Transcriptomic Signature and Pro-Osteoclastic Secreted Factors of Abnormal Bone-Marrow Stromal Cells in Fibrous Dysplasia.

Fibrous dysplasia (FD) is a mosaic skeletal disorder caused by somatic activating variants of GNAS encoding for Gαs and leading to excessive cyclic adenosine monophosphate signaling in bone-marrow stromal cells (BMSCs). The effect of Gαs activation in the BMSC transcriptome and how it influences FD lesion microenvironment are unclear. We analyzed changes induced by Gαs activation in the BMSC transcriptome and secretome. RNAseq analysis of differential gene expression of cultured BMSCs from patients with FD and healthy volunteers, and from an inducible mouse model of FD, was performed, and the transcriptomic profiles of both models were combined to build a robust FD BMSC genetic signature. Pathways related to Gαs activation, cytokine signaling, and extracellular matrix deposition were identified. To assess the modulation of several key secreted factors in FD pathogenesis, cytokines and other factors were measured in culture media. Cytokines were also screened in a collection of plasma samples from patients with FD, and positive correlations of several cytokines to their disease burden score, as well as to one another and bone turnover markers, were found. These data support the pro-inflammatory, pro-osteoclastic behavior of FD BMSCs and point to several cytokines and other secreted factors as possible therapeutic targets and/or circulating biomarkers for FD.

Transcriptomic signature and pro-osteoclastic secreted factors of abnormal bone marrow stromal cells in fibrous dysplasia.

Fibrous dysplasia (FD) is a mosaic skeletal disorder caused by somatic activating variants in GNAS, encoding for Gαs, which leads to excessive cAMP signaling in bone marrow stromal cells (BMSCs). Despite advancements in our understanding of FD pathophysiology, the effect of Gαs activation in the BMSC transcriptome remains unclear, as well as how this translates into their local influence in the lesional microenvironment. In this study, we analyzed changes induced by Gαs activation in BMSC transcriptome and performed a comprehensive analysis of their production of cytokines and other secreted factors. We performed RNAseq of cultured BMSCs from patients with FD and healthy volunteers, and from an inducible mouse model of FD, and combined their transcriptomic profiles to build a robust FD BMSC genetic signature. Pathways related to Gαs activation, cytokine signaling, and extracellular matrix deposition were identified. In addition, a comprehensive profile of their secreted cytokines and other factors was performed to identify modulation of several key factors we hypothesized to be involved in FD pathogenesis. We also screened circulating cytokines in a collection of plasma samples from patients with FD, finding positive correlations of several cytokines to their disease burden score, as well as to one another and bone turnover markers. Overall, these data support a pro-inflammatory, pro-osteoclastic behavior of BMSCs bearing hyperactive Gαs variants, and point to several cytokines and other secreted factors as possible therapeutic targets and/or circulating biomarkers for FD.

Neuropathic-like Pain in Fibrous Dysplasia/McCune-Albright Syndrome.

CONTEXT: Pain is a major symptom in adults with fibrous dysplasia/McCune-Albright syndrome (FD/MAS) and response to current treatments, including bisphosphonates and standard analgesics (nonsteroidal anti-inflammatory drugs and opiates) is unpredictable. No studies have explored whether the type of pain is variable in this patient group. OBJECTIVE: To determine the frequency of neuropathic-like pain in patients with FD/MAS. DESIGN: Retrospective, dual registry study. SETTING: Community. PATIENTS: FD/MAS online registries: the US-based Familial Dysautonomia Foundation (FDF) and the UK-based Rare and Undiagnosed Diseases (RUDY) study. INTERVENTION: Subjects completed questionnaires to evaluate the presence of features of neuropathic-like pain (painDETECT) and the impact on sleep quality (Pittsburgh Sleep Quality Index) and mental health (Hospital Anxiety and Depression Scale). Descriptive statistics were used to characterize the prevalence and associated burden of neuropathic-like pain. MAIN OUTCOME MEASURES: Incidence of neuropathic, nociceptive, and unclear pain. RESULTS: Of 249 participants, one third experienced neuropathic-like pain. This group had statistically significantly (P < 0.001) worse mental well-being and sleep in comparison to those with predominately nociceptive pain. CONCLUSIONS: Neuropathic-like pain is common in patients with FD/MAS and associated with worse quality of life. Evaluation of pain in patients with FD/MAS should include assessment of neuropathic-like pain to guide personalized approaches to treatment and inform future research.

Nontraumatic Exertional Fatalities in Football Players, Part 2: Excess in Conditioning Kills.

BACKGROUND: The incidence of nontraumatic fatalities in high school (HS) and National Collegiate Athletic Association (NCAA) football players has continued at a constant rate since the 1960s. PURPOSE: To describe the causes of nontraumatic fatalities in HS and NCAA football players and provide prevention strategies. STUDY DESIGN: Descriptive epidemiology study. METHODS: We reviewed 187 fatalities in HS and NCAA nontraumatic football players catalogued by the National Registry of Catastrophic Sports Injuries during a 20-year period between July 1998 and June 2018. RESULTS: The majority (n = 162; 86.6%) of fatalities occurred during a practice or conditioning session. Most fatalities, when timing was known, (n = 126; 70.6%) occurred outside of the regular playing season, with the highest incidence in the August preseason (n = 64; 34.2%). All documented conditioning sessions were supervised by a coach (n = 92) or strength and conditioning coach (n = 40). The exercise regimen at the time of the fatality involved high-intensity aerobic training in 94.7%. Punishment was identified as the intent in 36 fatalities. The average body mass index of the athletes was 32.6 kg/m2. For athletes who died due to exertional heat stroke, the average body mass index was 36.4 kg/m2, and 97.1% were linemen. CONCLUSION: Most nontraumatic fatalities in HS and NCAA football players occurred during coach-supervised conditioning sessions. The primary cause of exertion-related fatalities was high-intensity aerobic workouts that might have been intended as punishment and/or excess repetitions. Exertion-related fatalities are potentially preventable by applying standards in workout design, holding coaches accountable, and ensuring compliance with the athlete's health and current welfare policies.

The Clinical Spectrum of McCune-Albright Syndrome and Its Management.

McCune-Albright syndrome (MAS) is a rare, mosaic disorder presenting along a broad clinical spectrum. Disease arises from somatic-activating GNAS mutations, leading to constitutive Gαs activation and ligand-independent signaling of the Gαs-coupled protein receptor. The phenotype is largely determined by location and extent of tissues in which the GNAS mutation is expressed, as well as the pathophysiologic effects of Gαs activation within these tissues. Patients pre-sent clinically with a variable combination of fibrous dysplasia of bone (FD), café-au-lait skin macules, and hyperfunctioning endocrinopathies. In bone, Gαs leads to impaired differentiation of skeletal stem cells and formation of discrete, expansile FD lesions, resulting in fractures, pain, and functional impairment. A systematic approach to diagnosis and management is critically important to optimize outcomes for patients with FD/MAS. There are no medical therapies capable of altering the disease course in FD; however, screening and treatment for endocrinopathies can mitigate some skeletal morbidities. This review summarizes current understanding of MAS pathophysiology, describes the spectrum of clinical features, and includes a detailed discussion of the recommended approach to diagnosis and management.

Is Edema at the Posterior Medial Tibial Plateau Indicative of a Ramp Lesion? An Examination of 307 Patients With Anterior Cruciate Ligament Reconstruction and Medial Meniscal Tears.

BACKGROUND: Medial meniscal tears are commonly seen during anterior cruciate ligament reconstruction (ACLR). A subset of these injuries includes posterior meniscocapsular junction or "ramp" tears. One criterion that may correlate with a ramp lesion is the presence of posterior medial tibial plateau (PMTP) edema. PURPOSE: To compare patients with ramp lesions to patients with nonramp (meniscal body) medial meniscal tears and correlate PMTP edema on preoperative magnetic resonance imaging (MRI) to the incidence of ramp tears. STUDY DESIGN: Case-control study; Level of evidence, 3. METHODS: From 2006 to 2016, a total of 852 patients underwent ACLR and had operative reports available for review. Age, sex, laterality, mechanism of injury (contact/noncontact), sport, revision procedure, multiligament injury, time to MRI, and time to surgery were recorded. Preoperative MRI scans were reviewed for PMTP edema using axial, coronal, and sagittal T2 and proton-density sequences. Differences between groups were analyzed using a 2-sample t test and chi-square test. Univariate and multivariate logistic regression models examined correlations with tear type. RESULTS: Overall, 307 patients had medial meniscal tears identified during ACLR (127 ramp lesions, 180 meniscal body lesions). The ramp group was 7.5 years younger than the meniscal body group (P < .01). The groups were not different regarding sex, contact injury, revision surgery, laterality, or multiligament injury. Patients with delayed ACLR were significantly more likely to have a meniscal body tear than a ramp lesion (odds ratio, 3.3 [95% CI, 1.9-5.6]; P < .01). The sensitivity of PMTP edema for a ramp tear was 66.3%, and 54.5% of patients with ACLR and a medial meniscal tear had PMTP edema. Patients with PMTP edema were significantly more likely to have a ramp tear than a meniscal body tear (odds ratio, 2.1 [95% CI, 1.1-4.1]; P < .03). CONCLUSION: The overall incidence of ramp tears in patients undergoing ACLR was 14.9%, and these tears were more prevalent in younger patients. Meniscal body tears were significantly more likely than ramp tears with delayed ACLR. In patients undergoing ACLR with an associated medial meniscal tear, the presence of PMTP edema demonstrated significantly greater odds for ramp lesions compared with meniscal body tears.

Anatomic Repair of Posteromedial Meniscocapsular Separation Using an All-Inside Technique.

Separation of the posteromedial meniscocapsular junction (PMC) is a unique injury seen in patients with disruption of the anterior cruciate ligament. PMC tears may go unrecognized despite preoperative magnetic resonance imaging and diagnostic arthroscopy of the medial compartment. Unrepaired lesions may lead to persistent laxity of the knee after anterior cruciate ligament reconstruction. Inside-out repair techniques risk iatrogenic injury to the articular cartilage during needle passage and require dissection of the posteromedial knee for suture retrieval. Previous all-inside techniques have required specialized implants and repaired PMC lesions with direct visualization of the tear. The presented all-inside technique is an easily reproducible, cost-effective means to anatomically repair separation of the PMC. The technique provides the surgeon direct visualization and full arthroscopic access to the lesion, making repair technically easy and efficient.

Induction of oral tremor in mice by the acetylcholinesterase inhibitor galantamine: Reversal with adenosine A2A antagonism.

Tremulous jaw movements (TJMs) have become a commonly used rat model of Parkinsonian tremor. TJMs can be induced by a number of neurochemical conditions that parallel those seen in human Parkinsonism, including DA depletion, DA antagonism, and cholinomimetic administration, and can be reduced by various antiparkinsonian agents. TJMs typically occur in bursts with the peak frequency in the range of 3-7.5 Hz, which is similar to the Parkinsonian tremor frequency range. While the vast majority of this work has been done using rats, current efforts have focused on extending the TJM model to mice. The aim of the present studies was to establish a mouse model of Parkinsonian resting tremor using the anticholinesterase galantamine, and to investigate the effects of adenosine A2A antagonism on galantamine-induced TJMs. Galantamine significantly induced TJMs in a dose-dependent manner (0.5, 1.0, 1.5, 2.0, 2.5 mg/kg IP). The TJMs tended to occur in bursts in the 3-7.5 Hz frequency range, with a peak frequency of approximately 6 Hz. Systemic administration of the adenosine A2A antagonist MSX-3 (2.5, 5.0, 10.0 mg/kg) significantly attenuated galantamine-induced TJMs. Co-administration of MSX-3 also altered the local frequency of galantamine-induced TJMs, decreasing the peak frequency from approximately 6 Hz to 5 Hz, though the vast majority of TJMs remained in the frequency range characteristic of Parkinsonian resting tremor. These results indicate that adenosine A2A antagonism is capable of reducing anticholinesterase-induced TJMs in mice. Extending the TJM model to mice gives researchers an additional avenue for investigating drug-induced Parkinsonism and tremorogenesis, and could be a useful addition to the study of motor abnormalities observed in mouse genetic models of Parkinsonism.