Osteoblasts-derived exosomes as potential novel communicators in particle-induced periprosthetic osteolysis.

The inflammatory response to wear particles derived from hip prothesis is considered a hallmark of periprosthetic osteolysis, which can ultimately lead to the need for revision surgery. Exosomes (Exos) have been associated with various bone pathologies, and there is increasing recognition in the literature that they actively transport molecules throughout the body. The role of wear particles in osteoblast-derived Exos is unknown, and the potential contribution of Exos to osteoimmune communication and periprosthetic osteolysis niche is still in its infancy. Given this, we investigate how titanium dioxide nanoparticles (TiO2 NPs), similar in size and composition to prosthetic wear particles, affect Exos biogenesis. Two osteoblastic cell models commonly used to study the response of osteoblasts to wear particles were selected as a proof of concept. The contribution of Exos to periprosthetic osteolysis was assessed by functional assays in which primary human macrophages were stimulated with bone-derived Exos. We demonstrated that TiO2 NPs enter multivesicular bodies, the nascent of Exos, altering osteoblast-derived Exos secretion and molecular cargo. No significant differences were observed in Exos morphology and size. However, functional assays reveal that Exos cargo enriched in uPA stimulates macrophages to a mixed M1 and M2 phenotype, inducing the release of pro- and anti-inflammatory signals characteristic of periprosthetic osteolysis. In addition, we demonstrated the expression of uPA in exosomes derived from the urine of patients with osteolysis. These results suggest that uPA can be a potential biomarker of osteolysis. In the future, uPa may serve as a possible non-invasive biomarker to identify patients at risk for peri-implant osteolysis.

Network analysis of brain and bone tissue transcripts reveals shared molecular mechanisms underlying Alzheimer's Disease and related dementias (ADRD) and Osteoporosis.

Alzheimer's disease and related dementias (ADRD) and osteoporosis (OP) are two prevalent diseases of aging with demonstrated epidemiological association, but the underlying molecular mechanisms contributing to this association are unknown. We used network analysis of bone and brain transcriptomes to discover common molecular mechanisms underlying these two diseases. Our study included RNA-sequencing data from the dorsolateral prefrontal cortex tissue of autopsied brains in 629 participants from ROSMAP (Religious Orders Study and the Rush Memory and Aging Project), with a subgroup of 298 meeting criteria for inclusion in five ADRD categories, and RNA array data from transiliac bone biopsies in 84 participants from the Oslo study of postmenopausal women. After developing each network within each tissue, we analyzed associations between modules (groups of co-expressed genes) with multiple bone and neurological traits, examined overlap in modules between networks, and performed pathway enrichment analysis to discover conserved mechanisms. We discovered three modules in ROSMAP that showed significant associations with ADRD and bone related traits and four modules in Oslo that showed significant associations with multiple bone outcomes. We found significant module overlap between the two networks in modules linked to signaling, tissue homeostasis, and development, and Wingless-related integration site (Wnt) signaling was found to be highly enriched in OP and ADRD modules of interest. These results provide translational opportunities in the development of treatments and biomarkers for ADRD and OP.

Acute effects of aerobic exercise on corticomotor plasticity in individuals with and without depression.

BACKGROUND: Although complex in nature, the pathophysiology of depression involves reduced or impaired neuroplastic capabilities. Restoring or enhancing neuroplasticity may serve as a treatment target for developing therapies for depression. Aerobic exercise (AEx) has antidepressant benefits and may enhance neuroplasticity in depression although the latter has yet to be substantiated. Therefore, we sought to examine the acute effect of AEx on neuroplasticity in depression. METHODS: Sixteen individuals with (DEP; 13 female; age = 28.5 ± 7.3; Montgomery-Äsberg Depression Rating Scale [MADRS] = 21.3 ± 5.2) and without depression (HC; 13 female; age 27.2 ± 7.5; MADRS = 0.8 ± 1.2) completed three experimental visits consisting of 15 min of low intensity AEx (LO) at 35% heart rate reserve (HRR), high intensity AEx (HI) at 70% HRR, or sitting (CON). Following AEx, excitatory paired associative stimulation (PAS25ms) was employed to probe neuroplasticity. Motor evoked potentials (MEP) were assessed via transcranial magnetic stimulation before and after PAS25ms to indicate acute changes in neuroplasticity. RESULTS: PAS25ms primed with HI AEx led to significant increases in MEP amplitude compared to LO and CON. HI AEx elicited enhanced PAS25ms-induced neuroplasticity for up to 1-h post-PAS. There were no significant between-group differences. CONCLUSION: HI AEx enhances PAS measured neuroplasticity in individuals with and without depression. HI AEx may have a potent influence on the brain and serve as an effective primer, or adjunct, to therapies that seek to harness neuroplasticity.

Prevalence of Cardiovascular and Cancer Risk Factors Among Rheumatoid Arthritis Patients Prescribed JAK Inhibitors and Tumor Necrosis Factor Inhibitors: A Cross-Sectional Study.

OBJECTIVE: The study was to determine the prevalence of baseline risk factors for cardiovascular outcomes and cancer among commercially-insured patients with rheumatoid arthritis (RA) during their first dispensed treatment for either tumor necrosis factor inhibitors (TNFi) or JAK inhibitors (JAKi). METHODS: Patients with RA from August 16, 2019 to March 31, 2022 were identified in the Merative MarketScan Commercial and Medicare databases. The first date that a TNFi or JAKi was dispensed was the index date, and baseline risk factors were assessed among patients continuously eligible for 12 months before the index date. Patients who had the following were stratified into an elevated risk category: age ≥65 years, smoking, or a history of a major adverse cardiovascular event, venous thromboembolism, or cancer. The prevalence of modifiable risk factors was also reported: hypertension, hyperlipidemia, obesity, and diabetes. The crude prevalence and prevalence difference (PD) were reported. RESULTS: A total of 12,673 patients (TNFi [n = 7,748; 61%] and JAKi [n = 4,925; 39%]) met inclusion criteria. The prevalence of elevated risk was the same for all patients using TNFi (n = 2,051; 26%) and JAKi (n = 1,262; 26%). Compared with patients having low risk, patients with an elevated risk also had a higher prevalence of at least one primary modifiable risk factor for both patients using JAKi (79% vs 58%; PD 21%, 95% confidence interval [CI] 18%-24%) and TNFi (81% vs 60%; PD 21%, 95% CI 19%-23%). CONCLUSION: In recent years, JAKi and TNFi were used in similar proportions to treat RA among commercially-insured patients at elevated cardiovascular and cancer risk. Because uncontrolled disease, modifiable comorbidities, and treatment with JAKi are associated with these adverse events, future studies evaluating how practice patterns may be affected by the emergence of safety data will be of value.

The anti-HIV drug abacavir stimulates ß-catenin activity in osteoblast lineage cells.

Bone mineral density (BMD) loss in people living with HIV occurs with the initiation of combined antiretroviral therapy (cART), particularly with tenofovir disoproxil fumarate (TDF) containing cART. Switching from TDF to abacavir (ABC) or dolutegravir (DTG) leads to increased BMD. Whether BMD gains are due to cessation of TDF or anabolic effects of ABC or DTG is unclear. We investigated the effects of ABC and DTG on osteoblast lineage cells in vitro and in vivo. Primary human osteoblasts and male C57BL/6 mice were treated with individual antiretrovirals (ARVs) or a combination of ABC/DTG/lamivudine (3TC). Nearly all ARVs and cART inhibited osteogenic activity in vitro. Due to the importance of Wnt/ß-catenin in bone formation, we further investigated ARV effects on the Wnt/ß-catenin pathway. ABC, alone and as part of ABC/DTG/3TC, increased osteoblastic ß-catenin activity as indicated by increased TOPFlash activity, hypo-phosphorylated (active) ß-catenin staining, and ß-catenin targeted gene expression. Mice treated with TDF had decreased lumbar spine BMD and trabecular connectivity density in the vertebrae, while those treated with ABC/DTG/3TC reduced cortical area and thickness in the femur. Mice treated with ABC alone had no bone structural changes, increased circulating levels of the bone formation marker, P1NP, and elevated expression of the Wnt/ß-catenin target gene, Lef1, in osteocyte enriched samples. Further, bones from ARV-treated mice were isolated to evaluate ARV distribution. All ARVs were detected in the bone tissue, which was inclusive of bone marrow, but when bone marrow was removed, only TDF, ABC, and DTG were detected at ~0.1% of the circulating levels. Overall, our findings demonstrate that ABC activates Wnt/ß-catenin signaling, but whether this leads to increased bone formation requires further study. Assessing the impact of ARVs on bone is critical to informing ARV selection and/or discovery of regimens that do not negatively impact the skeleton.

Real-world total cost of care by line of therapy in relapsed/refractory diffuse large B-cell lymphoma.

AIMS: There are multiple recently approved treatments and a lack of clear standard-of-care therapies for relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL). While total cost of care (TCC) by the number of lines of therapy (LoTs) has been evaluated, more recent cost estimates using real-world data are needed. This analysis assessed real-world TCC of R/R DLBCL therapies by LoT using the IQVIA PharMetrics Plus database (1 January 2015-31 December 2021), in US patients aged ≥18 years treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) or an R-CHOP-like regimen as first-line therapy. METHODS: Treatment costs and resources in the R/R setting were assessed by LoT. A sensitivity analysis identified any potential confounding of the results caused by the impact of the COVID-19 pandemic on healthcare utilization and costs. Overall, 310 patients receiving a second- or later-line treatment were included; baseline characteristics were similar across LoTs. Inpatient costs represented the highest percentage of total costs, followed by outpatient and pharmacy costs. RESULTS: Mean TCC per-patient-per-month generally increased by LoT ($40,604, $48,630, and $59,499 for second-, third- and fourth-line treatments, respectively). Costs were highest for fourth-line treatment for all healthcare resource utilization categories. Sensitivity analysis findings were consistent with the overall analysis, indicating results were not confounded by the COVID-19 pandemic. LIMITATIONS: There was potential misclassification of LoT; claims data were processed through an algorithm, possibly introducing errors. A low number of patients met the inclusion criteria. Patients who switched insurance plans, had insurance terminated, or whose enrollment period met the end of data availability may have had truncated follow-up, potentially resulting in underestimated costs. CONCLUSION: Total healthcare costs increased with each additional LoT in the R/R DLBCL setting. Further improvements of first-line treatments that reduce the need for subsequent LoTs would potentially lessen the economic burden of DLBCL.

Relative handgrip strength as a vitality measure in US stroke survivors.

PURPOSE: Stroke is a leading cause of long-term disability in the US, yet a feasible assessment measure with predictive value for components of the International Classification of Functioning, Disability, and Health (ICF) Core Set for Stroke is lacking. The purpose of the present study was to explore the predictive value of potential assessment measures on factors within each ICF component in stroke survivors. MATERIALS AND METHODS: Demographic, anthropometric, blood-based biomarker, physical functioning, and Global Physical Activity Questionnaire data were collected on stroke survivors in the 2011-2018 NHANES cycles. Potential predictors (handgrip strength relative to weight, age, sex, race, education level, marital status, poverty ratio, stroke chronicity) of physical function, activities of daily living (ADLs), participation in social activities, metabolic syndrome, and meeting physical activity recommendations were evaluated using weighted linear and ordinal logistic regression. RESULTS: Relative handgrip strength was a significant predictor of physical function, difficulty participating in ADLs and social activities, and odds of meeting physical activity recommendations. As relative handgrip strength increased, these factors improved among stroke survivors. CONCLUSIONS: To decrease disability rates and optimize function among stroke survivors, the use of assessment measures like relative handgrip strength that may predict multiple ICF components is warranted.

Handgrip strength relative to weight may be a significant predictor of multiple components of the International Classification of Functioning, Disability, and Health (ICF) Core Set for Stroke, including physical function, difficulty completing activities of daily living, difficulty participating in social activities, and the odds of meeting physical activity recommendations.Environmental and personal factors, such as income and education, may influence outcomes; thus, education and appropriate resources may need to be included as an aspect of stroke rehabilitation.The heterogenous and pervasive effects of chronic stroke highlight the need to identify outcome measures, like relative handgrip strength, that can influence multiple domains of stroke recovery.

Epigenetic Aging and Musculoskeletal Outcomes in a Cohort of Women Living With HIV.

BACKGROUND: The relationship between accelerated epigenetic aging and musculoskeletal outcomes in women with HIV (WWH) has not been studied. METHODS: We measured DNA methylation age using the Infinium MethylationEPIC BeadChip in a cohort from the Women's Interagency HIV Study (n = 190) with measures of bone mineral density (BMD) and physical function. We estimated 6 biomarkers of epigenetic aging-epigenetic age acceleration (EAA), extrinsic EAA, intrinsic EAA, GrimAge, PhenoAge, and DNA methylation-estimated telomere length-and evaluated associations of epigenetic aging measures with BMD and physical function. We also performed epigenome-wide association studies to examine associations of DNA methylation signatures with BMD and physical function. RESULTS: This study included 118 WWH (mean age, 49.7 years; 69% Black) and 72 without HIV (mean age, 48.9 years; 69% Black). WWH had higher EAA (mean ± SD, 1.44 ± 5.36 vs -1.88 ± 5.07; P < .001) and lower DNA methylation-estimated telomere length (7.13 ± 0.31 vs 7.34 ± 0.23, P < .001) than women without HIV. There were no significant associations between accelerated epigenetic aging and BMD. Rather, measures of accelerated epigenetic aging were associated with lower physical function. CONCLUSIONS: Accelerated epigenetic aging was observed in WWH as compared with women without HIV and was associated with lower physical function in both groups.

Limited Durability of Extensor Mechanism Reconstruction Following Total Knee Arthroplasty: Mesh and Allograft Show Equivalent Outcomes at Five-Year Follow-Up.

BACKGROUND: Extensor mechanism disruption is a challenging complication following total knee arthroplasty. The purpose of this study was to compare outcomes between patients who received mesh versus allograft extensor mechanism reconstruction. METHODS: All patients who underwent extensor mechanism reconstruction at a single institution were screened. Demographic and surgical variables were recorded, including technique (ie, synthetic mesh versus allograft reconstruction). Patients were assessed for preoperative and postoperative extensor lag, revision, and duration of follow-up. Analyses, including Kaplan-Meier survivorships, were performed to compare mesh to allograft reconstruction. In total, 50 extensor mechanism reconstructions (30 mesh and 20 allograft) were conducted between January 1st, 2001, and December 31st, 2022. RESULTS: There were no differences between the cohorts with respect to revision (26.7 [8 of 30] versus 35.0% [7 of 20], P = .680) or failure defined as above knee amputation or fusion (6.7 [2 of 30] versus 5.0% [1 of 20], P = .808). There were also no differences in time to reoperation (average 27 months [range, 6.7 to 58.8] versus 29 months [range, 1.2 to 84.9], P = .910) or in postoperative extensor lag among patients who did not undergo a reoperation (13 [0 to 50] versus 11° [0 to 30], P = .921). The estimated 5-year Kaplan-Meier survival with extensor mechanism revision as the endpoint was similar between the 2 groups (52.1, 95% confidence interval [CI] = 25.4 to 73.3 versus 55.0%, 95% CI = 23.0 to 78.4%, P = .990). CONCLUSIONS: The purpose of this study was to present the findings of a large cohort of patients who required extensor mechanism reconstruction. Regardless of the reconstruction type, the 5-year outcomes of patients requiring extensor mechanism reconstruction are suboptimal.

Bone mineral density and the risk of incident dementia: A meta-analysis.

BACKGROUND: It is not known whether bone mineral density (BMD) measured at baseline or as the rate of decline prior to baseline (prior bone loss) is a stronger predictor of incident dementia or Alzheimer's disease (AD). METHODS: We performed a meta-analysis of three longitudinal studies, the Framingham Heart Study (FHS), the Rotterdam Study (RS), and the Rush Memory and Aging Project (MAP), modeling the time to diagnosis of dementia as a function of BMD measures accounting for covariates. We included individuals with one or two BMD assessments, aged ≥60 years, and free of dementia at baseline with follow-up available. BMD was measured at the hip femoral neck using dual-energy X-ray absorptiometry (DXA), or at the heel calcaneus using quantitative ultrasound to calculate estimated BMD (eBMD). BMD at study baseline ("baseline BMD") and annualized percentage change in BMD prior to baseline ("prior bone loss") were included as continuous measures. The primary outcome was incident dementia diagnosis within 10 years of baseline, and incident AD was a secondary outcome. Baseline covariates included age, sex, body mass index, ApoE4 genotype, and education. RESULTS: The combined sample size across all three studies was 4431 with 606 incident dementia diagnoses, 498 of which were AD. A meta-analysis of baseline BMD across three studies showed higher BMD to have a significant protective association with incident dementia with a hazard ratio of 0.47 (95% CI: 0.23-0.96; p = 0.038) per increase in g/cm2 , or 0.91 (95% CI: 0.84-0.995) per standard deviation increase. We observed a significant association between prior bone loss and incident dementia with a hazard ratio of 1.30 (95% CI: 1.12-1.51; p < 0.001) per percent increase in prior bone loss only in the FHS cohort. CONCLUSIONS: Baseline BMD but not prior bone loss was associated with incident dementia in a meta-analysis across three studies.

Zucker Diabetic-Sprague Dawley Rats Have Impaired Peri-Implant Bone Formation, Matrix Composition, and Implant Fixation Strength.

An increasing number of patients with type 2 diabetes (T2DM) will require total joint replacement (TJR) in the next decade. T2DM patients are at increased risk for TJR failure, but the mechanisms are not well understood. The current study used the Zucker Diabetic-Sprague Dawley (ZDSD) rat model of T2DM with Sprague Dawley (SPD) controls to investigate the effects of intramedullary implant placement on osseointegration, peri-implant bone structure and matrix composition, and fixation strength at 2 and 10 weeks post-implant placement. Postoperative inflammation was assessed with circulating MCP-1 and IL-10 2 days post-implant placement. In addition to comparing the two groups, stepwise linear regression modeling was performed to determine the relative contribution of glucose, cytokines, bone formation, bone structure, and bone matrix composition on osseointegration and implant fixation strength. ZDSD rats had decreased peri-implant bone formation and reduced trabecular bone volume per total volume compared with SPD controls. The osseointegrated bone matrix of ZDSD rats had decreased mineral-to-matrix and increased crystallinity compared with SPD controls. Osseointegrated bone volume per total volume was not different between the groups, whereas implant fixation was significantly decreased in ZDSD at 2 weeks but not at 10 weeks. A combination of trabecular mineral apposition rate and postoperative MCP-1 levels explained 55.6% of the variance in osseointegration, whereas cortical thickness, osseointegration mineral apposition rate, and matrix compositional parameters explained 69.2% of the variance in implant fixation strength. The results support the growing recognition that both peri-implant structure and matrix composition affect implant fixation and suggest that postoperative inflammation may contribute to poor outcomes after TJR surgeries in T2DM patients. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Sclerostin antibody improves alveolar bone quality in the Hyp mouse model of X-linked hypophosphatemia (XLH).

X-linked hypophosphatemia (XLH) is a rare disease of elevated fibroblast growth factor 23 (FGF23) production that leads to hypophosphatemia and impaired mineralization of bone and teeth. The clinical manifestations of XLH include a high prevalence of dental abscesses and periodontal disease, likely driven by poorly formed structures of the dentoalveolar complex, including the alveolar bone, cementum, dentin, and periodontal ligament. Our previous studies have demonstrated that sclerostin antibody (Scl-Ab) treatment improves phosphate homeostasis, and increases long bone mass, strength, and mineralization in the Hyp mouse model of XLH. In the current study, we investigated whether Scl-Ab impacts the dentoalveolar structures of Hyp mice. Male and female wild-type and Hyp littermates were injected with 25 mg·kg-1 of vehicle or Scl-Ab twice weekly beginning at 12 weeks of age and euthanized at 20 weeks of age. Scl-Ab increased alveolar bone mass in both male and female mice and alveolar tissue mineral density in the male mice. The positive effects of Scl-Ab were consistent with an increase in the fraction of active (nonphosphorylated) ß-catenin, dentin matrix protein 1 (DMP1) and osteopontin stained alveolar osteocytes. Scl-Ab had no effect on the mass and mineralization of dentin, enamel, acellular or cellular cementum. There was a nonsignificant trend toward increased periodontal ligament (PDL) attachment fraction within the Hyp mice. Additional PDL fiber structural parameters were not affected by Scl-Ab. The current study demonstrates that Scl-Ab can improve alveolar bone in adult Hyp mice.

Alcohol Use, Rape Myth Acceptance, Rape Empathy, and Sexual Assault History Influence the Believability of a Hypothetical Victim's Report of Sexual Assault.

College sexual assault is a common problem, and survivors often do not report their experience to college campus officials or law enforcement for fear of not being believed. This study examined how contextual factors such as alcohol use and whether the perpetrator was described as a student-athlete or student, and rater characteristics, such as the history of sexual assault and attitudes toward rape, influenced college students' perceptions of the believability of a hypothetical victim's sexual assault account. In all, 449 (N = 449) undergraduates read a vignette describing a hypothetical sexual assault and were assigned randomly to one of four conditions with varying contextual features: college athlete-no alcohol, college athlete-alcohol, college student-no alcohol, or college student-alcohol. They then rated how much they believed the victim in the vignette had been raped (0 [not at all] to 100 [completely]). The presence of alcohol use in the vignette was associated with lower ratings of believability, and participants who were higher in rape myth acceptance and lower in rape empathy rated the hypothetical victim's rape account as less believable. In addition, women who had been raped previously rated the victim in the vignette as more believable than women with no history of sexual assault. Implications for how college campuses might respond more effectively to reported sexual assaults are discussed.

Sexual Assaults, Bad Hookups, and Bad Dates: Comparisons of the Contextual Features Among College Women's Hypothetical and Real-Life Sexual and Dating Experiences.

Two hundred forty-seven (N = 247) undergraduate women at a medium-sized, Southwestern university provided written descriptions of a hypothetical sexual assault (SA). Women with a prior history of SA also described their actual SA experiences; women without a SA history provided a written description of a prior bad date or hookup. The contextual features of SA scripts were compared to those of actual SA experiences. Several characteristics of a stereotypical or "blitz rape" (e.g., physical force by a stranger) were more likely to be included in SA scripts relative to women's actual SA experiences. Victimized women were also more likely to include verbal coercion, a hangout/hookup context, and previous consensual kissing in their SA experiences, in comparison to their SA scripts. The contextual features of SA experiences were also compared to the contextual features of bad dates or bad hookups. SA experiences, relative to bad dates, were more likely to include alcohol use, physical and verbal coercion by the perpetrator, and passive resistance. SA experiences, relative to bad hookups, were more likely to include physical and verbal coercion by the perpetrator, and knowing the man for less than 1 week. Victimized participants SA experiences were also found to be less likely to include previous consensual kissing and consensual intercourse in comparison to bad hookup experiences of nonvictimized women. Overall, there was considerable overlap between the contextual features present across all experiences. The lack of differentiation among these events may explain why women experience difficulty acknowledging whether they have experienced SA.

Effect of power training on rate of torque development and spatiotemporal gait parameters post stroke.

BACKGROUND: Maximizing independence and function post-stroke are two common therapy goals. Rate of torque development in lower-extremity muscles was recently reported to be associated with walking speed; however, trainability and subsequent effect on gait is unknown. This study aimed to determine effect of power training on paretic and non-paretic limb torque parameters, spatiotemporal gait parameters, and walking speed in chronic stroke survivors. METHODS: Individuals with chronic stroke (n = 22; 7 females; 62.7 ± 8.8 yrs) completed 24 progressive power-training sessions over 8 weeks with pre and post assessments. Knee extensor strength was assessed via dynamometry with torque parameters measured from maximal voluntary isometric contractions. Gait speed and spatiotemporal gait parameters were assessed via an instrumented gait mat, and a 6-min walk test was performed. FINDINGS: Rate of torque development at 200 ms and peak torque improved 58.6% and 14.1%, respectively, in the quadricep of the paretic limb (p < 0.05); conversely the non-paretic limb was unchanged. On average, self-selected walking speed, fastest-comfortable walking speed, and 6-min walk test improved 21.7%, 21.1%, and 19.5%, respectively (all p < 0.05). Change in torque development at 100 ms in the quadricep of the non-paretic limb was positively associated with improvements in self-selected and fastest-comfortable walking speeds (both r = 0.70, p < 0.05) and 6-min walk (r = 0.78, p < 0.001). INTERPRETATIONS: These findings suggest power training may be an effective intervention for improving torque development in the quadricep of the paretic limb in individuals with chronic stroke. Further research to explore utility and mechanistic aspects of force development for gait function in chronic stroke survivors is warranted.

Sclerostin antibody improves alveolar bone quality in the Hyp mouse model of X-Linked Hypophosphatemia (XLH).

X-linked hypophosphatemia (XLH) is a rare disease of elevated fibroblast growth factor 23 (FGF23) production that leads to hypophosphatemia and poor mineralization of bone and teeth. The clinical manifestations of XLH include a high prevalence of dental abscesses, likely driven by poorly formed structures of the dentoalveolar complex, including the alveolar bone, cementum, dentin, and periodontal ligament. Our previous studies have demonstrated that sclerostin antibody (Scl-Ab) treatment improves phosphate homeostasis, and increases bone mass, strength and mineralization in the Hyp mouse model of XLH. In the current study, we investigated whether Scl-Ab impacts the dentoalveolar structures of Hyp mice. Male and female wild-type and Hyp littermates were injected with 25 mg/kg of vehicle or Scl-Ab twice weekly beginning at 12 weeks of age and euthanized at 20 weeks of age. Scl-Ab increased alveolar bone mass in both male and female mice and alveolar tissue mineral density in the male mice. The positive effects of Scl-Ab were consistent with an increase in the fraction of active (non-phosphorylated) ß-catenin stained alveolar osteocytes. Scl-Ab had no effect on mineralized tissues of the tooth - dentin, enamel, acellular and cellular cementum. There was a non-significant trend toward increased periodontal ligament (PDL) attachment fraction within the Hyp mice. Additional PDL fibral structural parameters were not affected by Scl-Ab. The current study demonstrates that Scl-Ab can improve alveolar bone in the Hyp mouse model of XLH.

An Efficient Humanized Mouse Model for Oral Anti-Retroviral Administration.

HIV anti-retrovirals (ARVs) have vastly improved the life expectancy of people living with HIV (PLWH). However, toxic effects attributed to long-term ARV use also contribute to HIV-related co-morbidities such as heart disease, bone loss and HIV-associated neurocognitive disorders (HAND). Unfortunately, mouse models used to study the effects of ARVs on viral suppression, toxicity and HIV latency/tissue reservoirs have not been widely established. Here, we demonstrate an effective mouse model utilizing immune-compromised mice, reconstituted with infected human peripheral blood mononuclear cell (PBMCs). ARVs areincorporated into mouse chow and administered daily with combination ARV regimens includingAtripla (efavirenz, tenofovir disoproxil fumarate, and emtricitabine) and Triumeq (abacavir, dolutegravir and lamivudine). This model measures HIV-infected human cell trafficking, and ARV penetration throughout most relevant HIV organs and plasma, with a large amount of trafficking to the secondary lymphoid organs. Furthermore, the HIV viral load within each organ and the plasma was reduced in ARV treated vs. untreated control. Overall, we have demonstrated a mouse model that is relatively easy and affordable to establish and utilize to study ARVs' effect on various tissues, including the co-morbid conditions associated with PLWH, such as HAND, and other toxic effects.

Combined Aerobic Exercise and Virtual Reality-Based Upper Extremity Rehabilitation Intervention for Chronic Stroke: Feasibility and Preliminary Effects on Physical Function and Quality of Life.

Objectives: To (1) examine the feasibility of combining lower extremity aerobic exercise (AEx) with a virtual reality (VR) upper extremity (UE) rehabilitation intervention and (2) provide an estimate of effect size for the combined intervention on UE function, aerobic capacity, and health-related quality of life. Design: Single-group feasibility trial. Setting: Research laboratory. Participants: Community-dwelling individuals with mild to moderate impairment of the UE at least 6 months post stroke (N=10; male, n=6; female n=4; mean age, 54 years). Intervention: All participants received 18 sessions over a nominal 2-3 sessions per week schedule of a combined AEx and VR-UE rehabilitation intervention. During each session, participants completed 15 minutes of lower extremity AEx followed by playing a VR-UE rehabilitation game for approximately 20 minutes. Main Outcome Measures: Feasibility was evaluated by metrics of adherence, retention, treatment acceptability, data completeness, and adverse events. UE function, aerobic capacity (peak oxygen consumption [Vo2peak]), and quality of life were assessed with the Fugl-Meyer Assessment of Upper Extremity (FMA-UE), expired gas exchange analysis, and Stroke Impact Scale (SIS), respectively. Results: Adherence was 100%, and there were no withdrawals or losses to follow-up to report. Participants completed the intervention in 49±14 days. Cohen's dz effect size calculations indicated the intervention elicited medium effects on FMA-UE (dz =0.50) and SIS memory domain (dz =0.46) and large effects on absolute Vo2peak (dz =1.46), relative Vo2peak (dz =1.21), SIS strength (dz =1.18), and SIS overall recovery domains (dz =0.81). Conclusions: Combining lower extremity AEx and VR-UE rehabilitation appears feasible in the clinical research setting. Fifteen minutes of lower extremity AEx performed at vigorous intensity appears to elicit clinically meaningful benefits in chronic stroke. Further examination of the combination of lower extremity AEx and VR-UE rehabilitation and its effects on physical function and quality of life is warranted.

SHP-1 Protein Tyrosine Phosphatase Affects Early Postnatal Bone Development in Mice.

The Src homology region 2 domain-containing phosphatase-1 (SHP-1) is an intracellular tyrosine phosphatase that plays a negative regulatory role in immune cell signaling. Absent or diminished SHP-1 catalytic activity results in reduced bone mass with enhanced bone resorption. Here, we sought to investigate if Shp1 overexpression leads to increased bone mass and improved mechanical properties. Male and female wildtype (WT) and SHP1-transgenic (Tg) mice at 28, 56, and 84 days of age were compared. We applied microcomputed tomography to assess femoral cortical bone geometry and trabecular architecture and 3-point mechanical bending to assess mid-diaphyseal structural and estimated material properties. Serum OPG, RANKL, P1NP, and CTX-1 concentrations were measured by enzyme-linked immunoassay. The majority of transgene effects were restricted to the 28-day-old mice. Trabecular bone volume per total volume, trabecular number, and connectivity density were greater in 28-day-old female SHP1-Tg mice when compared to WTs. SHP1-Tg female mice showed increased total and medullary areas, with no difference in cortical area and thickness. Cortical tissue mineral density was strongly genotype-dependent. Failure load, yield load, ultimate stress, and yield stress were all lower in 28-day-old SHP1-Tg females. In 28-day-old SHP1-Tg females, circulating levels of OPG and P1NP were higher and RANKL levels were lower than WT controls. Our study demonstrates a role for SHP-1 in early postnatal bone development; SHP-1 overexpression negatively impacted whole bone strength and material properties in females.