Incidence of Vitamin D Deficiency in Foot and Ankle Arthrodesis Nonunions.

Background Vitamin D has been found to be crucial in musculoskeletal health. The role of vitamin D levels in orthopedic patients has become a growing area of interest given its negative impact on fracture healing which can contribute to the development of nonunion following surgery. We sought to investigate the incidence of hypovitaminosis D in a cohort of patients who experienced a nonunion following a foot and ankle arthrodesis procedure. Methodology Patients who underwent a major elective foot and ankle arthrodesis procedure and developed a nonunion were given the opportunity to obtain serum vitamin D levels. All vitamin D levels were reported from percutaneous venous blood samples and compared to our institution's range of accepted normal values (25-80 ng/mL). Results A total of 13 patients who developed a nonunion agreed to have a vitamin D level obtained, and 11 of 13 patients had a low vitamin D level (average = 14.6 ng/mL, range = 9-24 ng/mL). Five patients underwent revision arthrodesis after normalization of vitamin D levels, and four out of five patients went on to successful union. Conclusions Hypovitaminosis D may be a modifiable risk factor for nonunion following a major foot and ankle arthrodesis procedure. Orthopedic surgeons should consider vitamin D screening and supplementation in patients undergoing elective arthrodesis procedures.

Resilience Improves Patient-Reported Outcomes After Orthopaedic Trauma.

OBJECTIVES: To analyze the relationship between patient resilience and patient-reported outcomes after orthopaedic trauma. DESIGN: Retrospective analysis of prospectively collected data. SETTING: Single Level 1 Trauma Center. PATIENT SELECTION CRITERIA: Patients were selected based on completion of the Patient-Reported Outcomes Measurement Information System (PROMIS) and Brief Resilience Scale (BRS) surveys 6 months after undergoing operative fracture fixation following orthopaedic trauma. Patients were excluded if they did not complete all PROMIS and BRS surveys. OUTCOME MEASURES AND COMPARISONS: Resilience, measured by the BRS, was analyzed for its effect on patient-reported outcomes, measured by PROMIS Global Physical Health, Physical Function, Pain Interference, Global Mental Health, Depression, and Anxiety. Variables collected were demographics (age, gender, race, body mass index), injury severity score, and postoperative complications (nonunion, infection). All variables were analyzed with univariate for effect on all PROMIS scores. Variables with significance were included in multivariate analysis. Patients were then separated into high resilience (BRS >4.3) and low resilience (BRS <3.0) groups for additional analysis. RESULTS: A total of 99 patients were included in the analysis. Most patients were male (53%) with an average age of 47 years. Postoperative BRS scores significantly correlated with PROMIS Global Physical Health, Pain Interference, Physical Function, Global Mental Health, Depression, and Anxiety ( P ≤ 0.001 for all scores) at 6 months after injury on both univariate and multivariate analyses. The high resilience group had significantly higher PROMIS Global Physical Health, Physical Function, and Global Mental Health scores and significantly lower PROMIS Pain Interference, Depression, and Anxiety scores ( P ≤ 0.001 for all scores). CONCLUSIONS: Resilience in orthopaedic trauma has a positive association with patient outcomes at 6 months postoperatively. Patients with higher resilience report higher scores in all PROMIS categories regardless of injury severity. Future studies directed at increasing resilience may improve outcomes in patients who experience orthopaedic trauma. LEVEL OF EVIDENCE: Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.

Incidence of thyroid disease in patients with forefoot deformity.

BACKGROUND: Hallux valgus and lesser toe deformities are common foot disorders with substantial functional consequences. While the exact etiologies are multi-factorial, it is unknown if certain endocrine abnormalities, such as thyroid dysfunction, may be associated with these pathologies. The current study sought to investigate the prevalence of thyroid disease in patients with hallux valgus or lesser toe deformities. METHODS: Every new patient who presented to our institution's foot and ankle clinic during a three-month time period was given a survey to determine the presence of a known thyroid disorder. The diagnosis for each visit was then recorded. Additionally, a national, publicly available database was queried for patients diagnosed with thyroid disease and concomitant hallux valgus or specific forefoot pathology. Odds ratios for the presence of thyroid dysfunction were then calculated for each patient group. RESULTS: Three-hundred and fifty initial visit patient surveys were collected, and 74 (21.1%) patients had a known diagnosis of thyroid disease. The most common diagnoses were primary hypothyroidism (n = 61, 17.4%), secondary hypothyroidism (n = 6, 1.7%), thyroiditis (n = 4, 1.1%), and hyperthyroidism (n = 3, 0.9%). Thyroid disease was present in 16 of 26 patients (61.5%) with a diagnosis of hallux valgus (OR 7.3, CI[3.16-16.99], p < 0.0001). Lesser toe deformities, including hammertoes, mallet toes, bunionettes and crossover toes, were also significantly associated with thyroid disease (OR 5.45, CI[1.83-16.26], p < 0.002). The national database revealed 905,924 patients with a diagnosis of a specific forefoot deformity, and 321,656 of these patients (35.5%) had a concomitant diagnosis of a thyroid condition (OR 2.11, CI[2.10-2.12], p < 0.0001). CONCLUSIONS: The current study suggests a significant association between forefoot pathology and thyroid dysfunction, especially hallux valgus and lesser toe deformities. Increased understanding of these correlations may offer an important opportunity in population health management, both in diagnosis and treatment. While further studies with long-term outcomes are necessary, the early diagnosis of thyroid disease may provide an opportunity to predict and potentially alter the course of forefoot pathology.

Long-term follow-up of total shoulder replacement surgery with inset glenoid implants for arthritis with deficient bone.

BACKGROUND: Total shoulder replacement surgery has been a successful treatment for patients with shoulder arthritis. However, long-term results are limited by complications such as glenoid loosening, wear, and instability. Also, glenoid bone deficiency limits available treatment options and outcomes. Successful short-term outcomes have been reported previously using inset glenoid implants for deficient arthritic bone, but long-term outcomes have not been reported using this technique. METHODS: A retrospective analysis was performed on 21 of 24 consecutive patients treated with inset glenoid implants for severe glenohumeral joint arthritis with bone deficiency with prospectively collected data. Inclusion criteria were patients with shoulder arthritis and severe glenoid bone deficiency, defined by perpendicular glenoid vault depth less than 15 mm. No bone grafts were used. All patients were evaluated preoperatively and after surgery with physical examination, radiographic studies, and outcome measures. There were 10 males and 11 females, 17 cases with osteoarthritis and 4 with inflammatory arthritis, and 5 patients with rotator cuff tears (3 full thickness and 2 partial tears). Mean age was 68 years. RESULTS: There were no surgical complications. At a mean follow-up of 8.7 years, there were statistically significant improvements (P < .001) in visual analog pain scores (7.7 to 0.1), American Shoulder and Elbow Surgeons outcome scores (23 to 95), and range of motion. There were no loose glenoids. No patients required any revision surgery. CONCLUSIONS: This study documents the long-term efficacy and safety of total shoulder replacement surgery with inset glenoid implants used to reconstruct deficient, arthritic glenoid bone.

Suppression of the GTPase-activating protein RGS10 increases Rheb-GTP and mTOR signaling in ovarian cancer cells.

The regulator of G protein signaling 10 (RGS10) protein is a GTPase activating protein that accelerates the hydrolysis of GTP and therefore canonically inactivates G proteins, ultimately terminating signaling. Rheb is a small GTPase protein that shuttles between its GDP- and GTP-bound forms to activate mTOR. Since RGS10 suppression augments ovarian cancer cell viability, we sought to elucidate the molecular mechanism. Following RGS10 suppression in serum-free conditions, phosphorylation of mTOR, the eukaryotic translation initiation factor 4E binding protein 1 (4E-BP1), p70S6K and S6 Ribosomal Protein appear. Furthermore, suppressing RGS10 increases activated Rheb, suggesting RGS10 antagonizes mTOR signaling via the small G-protein. The effects of RGS10 suppression are enhanced after stimulating cells with the growth factor, lysophosphatidic acid, and reduced with mTOR inhibitors, temsirolimus and INK-128. Suppression of RGS10 leads to an increase in cell proliferation, even in the presence of etoposide. In summary, the RGS10 suppression increases Rheb-GTP and mTOR signaling in ovarian cancer cells. Our results suggest that RGS10 could serve in a novel, and previously unknown, role by accelerating the hydrolysis of GTP from Rheb in ovarian cancer cells.

Vinyl sulfone analogs of lysophosphatidylcholine irreversibly inhibit autotaxin and prevent angiogenesis in melanoma.

Autotaxin (ATX) is an enzyme discovered in the conditioned medium of cultured melanoma cells and identified as a protein that strongly stimulates motility. This unique ectonucleotide pyrophosphatase and phosphodiesterase facilitates the removal of a choline headgroup from lysophosphatidylcholine (LPC) to yield lysophosphatidic acid (LPA), which is a potent lipid stimulator of tumorigenesis. Thus, ATX has received renewed attention because it has a prominent role in malignant progression with significant translational potential. Specifically, we sought to develop active site-targeted irreversible inhibitors as anti-cancer agents. Herein we describe the synthesis and biological activity of an LPC-mimetic electrophilic affinity label that targets the active site of ATX, which has a critical threonine residue that acts as a nucleophile in the lysophospholipase D reaction to liberate choline. We synthesized a set of quaternary ammonium derivative-containing vinyl sulfone analogs of LPC that function as irreversible inhibitors of ATX and inactivate the enzyme. The analogs were tested in cell viability assays using multiple cancer cell lines. The IC50 values ranged from 6.74 to 0.39 µM, consistent with a Ki of 3.50 µM for inhibition of ATX by the C16H33 vinyl sulfone analog CVS-16 (10b). A phenyl vinyl sulfone control compound, PVS-16, lacking the choline-like quaternary ammonium mimicking head group moiety, had little effect on cell viability and did not inhibit ATX. Most importantly, CVS-16 (10b) significantly inhibited melanoma progression in an in vivo tumor model by preventing angiogenesis. Taken together, this suggests that CVS-16 (10b) is a potent and irreversible ATX inhibitor with significant biological activity both in vitro and in vivo.

The Src homology 3 binding domain is required for lysophosphatidic acid 3 receptor-mediated cellular viability in melanoma cells.

The LPA3 receptor is a G protein-coupled receptor that binds extracellular lysophosphatidic acid and mediates intracellular signaling cascades. Although we previously reported that receptor inhibition using siRNA or chemical inhibition obliterates the viability of melanoma cells, the mechanism was unclear. Herein we hypothesized that amino acids comprising the Src homology 3 (SH3) ligand binding motif, R/K-X-X-V/P-X-X-P or (216)-KTNVLSP-(222), within the third intracellular loop of LPA3 were critical in mediating this outcome. Therefore, we performed site-directed mutagenesis of the lysine, valine and proline, replacing these amino acids with alanines, and evaluated the changes in viability, proliferation, ERK1/2 signaling and calcium in response to lysophosphatidic acid. Our results show that enforced LPA3 expression in SK-MEL-2 cells enhanced their resiliency by allowing these cells to oppose any loss of viability during growth in serum-free medium for up to 96 h, in contrast to parental SK-MEL-2 cells, which show a significant decline in viability. Similarly, site-directed alanine substitutions of valine and proline, V219A/P222A or 2aa-SK-MEL-2 cells, did not significantly alter viability, but adding a further alanine to replace the lysine, K216A/V219A/P222A or 3aa-SK-MEL-2 cells, obliterated this function. In addition, an inhibitor of the LPA3 receptor had no impact on the parental SK-MEL-2, 2aa-SK-MEL-2 or 3aa-SK-MEL-2 cells, but significantly reduced viability among wt-LPA3-SK-MEL-2 cells. Taken together, the data suggest that the SH3 ligand binding domain of LPA3 is required to mediate viability in melanoma cells.