Stefan Eberl

Genetic determinants of bone mass in adults. A twin study.

The relative importance of genetic factors in determining bone mass in different parts of the skeleton is poorly understood. Lumbar spine and proximal femur bone mineral density and forearm bone mineral content were measured by photon absorptiometry in 38 monozygotic and 27 dizygotic twin pairs. Bone mineral density was significantly more highly correlated in monozygotic than in dizygotic twins for the spine and proximal femur and in the forearm of premenopausal twin pairs, which is consistent with significant genetic contributions to bone mass at all these sites. The lesser genetic contribution to proximal femur and distal forearm bone mass compared with the spine suggests that environmental factors are of greater importance in the aetiology of osteopenia of the hip and wrist. This is the first demonstration of a genetic contribution to bone mass of the spine and proximal femur in adults and confirms similar findings of the forearm. Furthermore, bivariate analysis suggested that a single gene or set of genes determines bone mass at all sites.

Physical fitness is a major determinant of femoral neck and lumbar spine bone mineral density.

The relationship between physical fitness and bone mass in the femoral neck, lumbar spine, and forearm was studied in 84 normal women. Femoral neck and lumbar spine bone mineral density and forearm bone mineral content were estimated by absorptiometry. Fitness was quantitated from predicted maximal oxygen uptake. Femoral neck and lumbar bone mineral density were significantly correlated with fitness as well as age and weight. In the 46 postmenopausal subjects, fitness was the only significant predictor of femoral neck bone mineral density, and both weight and fitness predicted the lumbar bone mineral density. These data represent the first demonstration of a correlation between physical fitness, and, by implication, habitual physical activity, and bone mass in the femoral neck; they also support the previous reported correlation between lumbar bone mass and physical activity. The data suggest that increased physical fitness may increase bone mass at the sites of clinically important fractures in osteoporosis.

Correction for head movements in positron emission tomography using an optical motion tracking system

Methods capable of correcting for head motion in all six degrees of freedom have been proposed for positron emission tomography (PET) brain imaging but not yet demonstrated in human studies. These methods rely on the accurate measurement of head motion in relation to the reconstruction coordinate frame. We present methodology for the direct calibration of an optical motion-tracking system to the reconstruction coordinate frame using paired coordinate measurements obtained simultaneously from a PET scanner and tracking system. We also describe the implementation of motion correction, based on the multiple acquisition frame method originally described by Picard and Thompson (1997), using data provided by the motion tracking system. Effective compensation for multiple six-degree-of-freedom movements is demonstrated in dynamic PET scans of the Hoffman brain phantom and a normal volunteer. We conclude that reduced distortion and improved quantitative accuracy can be achieved with this method in PET brain studies degraded by head movements.

Osteoporosis in rheumatoid arthritis: safety of low dose corticosteroids.

Fear of inducing generalised osteoporosis is one reason why corticosteroids are withheld in patients with rheumatoid arthritis (RA). No studies, however, have directly measured bone density in such patients at clinically relevant sites. To assess this risk we measured bone mineral density in the lumbar spine and femoral neck by dual photon absorptiometry in 84 patients with RA, 44 of whom had been treated with low dose prednis(ol)one (mean dose +/- SE 8.0 +/- 0.5 mg/day; mean duration of treatment 89.6 +/- 12.0 months). There were significant reductions in bone mineral density in patients treated with corticosteroids (lumbar 9.6%, p less than 0.001; femoral 12.2%, p less than 0.001) and in those who had not received corticosteroids (lumbar 6.9%, p less than 0.01; femoral 8.9%, p less than 0.001), but the differences between the two groups were not significant. We conclude on the basis of these studies that low dose oral corticosteroids do not increase the risk of generalised osteoporosis in patients with rheumatoid arthritis.

Inhalation of hypertonic saline aerosol enhances mucociliary clearance in asthmatic and healthy subjects

Hyperosmolarity of the airway surface liquid (ASL) has been proposed as the stimulus for hyperpnoea-induced asthma. We found previously that mucociliary clearance (MCC) was increased after isocapnic hyperventilation (ISH) with dry air, and we proposed that the increase related to transient hyperosmolarity of the ASL. We investigated the effect of increasing the osmolarity of the ASL on MCC, by administering an aerosol of concentrated salt solution. MCC was measured using 99mTc-sulphur colloid, gamma camera and computer analysis in 12 asthmatic and 10 healthy subjects on three separate days, involving administration of each of the following: 1) ultrasonically nebulized 14.4% saline; 2) ultrasonically nebulized 0.9% saline; and 3) no aerosol intervention (control). The (mean +/- SD) volume of nebulized 14.4% saline was 2.2 +/- 1.2 mL for asthmatics and 3.2 +/- 0.7 mL for healthy subjects. This volume was delivered over a period of 5.4 +/- 1.3 and 6.4 +/- 0.7 min for asthmatic and healthy subjects, respectively. The airway response to 14.4% saline was assessed on a separate visit and the fall in forced expiratory volume in one second (FEV1) was 22 +/- 4% in the asthmatic and 3 +/- 2% in the healthy subjects. Compared to the MCC with the 0.9% saline and control, the hypertonic aerosol increased MCC in both groups. In asthmatic subjects, MCC of the whole right lung in 1 h was 68 +/- 10% with 14.4% saline vs 44 +/- 14% with 0.9% saline and 39 +/- 13% with control. In healthy subjects, MCC of the whole right lung in 1 h was 53 +/- 12% with 14.4% saline vs 41 +/- 15% with 0.9% saline and 36 +/- 13% with control. We conclude that an increase in osmolarity of the airway surface liquid increases mucociliary clearance both in asthmatic and healthy subjects. These findings are in keeping with our previous suggestion that the increase in mucociliary clearance after isotonic hyperventilation with dry air is due to a transient hyperosmolarity of the airway surface liquid.

Evaluation of two population-based input functions for quantitative neurological FDG PET studies

The conventional measurement of the regional cerebral metabolic rate of glucose (rCMRGlc) with fluorodeoxyglucose (FDG) and positron emission tomography (PET) requires arterial or arterialised-venous (a–v) blood sampling at frequent intervals to obtain the plasma input function (IF). We evaluated the accuracy of rCMRGlc measurements using population-based IFs that were calibrated with two a–v blood samples. Population-based IFs were derived from: (1) the average of a–v IFs from 26 patients (Standard IF) and (2) a published model of FDG plasma concentration (Feng IF). Values for rCMRGlc calculated from the population-based IFs were compared with values obtained with IFs derived from frequent a–v blood sampling in 20 non-diabetic and six diabetic patients. Values for rCMRGlc calculated with the different IFs were highly correlated for both patient groups (r≥0.992) and root mean square residuals about the regression line were less than 0.24 mg/min/100 g. The Feng IF tended to underestimate high rCMRGlc. Both population-based IFs simplify the measurement of rCMRGlc with minimal loss in accuracy and require only two a–v blood samples for calibration. The reduced blood sampling requirements markedly reduce radiation exposure to the blood sampler.

Monte Carlo and experimental evaluation of accuracy and noise properties of two scatter correction methods for SPECT

Scatter correction is a prerequisite for quantitative SPECT, but potentially increases noise. Monte Carlo simulations (EGS4) and physical phantom measurements were used to compare accuracy and noise properties of two scatter correction techniques: the triple-energy window (TEW), and the transmission dependent convolution subtraction (TDCS) techniques. Two scatter functions were investigated for TDCS: (i) the originally proposed mono-exponential function (TDCSmono) and (ii) an exponential plus Gaussian scatter function (TDCSGauss) demonstrated to be superior from our Monte Carlo simulations. Signal to noise ratio (S/N) and accuracy were investigated in cylindrical phantoms and a chest phantom. Results from each method were compared to the true primary counts (simulations), or known activity concentrations (phantom studies). 99mTc was used in all cases. The optimized TDCS(Gauss) method overall performed best, with an accuracy of better than 4% for all simulations and physical phantom studies. Maximum errors for TEW and TDCS(mono) of -30 and -22%, respectively, were observed in the heart chamber of the simulated chest phantom. TEW had the worst S/N ratio of the three techniques. The S/N ratios of the two TDCS methods were similar and only slightly lower than those of simulated true primary data. Thus, accurate quantitation can be obtained with TDCS(Gauss), with a relatively small reduction in S/N ratio.

Inhalation of dry-powder mannitol increases mucociliary clearance

Inhalation of hypertonic saline stimulates mucociliary clearance (MCC) in healthy subjects and those with obstructive lung disease. We investigated the effect of inhaling the osmotic agent mannitol on MCC. We used a dry-powder preparation of mannitol British Pharmacopea (BP) which was encapsulated and delivered using a Dinkihaler. MCC was measured for 75 min in six asthmatic and six healthy subjects on two occasions before and after the mannitol inhalation or its control, using 99mTc-sulphur colloid and a gamma camera. The inhaled dose of mannitol was 267+/-171 mg (mean+/-SD) and 400 mg and the percentage fall in forced expiratory volume in one second (FEV1) was 22+/-3 and 4+/-2% in the asthmatic and healthy subjects, respectively. The total clearance in the whole right lung for the 60 min from the start of inhalation of mannitol was greater by 263+/-11.9% in the asthmatic and 18.1+/-4.9% in the healthy subjects compared to the control. The total clearance over 75 min was 54.7+/-9.6% and 33.6+/-9.4% on the mannitol and control day (p<0.002), respectively, in the asthmatic subjects and 40.5+/-7.1% and 24.8+/-7.8% (p<0.002) in the healthy subjects. In conclusion, inhalation of dry-powder mannitol increases mucociliary clearance in asthmatic and healthy subjects and may benefit patients with abnormal mucociliary clearance.

Effect of increasing doses of mannitol on mucus clearance in patients with bronchiectasis

Bronchiectasis is characterised by hypersecretion and impaired clearance of mucus. A 400-mg dose of inhaled mannitol improves mucus clearance however, the effect of other doses is unknown. A total of 14 patients, aged 63.3±5.7 yrs, were studied on five visits. Mucus clearance at baseline and with mannitol (160, 320 and 480 mg) was measured using technetium-99m-sulphur colloid and imaging with a gamma camera over 45 min, followed by a further 30 min involving 100 voluntary coughs. A control study assessed the effect of cough provoked by mannitol during the intervention. Whole right lung clearance over 45 min was 4.7±1.2 and 10.6±2.6% on baseline and control days, respectively, and increased to 16.7±4.2, 22.8±4.2 and 31±4.7% with 160, 320 and 480 mg mannitol, respectively. Clearance over 45 min with 480 mg mannitol was greater than clearance with 320 and 160 mg. Total clearance over 75 min, after mannitol administration and voluntary coughs, was 36.1±5.5, 40.9±5.6 and 46.0±5.2% with 160, 320 and 480 mg mannitol, respectively, all significantly different from baseline (24.1±6.0%) and control (13.1±3.0%). Total clearance over 75 min with 480 mg mannitol was greater compared with 160 mg. In conclusion, mucus clearance increases with increasing doses of mannitol and can be further increased by cough in patients with bronchiectasis.

Quantitation of regional cerebral blood flow corrected for partial volume effect using O-15 water and PET: I. Theory, error analysis, and stereologic comparison.

Limited spatial resolution of positron emission tomography (PET) can cause significant underestimation in the observed regional radioactivity concentration (so-called partial volume effect or PVE) resulting in systematic errors in estimating quantitative physiologic parameters. The authors have formulated four mathematical models that describe the dynamic behavior of a freely diffusible tracer (H215O) in a region of interest (ROI) incorporating estimates of regional tissue flow that are independent of PVE. The current study was intended to evaluate the feasibility of these models and to establish a methodology to accurately quantify regional cerebral blood flow (CBF) corrected for PVE in cortical gray matter regions. Five monkeys were studied with PET after IV H215O two times (n = 3) or three times (n = 2) in a row. Two ROIs were drawn on structural magnetic resonance imaging (MRI) scans and projected onto the PET images in which regional CBF values and the water perfusable tissue fraction for the cortical gray matter tissue (hence the volume of gray matter) were estimated. After the PET study, the animals were killed and stereologic analysis was performed to assess the gray matter mass in the corresponding ROIs. Reproducibility of the estimated parameters and sensitivity to various error sources were also evaluated. All models tested in the current study yielded PVE-corrected regional CBF values (approximately 0.8 mL · min−1 · g−1 for models with a term for gray matter tissue and 0.5 mL · min−1 · g−1 for models with a term for a mixture of gray matter and white matter tissues). These values were greater than those obtained from ROIs tracing the gray matter cortex using conventional H215O autoradiography (approximately 0.40 mL · min−1 · g−1). Among the four models, configurations that included two parallel tissue compartments demonstrated better results with regards to the agreement of tissue time-activity curve and the Akaikes Information Criteria. Error sensitivity analysis suggested the model that fits three parameters of the gray matter CBF, the gray matter fraction, and the white matter fraction with fixed white matter CBF as the most reliable and suitable for estimating the gray matter CBF. Reproducibility with this model was 11% for estimating the gray matter CBF. The volume of gray matter tissue can also be estimated using this model and was significantly correlated with the results from the stereologic analysis. However, values were significantly smaller compared with those measured by stereologic analysis by 40%, which can not be explained by the methodologic errors. In conclusion, the partial volume correction was essential in quantitation of regional CBF. The method presented in this article provided the PVE-corrected regional CBF in the cortical gray matter tissue. This study also suggests that further studies are required before using MRI derived anatomic information for PVE correction in PET.