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Methods are developed to acquire and track Orthogonal Frequency Division Multiplexing (OFDM) digital FM radio broadcast signals using standard OFDM acquisition techniques and using a new Delay-Lock Loop (DLL) to determine digital symbol “code” start times and a Phase-Lock Loop (PLL) to determine beat carrier phase. These tracking algorithms are being developed with the goal of using their derived observables to navigate by fusing them with corresponding observables from a reference station and with pressure altimeter data. The DLL and PLL feedback discriminator outputs are computed by solving an optimal fitting problem in the frequency domain for each OFDM symbol. A second-order DLL is used to cope with significant transmitter-induced code/carrier divergence. The outputs of the DLL and the PLL and used to determine, respectively, standard pseudorange and accumulated delta range observables. Single-differencing of these observables between a roving user receiver and a reference station receiver at a known location can remove the transmitter clock drift effects to yield navigation observables. Wideband data collected in Roanoke, VA, and in Charlotte, NC, have been processed off-line and used to study the suitability of such signals for navigation purposes. Pseudorange measurement and bias errors can be on the order of 100 m, but accumulated delta range precision can be better than 0.1 m. Multipath, however, can cause significant degradation of a receiver’s tracking capability and of the quality of its navigation observables. Examples of these effects are presented as are potential mitigation techniques. A system that uses accumulated delta range may be able to yield 5-m level positioning accuracy if multipath effects can be compensated. Current pseudorange-only solutions, however, exhibit errors on the order of 100s of m.

Summary 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.

The genetic bases of peak bone mass determinants are still poorly understood, particularly in males. We investigated the relationship between vitamin D receptor (VDR) 3'- and 5'-gene polymorphisms (as determined by the restriction enzymes BsmI and FokI) and bone mineral mass, and calcium and inorganic phosphate (Pi) metabolism in an homogeneous cohort of young healthy men. In 104 healthy subjects, aged 24.3 +/- 3.1 yr (mean +/- SD; range, 20.7-38.7), standardized bone mineral density (BMD; z-scores) at the levels of lumbar spine and femoral trochanter, i.e. bone mineral content adjusted for age, body size, and bone area, significantly differed between VDR 3'-end alleles (BsmI), whereas crude areal BMD or bone mineral content did not. Among BsmI homozygotes BB, BMD (z-scores) were significantly lower only in subjects also carrying the f allele at the VDR-5' polymorphic site (FokI). Serum PTH levels were significantly higher in the BB genotype at baseline and remained so under either a low or a high calcium-phosphorus diet. Moreover, on the low calcium-phosphorus diet, BB subjects had significantly decreased tubular Pi reabsorptive capacity and plasma Pi levels. Our results underline the importance of identifying multiple single base mutation polymorphisms within candidate genes of bone mineral mass and suggest a role for environmental/dietary factor interactions with VDR gene polymorphisms in peak bone mineral mass in men.

Genetic factors are known to explain a major proportion of peak bone mineral mass variance. Whether the influence of these genetic factors is expressed before the pubertal bone mineral mass accrual and whether there is tracking of bone mineral mass during pubertal growth, however, are not clearly established. We prospectively investigated correlations for bone mineral content (BMC), density, and bone size between prepubertal daughters and their premenopausal mothers. Height, weight, lumbar spine (LS), femoral neck (FN) and midfemoral diaphysis BMC, bone area (BA), areal bone mineral density (aBMD), and volumetric bone mineral apparent density (BMAD) were evaluated in 138 mothers (mean age ± sd, 40.0 ± 4.0 yr) and their daughters (8.1 ± 0.7 yr), who were then remeasured at yearly intervals for 2 yr. Eight-year-old prepubertal daughters had reached 78% and 44% of their mothers’ height and weight, respectively. At the various skeletal sites, they had reached 33–43% of their mothers’ BMC, 47–69% of their BA, 59–78% of their aBMD, and 75–105% of their BMAD. All body size and bone traits (age-adjusted Z-scores) were significantly correlated between prepubertal daughters and their mothers (r: 0.22–0.36, P < 0.01), except midfemoral diaphysis BMAD. Heritability estimates (1/2 h2), after adjustment for body size and dietary calcium intake, showed that 18–37% of bone traits were directly determined by maternal descent. During the next 2 yr, growth was accompanied by a marked increase of BMC, aBMD, and BA, whereas BMAD changed very little. In contrast, during this period, there were only minor changes in body size or bone trait Z-scores (i.e. Although more than 60% of peak bone mineral mass is gained during puberty (mostly at the expense of an increase in bone size while volumetric bone density slightly changes), familial resemblance for most bone traits is already present between daughters and their mothers before puberty. In the girls, moreover, yearly measurements were highly correlated, suggesting tracking of bone traits during pubertal growth. These results indicate that genetic susceptibility to osteoporosis may already be detectable in early childhood.

Resume Le pic de masse osseuse peut se definir comme la quantite de tissu osseux presente a la fin de la maturation squelettique. Il suscite beaucoup d'interet depuis quelques annees car il est un determinant important du risque de fracture osteoporotique a l'âge adulte. Actuellement, la technique la plus utilisee pour sa mesure est l'absorptiometrie biphotonique dont il faut noter qu'elle mesure la densite minerale osseuse (DMO) « de surface a (en g/cm 2 ), variable dont on a pu montrer qu'elle est un bon reflet de la resistance osseuse. C'est au moment de la puberte que se manifeste la difference de masse osseuse entre les sexes, difference qui est due essentiellement a une croissance de la masse osseuse plus prolongee, avec un accroissement plus important de la taille des os et de l'epaisseur corticale, chez les garcons que chez les filles. Il n'y a, en effet, pas de difference significative entre les sexes en ce qui concerne la densite trabeculaire volumetrique (en g/cm 3 ) a la fin de la maturation osseuse. Au terme de la maturation osseuse, il existe de grandes variations individuelles des valeurs de la DMO de surface du squelette axial et du squelette des membres. Cette large variance biologique n'a pas de relation avec la taille et ne parait pas s'accroitre de facon substantielle par la suite au cours de la vie adulte. Il est generalement admis que le pic de masse osseuse est atteint quel que soit le site squelettique et dans les deux sexes, aux alentours de l'âge de 35 ans. Il semble bien toutefois, au vu des resultats d'etudes recentes, que le pic de masse osseuse culmine vers la fin de la deuxieme decennie, tout particulierement pour les vertebres lombaires et le col femoral. Plusieurs facteurs sont sans doute a l'origine des larges variations individuelles de la masse osseuse en fin de maturation: facteurs genetiques, facteurs environnementaux, steroides sexuels, composition de l'alimentation, forces mecaniques, exposition a des facteurs de risque. Les facteurs genetiques sont sans doute tres importants, comme le demontrent les etudes realisees chez les jumeaux monozygotes ou dizygotes. En ce qui concerne l'alimentation, le role du contenu alimentaire en calcium durant la croissance n'est pas encore clairement etabli et il en est de meme de l'impact de l'activite physique. Il reste egalement a determiner quelles sont les annees les plus critiques de l'intervention de ces facteurs externes dans l'accumulation de la masse osseuse, avant de pouvoir faire des recommandations credibles et bien ciblees pour des programmes de prevention de l'osteoporose visant a optimaliser le pic de masse osseuse.

Corticosteroid-induced osteoporosis, which particularly affects the axial skeleton and the proximal femur, is characterized by a state of low bone remodelling. Fluoride is a potent stimulator of trabecular bone formation which could potentially be useful in the treatment of corticosteroid-induced osteoporosis. We investigated the effects of sodium monofluorophosphate (26 mg/day of fluoride) combined with 1000 mg of calcium (MFP-calcium-treated group), or of calcium alone (control), given for 18 months, on bone mineral density (BMD) of lumbar spine (LS), femoral neck (FN) and midfemoral shaft (FS) in 48 patients with corticosteroid-induced osteoporosis. Mean ages were 49.4±3.1 and 51.6±3.0 years (mean± SEM), duration of corticosteroid therapy 7.5±1.8 and 9.3±1.7 years, and mean daily dose of prednisone 18.2±2.3 and 12.1±1.1 mg in the MFP-calcium-treated group and controls, respectively. Initial BMDs (expressed as theZ-score, i.e. the difference in standard deviations from age- and sex-matched normal subjects) were −1.5±0.2 and −1.2±0.2 for LS, −1.4± 0.2 and −1.3±0.2 for FN, and −0.8±0.3 and −0.6±0.3 for FS, in the MFP-calcium-treated group and controls, respectively. Analysis by linear regression of 6-monthly measurement values revealed BMD changes of +7.8 ±2.2 versus + 3.6±1.3% (p

The so-called peak bone mass (PBM) represents the highest amount of bony tissue achieved during life at a given site of the skeleton. It has been suggested that PBM might be achieved as late as the fourth decade, but recent data have indicated that PBM is already achieved by the end of sexual maturation, namely at the end of the second decade. The solving of this apparent controversy is of interest for a better understanding of bone homeostasis and for defining the cohort of normal subjects to be evaluated in order to establish a PBM reference range--necessary for the diagnosis of osteoporosis and evaluation of the fracture risk. To study bone mass evolution in young healthy adults and to determine whether such a cohort can be used to establish PBM reference values, we measured bone mineral density (BMD) in sixty 20- to 35-year-old young healthy adults by dual-energy X-ray absorptiometry at the levels of the lumbar spine (in both anteroposterior and lateral views), femoral neck, trochanter region, total hip and of Ward's triangle, as well as whole-body BMD and bone mineral content (BMC) in cross-sectional and longitudinal studies. In the cross-sectional analysis, none of the bone mass variables was dependent on age using linear regression analysis. The longitudinal study indicated that the mean changes in lumbar spine, proximal femur and whole body BMD or BMC determined after a 1-year interval were not statistically different from zero in either females or males aged 20-35 years.(ABSTRACT TRUNCATED AT 250 WORDS)

Peak bone mass, which can be defined as the amount of bony tissue present at the end of the skeletal maturation, is an important determinant of osteoporotic fracture risk.Measurement of bone mass development. The bone mass of a given part of the skeleton is directly dependent upon both its volume or size and the density of the mineralized tissue contained within the periosteal envelope. The techniques of single-1 and dual-energy photon or X-ray absorptiometry measure the so-called ‘areal’ or ‘surface’ bone mineral density (BMD), a variable which has been shown to be directly related to bone strength.Bone mass gain during puberty. During puberty the gender difference in bone mass becomes expressed. This difference appears to be essentially due to a more prolonged bone maturation period in males than in females, with a larger increase in bone size and cortical thickness. Puberty affects bone size much more than the volumetric mineral density. There is no significant sex difference in the volumetric trabecular density at the end of pubertal maturation. During puberty, the accumulation rate in areal BMD at both the lumbar spine and femoral neck levels increases to four- to sixfold over a 3-and 4-year period in females and males, respectively. Change in bone mass accumulation rate is less marked in long bone diaphyses. There is an asynchrony between the gain in statural height and bone mass growth. This phenomenon may be responsible for the occurrence of a transient period of a relative increase in bone fragility that may account for the pattern of fracture incidence during adolescence.Variance in peak bone mass. At the beginning of the third decade there is a large variability in the normal values of areal BMD in the axial and appendicular skeleton. This large variance, which is observed at sites particularly susceptible to osteoporotic fractures such as lumbar spine and femoral neck, is barely reduced after correction for statural height, and does not appear to increase substantially during adult life. The height-independent broad variance in bone mass develops during puberty at sites such as lumbar spine and femoral neck, where the accretion rate is markedly increased.Time of peak bone mass attainment. Despite the fact that a majority of studies did not indicate that bone mass continues to accumulate significantly during the third and fourth decades, it has been generally accepted that peak bone mass at any skeletal site is attained in both sexes during the mid-thirties. However, recent studies indicate that in healthy Caucasian females with apparently adequate intakes of energy and calcium, bone mass accumulation can virtually be completed before the end of the second decade, for both lumbar spine and femoral neck. It is possible that both genetic and environmental factors could influence the time of peak bone mass achievement.Determinants of peaks bone mass. Several variables, more or less independent, are supposed to influence bone mass accumulation during growth; heredity, sex, dietary components, endocrine factors, mechanical forces, and exposure to risk factors. Quantitatively, the most prominent factor appears to be the genetic determinant, as estimated by studies comparing monozygotic and dizygotic twins. That heredity is not to be the only determinant of peak bone mass is of practical interest, since environmental factors can be modified. With respect to nutrition, the quantitative importance of calcium intake in bone mass accumulation during growth, particularly at sites prone to osteoporotic fractures, remains to be clearly determined. The same can be said for the impact of physical activity. Finally, the crucial years when these external factors will be particularly effective on bone mass accumulation remain to be determined by longitudinal prospective studies in order to produce credible and well targeted recommendations for the setting up of osteoporosis prevention programs aimed at maximizing peak bone mass.

Dietary protein and/or calorie insufficiencies represent an important problem in elderly patients. The biological and clinical implications, and particularly the influence on bone mass of undernutrition in the elderly, have not been completely defined, although several studies have demonstrated a high prevalence of dietary insufficiencies in patients with a recent fracture of the proximal femur. In the present study the relationship between dietary intakes, physical performance and bone mineral density (BMD) was examined in hospitalized elderly patients. The study comprised 74 patients (48 women, mean age 82 years; and 26 men, mean age 80 years) who were hospitalized for various medical indications. They were divided into two groups according to their dietary protein intakes, evaluated during the first 28 days in hospital while on a regular diet. The first group consisted of 26 patients (14 women and 12 men) whose protein intake was equal to or greater than 1 g per kilogram of ideal body weight. The second group consisted of 48 patients (34 women and 14 men) who consumed less than 1 g of protein per kilogram of ideal body weight. The two groups differed also in their energy, carbohydrate, lipid and calcium intakes. Patients in the group with the higher protein intake displayed higher BMD at the level of the femoral neck as measured by dual-photon absorptiometry. The men in this group also had higher lumbar spine BMD. After 4 weeks in hospital the women with a higher protein intake had significantly enhanced bicipital and quadricipital muscle strength and better performance as indicated by the increased capacity to climb stairs. These results indicate that lower dietary intakes in hospitalized elderly patients without fractures are associated with lower physical performance and lower femoral neck BMD. Thus, the role of dietary factors, including protein, in the risk of proximal femoral fractures deserves further investigation.

Malnutrition has been often suggested as contributing to both the high incidence of hip fracture in elderly people and its complications. In a recent prospective controlled randomized study, the clinical outcome of elderly patients with osteoporotic fracture of the proximal femur (hip fracture) improved by giving a simple oral dietary supplement. This study, however, did not prove that protein was responsible for the clinical improvement since the supplement also contained vitamins and minerals. We addressed this question by comparing the clinical outcome and bone mineral density (BMD) changes in elderly patients with hip fracture, receiving two different dietary supplements with different protein contents. Sixty-two patients (mean age 82) admitted into the orthopedic ward for fracture of the proximal femur were randomized into two groups. One group (n = 33) received 250 ml/day of an oral nutritional supplement containing protein (20.4 g), mineral salts (Ca: 0.525 g) and vitamins A = 750 IU; D3 = 25 IU) for a mean of 38 days. A control group (n = 29) received the same supplement dose, but with no protein, for the same period of time. The clinical course was significantly better in the group receiving protein, with 79% having a favorable course as compared to 36% (p less than 0.02) in the control group during the stay in the recovery hospital. The rate of complications and deaths was also significantly lower in the protein-supplemented vs the control group (52 vs 80%, p less than 0.05) 7 months after hip fracture. The median hospital stay was significantly lower in the protein-supplemented group (69 vs 102 days, p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Bone mass is an important determinant of resistance to fractures. Whether bone mineral density (BMD) in subjects with a fracture of the proximal femur (hip fracture) is different from that of age-matched controls is still debated. We measured BMD of the femoral neck (FN) on the opposite side to the fracture, as well as femoral shaft (FS) and lumbar spine (LS) BMD by dual-photon absorptiometry in 68 patients (57 women and 11 men, mean age 78.8±1.0) 12.4±0.8 days after hip fracture following a moderate trauma. These values were compared with BMD of 93 non-fractured elderly control subjects (82 women and 11 men), measured during the same period. As compared with the controls, FN BMD was significantly lower in fractured women (0.592±0.013 v. 0.728±0.014 g/cm2,P

Pulmonary embolism (PE) may encompass a wide spectrum of severity. To determine whether clinical findings, D-dimer (DD) concentration, and deep vein thrombosis (DVT) shown by lower-limb venous compression ultrasonography (US) might predict the scintigraphic extent of PE, we studied 104 hemodynamically stable consecutive outpatients with acute PE diagnosed by a high-probability ventilation-perfusion lung scan. Scintigraphic extent of PE was classified into three categories: perfusion defects corresponding to30%, 30-50%, or50% of the total lung area. Median respiratory and heart rates were found to be significantly related to the extent of PE. Higher median alveolar-arterial oxygen difference values were observed as the proportion of lung perfusion defects increased (50% vs.30%, 6.3 vs. 3.6 kPa, P.0001). Median plasma DD concentration was 7950 microg/L in patients with50% perfusion defects compared to 2731 microg/L in those with30% defects (P = .0001). DD levels above 4000 microg/L were associated to more extensive perfusion defects (50% vs.30% defects, OR 30; 95% CI 5.8-155). Finally, a proximal DVT was more likely among patients with larger perfusion defects (50% vs.30% defects, OR 4.5; 95% CI 1.5-13.6). In conclusion, clinical signs such as tachypnea and tachycardia, alveolar-arterial oxygen difference, plasma DD concentration, and presence of DVT on US are predictors of a larger PE, as assessed by the extent of perfusion defects on high probability lung scans.

The genetic bases of peak bone mass determinants are still poorly understood, particularly in males. We investigated the relationship between vitamin D receptor (VDR) 3'- and 5'-gene polymorphisms (as determined by the restriction enzymes BsmI and FokI) and bone mineral mass, and calcium and inorganic phosphate (Pi) metabolism in an homogeneous cohort of young healthy men. In 104 healthy subjects, aged 24.3 +/- 3.1 yr (mean +/- SD; range, 20.7-38.7), standardized bone mineral density (BMD; z-scores) at the levels of lumbar spine and femoral trochanter, i.e. bone mineral content adjusted for age, body size, and bone area, significantly differed between VDR 3'-end alleles (BsmI), whereas crude areal BMD or bone mineral content did not. Among BsmI homozygotes BB, BMD (z-scores) were significantly lower only in subjects also carrying the f allele at the VDR-5' polymorphic site (FokI). Serum PTH levels were significantly higher in the BB genotype at baseline and remained so under either a low or a high calcium-phosphorus diet. Moreover, on the low calcium-phosphorus diet, BB subjects had significantly decreased tubular Pi reabsorptive capacity and plasma Pi levels. Our results underline the importance of identifying multiple single base mutation polymorphisms within candidate genes of bone mineral mass and suggest a role for environmental/dietary factor interactions with VDR gene polymorphisms in peak bone mineral mass in men.

Genetic factors are known to explain a major proportion of peak bone mineral mass variance. Whether the influence of these genetic factors is expressed before the pubertal bone mineral mass accrual and whether there is tracking of bone mineral mass during pubertal growth, however, are not clearly established. We prospectively investigated correlations for bone mineral content (BMC), density, and bone size between prepubertal daughters and their premenopausal mothers. Height, weight, lumbar spine (LS), femoral neck (FN) and mid-femoral diaphysis BMC, bone area (BA), areal bone mineral density (aBMD), and volumetric bone mineral apparent density (BMAD) were evaluated in 138 mothers (mean age +/- SD, 40.0 +/- 4.0 yr) and their daughters (8.1 +/- 0.7 yr), who were then remeasured at yearly intervals for 2 yr. Eight-year-old prepubertal daughters had reached 78% and 44% of their mothers' height and weight, respectively. At the various skeletal sites, they had reached 33-43% of their mothers' BMC, 47-69% of their BA, 59-78% of their aBMD, and 75-105% of their BMAD. All body size and bone traits (age-adjusted Z-scores) were significantly correlated between prepubertal daughters and their mothers (r: 0.22-0.36, P0.01), except midfemoral diaphysis BMAD. Heritability estimates (1/2 h2), after adjustment for body size and dietary calcium intake, showed that 18-37% of bone traits were directly determined by maternal descent. During the next 2 yr, growth was accompanied by a marked increase of BMC, aBMD, and BA, whereas BMAD changed very little. In contrast, during this period, there were only minor changes in body size or bone trait Z-scores (i.e.0.5 Z-scores), which were thus highly correlated between consecutive measurements (r: 0.75-0.92, P0.0001). Accordingly, mother-daughter correlations remained unchanged over that period. Although more than 60% of peak bone mineral mass is gained during puberty (mostly at the expense of an increase in bone size while volumetric bone density slightly changes), familial resemblance for most bone traits is already present between daughters and their mothers before puberty. In the girls, moreover, yearly measurements were highly correlated, suggesting tracking of bone traits during pubertal growth. These results indicate that genetic susceptibility to osteoporosis may already be detectable in early childhood.

Noninvasive instruments such as plasma D-dimer measurement (DD) and lower-limb compression ultrasonography (US) are being increasingly advocated to reduce the number of necessary angiograms in patients having suspected pulmonary embolism (PE) and a nondiagnostic lung scan. We therefore designed a decision analysis model (1) to evaluate the cost-effectiveness of combining these noninvasive diagnostic aids with lung scan and angiography in the diagnosis of PE and (2) to determine the optimal sequence and combination of tests taking into account the clinical probability of PE.We performed a cost-effectiveness analysis based on literature data, including data from a management study in our institution. Six diagnostic strategies were compared with the reference, ie, lung scan followed when nondiagnostic (low or intermediate probability) by angiography. In all strategies, PE was ruled out by a normal or near-normal scan, a negative DD (plasma level below 500 micrograms/L), or a negative angiogram. Pulmonary embolism was diagnosed and anticoagulant treatment was undertaken in the presence of a high-probability lung scan, deep vein thrombosis showed by US, or a positive angiogram. In case of a nondiagnostic scan (low or intermediate probability), patients could be either treated or not treated, or undergo other tests, according to the selected strategy.Under baseline conditions (prevalence of PE, 35%), strategies combining DD and US with lung scan, angiography being done only in case of an inconclusive noninvasive workup (DD level500 micrograms/L, normal US, and nondiagnostic lung scan), were most cost-effective. This approach yielded a 9% incremental cost reduction and a 37% to 47% decrease in the number of necessary angiograms compared with the reference strategy (scan +/- angiography). For patients with a low clinical probability of PE (or = 20%), withholding treatment from those with a low-probability lung scan without performing an angiogram proved safe and highly cost-effective (30% cost reduction), provided US showed no deep vein thrombosis.The DD test and US are cost-effective in the diagnostic workup of PE, whether performed after or before lung scan, thus allowing centers devoid of lung scanning and/or angiography facilities to screen patients with suspected PE and avoid costly referrals. In patients with a low clinical probability, a low-probability lung scan, and a normal US, treatment may be withheld without resorting to angiography.

High calcium intake during childhood has been suggested to increase bone mass accrual, potentially resulting in a greater peak bone mass. Whether the effects of calcium supplementation on bone mass accrual vary from one skeletal region to another, and to what extent the level of spontaneous calcium intake may affect the magnitude of the response has, however, not yet been clearly established. In a double-blind, placebo-controlled study, 149 healthy prepubertal girls aged 7.9+/-0.1 yr (mean+/-SEM) were either allocated two food products containing 850 mg of calcium (Ca-suppl.) or not (placebo) on a daily basis for 1 yr. Areal bone mineral density (BMD), bone mineral content (BMC), and bone size were determined at six sites by dual-energy x-ray absorptiometry. The difference in BMD gain between calcium-supplemented (Ca-suppl.) and placebo was greater at radial (metaphysis and diaphysis) and femoral (neck, trochanter, and diaphyses) sites (7-12 mg/cm2 per yr) than in the lumbar spine (2 mg/cm2 per yr). The difference in BMD gains between Ca-suppl. and placebo was greatest in girls with a spontaneous calcium intake below the median of 880 mg/d. The increase in mean BMD of the 6 sites in the low-calcium consumers was accompanied by increased gains in mean BMC, bone size, and statural height. These results suggest a possible positive effect of calcium supplementation on skeletal growth at that age. In conclusion, calcium-enriched foods significantly increased bone mass accrual in prepubertal girls, with a preferential effect in the appendicular skeleton, and greater benefit at lower spontaneous calcium intake.

Common vitamin-D-receptor (VDR) gene allelic variants predict bone mineral density. We analysed VDR alleles and rate of change of lumbar-spine bone mineral density over 18 months in 72 elderly subjects. 9 BB homozygotes lost bone mineral density but 26 homozygotes for the alternative genotype (bb) did not (mean change -2.3 [SE 1.0] vs 0.9 [0.7]% per year, p < 0.05), irrespective of calcium intake. Among 37 heterozygotes (Bb), however, change in bone mineral density correlated with calcium intake (r = 0.35, p < 0.03). This association between a genetic marker and rate of bone loss in the elderly suggests that the effect of calcium intake on maintenance of bone mass could relate to VDR gene polymorphisms.

✔ une seule paire sur les 34 paires de TEP scans etudies (2.9%) possede une combinaison des trois valeurs SUVmoyen en dehors des parametres de controle qualite. Ce cas pourrait s’expliquer par la mauvaise lisibilite de l’examen causee par une forte augmentation du poids de ce patient entre les deux visites. En effet, cette prise de poids a tres vraisemblablement une incidence sur les mesures de SUV ce qui explique alors la variation importante ∆SUV dans cette paire d’examen.

The efficacy of calcium (Ca) in reducing bone loss is debated. In a randomized placebo-controlled double-masked study, we investigated the effects of oral Ca supplements on femoral shaft (FS), femoral neck (FN) and lumbar spine (LS) bone mineral density (BMD), and on the incidence of vertebral fracture in vitamin-D-replete elderly. Ninety-three healthy subjects (72.1 +/- 0.6 years) were randomly allocated to three groups receiving 800 mg/day Ca in two different forms or a placebo for 18 months. Sixty-three patients (78.4 +/- 1.0 years) with a recent hip fracture were allocated to two groups receiving the two forms of Ca without placebo. FS BMD changes in Ca-supplemented non-fractured women were significantly different from those in the placebo group (+0.6 +/- 0.5% v -1.2 +/- 0.7%, p0.05). There was no difference in effect between the two forms of Ca. The changes of +0.7 +/- 0.8% v -1.7 +/- 1.6% in FN BMD of Ca-supplemented women and the placebo group did not reach statistical significance. In fractured patients, FS, FN and LS BMD changes were -1.3 +/- 0.8, +0.3 +/- 1.6 and +3.1 +/- 1.2% (p0.05 for the last). The rate of new vertebral fractures was 74.3 and 106.2 fractures per 1000 patient-years in Ca-supplemented non-fractured subjects and in the placebo group, respectively, and 144.0 in Ca-supplemented fractured patients. Thus, oral Ca supplements prevented a femoral BMD decrease and lowered vertebral fracture rate in the elderly.

Effects of oral calcitriol on bone mineral density in patients with end-stage renal failure. Evolution of bone mineral density (BMD) at various skeletal sites and the influence of calcitriol on BMD are still poorly documented in patients with terminal renal failure. Using dual photon absorptiometry, we investigated the changes in BMD at the levels of lumbar spine, femoral neck and midfemoral shaft in 21 patients with end-stage renal failure (ESRF) treated with calcitriol (mean dosage ± SEM: 0.21 ± 0.02 µg/day) and compared them to 25 patients with ESRF but not treated with calcitriol (control group) over a period of 20.3 ± 1.5 and 17.2 ± 1.2 months, respectively. Lumbar spine BMD increased by 7.7 ± 3.2%/year in the treated group and decreased by 2.5 ± 1.3%/year in the control group (P < 0.005). Femoral shaft BMD increased more in treated than in control group (+ 6.7 ± 2.3 vs. + 1.4 ± 2.0%/year; P < 0.05) and femoral neck BMD remained stable. PTH levels increased by 92 ± 121 and 1033 ± 254 pmol/year (P < 0.01) in the treated group and the controls, respectively. Osteocalcin changes were -2.7 ± 3.7 and +20.1 ± 11.7 µg/liter (P < 0.05) per year in the same groups. These results indicate that low doses of oral calcitriol in patients with end-stage renal failure were associated with an increase in BMD at the levels of lumbar spine and femoral shaft, and with a stabilization of serum PTH and osteocalcin concentrations.

Effects induced by insulin-like growth factor I (IGF-I) and/or the bisphosphonate pamidronate (APD) on bone mineral density (BMD) of the lumbar spine and proximal and midshaft tibia were studied in adult rats made osteopenic by ovariectomy, using dual-energy X-ray absorptiometry. IGF-I, which was administered by osmotic minipumps implanted subcutaneously for 6 wk, caused a dose-dependent increase of BMD at the three investigated sites. A 4-wk course of IGF-I, followed by intermittent cyclical APD administration, induced significant increases of BMD at the levels of spine and proximal tibia. At midshaft tibia, where cortical bone predominates, BMD was increased by IGF-I only. In conclusion, IGF-I increased BMD at sites with trabecular and/or cortical bone, whereas the APD influence was mainly detectable in the former site only.

Consequences of protein-calorie malnutrition (PCM) have mostly been approached in terms of changes in body cell mass, or in body compartments as lean and fat masses. Such an approach exaggerates the relationship between tissue composition and tissue function. In addition, evidence of body compartment alterations does not provide any information about the pathophysiological consequences of such changes. For instance, does a reduction in muscle mass reduce the muscle performance in terms of power and endurance? In contrast, a function-oriented approach gives an overall appreciation of the integrity of a given mechanism which might be altered by malnutrition. Functions might be studied at different levels: a whole organism (i.e. heat production), an organ (i.e. muscle power), or an individual cell (i.e. membrane potential). At the cellular level, the relationship between ions content and membrane properties reflects that between PCM and cellular function.

The amount of skeletal mass acquired during adolescence is one of the most important determinants for the risk of postmenopausal and involutional osteoporosis. In both sexes, a large variance in bone mineral density (BMD) and content (BMC) is observed among healthy individuals at the beginning of the third decade. To determine the crucial pubertal years during which bone mass accumulation mainly occurs, we longitudinally monitored the gain in BMD/BMC at clinically important sites, such as lumbar spine and femoral neck, with respect to osteoporotic fracture risk. The changes in BMD (grams per cm2) and BMC (grams) were determined at 1-yr intervals at the level of lumbar spine vertebrae (L2-L4), femoral neck, and midfemoral shaft, using dual energy x-ray absorptiometry (Hologic QDR 1000), in 198 healthy adolescents (98 females and 100 males), aged 9-19 yr. Mean daily energy and calcium intakes, height, weight, and body mass index of the studied cohort were within the normal range for age. In females, the increment rate in BMD/BMC was particularly pronounced over a 3-yr period, i.e. from 11-14 yr of age. This increment dramatically fell after 16 yr and/or 2 yr after menarche. The mean gains in lumbar, femoral neck, and midfemoral shaft BMD were not statistically significant between 17-20 yr. In males, the gain in BMD/BMC was particularly high over a 4-yr period, i.e. from 13-17 yr. Then the increment rate markedly declined, but remained significant between 17-20 yr for L2-L4 BMD/BMC and midfemoral shaft BMD. In contrast, no significant increase was observed for femoral neck BMD. An impressive interindividual variation was observed between the yearly height increment and the bone mass accumulation. The bone mass-height gains relationship during puberty evolved according to a loop pattern, with maximal variance at Tanner stages P3-P4. This longitudinal study delineates the crucial pubertal years during which the skeletal mass accumulates at high, but various, rates at skeletal sites where the consequences of the osteoporosis are particularly dramatic. Furthermore, the results indicate that in a cohort of healthy females with apparently adequate intakes of energy and calcium, bone mass accumulation is drastically reduced by 16 yr of age in both lumbar spine and femoral neck.

Background: BN83495/STX64 is an irreversible steroid sulfatase (STS) inhibitor blocking the hydrolysis of sulfated estrone E1S and dehydroepiandrosterone DHEAS to their unsulfated active forms and thereby preventing conversion to Estradiol (E2) and Androstenediol (adiol), respectively. A phase I dose escalation study was conducted in post-menopausal women (PW) with ER+ metastatic breast cancer (MBC). The aim of the study was to determine the optimal biological dose (OBD) defined as the dose at which STS inhibition in peripheral blood mononuclear cells (PBMCs) ≥ 95% after 7 (D7) and 28 (D28) days of repeated oral daily administration and which also showed a maximal reduction in plasma E2 and adiol levels at D28 with no drug-related Grade 3 (Gr 3) or higher toxicity. Pharmacokinetics (PK), safety, tolerability and anti-tumour activity of BN83495 were also assessed.Methods: Patients (pts) had received at least one line of hormone therapy (HT) and at most 2 lines of chemotherapy (CT) in the adjuvant and/or advanced disease setting. Three to six pts were recruited into each of 5 sequential dose cohorts (1, 5, 20, 40 and 80 mg). The steady-state PK of BN83495 were assessed in all pts. Serum concentrations of E2 and Adiol were determined pre-dose, on D7 and D28 by HPLC-MS/MS analysis. Objective antitumor response was assessed according to RECIST criteria (version 1.0).Results: 29 pts were evaluable for safety. All had received one prior HT for MBC (Aromatase Inhibitors (AI): 86.2% Tamoxifen: 13.8%) and 12 (41.4%) received 2 lines of HT for MBC. BN83495 was well tolerated at doses up to 40 mg. Gr 3 fatigue with positive rechallenge was observed after 3 months of treatment in one pt at 80 mg. The main toxicity was dry skin Gr≤2 (N=12) that was observed in some pts in all cohorts from 20 mg up and was treated with emollient creams. Other toxicities included Gr 1/2 fatigue (N=6), hot flushes (N=3) and nausea (N=2).27 pts were evaluable for efficacy and hormone and STS evaluation. 14 pts received ≥ 3 months treatment. There were 3 SD ≥ 6 months, one each at 13 months (#020, 40 mg), 8 months (#015, 20 mg) and 7 months (#027, 80 mg, hormone resistant pt). Biopsy-proven erythematous skin infiltration in one patient (#027) was no longer visible after 1 month of treatment. Nearly complete STS enzyme inhibition was observed at all doses. The OBD was determined to be 40 mg. At this dose, mean Adiol reduction was -54.0% (-74.0—34.0) and E2 was –27.4% (-47.6- -7.2).An additional cohort (6 pts) was enrolled at 40 mg and FDG PET-scan was performed. Decrease >25% in hypermetabolic volume was noted in 2/5 lesions in 2 patients for whom data are available.Conclusion: BN83495 was well tolerated. Disease stabilizations ≥ 6 months were observed in this heavily pre-treated population including in one hormone resistant pt. The OBD was determined to be 40 mg. Complete FDG-PET scan data will be presented. Based on data obtained so far, BN83495 has shown activity. The study is ongoing. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 4097.

Bone mineral density (BMD, gr/cm2) and content (BMC, gr) were determined at the levels of the lumbar vertebrae (L2-L4), femoral neck (FN) and midfemoral shaft (FS) using DEX absorptiometry at 1-yr interval in 198 healthy adolescents (98 females, 100 males) aged 9-19 yrs. BMD/ BMC values were related to age, height, weight, pubertal stage and to environmental variables such as calcium intake and the level of physical activity. In females, the gain in BMD/BMC was sustained from 11 to 14 yrs but fell dramatically after 16 yrs and/ or 2 yrs after menarche. In males, the BMD/ BMC gain was elevated from 13 to 17 yrs and then declined markedly, remaining significant between 17 and 20 yrs for L2-L4 BMD/BMC and FS BMD only. Large interindividual variations were observed between height increments and bone mass gain with a relationship evolving according to a loop pattern. Multiple regression analysis showed that weight was the strongest predictor of bone mass at each site. Nutrition and exercise improved the R2 of the overall model by only 6% at L2-L4 and 4.1% at FN. Their effect on FS was negligible (+0.7%). During the normal pubertal development of average subjects, the effects of environmental factors appear to be outweighed by the large gain of bone mass due to puberty itself. These effects should therefore be easier to demonstrate in prepubertal children: this point appears of relevance for future intervention programmes aiming at maximizing bone mass gain during growth.

The sensitivity and specificity of single photon emission tomography with 57Co-labelled bleomycin (57Co-BLM) for the detection of cancer was determined from a prospective study involving a large group of patients selected to investigate roentgenographic abnormalities. Eighty-four of the 104 patients studied had malignant disease, of whom 76 had a positive scintigram. Eighteen of the 20 patients with benign disorders had a negative scintigram. The sensitivity and specificity was therefore 90.5 and 90% respectively. For the subset of patients who underwent investigation below the diaphragm, the sensitivity was 85.7%, while for investigation above the diaphragm, it reached 95.2% (this excluded reconstructions on the bladder level, because it produced large artifacts). This study leads to the conclusion that SPECT can be used specifically to investigate unidentified X-ray abnormality and diagnose malignancy using 57Co-BLM. In addition, we propose further investigation to evaluate the usefulness of this method in staging cancer.

The sensitivity and specificity of scanning with 57Co-labelled bleomycin for the diagnosis of lung cancer were determined from a prospective study involving a large group of patients with an abnormal chest roentgenogram. A semi-quantitative analysis of the scintigram was obtained by defining an index in terms of the excess isotope uptake within the tumour. Malignant pulmonary lesions were found in 121/175 patients and 113 had a positive scan. Benign pulmonary disorders were found in 54 patients, 45 of whom had a negative scan. The sensitivity and specificity were therefore 93% and 83% respectively. Bayes' theorem was then used to determine the predictive value of this test, either positive or negative, when the prevalence of disease varied from 10 to 90%. A receiver operating characteristic curve permits the choice of an appropriate value of the tumour uptake index to minimize the false positive fraction without classifying too many true positives as false negatives.

The meaning of 81Krm counts obtained in a dynamic series of gated lung ventilation scans was evaluated in terms of flow rate, lung volume, or the flow/volume ratio. Flow and volume signals were recorded together with scintigraphic events in 29 subjects breathing 81Krm and after its decay, 127Xe as a tracer of lung volume. Gated ventilation scans and respiratory signals were reconstructed. Statistical analyses were carried out for linear regressions between total normalized counts detected by the gamma camera and (1) flow rate, (2) lung volume and (3) flow/volume ratio. Inspiration and expiration were analysed separately. For both isotopes, the best correlation was obtained between counts and lung volume (r greater than 0.93). No correlation was obtained between counts and flow rate or flow/volume ratio. Thus, we conclude that 81Krm count variations in gated scans correlate well with tidal volume.

Only limited progress has been achieved in the treatment of ovarian cancer, the most common fatal gynaecological malignancy. Peritoneal dialysis with drugs known to be effective in ovarian cancer and large intraperitoneal fluid volumes (Belly Bath) have been used. The two critical determinants for a successful intraperitoneal chemotherapy programme are: (1) complete accessibility of the drug to all tumour-bearing areas; and (2) drug penetration into the residual tumour masses. We show that the scintigraphic technique in tomographic mode after administration of MAA-99Tcm-containing dialysate is a valuable adjunct for evaluation of patients undergoing intraperitoneal chemotherapy.

Temporal Fourier analysis was applied to Kr-81m ventilation scintigraphy to determine the amplitude (AMP1) and phase (PHA1) of the first harmonic of a single composite respiratory cycle and to compare regional patterns in subjects with obstructive pulmonary disease (COPD) and nonobstructed subjects. Six nonobstructed subjects, three subjects with small airway disease, six subjects with COPD, and one subject with restrictive disease were investigated. The mean value of the functional PHA1 image (PHA1m) correlated negatively with 1-second forced expiratory volume (FEV1) (r = -0.801, P less than .001), with %FEV1/FVC (r = -0.636, P less than .01) and maximum midexpiratory flow rate (FEF25-75%) (r = -0.723, P less than .002), and correlated positively with residual volume (r = 0.640, P less than .01). PHA1m values for the six subjects with COPD were significantly higher (t = 2.359, P less than .05) than for the ten nonobstructed subjects. Display of phase and amplitude functional images permits a visual evaluation of the regional distribution of ventilation to be made. Regional abnormalities of air flow were detected in obstructed subjects, and the presence of airway obstruction could be predicted. Dynamic ventilation imaging, therefore, appears to be a potentially useful noninvasive technique to assess lung impairment on a localized level.