Sexually Dimorphic Increases in Bone Mass Following Tissue-specific Overexpression of Runx1 in Osteoclast Precursors.

Many metabolic bone diseases arise as a result excessive osteoclastic bone resorption, which has motivated efforts to identify new molecular targets that can inhibit the formation or activity of these bone-resorbing cells. Mounting evidence indicates that the transcription factor Runx1 acts as a transcriptional repressor of osteoclast formation. Prior studies using a conditional knockout approach suggested that Runx1 in osteoclast precursors acts as an inhibitor of osteoclastogenesis; however, the effects of upregulation of Runx1 on osteoclast formation remain unknown. In this study, we investigated the skeletal effects of conditional overexpression of Runx1 in preosteoclasts by crossing novel Runx1 gain-of-function mice (Rosa26-LSL-Runx1) with LysM-Cre transgenic mice. We observed a sex-dependent effect whereby overexpression of Runx1 in female mice increased trabecular bone microarchitectural indices and improved torsion biomechanical properties. These effects were likely mediated by delayed osteoclastogenesis and decreased bone resorption. Transcriptomics analyses during osteoclastogenesis revealed a distinct transcriptomic profile in the Runx1-overexpressing cells, with enrichment of genes related to redox signaling, apoptosis, osteoclast differentiation, and bone remodeling. These data further confirm the antiosteoclastogenic activities of Runx1 and provide new insight into the molecular targets that may mediate these effects.

Generation and Experimental Outcomes of Closed Femoral Fracture in Mice.

Fracture healing requires the integration of many cell types, growth factors, and cytokines that cannot be adequately studied using in vitro and in silico models. This has prompted the development of highly informative in vivo animal models to understand the complexities of fracture repair. Here, we describe a modified procedure for mice, first developed for rats by Bonnarens and Einhorn, that does not require a skin incision or suturing. This procedure involves boring a hole through the skin and articular surface of the femoral condyle with a 25-gauge needle, fixation with a K-wire, and creation of a transverse mid-diaphyseal fracture using a three-point bending fracture device. Fracture healing can be assessed using a variety of techniques, including microcomputed tomography, torsion testing, histological and histomorphometric analyses, and assessment of gene expression. There are many orthopedic trauma applications of this murine femoral fracture model ranging from assessment of safety and efficacy of novel therapeutics to the influence of specific genes on bone repair.

The Effects of Body Mass Index on In-hospital mortality following first ischemic or hemorrhagic stroke events: Does the "obesity paradox" apply?

BACKGROUND: While it is widely held that obesity is a risk factor for stroke, its role in mortality after stroke is less understood. We aim to examine effects of Body Mass Index (BMI) on in-hospital mortality after non-subarachnoid, subarachnoid, and ischemic stroke. METHODS: Retrospective cohort study. Patients aged ≥18 years, who were hospitalized in Florida hospitals between 2008 and 2012 with a diagnosis of first-time stroke as reported by the Agency for Health Care Administration (AHCA). The main independent variable was BMI category, which was divided into non-overweight/non-obese, obese, and morbidly obese. The primary outcome was the adjusted odds ratio (aOR) for in-hospital mortality for subarachnoid and non-subarachnoid hemorrhagic stroke, and ischemic stroke. Logistic regression modeling was utilized to examine the association between each BMI category and in-hospital mortality, while controlling for several potential confounders. This study was reported in line with the STROCSS criteria. RESULTS: Of the 333,367 patients included in the database, 150,153 (45.0%) patients met inclusion criteria. After adjusting for age, gender, ethnicity and other possible confounders, obese patients were 21% less likely to die during their hospitalization following a first ischemic stroke (0.79 aOR, 0.69-0.92, 95% CI, p = 0.002), and 32% less likely following a first non-subarachnoid hemorrhage (0.68 aOR, 0.57-0.82, 95% CI, p = 0.0001) compared to non-overweight/non-obese counterparts. CONCLUSION: Obese patients are less likely to die during hospitalization following first-time non-subarachnoid hemorrhage and ischemic stroke than non-overweight/non-obese patients. These findings support the "obesity paradox" concept, though more research is needed for recurrent stroke patients.

Lesser Metatarsophalangeal Instability: Diagnosis and Conservative Management of a Common Cause of Metatarsalgia.

CONTEXT: Lesser metatarsophalangeal (MTP) instability is a common condition that can become debilitating and require surgery. EVIDENCE ACQUISITION: An extensive literature review was performed through MEDLINE and Google Scholar for publications relating to the etiology, diagnosis, and treatment of lesser MTP instability using the keywords metatarsophalangeal instability, athlete, forefoot pain, and metatarsalgia from database inception to 2019. STUDY DESIGN: Clinical review. LEVEL OF EVIDENCE: Level 4. RESULTS: Lesser MTP instability is a common condition, especially in the active and aging populations. It is frequently misdiagnosed, causing delays in treatment that allow for progressive pain and deformity, which prevents an active lifestyle. Fortunately, MTP instability can be diagnosed easily with the drawer test. Magnetic resonance imaging is helpful when still in doubt. Conservative treatment entails joint immobilization and gradual return to play with taping and offloading metatarsal pads. CONCLUSION: Lesser MTP instability is a common diagnosis. Its early detection and conservative treatment can help the patient regain their previous level of activity and avoid surgery.

Droxidopa as an effective treatment for refractory neurogenic orthostatic hypotension and reflex bradycardia in amyloid light-chain amyloidosis: a case report.

BACKGROUND: Droxidopa is an oral treatment for the stepwise treatment of neurogenic orthostatic hypotension from autonomic dysfunction. It has been shown to be useful predominantly with neurogenic orthostatic hypotension secondary to Parkinson's disease, but only a few cases have documented its usefulness in patients with neurogenic orthostatic hypotension due to amyloidosis, which is often severe and refractory. In addition, only one source in the literature reports the concomitant use of midodrine and droxidopa for such patients. Finally, we argue that droxidopa seems to have a protective effect against episodes of reflex bradycardia, which is not previously reported. CASE PRESENTATION: A 64-year-old white man was admitted for 1 year of worsening syncopal episodes, diarrhea, failure to thrive, heart failure, and neuropathy. Medical emergencies were called five times on the overhead hospital intercom over a 4-day period in the beginning of his admission due to severe hypotension and bradycardia. He was eventually diagnosed as having amyloid light-chain amyloidosis and myeloma. After starting droxidopa, both his systolic blood pressure and reflex bradycardia improved, and no more medical emergency events were called during the remaining 30 days of admission. He felt much better subjectively and was able to sit upright and engage in physical therapy. CONCLUSIONS: We show that droxidopa is effective when used with midodrine to treat refractory neurogenic orthostatic hypotension in patients with amyloidosis. There are very few cases reporting the use of droxidopa in amyloidosis, with only one study that uses droxidopa and midodrine concomitantly. In addition, our patient's reflex bradycardia improved drastically after starting droxidopa, which we believe is mediated by increased systemic norepinephrine. There were no side effects to droxidopa, and the benefits lasted well beyond the reported duration of 1-2 weeks that was noted to be a limitation in some studies.

Deletion of Wnt5a in osteoclasts results in bone loss through decreased bone formation.

Bone remodeling is achieved through the coupled activities of osteoclasts and osteoblasts that are controlled by many locally generated secreted factors, including WNT5A. While previous studies have demonstrated that osteoblast-derived WNT5A promotes osteoclastogenesis, the function of osteoclast-derived WNT5A on bone remodeling has remained unexplored. We examined the effects of osteoclast-derived WNT5A on bone homeostasis by utilizing the Cathepsin K-Cre (Ctsk-Cre) mouse to conditionally delete Wnt5a in mature osteoclasts. These mice exhibited reduced trabecular and cortical bone. The low bone-mass phenotype was driven by decreased bone formation, not osteoclast-mediated bone resorption, as osteoclast number and serum CTX marker were unchanged. Furthermore, molecular analysis of osteoclast- and osteoblast-derived WNT5A identified a serine-phosphorylated WNT5A that is unique to RANKL-treated macrophages mimicking osteoclasts. This study suggests a new paradigm in which WNT5A has opposing effects on bone remodeling that are dependent on the cell of origin, an effect that may result from cell type-specific differential posttranslational modifications of WNT5A.

Pseudoaneurysm of the Second Dorsal Metatarsal Artery: Case Report and Literature Review.

Pseudoaneurysms are a rare complication of foot and ankle surgeries that can potentially lead to serious sequelae, especially when there is delay in the diagnosis. Due to the rarity of this occurrence, guidelines for management are limited for orthopedic surgeons. Once diagnosed, the surgeon has to decide quickly on many options for how to best manage the patient. In this case report, we present the occurrence of a dorsal second metatarsal artery pseudoaneurysm that occurred after removal of hardware. We also discuss the most current literature on the subject to help guide other surgeons in the diagnosis and management of this condition.