Development of a DXA-derived Body Volume Equation in Hispanic Adults for Administering in a 4-compartment Model

The necessity of using underwater weighing (UWW) or air displacement plethysmography (ADP) for body volume (BV) restricts the use of a four-compartment (4C) model to research settings. As a result, dual energy X-ray absorptiometry (DXA) has been proposed as an alternative, which would be useful for clinical settings. Nonetheless, it is unknown whether DXA-derived BV is valid in a 4C model for Hispanics. PURPOSE: The purpose of the current study was two-fold: 1) to develop a new DXA-derived BV equation with the GE-Lunar Prodigy while utilizing UWW as a criterion and 2) cross-validate 4C models when utilizing the new DXA-derived BV equation (4C-DXANICKERSON), Wilson DXA-derived BV equation (4C-DXAWILSON), and air displacement plethysmography (ADP)-derived BV (4C-ADP) in Hispanic adults. METHODS: 191 Hispanic adults (18-45yrs) participated in the current study. The development sample consisted of 60 females and 60 males whereas the cross-validation sample comprised of 41 females and 30 males. Criterion body fat percentage (BF%) and fat-free mass (FFM) were determined using a 4C model with UWW as a criterion for BV (4C-UWW). The new DXA-derived BV equation (Nickerson) was developed by linearly regressing UWW-derived BV with DXA fat mass (FM), lean mass (LM), and bone mineral content (BMC). 4C-DXANICKERSON, 4C-DXAWILSON, and 4C-ADP were compared against 4C-UWW in the cross-validation sample. RESULTS: The new DXA-derived BV equation (L) was generated in the development sample as follows: (FM/0.91) + (LM/1.06) + (BMC/16.95) + 0.268. 4C-DXANICKERSON, 4C-DXAWILSON, and 4C-ADP all produced similar mean values (BF%=21.04±5.99, 22.23±6.93, and 20.62±6.26%, respectively) when compared to 4C-UWW (21.29±6.14%) in Hispanic males (all p\u3e0.05). 4C-DXANICKERSON also yielded similar BF% and FFM values as 4C-UWW when evaluating the constant error (CE) in Hispanic females (CE=-0.79% and 0.38kg; p=0.060 and 0.174, respectively). However, 4C-DXAWILSON produced significantly different BF% and FFM values (CE=3.22% and -2.20kg, respectively; both pWILSON yielded significant proportional bias when estimating BF% (coefficient=0.226; pCONCLUSION: Current study findings demonstrate that 4C-DXANICKERSON is a valid measure of BV in Hispanics and is recommended for use in clinics where DXA is the main body composition assessment technique

Induction of Lrp5 HBM-causing mutations in Cathepsin-K expressing cells alters bone metabolism

High-bone-mass (HBM)-causing missense mutations in the low density lipoprotein receptor-related protein-5 (Lrp5) are associated with increased osteoanabolic action and protection from disuse- and ovariectomy-induced osteopenia. These mutations (e.g., A214V and G171V) confer resistance to endogenous secreted Lrp5/6 inhibitors, such as sclerostin (SOST) and Dickkopf homolog-1 (DKK1). Cells in the osteoblast lineage are responsive to canonical Wnt stimulation, but recent work has indicated that osteoclasts exhibit both indirect and direct responsiveness to canonical Wnt. Whether Lrp5-HBM receptors, expressed in osteoclasts, might alter osteoclast differentiation, activity, and consequent net bone balance in the skeleton, is not known. To address this, we bred mice harboring heterozygous Lrp5 HBM-causing conditional knock-in alleles to Ctsk-Cre transgenic mice and studied the phenotype using DXA, μCT, histomorphometry, serum assays, and primary cell culture. Mice with HBM alleles induced in Ctsk-expressing cells (TG) exhibited higher bone mass and architectural properties compared to non-transgenic (NTG) counterparts. In vivo and in vitro measurements of osteoclast activity, population density, and differentiation yielded significant reductions in osteoclast-related parameters in female but not male TG mice. Droplet digital PCR performed on osteocyte enriched cortical bone tubes from TG and NTG mice revealed that ~8–17% of the osteocyte population (depending on sex) underwent recombination of the conditional Lrp5 allele in the presence of Ctsk-Cre. Further, bone formation parameters in the midshaft femur cortex show a small but significant increase in anabolic action on the endocortical but not periosteal surface. These findings suggest that Wnt/Lrp5 signaling in osteoclasts affects osteoclastogenesis and activity in female mice, but also that some of the changes in bone mass in TG mice might be due to Cre expression in the osteocyte population

Sclerostin neutralization unleashes the osteoanabolic effects of Dkk1 inhibition

The WNT pathway has become an attractive target for skeletal therapies. High-bone-mass phenotypes in patients with loss-of-function mutations in the LRP5/6 inhibitor Sost (sclerosteosis), or in its downstream enhancer region (van Buchem disease), highlight the utility of targeting Sost/sclerostin to improve bone properties. Sclerostin-neutralizing antibody is highly osteoanabolic in animal models and in human clinical trials, but antibody-based inhibition of another potent LRP5/6 antagonist, Dkk1, is largely inefficacious for building bone in the unperturbed adult skeleton. Here, we show that conditional deletion of Dkk1 from bone also has negligible effects on bone mass. Dkk1 inhibition increases Sost expression, suggesting a potential compensatory mechanism that might explain why Dkk1 suppression lacks anabolic action. To test this concept, we deleted Sost from osteocytes in, or administered sclerostin neutralizing antibody to, mice with a Dkk1-deficient skeleton. A robust anabolic response to Dkk1 deletion was manifest only when Sost/sclerostin was impaired. Whole-body DXA scans, μCT measurements of the femur and spine, histomorphometric measures of femoral bone formation rates, and biomechanical properties of whole bones confirmed the anabolic potential of Dkk1 inhibition in the absence of sclerostin. Further, combined administration of sclerostin and Dkk1 antibody in WT mice produced a synergistic effect on bone gain that greatly exceeded individual or additive effects of the therapies, confirming the therapeutic potential of inhibiting multiple WNT antagonists for skeletal health. In conclusion, the osteoanabolic effects of Dkk1 inhibition can be realized if sclerostin upregulation is prevented. Anabolic therapies for patients with low bone mass might benefit from a strategy that accounts for the compensatory milieu of WNT inhibitors in bone tissue

Clcn7F318L/+ as a new mouse model of Albers-Schönberg disease

Dominant negative mutations in CLCN7, which encodes a homodimeric chloride channel needed for matrix acidification by osteoclasts, cause Albers-Schönberg disease (also known as autosomal dominant osteopetrosis type 2). More than 25 different CLCN7 mutations have been identified in patients affected with Albers-Schönberg disease, but only one mutation (Clcn7G213R) has been introduced in mice to create an animal model of this disease. Here we describe a mouse with a different osteopetrosis-causing mutation (Clcn7F318L). Compared to Clcn7+/+ mice, 12-week-old Clcn7F318L/+ mice have significantly increased trabecular bone volume, consistent with Clcn7F318L acting as a dominant negative mutation. Clcn7F318L/F318L and Clcn7F318L/G213R mice die by 1 month of age and resemble Clcn7 knockout mice, which indicate that p.F318L mutant protein is non-functional and p.F318L and p.G213R mutant proteins do not complement one another. Since it has been reported that treatment with interferon gamma (IFN-G) improves bone properties in Clcn7G213R/+ mice, we treated Clcn7F318L/+ mice with IFN-G and observed a decrease in osteoclast number and mineral apposition rate, but no overall improvement in bone properties. Our results suggest that the benefits of IFN-G therapy in patients with Albers-Schönberg disease may be mutation-specific

Effects of Heat Exposure on Body Water Assessed using Single-Frequency Bioelectrical Impedance Analysis and Bioimpedance Spectroscopy

International Journal of Exercise Science 10(7): 1085-1093, 2017. The purpose of this study was to determine if heat exposure alters the measures of total body water (TBW), extracellular water (ECW), and intracellular water (ICW) in both single-frequency bioelectrical impedance analysis (BIA) and bioimpedance spectroscopy (BIS). Additionally, we sought to determine if any differences exist between the BIA and BIS techniques before and after brief exposure to heat. Body water was evaluated for twenty men (age=24±4 years) in a thermoneutral environment (22°C) before (PRE) and immediately after (POST) 15 min of passive heating (35°C) in an environmental chamber. The mean difference and 95% limits of agreement at PRE demonstrated that BIS yielded significantly higher body water values than BIA (all p0.05; 0.2±1.5kg). Additionally, the ES of the mean differences at POST were trivial to small and the r-values were high (r≥0.96). When analyzing the changes in body water before and after heat exposure, POST values for BIS were significantly higher than PRE (all

Biological Brain Age Prediction Using Cortical Thickness Data: A Large Scale Cohort Study

Brain age estimation from anatomical features has been attracting more attention in recent years. This interest in brain age estimation is motivated by the importance of biological age prediction in health informatics, with an application to early prediction of neurocognitive disorders. It is well-known that normal brain aging follows a specific pattern, which enables researchers and practitioners to predict the age of a human's brain from its degeneration. In this paper, we model brain age predicted by cortical thickness data gathered from large cohort brain images. We collected 2,911 cognitively normal subjects (age 45–91 years) at a single medical center and acquired their brain magnetic resonance (MR) images. All images were acquired using the same scanner with the same protocol. We propose to first apply Sparse Group Lasso (SGL) for feature selection by utilizing the brain's anatomical grouping. Once the features are selected, a non-parametric non-linear regression using the Gaussian Process Regression (GPR) algorithm is applied to fit the final age prediction model. Experimental results demonstrate that the proposed method achieves the mean absolute error of 4.05 years, which is comparable with or superior to several recent methods. Our method can also be a critical tool for clinicians to differentiate patients with neurodegenerative brain disease by extracting a cortical thinning pattern associated with normal aging

Intracranial metastasis from primary transitional cell carcinoma of female urethra: case report & review of the literature

<p>Abstract</p> <p>Background</p> <p>Transitional cell carcinoma (TCC) of the female urethra is a rare urological malignancy, and intracranial metastasis of this cancer has not yet been reported in the literature. This review is intended to present a case of multiple intracranial metastasis in a female patient with a remote history of primary urethral TCC.</p> <p>Case Presentation</p> <p>A 49-year-old woman, presented with a prolapsed mass in urethral orifice that was diagnosed as primary urethral TCC with distant lung and multiple bone metastases. The patient subsequently underwent chemotherapy under various regimens. A year later, the patient developed headache and vomiting which as was found to be due to multiple intracranial metastasis. The patient underwent surgical resection of the largest lesion located on the cerebellum, and consecutively gamma knife radiosurgery was performed for other small-sized lesions. Pathological examination of the resected mass revealed a metastatic carcinoma from a known urethral TCC. Serial work-up of systemic metastasis revealed concomitant aggravation of lung, spleen, and liver metastasis. The patient died of lung complication 2 months after the diagnosis of brain metastasis.</p> <p>Conclusion</p> <p>To the best of our knowledge, this is the first reported case of cerebral metastasis from primary urethral TCC, with pathological confirmation. As shown in intracranial metastasis of other urinary tract carcinoma, this case occurred in the setting of uncontrolled systemic disease and led to dismal prognosis in spite of aggressive interventional modalities.</p

A Multilevel Product Model for Simulation-Based Design of Mechanical Systems

This paper presents a multilevel product model that supports Simulation-Based Design (SBD) of mechanical systems, from pre liminary to detailed design stages The pnmary goal of the SBD is to achieve product designs featuring better performance and greater du rability and reliability through computer-based modeling, engineering analysis, and design trade-off. A Computer-Aided Design (CAD) model combined with engineering parameters and mathematical equations that simulate physical behavior of the mechanical system constitute its product model for SBD. For preliminary design, improvement of system performance, including dynamics and human factors, is usually the primary focus A CAD model with reasonably accurate physical parameters, such as mass properties of major components or assemblies, is defined as the base definition of the product model for SBD. A number of simulation models are derived from the base definition to sup port simulation of the mechanical system performance A parametric study can be conducted to search for design alternatives using dimen sion parameters created in the parameterized CAD model. The CAD model and base definition are then refined from the preliminary design stage to support intermediate designs. Intermediate designs will primarily focus on product subsystem performance. A product model is evolved by refining geometric representation of mechanical components in CAD, and expanding product assembly into parts and sub assemblies for further engineering analysis Component designs for performance, such as fatigue, mechanical reliability, and structural per formance, as well as maintainability are the primary focus in the detailed design stage. A detailed product model evolved from that of the previous design is needed In the detailed design stage, a systematic design trade-off method supports design improvement. A High Mobil ity Multi-Purpose Wheeled Vehicle (HMMWV) is employed to illustrate and demonstrate the proposed product model.Yeshttps://us.sagepub.com/en-us/nam/manuscript-submission-guideline