A unique mutation in LRP5 is associated with high bone mass in man. Transgenic mice expressing this LRP5 mutation have a similar phenotype with high bone mass and enhanced strength. These results underscore the importance of LRP5 in skeletal regulation and suggest targets for therapies for bone disease.A mutation (G171V) in the low-density lipoprotein receptor related protein 5 (LRP5) has been associated with high bone mass (HBM) in two independent human kindreds. To validate the role of the mutation, several lines of transgenic mice were created expressing either the human LRP5 G171V substitution or the wildtype LRP5 gene in bone. Volumetric bone mineral density (vBMD) analysis by pQCT showed dramatic increases in both total vBMD (30 -55%) and trabecular vBMD (103-250%) of the distal femoral metaphysis and increased cortical size of the femoral diaphysis in mutant G171V transgenics at 5, 9, 17, 26, and 52 weeks of age (p < 0.01 for all). In addition, high-resolution microcomputed tomography (microCT) analysis of the distal femorae and lumbar vertebrae revealed an increase (110 -232%) in trabecular bone volume fraction caused by both increased trabecular number (41-74%) and increased trabecular thickness (34 -46%; p < 0.01 for all) in the mutant G171V mice. The increased bone mass was associated with significant increases in vertebral compressive strength (80 -140%) and the increased cortical size with significant increases in femoral bending strength (50 -130%). There were no differences in osteoclast number at 17 weeks of age. However, compared with littermate controls, the mutant G171V transgenic mice showed an increase in actively mineralizing bone surface, enhanced alkaline phosphatase staining in osteoblasts, and a significant reduction in the number of TUNEL-positive osteoblasts and osteocytes. These results suggest that the increased bone mineral density in mutant G171V mice was caused by increased numbers of active osteoblasts, which could in part be because of their increased functional lifespan. While slight bone anabolic activity was observed from overexpression of the wildtype LRP5 gene, it is clear that the G171V mutation, rather than overexpression of the receptor itself, is primarily responsible for the dramatic HBM bone effects. Together, these findings establish the importance of this novel and unexpected role of a lipoprotein receptor in regulating bone mass and afford a new model to explore LRP5 and its recent association with Wnt signaling in bone biology. (J Bone Miner Res 2003;18:960 -974)

The discovery of a second estrogen receptor (ER), called ERbeta, in 1996 sparked intense interest within the scientific community to discover its role in mediating estrogen action. However, despite more than 6 yr of research into the function of this receptor, its physiological role in mediating estrogen action remains unclear and controversial. We have developed a series of highly selective agonists for ERbeta and have characterized their activity in several clinically relevant rodent models of human disease. The activity of one such compound, ERB-041, is reported here. We conclude from these studies that ERbeta does not mediate the bone-sparing activity of estrogen on the rat skeleton and that it does not affect ovulation or ovariectomy-induced weight gain. In addition, these compounds are nonuterotrophic and nonmammotrophic. However, ERB-041 has a dramatic beneficial effect in the HLA-B27 transgenic rat model of inflammatory bowel disease and the Lewis rat adjuvant-induced arthritis model. Daily oral doses as low as 1 mg/kg reverse the chronic diarrhea of HLA-B27 transgenic rats and dramatically improve histological disease scores in the colon. The same dosing regimen in the therapeutic adjuvant-induced arthritis model reduces joint scores from 12 (maximal inflammation) to 1 over a period of 10 d. Synovitis and Mankin (articular cartilage) histological scores are also significantly lowered (50-75%). These data suggest that one function of ERbeta may be to modulate the immune response, and that ERbeta-selective ligands may be therapeutically useful agents to treat chronic intestinal and joint inflammation.

BackgroundLarge numbers of post-deployment U.S. veterans are diagnosed with post-traumatic stress disorder (PTSD) and/or traumatic brain injury (TBI), leading to an urgent need for effective interventions to reduce symptoms and increase veterans’ coping. PTSD includes anxiety, flashbacks, and emotional numbing. The symptoms increase health care costs for stress-related illnesses and can make veterans’ civilian life difficult.MethodsWe used a randomized wait-list controlled design with repeated measures of U.S. military veterans to address our specific aim to test the efficacy of a 6-week therapeutic horseback riding (THR) program for decreasing PTSD symptoms and increasing coping self-efficacy, emotion regulation, social and emotional loneliness.Fifty-seven participants were recruited and 29 enrolled in the randomized trial. They were randomly assigned to either the horse riding group (n = 15) or a wait-list control group (n = 14). The wait-list control group experienced a 6-week waiting period, while the horse riding group began THR. The wait-list control group began riding after 6 weeks of participating in the control group.Demographic and health history information was obtained from all the participants. PTSD symptoms were measured using the standardized PTSD Checklist-Military Version (PCL-M).The PCL-M as well as other instruments including, The Coping Self Efficacy Scale (CSES), The Difficulties in Emotion Regulation Scale (DERS) and The Social and Emotional Loneliness Scale for Adults-short version (SELSA) were used to access different aspects of individual well-being and the PTSD symptoms.ResultsParticipants had a statistically significant decrease in PTSD scores after 3 weeks of THR (P ≤ 0.01) as well as a statistically and clinically significant decrease after 6 weeks of THR (P ≤ 0.01). Logistic regression showed that participants had a 66.7% likelihood of having lower PTSD scores at 3 weeks and 87.5% likelihood at 6 weeks. Under the generalized linear model(GLM), our ANOVA findings for the coping self-efficacy, emotion regulation, and social and emotional loneliness did not reach statistical significance. The results for coping self-efficacy and emotion regulation trended in the predicted direction. Results for emotional loneliness were opposite the predicted direction. Logistic regression provided validation that outcome effects were caused by riding longer.ConclusionThe findings suggest that THR may be a clinically effective intervention for alleviating PTSD symptoms in military veterans.

Introduction Veterans Health Administration (VHA) is undergoing changes in the practice of health care focusing on approaches that prioritize veteran well-being. Given transformation efforts, opportunities exist to enhance the health and well-being of patients and employees alike – a significant proportion of whom are veterans. To date, differences in health status between veteran and civilian employees within VHA have not been examined. Materials and Methods Data from an annual organizational census survey with health promotion module conducted in 2015 were analyzed to estimate the prevalence of health risk behaviors, mental health, and chronic health conditions by veteran status within genders (n = 86,257). To further examine associations by gender between veteran status and health measures controlling for covariates, multivariate logistic regression analyses were utilized. Results Prevalence estimates generally indicated veterans have worse health status and health risk behaviors than their civilian counterparts. Results from multivariate logistic regression analyses indicated many significant associations between veteran status and health by gender controlling for other important demographic variables and a total comorbidity score. Compared to civilian employees within respective genders, both male and female veteran employees have increased odds of being a current smoker. Both male and female veteran employees have decreased odds of physical inactivity compared to civilian employees. For mental health and chronic health conditions, there are several conditions that veteran employees have increased odds for when compared to civilian employees of like gender; these include low back problems, arthritis, anxiety, depression, and sleep disorders. Conclusions Veteran employees in VHA have worse health status than their civilian counterparts on a number of measures of health risk behaviors, mental health, and chronic health conditions. Given current organizational priorities aimed at cultural transformation, the present time is an optimal one to work collaboratively to enhance the health and well-being services that are available for patients and employees alike. All employees, particularly our unique population of veteran employees, will benefit from such an approach.

Introduction COVID-19 poses a chronic threat to inflammatory systems, reinforcing the need for efficient anti-inflammatory strategies. The purpose of this review and analysis was to determine the efficacy of various interventions upon the inflammatory markers most affected by COVID-19. The focus was on the markers associated with COVID-19, not the etiology of the virus itself. Methods Based on 27 reviewed papers, information was extracted on the effects of COVID-19 upon inflammatory markers, then the effects of standard treatments (Remdesivir, Tocilizumab) and adjunctive interventions (vitamin D 3 , melatonin, and meditation) were extracted for those markers. These data were used to approximate effect sizes for the disease or interventions via standardized mean differences (SMD). Results The data that were available indicated that adjunctive interventions affected 68.4% of the inflammatory markers impacted by COVID-19, while standard pharmaceutical medication affected 26.3%. Discussion Nonstandard adjunctive care appeared to have comparable or superior effects in comparison to Remdesivir and Tocilizumab on the inflammatory markers most impacted by COVID-19. Alongside standards of care, melatonin, vitamin D 3 , and meditation should be considered for treatment of SARS-COV-2 infection and COVID-19 disease.

Posttraumatic stress disorder commonly occurs among U.S. military veterans. Therapeutic horseback riding (THR) has emerged as an adjunct therapy. We explored 20 veterans’ perceived benefits, drawbacks and views of a 6-week THR program. Participants had confirmed diagnoses of posttraumatic stress disorder, traumatic brain injury, or both. Veterans rode the same horse weekly, the same day, at the same time. Data were collected as part of a randomized clinical trial testing the effects of THR on Post-Traumatic Stress Disorder. Veterans responded to an open-ended questionnaire. Content analysis was used for data analysis. Benefits were “Connection to the Horse,” “Relaxing,” “180 Degree Change,” and “Meeting New People.” Drawbacks were “None,” “Struggle to Get There,” “Pain,” “Too Short,” and “It is Structured.” Overall perceptions were “I Absolutely Loved It,” “Feel Again,” “The Horse,” “The People,” and “No Worries.” Participants viewed THR as positive. Findings may elucidate why THR may be clinically beneficial.

Background Current payment models in the U.S. healthcare system are neither sustainable nor desirable. Expenses outpace revenue for most healthcare providers, while patients experience rising prices contrasted with inadequate health outcomes. Objective There is not a single, small adjustment that can remedy these issues; systemic problems require systemic solutions. One such solution involves whole-person care, an approach that emphasizes using diverse healthcare resources to align care with a patient’s values and goals as well as treat a patient’s physical, behavioral, emotional, and social risk factors. Methods In order to be most effective, whole-person care must be paired with a viable payment system that prioritizes positive outcomes and efficiency. The predominant fee-for-service payment system is not conducive to whole-person strategies. Results This paper examines the role of capitated payments, risk adjustments, social and structural determinants of health, and expense trends in an interdependent approach to healthcare industry system reform. Conclusion The Whole Health paradigm is optimized to improve both the financial performance of healthcare providers and the healthcare results of patients. Phased implementation is both feasible and sustainable.