17.03% +/- 8.4%, P < 0.01) on the latter images, whereas no proof of statistically significant differences on the average SUVs was observed. Finally, the potential of the FCM algorithm as a segmentation method and its limitations as well as other prospective applications of the technique are discussed.

Strontium ranelate: dose-dependent effects in established postmenopausal vertebral osteoporosis--a 2-year randomized placebo controlled trial.

The aim of the strontium ranelate (SR) for treatment of osteoporosis (STRATOS) trial was to investigate the efficacy and safety of different doses of SR, a novel agent in the treatment of postmenopausal osteoporosis. A randomized, multicenter, double-blind, placebo-controlled trial was undertaken in 353 osteoporotic women with at least one previous vertebral fracture and a lumbar T-score <-2.4. Patients were randomized to receive placebo, 0.5 g, 1 g, or 2 g SR/d for 2 yr. The primary efficacy endpoint was lumbar bone mineral density (BMD), assessed by dual-energy x-ray absorptiometry. Secondary outcome measures included femoral BMD, incidence of new vertebral deformities, and biochemical markers of bone metabolism. Lumbar BMD, adjusted for bone strontium content, increased in a dose-dependent manner in the intention-to-treat population: mean annual slope increased from 1.4% with 0.5 g/d SR to 3.0% with 2 g/d SR, which was significantly higher than placebo (P < 0.01). There was a significant reduction in the number of patients experiencing new vertebral deformities in the second year of treatment with 2 g/d SR [relative risk 0.56; 95% confidence interval (0.35; 0.89)]. In the 2 g/d group, there was a significant increase in serum levels of bone alkaline phosphatase, whereas urinary excretion of cross-linked N-telopeptide, a marker of bone resorption, was lower with SR than with placebo. All tested doses were well tolerated; the 2 g/d dose was considered to offer the best combination of efficacy and safety. In conclusion, SR therapy increased vertebral BMD and reduced the incidence of vertebral fractures.

Contribution of body composition to nutritional assessment at hospital admission in 995 patients: a controlled population study.

Body weight, weight changes and BMI are easily obtainable indicators of nutritional status, but they do not provide information on the amount of fat-free and fat masses. The purpose of the present study was to determine if fat-free mass (FFM) and fat mass were depleted in patients with normal BMI or serum albumin at hospital admission. A group of 995 consecutive patients were evaluated for malnutrition by BMI, serum albumin, and 50 kHz bioelectrical impedance analysis and compared with 995 healthy adults, matched for age and height, and then compared with FFM and fat mass percentiles previously determined in 5225 healthy adults. A BMI of

Lower femoral neck bone mineral density in prepubertal former preterm girls.

The purpose of this case-control study was to determine bone mineral content and areal bone mineral density at various skeletal sites in former preterm girls, aged 7-9 years, and to compare these data with age-matched term controls. Subjects included 25 white, prepubertal, former preterm girls (gestational age 30.8 +/- 0.3 weeks, birthweight 1461 +/- 56 g [mean +/- SEM]). Controls included 50 healthy, white, prepubertal girls born at term and matched for age (two controls per case). Measurements included anthropometric variables, calcium intake according to a food-frequency questionnaire, bone mineral content (BMC; grams), and areal bone mineral density (aBMD; grams per square centimeter), using dual-energy X-ray absorptiometry (DXA) at six skeletal sites. Thirteen preterm girls and 13 age-matched term controls were reassessed 1 year after the first DXA measurement. The former preterm girls were similar to controls in terms of age and height, but were lighter (24.6 +/- 0.6 vs. 27.0 +/- 0.6 kg, p = 0.02). They also reported a higher median calcium intake (1058 vs. 759 mg/day, p = 0.004). aBMD was lower in former preterms compared with controls at the level of the radial metaphysis (0.283 +/- 0.006 vs. 0.298 +/- 0.004, p = 0.04), femoral neck (0.593 +/- 0.011 vs. 0.638 +/- 0.010, p = 0.007), and total hip (0.596 +/- 0.012 vs. 0.640 +/- 0.010, p = 0.007), but was similar between the two groups at the radial diaphysis (0.437 +/- 0.004 vs. 0.436 +/- 0.004) and femoral diaphysis (1.026 +/- 0.015 vs. 1.030 +/- 0.011). Femoral neck aBMD remained lower compared with controls in the subgroup of preterm girls reassessed after 1 year (0.608 +/- 0.017 vs. 0.672 +/- 0.020, p = 0.02). In random effects models for longitudinal data, taking into account the effects of age, weight, and height on aBMD (dependent variable), femoral neck aBMD remained lower in former preterms (p < 0.001). Prepubertal former preterm girls showed growth recovery, but had lower aBMD at the hip and radial metaphysis than age-matched term controls, despite spontaneously higher calcium intake. Preterm girls had similar aBMD results compared with controls at sites with predominantly cortical bone (radial and femoral diaphysis), which are known to be more sensitive to calcium intake.

Fluorodeoxyuridine improves imaging of human glioblastoma xenografts with radiolabeled iododeoxyuridine.

Use of radiolabeled nucleotides for tumor imaging is hampered by rapid in vivo degradation and low DNA-incorporation rates. We evaluated whether blocking of thymidine (dThd) synthesis by 5-fluoro-2'-deoxyuridine (FdUrd) could improve scintigraphy with radio-dThd analogues, such as 5-iodo-2'-deoxyuridine (IdUrd). We first show in vitro that coincubation with FdUrd substantially increased incorporation of [125I]IdUrd and [3H]dThd in the three tested human glioblastoma lines. Flow cytometry analysis showed that a short coincubation with FdUrd (1 h) produces a signal increase per labeled cell. We then measured biodistribution 24 h after i.v. injection of [125I]IdUrd in nude mice s.c. xenografted with the three glioblastoma lines. Compared with animals given [125I]IdUrd alone, i.v. preadministration for 1 h of 10 mg/kg FdUrd increased the uptake of [125I]IdUrd in the three tumors 4.8-6.8-fold. Compatible with previous reports, there were no side effects in mice observed for 2 months after receiving such a treatment. The tumor uptake of [125I]IdUrd was increased < or =13.6-fold when FdUrd preadministration was stepwise reduced to 1.1 mg/kg. Uptake increases remained lower (between 1.7- and 5.8-fold) in normal proliferating tissues (i.e., bone marrow, spleen, and intestine) and negligible in quiescent tissues. DNA extraction showed that 72-80% of radioactivity in tumor and intestine was bound to DNA. Scintigraphy of xenografted mice was performed at different times after i.v. injection of 3.7 MBq [125I]IdUrd. Tumor detection was significantly improved after FdUrd preadministration while still equivocal after 24 h in mice given [125I]IdUrd alone. Furthermore, background activity could be greatly reduced by p.o. administration of KClO4 in addition to potassium iodide. We conclude that FdUrd preadministration may improve positron or single photon emission tomography with cell division tracers, such as radio-IdUrd and possibly other dThd analogues.

Allogeneic bone marrow transplantation is associated with a preferential femoral neck bone loss.

Osteoporosis is a major complication of organ transplantation. Little is known about the risk of developing osteoporosis in bone marrow transplant (BMT) recipients. We studied early and late changes in bone mineral density (BMD), as well as biochemical markers of bone remodeling, in patients at the time of allogeneic BMT (alloBMT) and up to 13 years thereafter. In a cross-sectional study, 102 patients (40 women, 62 men, mean age +/- SEM, 38.9 +/- 1.6 years) were segregated into a first group (A, n = 48) and evaluated before or during the first weeks (mean +/- SD 0.3 +/- 0.1 month, range -0.5 to 3 months) following alloBMT, and a second group (B, n = 54) studied 60.1 +/- 5.6 months (range 6-156 months) following alloBMT. Lumbar spine (LS) BMD was similar in groups A and B and was within normal limits. In contrast, femoral neck (FN) Z- and T-scores were significantly decreased in group B compared with group A (-0.68 +/- 0.14 vs -0.03 +/- 0.14 SD and -0.84 +/- 0.14 vs -0.22 +/- 0.14 SD, respectively; p < or = 0.002). Osteopenia (T-score between -1 and -2.5 SD) was present in 35% of group A and 43% of group B patients (NS). Osteoporosis (T-score < -2.5 SD) was detected in 7% of group B patients, but in none of those in group A (p = 0.05). In a longitudinal study, 56 subjects were evaluated at the time of alloBMT, and 33 and 23 were studied 6 or 12 months later, respectively (13 women, 20 men, 37.5 +/- 1.6 years). All were treated with supplements of calcium and vitamin D. Amenorrheic women received hormone replacement therapy (HRT). Three-monthly pamidronate infusions were given to 15 men and 10 non-amenorrheic women who were osteopenic/osteoporotic or had elevated baseline bone turnover markers. Mean baseline LS and FN Z- and T-scores were within normal range. Six months after BMT, FN BMD decreased by 4.2 +/- 0.7% (p < 0.001), and whole body BMD and bone mineral content by 1.5 +/- 0.4% and 3.1 +/- 0.6%, respectively (p < or = 0.0001). Twelve months after the graft, there was no further significant bone loss and only FN BMD decrease remained significantly different compared with baseline (-5.6 +/- 1.1%, p < or = 0.0001). These results indicate that the risk of decreased BMD is higher for the femoral neck than the lumbar spine and whole body levels in patients with allogeneic bone marrow transplantation, and that bone loss occurs mainly during the first 6 months after the graft.

Brain energy metabolism in Alzheimer's disease: 99mTc-HMPAO SPECT imaging during verbal fluency and role of astrocytes in the cellular mechanism of 99mTc-HMPAO retention.

The central hypothesis of the study which has been carried out as part of the NRP38 program, is that perturbations of brain energy metabolism are critically involved in the neurodegeneration occurring in Alzheimer's disease (AD) and that they may correlate with early cognitive dysfunctioning. In the present multidisciplinary study we set out to monitor brain energy metabolism using FDG-PET and HMPAO-SPECT imaging in a cohort of individuals over 65 years of age, drawn from the general population. HMPAO-SPECT imaging, which is a simpler and more widely accessible imaging procedure than FDG-PET, was performed under basal conditions and during the performance of a cognitive task (verbal fluency test). Three groups were studied. Two groups (groups I and II) included individuals age 65 or more, with no cognitive impairment and carrying an APOE4 positive or APOE4 negative phenotype, respectively; a third group (group III) included patients with clinical signs of AD. Each subject entering the study underwent an FDG-PET, an HMPAO-SPECT and an extensive battery of neuropsychological tests which assess various aspects of cognitive functioning, with a strong emphasis on working memory, divided attention and executive functions. A total of 101 participants were submitted to brain imaging and neuropsychological testing. Among these, 60 participants received the same set of imaging and neuropsychological tasks 24-36 months after the first set (phase II). In this article, we present a preliminary analysis performed on ten subjects from groups I and II and nine subjects from group III: activation (verbal fluency task) induced a specific pattern of increase in HMPAO retention (including BA 9/10, BA 18 bilaterally and right BA 17). In contrast to controls, in nine AD subjects no significant differences in HMPAO retention were observed when comparing activation and basal conditions. The cellular and molecular mechanisms that underlie the retention of HMPAO, the tracer used for single photon emission computed tomography (SPECT) imaging, has been studied in vitro in purified preparations of neurons and astrocytes with the aim of investigating the contribution of different cell types to hexamethyl-propyleneamineoxime labeled with technetium-99m (99mTc-HMPAO) retention in vitro. Results show that 99mTc-HMPAO retention predominates in astrocytes over neurons by a factor of approximately 2.5. Diethyl maleate, ethacrynic acid and buthionine sulfoximine, three agents which significantly reduce glutathione levels, also decreased 99mTc-HMPAO retention in both astrocytes and in neurons. Decrease did not always correlate with glutathione levels however, thus suggesting that other factors could be involved. The data presented indicate that astrocytes might constitute a prominent site of 99mTc-HMPAO retention and most likely contribute significantly to the SPECT signal. In addition, they also suggest that specific alterations in glial cell metabolism could explain flow-independent changes in 99mTc-HMPAO retention in the brain as observed by SPECT in certain pathologies (including Alzheimer's disease). In particular, these observations suggest a key role of astrocytes in the signal detected with the imaging procedure, which is altered in the Alzheimer's cohort subjected to the verbal fluency activation task.

Gain in bone mineral mass in prepubertal girls 3.5 years after discontinuation of calcium supplementation: a follow-up study.

BACKGROUND: Calcium supplementation during childhood and adolescence increases bone-mass accrual. Whether or not this benefit persists after discontinuation of supplementation is not known. We previously showed a favourable effect of milk-extracted calcium phosphate incorporated in various foods on accumulation of bone mineral mass in 8-year-old girls. We now report the results of a follow-up study undertaken more than 3 years after the end of calcium supplementation. METHODS: Anthropometric and bone variables were measured in 116 of the 144 girls whose data had been studied at the end of the supplementation period. The mean time elapsed between the end of the intervention period and this follow-up measurement was 3.5 years. Areal bone mineral density was measured by dual-energy X-ray absorptiometry at the same six skeletal sites as those studied during the intervention phase. FINDINGS: We were able to remeasure 62 and 54 girls of the calcium-supplemented and placebo groups, respectively. The increase from baseline in the overall mean bone mineral density of the six skeletal sites was still highly significant (calcium-supplemented group 179 mg/cm(2) [SE 8] vs placebo group 151 mg/cm(2) [7], p=0.012). A significant difference in favour of the supplemented group was also seen with respect to mean bone mineral content (p=0.031) and mean bone area (p=0.04). Difference in pubertal maturation did not seem to account for the recorded differences. INTERPRETATION: Our results suggest that this form of milk-extracted calcium phosphate taken during the prepubertal period can modify the trajectory of bone mass growth and cause a long-standing increase in bone mass accrual, which lasts beyond the end of supplementation.

Age-related differences in fat-free mass, skeletal muscle, body cell mass and fat mass between 18 and 94 years.

OBJECTIVE: To determine (1) lean and fat body compartments, reflected by fat-free mass (FFM), appendicular skeletal muscle mass (ASMM), body cell mass (BCM), total body potassium (TBK), fat mass and percentage fat mass, and their differences between age groups in healthy, physically active subjects from 18 to 94 y of age; and (2) if the rate of decrease in any one of the parameters by age might be accelerated compared to others. METHODS: A total of 433 healthy ambulatory Caucasians (253 men and 180 women) aged 18--94 y were measured by dual-energy X-ray absorptiometry (DXA) and whole body scintillation counter (TBK counter) using a large sodium iodide crystal (203 mm diameter). RESULTS: The ASMM change (-16.4 and -12.3% in men and women, respectively) in >75 y-old compared to 18 to 34-y-old subjects was greater than the FFM change (-11.8 and -9.7% in men and women, respectively) and this suggests that skeletal muscle mass decrease in older subjects was proportionally greater than non-skeletal muscle mass. BCM (-25.1 and -23.2% in men and women, respectively) and TBK differences were greater than the differences in FFM or ASMM suggesting altered composition of FFM in older subjects. Women had lower peak FFM, ASMM, BCM and TBK than men. CONCLUSIONS: The decline in FFM, ASMM, BCM and TBK is accelerated in men and women after 60 y of age and FFM, ASMM, BCM and TBK are significantly lower than in younger subjects. Fat mass continued to increase until around 75 y.

Fat-free and fat mass percentiles in 5225 healthy subjects aged 15 to 98 years.

OBJECTIVES: Fat-free mass (FFM) and fat mass (FM) are important in the evaluation of nutritional status. Bioelectrical impedance analysis (BIA) is a simple, reproducible method used to determine FFM and FM. Because normal values for FFM and FM have not yet been established in adults aged 15 to 98 y, its use is limited in the evaluation of nutritional status. The aims of this study were to determine reference values for FFM, FM, and percentage of FM by BIA in a white population of healthy adults, observe their differences with age, and develop percentile distributions for these parameters between ages 15 and 98 y. METHODS: Whole-body resistance and reactance of 2735 healthy white men and 2490 healthy white women, aged 15 to 98 y, was determined by 50-kHz BIA, with four skin electrodes on the right hand and foot. FFM and FM were calculated by a previously validated, single BIA formula and analyzed for age decades. RESULTS: Mean FFM peaked in 35- to 44-y-old men and 45- to 54-y-old women and declined thereafter. Mean FFM was 8.9 kg or 14.8% lower in men older than 85 y than in men 35 to 44 y old and 6.2 kg or 14.3% lower in women older than 85 y than in women 45 to 54 y old. Mean FM and percentage of FM increased progressively in men and women between ages 15 and 98 y. The results suggested that the greater weight noted in older subjects is due to larger FM. CONCLUSIONS: The percentile data presented serve as reference to evaluate deviations from normal values of FFM and FM in healthy adult men and women at a given age.

Performance of helical computed tomography in unselected outpatients with suspected pulmonary embolism.

BACKGROUND: Helical computed tomography (CT) is commonly used to diagnose pulmonary embolism, although its operating characteristics have been insufficiently evaluated. OBJECTIVE: To assess the sensitivity and specificity of helical CT in suspected pulmonary embolism. DESIGN: Observational study. SETTING: Emergency department of a teaching and community hospital. PATIENTS: 299 patients with clinically suspected pulmonary embolism and a plasma D -dimer level greater than 500 microgram/L. INTERVENTION: Pulmonary embolism was established by using a validated algorithm that included clinical assessment, lower-limb compression ultrasonography, lung scanning, and pulmonary angiography. MEASUREMENTS: Sensitivity, specificity, and likelihood ratios of helical CT and interobserver agreement. Helical CT scans were withheld from clinicians and were read 3 months after acquisition by radiologists blinded to all clinical data. RESULTS: 118 patients (39%) had pulmonary embolism. In 12 patients (4%), 2 of whom had pulmonary embolism, results of helical CT were inconclusive. For patients with conclusive results, sensitivity of helical CT was 70% (95% CI, 62% to 78%) and specificity was 91% (CI, 86% to 95%). Interobserver agreement was high (kappa = 0.823 to 0.902). The false-negative rate was lower for helical CT used after initial negative results on ultrasonography than for helical CT alone (21% vs. 30%). Use of helical CT after normal results on initial ultrasonography and nondiagnostic results on lung scanning had a false-negative rate of only 5% and a false-positive rate of only 7%. CONCLUSION: Helical CT should not be used alone for suspected pulmonary embolism but could replace angiography in combined strategies that include ultrasonography and lung scanning.

SPECT in periodic lateralized epileptiform discharges (PLEDs): a form of partial status epilepticus?

Periodic lateralized epileptiform discharges (PLEDs) are a well defined electroencephalographic entity but whether PLEDs represent an ictal condition or not remains debated. Much work has been done using electroencephalography (EEG) but new approaches using cerebral perfusion imaging may give more information about this question. We aimed to evaluate if PLEDs were associated with high regional cerebral blood flow (rCBF). We studied 18 patients with PLEDs and different pathologies, and performed brain single-photon-emission computed tomography (SPECT) during and, for three cases, after the disappearance of PLEDs. Qualitative variations and locations of rCBF were compared with PLEDs. Association with seizures and type of seizures were also assessed. SPECT showed high rCBF in 18/18 patients (100%). The location of PLEDs and high rCBF matched in 17/18 cases (94%). In the three cases where SPECT was performed after PLEDs disappeared, the high rCBF had cleared (100%). Eighteen cases (100%) presented seizures before recording of PLEDs, mainly motor (partial motor or generalized tonic-clonic). Where there was a decreased rCBF (related to a lesion) there was little relationship to PLEDs and all patients with decreased rCBF had an adjacent increased rCBF. These results confirm preliminary case reports. Hyperperfusion adds further to the argument that PLEDs may be related to a form of partial status epilepticus.

(133)Xe SPECT cerebral blood flow study in a healthy population: determination of T-scores.

UNLABELLED: Dementia is becoming a major health problem as the population of the Northern Hemisphere ages. Early differential diagnosis between normal cognitive decline and dementia is particularly difficult. If psychometric evaluation can contribute to the diagnosis, quantitative cerebral functional imaging would play an important role. We therefore proposed, first, to constitute a normative dataset that could later be used to identify subjects at risk for neurodegenerative processes and, second, to describe the risk of abnormal global cerebral blood flow (gCBF) by defining categories based on the standardized cutoff scores of a young, healthy population (T-score). METHODS: Of a total of 203 healthy volunteers, 187 were included in the protocol, which included evaluation of medical history, neurologic and neuropsychologic status, and body composition; analysis of blood; and measurement of gCBF by means of (133)Xe SPECT. RESULTS: With ANOVA analysis using age and sex as between-subject factors and gCBF as a within-subject factor, a significantly higher gCBF was found in women than in men. In addition, a linear reduction as a function of age was observed for both sexes (-0.3%/y). T-score was determined for the 18- to 28-y-old age group, for whom gCBF was found to be 46.7 +/- 5.1 mL/min/100 g tissue in men and 49.0 +/- 5.0 mL/min/100 g tissue in women. The age-dependent decrease could thus be expressed in T-scores and, in the 29- to 38-y-old, 39- to 48-y-old, and >48-y-old age groups, averaged -0.63, -1.29, and -1.92, respectively, in men and -0.63, -0.83, and-2.40, respectively, in women. Cognitive performance, body composition, and blood analysis revealed the expected significant effects from sex and age. CONCLUSION: The large-scale reference database of gCBF measurements constituted from a healthy, well-controlled population enabled age and sex stratification, which showed significant differences between the sexes and a significant decline as a function of age. T-scores were determined and warrant further studies on the prospective identification of early dementia by (133)Xe SPECT in elderly individuals.