A Fluorescence Polarization Activity-Based Protein Profiling Assay in the Discovery of Potent, Selective Inhibitors for Human Nonlysosomal Glucosylceramidase

Human nonlysosomal glucosylceramidase (GBA2) is one of several enzymes that controls levels of glycolipids and whose activity is linked to several human disease states. There is a major need to design or discover selective GBA2 inhibitors both as chemical tools and as potential therapeutic agents. Here, we describe the development of a fluorescence polarization activity-based protein profiling (FluoPol-ABPP) assay for the rapid identification, from a 350+ library of iminosugars, of GBA2 inhibitors. A focused library is generated based on leads from the FluoPol-ABPP screen and assessed on GBA2 selectivity offset against the other glucosylceramide metabolizing enzymes, glucosylceramide synthase (GCS), lysosomal glucosylceramidase (GBA), and the cytosolic retaining β-glucosidase, GBA3. Our work, yielding potent and selective GBA2 inhibitors, also provides a roadmap for the development of high-throughput assays for identifying retaining glycosidase inhibitors by FluoPol-ABPP on cell extracts containing recombinant, overexpressed glycosidase as the easily accessible enzyme source

A Multi-Element Detector System for Intelligent Imaging: I-ImaS

I-ImaS is a European project aiming to produce new, intelligent x-ray imaging systems using novel APS sensors to create optimal diagnostic images. Initial systems concentrate on mammography and encephalography. Later development will yield systems for other types of radiography such as industrial QA and homeland security. The I-ImaS system intelligence, due to APS technology and FPGAs, allows real-time analysis of data during image acquisition, giving the capability to build a truly adaptive imaging system with the potential to create images with maximum diagnostic information within given dose constraints. A companion paper deals with the DAQ system and preliminary characterization. This paper considers the laboratory x-ray characterization of the detector elements of the I-ImaS system. The characterization of the sensors when tiled to form a strip detector will be discussed, along with the appropriate correction techniques formulated to take into account the misalignments between individual sensors within the array. Preliminary results show that the detectors have sufficient performance to be used successfully in the initial mammographic and encephalographic I-ImaS systems under construction and this paper will further discuss the testing of these systems and the iterative processes used for intelligence upgrade in order to obtain the optimal algorithms and setting

Long‐term effect of calcium supplementation on bone loss in perimenopausal women

We observed in a controlled 2 year longitudinal trial in 248 perimenopausal women that a daily calcium supplement of either 1000 or 2000 mg Ca2+ significantly reduced lumbar bone loss and bone turnover in the first year of calcium supplementation. In the second supplementation year the rate of lumbar bone loss in the treated subjects was not significantly different from that in the control group, although two of the three biochemical parameters of bone turnover remained decreased throughout the study. To quantify further the long‐term effect of calcium supplementation, we extended the study for another year in 214 women. In the women of the control group who were menstruating until the last year of the trial, the mean change in lumbar bone mineral density after 3 years was –3.2% of the initial value versus 1.6% in the calcium‐supplemented groups (p < 0.01). The decrease in lumbar bone loss in these supplemented premenopausal and early perimenopausal women remained statistically significant in the second and third years of supplementation. In the women who stopped menstruating before or during the study, the long‐term reduction in lumbar bone loss was not significant (mean difference between control and treatment groups <0.6% points after 3 years). The decrease in metacarpal cortical thickness (MCT) in the treated subjects during 3 years was on average –3.0% of the initial value in the control versus–2.0% in the supplemented subjects (P < 0.01). The effect of calcium supplementation on MCT was not significantly related to the menopausal status of the subjects. Serum alkaline phosphatase, osteocalcin, and urinary hydroxyproline excretion decreased after calcium supplementation in all menopausal groups. These parameters remained decreased throughout the trial, with exception of alkaline phosphatase in the 1000 mg calcium group. We conclude that calcium supplementation substantially reduces cortical and trabecular bone loss in the years immediately preceding menopause. Although it reduces postmenopausal cortical bone loss to some extent, it does not prevent the menopause‐related lumbar bone loss. Copyright © 1994 ASBM

A new method for automatic recognition of the radiographic trabecular pattern

This study reports a method to describe and analyze the structure of the trabecular pattern seen on radiographs of the distal radius. The structure is measured and related to the bone mineral density (BMD) of the lumbar spine measured by dual‐photon absorptiometry. Radiographs of hand and wrist combined with additional information of the bone mineral density of the vertebrae serve as testing material. With a computer‐aided imaging system, a part of the depicted radius is scanned. The image is filtered and segmented into a bilevel picture consisting of a light network with dark meshes. Seven features of the bilevel picture are measured and analyzed. It is shown that six features correlate significantly with the bone mineral density measured at the lumbar spine, although the correlations between the trabecular pattern and the BMD are too weak to allow precise predictions of BMD values for individuals. Nevertheless, the correlations confirm the existence of a relationship between the radiographic trabecular pattern and the bone mineral density of the lumbar spine. The method is worth being further developed for use on individual patients. It provides a noninvasive tool to make an objective and quantitative assessment of the trabecular pattern. Copyright © 1990 ASBM

Perimenopausal bone mass and risk factors

We studied the effect of menopausal status and risk factors on lumbar bone mineral densisty (BMD) and metacarpal cortical thickness (MCT) in 286 women of 46-55 years of age. Body mass index (height/ weight2) was measured and the family history of osteoporosis, reproductive history, menopausal status, calcium intake, amount of physical activity and the consumption of tobacco and alcohol were assessed. Lumbar BMD and MCT decreased substantially in the perimenopausal and postmenopausal period. In the premenopausal women a significant (P = 0.03) lower lumbar BMD was observed in the lowest fertile of calcium intake (≤900 mg/day) compared to the highest tertile (≥1200 mg/day). This difference was not apparent in the peri- and postmenopausal women. This suggests that dietary calcium intake is more important in the development and/or maintenance of peak bone mass, than in the modulation of postmenopausal bone loss. Apart from menopausal status and low calcium intake, no other significant determinant of bone mass could be identified. We conclude, therefore, that the assessment of risk factor status is not an efficient tool for the identification of perimenopausal women with low bone mass. © 1989

A comparison of manual and computer-assessed measurements of mandibular cortical width as predictiors of osteoporsis : the OSTEODENT project

Objective: Manual measurement of mandibular cortical width has been shown to be significantly correlated with bone mineral density (BMD) at the hip,spine and forearm.These latter sites are fracture-prone in post-menopausal osteoporosis. We have developed computer software technology, based on active shape modelling, that will automatically detect the mandibular cortex on panoramic radiographs and then measure its width. We wanted to compare manual measurement of mandibular cortical width with semi-automated constrained fit and automated unconstrained fit methods. Material and Methods:The diagnostic ability of these different methods at detecting osteoporosis of the femoral neck was compared using dual energy X-ray absorptiometry as the “gold standard “at these sites. 671 subjects were recruited and their BMD measured at the femoral neck.143 (21.4%) subjects were osteoporotic, classified as a standardized t-score of 0.05)

Comparison of anatomic and aerodynamic characteristics of the upper airway among edentulous mild, moderate, and severe obstructive sleep apnea in older adults

STUDY OBJECTIVES: First, to compare the upper airway's anatomic and aerodynamic characteristics of the edentulous older adults who experience mild, moderate, and severe obstructive sleep apnea (OSA). Second, to examine the correlation between the severity of OSA and the anatomic and aerodynamic characteristic(s) of the upper airway in these edentulous individuals. METHODS: NewTom5G cone beam computed tomography scans of 58 edentulous individuals with mild, moderate, and severe OSA were included in this analysis. 1) Computational models of the upper airway were reconstructed based on cone beam computed tomography images and the anatomical and aerodynamic characteristics of the upper airway were examined by an observer blind to OSA severity. 2) Pearson correlation analysis was used to determine the correlation between apnea-hypopnea index and the anatomic and aerodynamic characteristics of the upper airway. RESULTS: Compared with edentulous patients with mild and moderate OSA, those with severe OSA have a more hourglass-shaped upper airway. The severity of OSA, namely, apnea-hypopnea index, was significantly correlated with the length, shape, and minimum cross-sectional area of the upper airway. During inspiration, the mean velocity of the airflow within the upper airway of the edentulous patients with severe OSA was higher than that of patients with mild and moderate OSA. During both inspiration and expiration, apnea-hypopnea index was found to be significantly correlated with maximum velocity (P = .05) and airway resistance (P = .024, 0.038). CONCLUSIONS: The edentulous patients with severe OSA have a more hourglass-shaped upper airway. The findings also suggest that, during inspiration, the airflow travels faster in edentulous patients with severe OSA than in those with mild or moderate OSA. CLINICAL TRIAL REGISTRATION: Registry: ClinicalTrials.gov; Name: The Effect of Nocturnal Wear of Dentures on Sleep and Oral Health Related Quality of Life; URL: https://clinicaltrials.gov/ct2/show/NCT01868295; Identifier: NCT01868295. CITATION: Chen H, Elham E, Li Y, et al. Comparison of anatomic and aerodynamic characteristics of the upper airway among edentulous mild, moderate, and severe obstructive sleep apnea in older adults. J Clin Sleep Med. 2022;18(3):759-768