Differential effects of teriparatide, denosumab and zoledronate on hip structural and mechanical parameters in osteoporosis; a real-life study.

PURPOSE: The aim of this study was to evaluate changes in hip geometry parameters following treatment with teriparatide (TPD), denosumab (Dmab) and zoledronate (ZOL) in real-life setting. METHODS: We studied 249 patients with osteoporosis (OP) with mean [SD] age of 71.5 [11.1] years divided into 3 treatment groups; Group A received TPD; n = 55, Group B (Dmab); n = 116 and Group C (ZOL); n = 78 attending a routine metabolic bone clinic. Bone mineral density (BMD) was measured by DXA at the lumbar spine (LS), total hip (TH) and femoral neck (FN) prior to treatment and after 2 years (Group A), after a mean treatment duration of 3.3 [1.3] years (Group B) and after 1, 2 and 3 doses of ZOL (Group C) to assess treatment response. Hip structural analysis (HSA) was carried out retrospectively from DXA-acquired femur images at the narrow neck (NN), the intertrochanter (IT) and femoral shaft (FS). RESULTS: Changes in parameters of hip geometry and mechanical strength were seen in the following treatment. Percentage change in cross-sectional area (CSA): 3.56[1.6] % p = 0.01 and cross-sectional moment of inertia (CSMI): 4.1[1.8] % p = 0.029 increased at the NN only in Group A. Improvement in HSA parameters at the IT were seen in group B: CSA: 3.3[0.67]% p < 0.001, cortical thickness (Co Th): 2.8[0.78]% p = 0.001, CSMI: 5.9[1.3]% p < 0.001, section modulus (Z):6.2[1.1]% p < 0.001 and buckling ratio (BR): - 3.0[0.86]% p = 0.001 with small changes at the FS: CSA: 1.2[0.4]% p = 0.005, Z:1.6 [0.76]%, p = 0.04. Changes at the IT were also seen in Group C (after 2 doses): CSA: 2.5[0.77]% p = 0.017, Co Th: 2.4[0.84]% p = 0.012, CSMI: 3.9[1.3]% p = 0.017, Z:5.2[1.16]% p < 0.001 and BR: - 3.1[0.88]% p = 0.001 and at the NN (following 3 doses): outer diameter (OD): 4.0[1.4]% p = 0.0005, endocortical diameter(ED): 4.3[1.67% p = 0.009, CSA:5.2[1.8]% p = 0.003, CSMI: 9.3[3.8]% p = 0.019. CONCLUSIONS: Analysis of the effect of OP therapies on hip geometry is useful in understanding the mechanisms of their anti-fracture effect and may provide additional information on their efficacy.

Transplantation of autologous endothelial progenitor cells in porous PLGA scaffolds create a microenvironment for the regeneration of hyaline cartilage in rabbits.

OBJECTIVE: Repairing articular cartilage is clinically challenging. We investigated a simple, effective and clinically feasible cell-based therapeutic approach using a poly(lactide-co-glycolide) (PLGA) scaffold seeded with autologous endothelial progenitor cells (EPC) to repair a full-thickness osteochondral defect in rabbits using a one-step surgery. METHODS: EPC obtained by purifying a small amount of peripheral blood from rabbits were seeded into a highly porous, biocompatible PLGA scaffold, namely, EPC-PLGA, and implanted into the osteochondral defect in the medial femoral condyle. Twenty two rabbits were randomized into one of three groups: the empty defect group (ED), the PLGA-only group or the EPC-PLGA group. The defect sites were evaluated 4 and 12 weeks after implantation. RESULTS: At the end of testing, only the EPC-PLGA group showed the development of new cartilage tissue with a smooth, transparent and integrated articular surface. Moreover, histological analysis showed obvious differences in cartilage regeneration. At week 4, the EPC-PLGA group showed considerably higher TGF-ß2 and TGF-ß3 expression, a greater amount of synthesized glycosaminoglycan (GAG) content, and a higher degree of osteochondral angiogenesis in repaired tissues. At week 12, the EPC-PLGA group showed enhanced hyaline cartilage regeneration with a normal columnar chondrocyte arrangement, higher SOX9 expression, and greater GAG and collagen type II (COLII) content. Moreover, the EPC-PLGA group showed organized osteochondral integration, the formation of vessel-rich tubercular bone and significantly higher bone volume per tissue volume and trabecular thickness (Tb.Th). CONCLUSION: The present EPC-PLGA cell delivery system generates a suitable in situ microenvironment for osteochondral regeneration without the supplement of exogenous growth factors.

The effects of inhalation of a novel nitric oxide donor, DETA/NO, in a patient with severe hypoxaemia due to acute respiratory distress syndrome.

Aerosolized NONOates have been investigated in animal models in acute pulmonary hypertension, but none have been used in humans. We report the first use of aerosolized diethylenetriamine nitric oxide adduct (DETA/NO), a NONOate, in a patient with severe acute respiratory distress syndrome. Both pulmonary vascular resistance index and mean pulmonary arterial pressure were reduced by a mean of 26% and 18% respectively after the administration of a single dose of DETA/NO (150 micromol). Intrapulmonary shunting also improved. There were no significant changes in systemic arterial pressure or arterial methaemoglobin concentration after DETA/NO inhalation. We conclude that DETA/NO aerosol produced selective pulmonary vasodilation, with an improvement in pulmonary haemodynamics and oxygenation, while having no measurable effect on the systemic circulation.

Determination of optimal data placement for psychometric function estimation: a computer simulation.

Psychometric functions are used to relate the responses of a subject to physical stimuli in a variety of psychophysical tasks. However, it is time consuming to obtain data to determine a psychometric function if many stimulus levels and many trials are required. A computer simulation was conducted to determine the minimum number of data points needed for such a determination. The computer simulation also determined the optimal placements of the stimuli and the number of trials per datum point for psychometric function determinations. Results indicate that a 2-point sampling method with 30-50 trials per point at optimal locations can produce a psychometric function with accurate spread and threshold estimates in a yes-no paradigm. However, the 4-point sampling method yields statistically smaller variances of the estimates. For the 2-alternative forced-choice paradigm, at least 120 trials per point are needed for the 2-point sampling method's estimated parameters to differ from the known parameter values by less than 5%. The simulation results suggest that 3-alternative or 4-alternative forced-choice is preferable to 2-alternative. Furthermore, when a criterion-free paradigm is not required, the yes-no paradigm is a better procedure than m-alternative forced-choice for obtaining the corresponding psychometric function because of smaller standard deviation of the estimates and smaller number of trials/point required.

A systematic study of low-resolution recognition in protein--protein complexes.

A comprehensive nonredundant database of 475 cocrystallized protein-protein complexes was used to study low-resolution recognition, which was reported in earlier docking experiments with a small number of proteins. The docking program GRAMM was used to delete the atom-size structural details and systematically dock the resulting molecular images. The results reveal the existence of the low-resolution recognition in 52% of all complexes in the database and in 76% of the 113 complexes with an interface area >4,000 A(2). Limitations of the docking and analysis tools used in this study suggest that the actual number of complexes with the low-resolution recognition is higher. However, the results already prove the existence of the low-resolution recognition on a broad scale.

An efficient method for small field treatment dose calculation for stereotactic radiosurgery using a LINAC.

The normal procedure for a physician-physicist team designing a treatment plan for multiarc stereotactic radiosurgery is the trial-and-error approach of changing the collimator size and the location of the isocenter of radiation and viewing the isodose curves on two-dimensional computed tomography (CT) or magnetic resonance imaging (MRI) image planes. Automatic optimization procedures have also been used to optimize beam weight or beam size. However, either process is very time consuming. To improve the speed of the dose calculation, a random sampling method has been proposed. Unfortunately, the sampled values of an objective function are different from one sample to another. Such a sampling method cannot be used in automatic optimization because the next move in an optimization process is based on the current and past objective function values. To this end, an adaptive method based on the size of the collimators is proposed and used to determine a small volume in the shape of a hollow sphere for which the dose is calculated. With an appropriate choice of an adaptive hollow sphere, the objective function calculated based on such a hollow sphere is the same as that calculated with the traditional three-dimensional (3-D) cube matrix. However, with the new adaptive method, the speed of calculating a dose can be improved by a factor of 4 to a factor of 100. Because of the improvement in the speed of calculating a treatment dose, the new adaptive hollow sphere method for calculating a treatment dose can be used routinely in designing a treatment plan.

C1 inhibitor removes the entire C1qr2s2 complex from anti-C1Q monoclonal antibodies with low binding affinities.

Evidence is presented for a new C1 Inhibitor (C1 INH) function. C1 INH was capable of dislodging the entire C1qr2s2 complex from C1-activating substances that bound weakly to the globular heads of C1q. Two different mouse IgG1 monoclonal antibodies with different affinities for C1q globular heads were compared for their complement-activating properties in the presence of normal human serum. As expected the higher affinity monoclonal antibody (Qu) was more effective in binding C1q and causing C1-mediated C4b deposition. Unexpectedly, time responses of C1 (C1q) binding to immobilized 3C7 reached a peak then gradually decreased. However, C1q remained constantly bound to immobilized Qu. These results indicated that after C1 activation in human serum, the entire C1 complex (including C1q) was dislodged from 3C7, but not from immobilized Qu. The addition of purified C1 INH to purified C1, which had bound to immobilized 3C7, resulted in removal of C1 (C1q). Removal of the entire C1qr2s2 did not occur when C1 INH preparations were first neutralized by the addition of purified activated C1s. In summary, it is suggested that C1 INH plays a prominent role in dislodging the entire C1qr2s2 from immunoglobulin preparations which have a low binding affinity for the globular heads of C1q.

Two-dimensional photonic-crystal vertical-cavity array for nonlinear optical image processing.

We investigate the electromagnetic properties of a two-dimensional (2-D) photonic-crystal array of vertical cavities for use in nonlinear optical image processing. We determine the 2-D photonic band structure of the array, and we discuss how it is influenced by the degree of interaction between cavities. We study the properties of defects in the 2-D lattice and show that neighboring cavities interact through their overlapping wave functions. This interaction can be used to produce nearest-neighbor nonlinear Boolean functions such asand, or, and xor, which are useful for optical image processing. We demonstrate the use of 2-D photonic bandgap structures for image processing by removing noise from a sample image with a nearest-neighbor and function.

Relationship between external load and isolated myocyte contractile function with CHF in pigs.

Past studies have demonstrated that the negative relationship between afterload and contractile performance of papillary muscles is shifted downward and to the left with the development of hypertrophy. However, it remained unclear whether a similar load-contractility relationship could be constructed for isolated myocytes, particularly with the development of congestive heart failure (CHF). Accordingly, the effect of incrementally increased external loads on the contractile performance of left ventricular (LV) myocytes isolated from pigs in the normal state (n = 5) and after the development of chronic supraventricular tachycardia (SVT)-induced CHF (SVT-CHF; 240 beats/min, 3 wk; n = 5) was examined. This study used precalibrated microspheres to impose a quantifiable load on isolated myocytes, and myocyte contractility was assessed by videomicroscopy. Steady-state unloaded extent of shortening was 5.4 +/- 0.2 microns in control myocytes (n = 80) and was significantly reduced in the myocytes with the development of SVT-CHF (4.4 +/- 0.2 microns, n = 93; P < 0.05). Inverse relationships between relative resistive load and myocyte contractile function were observed at both normal and CHF states (r2 > 0.85). For myocyte velocity of shortening, the slope of this relationship was significantly reduced in the SVT-CHF state compared with controls (-46.3 x 10(-6) and -34.6 x 10(-6) microns3.microN-1.s-1, respectively; P < 0.05). At higher relative resistive loads (> 0.18 x 10(-6) microN/microns2), the reduction in myocyte shortening extent under an equivalent relative resistive load was significantly greater in the SVT-CHF myocytes compared with controls (62.8 +/- 3.9 vs. 45.6 +/- 4.7%, respectively, P < 0.05). The present study demonstrated for the first time that a load-dependent relationship can be derived for intact isolated LV myocytes in both normal and CHF states. The defect in the capacity of SVT-CHF myocytes to respond to an increased relative resistive load is a likely contributory mechanism for the LV pump dysfunction that occurs in this model of CHF.

Decline in the endocochlear potential corresponds to decreased Na,K-ATPase activity in the lateral wall of quiet-aged gerbils.

The ion transport-mediating enzyme, Na,K-ATPase, is abundantly present in the cochlear lateral wall. This enzyme is essential for the generation and maintenance of the endocochlear potential. Diminished enzyme activity has been observed previously in the lateral wall of quiet-aged gerbils. The present study was designed to investigate the impact of the age-related decline in Na,K-ATPase specific activity upon auditory function. Measures of the resting endocochlear potential value and the level of Na,K-ATPase specific activity were made in cochleae obtained from gerbils aged in quiet conditions. Analysis revealed a high degree of correspondence between the level of lateral wall Na,K-ATPase specific activity and the value of the endocochlear potential measured in the round window/turn 1 region of the cochlea. Nonlinear regression models showed a strong relationship between the age-related reductions in enzyme activity and the magnitude of the endocochlear potential. The data suggest that during metabolic presbyacusis a decrease in Na,K-ATPase specific activity can explain most, but not all, of the decline in the endocochlear potential.

Estimating parameters for psychometric functions using the four-point sampling method.

Although a psychometric function describing a subject's responses to some physical stimuli is of considerable value, characterizing such functions is time consuming and, hence, is not carried out routinely in psychophysical experiments. A principal reason for the lack of efficiency in characterizing a psychometric function is the use of sampling methods that either converge on a single point on the psychometric function, such as the PEST method, or which distribute observations uniformly over a wide range, such as the constant stimuli method. As an alternative, a multimodal four-point sampling method has been proposed [C. F. Lam, J. H. Mills, and J. R. Dubno, J. Acoust. Soc. Am. 99, 3689-3693 (1996)]. A psychometric function is then fitted to the four points (each with several trials) to estimate the threshold and slope parameters of the psychometric function. Adaptive methods, such as the up-down methods [H. Levitt, J. Acoust. Soc. Am. 49, 467-477 (1971)], can be used to provide good initial estimates of the threshold and spread parameters of a psychometric function described by a logistic function. In ongoing studies of age-related changes in auditory masking and discrimination, this new four-point sampling method has been applied to determine psychometric functions for absolute thresholds as a function of duration, thresholds in simultaneous and forward masking, frequency discrimination, and intensity discrimination in both young and aged human subjects. Results indicate that a reduction in data collection time of about 50% with no increase in variance can be achieved. This increase in efficiency applies to simple detection tasks by normal hearing subjects as well as to complex discrimination tasks by older subjects with hearing loss.

Placement of observations for the efficient estimation of a psychometric function.

Psychometric functions for different psychophysical tasks describe the relationship between physical stimuli and subjects' responses. Although a psychometric function is of considerable value, characterizing the function is time consuming and, hence, is not carried out routinely in psychophysical experiments. A principal reason for the lack of efficiency in characterizing the psychometric function is the use of unimodal (e.g., Gaussian and uniform) sampling methods. As an alternative, a multimodal four-point sampling method is proposed. A psychometric function is then fitted to the four data points (each with several trials) to estimate the threshold and slope parameters of the psychometric function. Results from three examples demonstrate that a 60% savings in data-collection time can be achieved.

Spatial characterization of contracting cardiac myocytes by computer-assisted, video-based image processing.

The goals of the present study were to develop and validate a computer-assisted, video-based image processing (CAVIP) system to measure time-dependent changes in isolated myocyte geometry during contraction and to use the CAVIP system to examine spatial characteristics of the myocyte during contraction in normal myocytes and in myocytes after development of dilated cardiomyopathy (DCM). Myocytes were isolated from the left ventricles of five control pigs and five pigs that developed chronic tachycardia (240 beats/min; 3 wk)-induced DCM. Isolated myocytes were stimulated and recorded using a high-speed camera interfaced with a standard video recording system. There was a significant linear relation between the indexes of time-dependent changes in myocyte length as measured by a conventional video edge-detector system and by the CAVIP system (r > 0.96; P < 0.01). After this validation procedure, dynamic changes in myocyte width and profile area with DCM were examined. Myocyte resting profile area was 33% larger in DCM myocytes compared with controls. However, there was no difference in the rate of area change with contraction between the two groups. Percent changes in myocyte width and profile area at peak contraction were significantly lower in the DCM group (43 and 46% respectively, P < 0.05). Therefore, the present study demonstrated that the CAVIP system provides unique information on time-dependent changes in myocyte geometry during contraction, particularly with the development of cardiomyopathic disease.

Treatment planning optimization for multiple arcs stereotactic radiosurgery using a linear accelerator.

PURPOSE: Multiarc stereotactic radiosurgery is a technique used to irradiate an intracranial tumor with minimal damage to the surrounding normal tissue. The purpose of this paper is to present a method for and the results from optimizing three dimensional (3D) treatment dose for multiarc stereotactic radiosurgery. METHODS AND MATERIALS: The normal procedure for a physician-physicist team designing a treatment plan for multiarc stereotactic radiosurgery is the trial-and-error approach of changing the collimator size and the isocenter of radiation by viewing the isodose curves on a two dimensional (2D) computed tomography (CT) or magnetic resonance imaging (MRI) image plane. Not only is this time consuming, but the resulting treatment plan is not optimal in most, if not all, cases. One reason for such nonconformal isodose curves is that the same collimator size is used for all arcs. However, it is very difficult to determine manually the different collimator sizes for different arcs. A derivative free optimization method is used to optimize the collimator size for each arc, as well as the 3D coordinates of the isocenter(s). RESULTS: One spherical and two ellipsoidal artificial tumors, and one actual tumor, were used to show the utilities of the optimization process. The 90% isodose curves resulting from optimization conform very well with the tumor; whereas the 90% isodose curves from the conventional method either do not envelop the entire tumor when the collimator size is too small, or a large volume of normal tissue is also irradiated by the 90% dose when the next larger collimator size is used. CONCLUSIONS: When the collimator size for each arc and the location of the isocenters(s) are optimized in a multiarc stereotactic surgery treatment plan, the 90% isodose curve conforms to the tumor much better than when the same collimator size is used for all arcs.

A new sigmoidal function describing the small field dose profile data from a linear accelerator.

Dose profile data from small circular fields have been used in treatment dose planning for stereotactic radiosurgery. Generally, a two-dimensional interpolation of the measured beam profiles from circular collimators is used to calculate the dose at any axial depth and radial distance from the central axis. Instead, the dose profile data can be transformed into a sigmoidal form. A new three parameter sigmoidal function was developed to fit the transformed (sigmoidal) dose profile data. The values of the three estimated parameters were found to follow either linearly or exponentially as a function of axial depth. Thus, instead of linear interpolation, these formulas can be used to calculate dose at any axial depth and radial distance from the central axis for circular collimators of various diameters. This new sigmoidal function provides another formula to describe dose profile data from circular collimator of small fields.

Confidence limits for maximum word-recognition scores.

Clinical judgments are often made regarding whether maximum word-recognition scores (PBmax) are appropriate in relation to degree of sensorineural hearing loss. In order to determine if word recognition is significantly poorer than expected, it is necessary to consider the lower boundary of PBmax associated with a particular degree of hearing loss for speech materials commonly used to measure word recognition. The purpose of this experiment was to define a confidence limit for PBmax from Northwestern University Test #6 (NU-6) word-recognition scores obtained from a large group of young and aged subjects with confirmed cochlear hearing loss. Word-recognition scores at several speech levels were obtained from 407 ears with a wide range of pure-tone averages. Because the characteristics of the distribution of maximum scores are not known, a procedure was developed using computer simulations to approximate the distribution of word-recognition scores corresponding to PBmax and determine the 95% confidence limit (CL). Results of the simulation were confirmed by comparing means and standard deviations of PBmax derived from experimental and simulation data. Percentages of young and aged subjects with scores outside the 95% CL are equal to their proportions in the entire subject sample. If PBmax determined from a score-level psychometric function is poorer than the 95% CL, PBmax may be considered "disproportionately" poor in relation to the degree of hearing loss. One score measured at a single arbitrary suprathreshold level that is poorer than the 95% CL suggests that the score may underestimate PBmax and that word recognition should be measured at additional levels to obtain a more reasonable estimate of the listener's maximum word-recognition score.

Modeling the fine structure of the 2f1-f2 acoustic distortion product. I. Model development.

The fine structure of the 2f1-f2 acoustic distortion product (ADP) as a function of frequency has been measured in human subjects and shows a series of sharp peaks and valleys (rippling) with peak-to-valley level differences of up to 15-20 dB. In order to delineate the cause of the ADP rippling pattern, a computer model was developed to simulate the behavior of the ADP, specifically the ADP fine structure. The ADP model includes the middle ear and cochlea. The middle ear was treated as a simple signal delivery system in both the forward and reverse directions. The ADP was assumed to be generated within the cochlea by nonlinear elements taken to be the outer hair cells (OHCs), and an array of ADP generators was used to simulate the OHCs along the basilar membrane (BM). The magnitude and phase of the output of each of the ADP generators were functions of the local responses of the two primary traveling waves. The traveling waves were calculated from a passive transmission line model of the BM using the WKB approximation, coupled to a second-order resonance to mimic the contribution from active OHC feedback. The system output of ADP in dB was proportional to the weighted vectorial sum of all the components, arriving at the stapes. Parameters such as lateral coupling and feedback gain were examined.

Modeling the fine structure of the 2f1-f2 acoustic distortion product. II. Model evaluation.

In a previous article, a vector sum model was developed that successfully reproduces the ADP rippling pattern when a nonuniformity is introduced in the active damping factor, a parameter that is inversely related to the energy gain contribution of the outer hair cells [OHCs, Sun et al., J. Acoust. Soc. Am. 96, 2166-2174 (1994)]. Here, the mean of the damping factor is increased nonlinearly with input level, mimicking the saturation of the active feedback of the OHCs. The passive damping factor in the transmission line model was also nonlinearly increased with input level to reproduce the frequency shift of the peak of the traveling wave observed in experimental data. The resulting model simulates an ADP that is compatible with data from human subjects wherein the ADP fine structure does not saturate with level. Moreover, the model suggests that the shifting of the ADP pattern with level is a direct result of the peak shift of the traveling wave, thus implicating the nonlinear damping factors as the underlying basis of this phenomenon. The input/output (I/O) functions of the simulated ADP emissions at specific frequencies were also examined. The resulting functions show a variety of shapes, depending on the pattern of ADP fine structure around the I/O frequency, and the way the fine structure shifts as primary levels increase. These I/O functions are also similar to those observed in human subjects, even with regard to overall slopes which approximate one. Thus the model illustrates how cubic distortion generators coupled with damping on linearities can yield I/O function slopes on the order of one, rather than the expected three.(ABSTRACT TRUNCATED AT 250 WORDS)

Predictor-corrector with cubic spline method for spectrum estimation in Compton scatter correction of SPECT.

In single photon emission computed tomography (SPECT), Compton scattered photons degrade image contrast and cause erroneous regional activity quantification. A predictor-corrector and cubic spline (PCCS) method for the compensation of Compton scatter in SPECT is proposed. Using spectral information recorded at four energy windows, the PCCS method estimates scatter counts at each window and constructs the scatter spectrum with cubic spline interpolation. We have shown in simulated noise-free situations that this method provides accurate estimation of scatter fractions. A scatter correction employing PCCS method can be implemented on many existing SPECT systems without hardware modification and complicated calibration.

An efficient method for computer-aided dosage form design.

It is desirable to have slow-release dosage form to be taken once daily, or at most twice daily, as compared to three or four times in a single day. However, the existing computer-aided dosage form design method requires a large amount of computer time when applied to nonlinear disposition drugs. This large commitment of computer time makes it inconvenient to study the feasibility for prolonged-release products containing such drugs. Instead of evaluating all possible combinations of the amount of dose and release rates that produce acceptable steady-state plasma concentrations, only the contour of the dose-release rate domain needs to be determined. An image boundary tracking method has been used to determine such contours. When combined with several modifications of the numerical solution process, the acceptable dose and release rate constants can be determined efficiently. When this modified boundary tracking method was applied to phenytoin, which exhibits nonlinear disposition, the required computer time was reduced to about 5% of the previous method, making the dosage form feasibility assessment practical.