Congenital Generalized Lipodystrophy in a Division 1 Female Sprinter.

ABSTRACT: A 21-year-old African American Division 1 female sprinter presented with 3-weeks history of right great toe and forefoot pain, fatigue, and a 30-day continuous menstrual cycle despite implanted etonogestrel (Nexplanon) inserted 3 years prior. An magnetic resonance imagine (MRI) identified likely stress fracture of the second metatarsal base with a diffusely low T1 signal indicating hyperactive red marrow. Due to persistent pain, a follow-up MRI was ordered 6 months later and indicated serous atrophy of the bone marrow, prompting a further metabolic workup notable for triglycerides exceeding 4000 mg/dL and a hemoglobin A1c of 10.9%. This case highlights the manifestation of a rare congenital lipodystrophy that initially presented as a relatively classic stress fracture and metrorrhagia in a female athlete.

Nonoperative management of anterior shoulder instability can result in high rates of recurrent instability and pain at long-term follow-up.

BACKGROUND: Data on the long-term outcomes of nonoperative treatment of anterior shoulder instability are lacking, particularly for the US population. The purpose was to (1) describe the characteristics of patients with anterior shoulder instability treated nonoperatively, (2) assess the long-term outcomes of nonoperative management in a US population, and (3) identify risk factors for poor outcomes following nonoperative management. METHODS: A geographic cohort of >500,000 subjects was used to identify patients treated nonoperatively for anterior shoulder instability. Only patients aged <40 years at the time of initial instability with minimum 10-year follow-up were included. Medical records were reviewed to obtain demographic characteristics, physical examination findings, clinical history data, imaging results, treatment details, and clinical and/or radiographic progression. Recurrent pain, recurrent instability, and the development of symptomatic osteoarthritis (OA) were the primary outcomes evaluated. RESULTS: The study included 254 patients (73% male) with a median age of 19 years (range, 16-26 years) at the time of initial instability. At median 17-year follow-up, 37.5% experienced recurrent instability, 58.4% had recurrent pain, and 12.2% had symptomatic OA development. Factors associated with recurrent pain at final follow-up were multiple instability events prior to presentation (hazard ratio [HR], 2.43; P < .01) and increased pain at the initial visit (HRs of 0.79 for mild, 1.74 for moderate, and 1.39 for severe; P < .01); patients with multiple instability events prior to presentation also had an increased risk of recurrence (P < .01). Factors increasing the risk of the development of symptomatic OA included increased pain at the initial visit (P = .05), seizure disorder (HR, 27.01; P < .01), and smoking (HR, 5.15; P < .01). CONCLUSIONS: At long-term follow-up of 17 years, a high rate of poor outcomes was observed following nonoperative management of anterior shoulder instability. Overall, 37.5% of patients experienced recurrent shoulder instability, 58.4% had recurrent shoulder pain, and 12.2% had symptomatic OA development. Risk factors associated with adverse clinical outcomes included increased pain at the initial visit, recurrent instability prior to presentation, seizure disorder, and smoking.

High-Resolution Methods for Diagnosing Cartilage Damage In Vivo.

Advances in current clinical modalities, including magnetic resonance imaging and computed tomography, allow for earlier diagnoses of cartilage damage that could mitigate progression to osteoarthritis. However, current imaging modalities do not detect submicrometer damage. Developments in in vivo or arthroscopic techniques, including optical coherence tomography, ultrasonography, bioelectricity including streaming potential measurement, noninvasive electroarthrography, and multiphoton microscopy can detect damage at an earlier time point, but they are limited by a lack of penetration and the ability to assess an entire joint. This article reviews current advancements in clinical and developing modalities that can aid in the early diagnosis of cartilage injury and facilitate studies of interventional therapeutics.

Telomerase Activity in Articular Chondrocytes Is Lost after Puberty.

OBJECTIVE: Telomere length and telomerase activity are important indicators of cellular senescence and replicative ability. Loss of telomerase is associated with ageing and the development of osteoarthritis. Implantation of telomerase-positive cells, chondrocytes, or stem cells expressing a normal chondrocyte phenotype is desired for cartilage repair procedures. The objective of this study was to identify at what age chondrocytes and at what passage bone marrow-derived mesenchymal stem cells (MSCs) become senescent based on telomerase activity. The effect of osteogenic protein-1 (OP-1) or interleukin-1α (IL-1α) treatment on telomerase activity in chondrocytes was also measured to determine the response to anabolic or catabolic stimuli. METHODS: Articular cartilage was collected from horses (n = 12) aged 1 month to 18 years. Chondrocytes from prepubescent horses (<15 months) were treated with OP-1 or IL-1α. Bone marrow aspirate from adult horses was collected and cultured for up to 10 days to isolate MSCs. Telomerase activity was measured using the TeloTAGGG Telomerase PCR ELISA kit. RESULTS: Chondrocytes from prepubescent horses were positive for telomerase activity. Treatment with IL-1α resulted in a decrease in chondrocyte telomerase activity; however, treatment with OP-1 did not change telomerase activity. One MSC culture sample was positive for telomerase activity on day 2; all samples were negative for telomerase activity on day 10. CONCLUSIONS: These results suggest that chondrocytes from prepubescent donors are potentially more suitable for cartilage repair procedures and that telomerase activity is diminished by anabolic and catabolic cytokine stimulation. If MSCs are utilized in cartilage repair, minimal passaging should be performed prior to implantation.

Interleukin-1α, -6, and -8 decrease Cdc42 activity resulting in loss of articular chondrocyte phenotype.

Small GTPase proteins mediate changes in cellular morphology and other cellular functions. The aim of this study was to examine signaling of the small GTPase Cdc42 by stimulating chondrocytes grown in monolayer with long- (96 h) or short- (2 and 30 min) term exposure to interleukin-1α (IL-1α), IL-6, or IL-8. Quantitative PCR was used to determine changes in collagen type IIB (COL2A1), aggrecan (AGG), and matrix metalloproteinase-13 (MMP-13) gene expression after prolonged cytokine exposure. Effects of short-term treatment with IL-α, IL-6, or IL-8 on endogenous GTP-bound Cdc42 levels were assessed using an affinity assay, and on actin filament organization using confocal microscopy. Cytokine treatments significantly decreased COL2A1 and AGG expression and increased MMP-13 expression. Short exposure to IL-1α, IL-6, or IL-8 decreased endogenous GTP-Cdc42 and increased stress fibers, which were reversed with cytochalasin D treatment. These results show that IL-mediated Cdc42 signaling modifies chondrocyte phenotype and morphology. This may lend insight into the altered chondrocyte phenotype in catabolic conditions such as osteoarthritis.

Comparison of gene-specific DNA methylation patterns in equine induced pluripotent stem cell lines with cells derived from equine adult and fetal tissues.

Cellular pluripotency is associated with expression of the homeobox transcription factor genes NANOG, SOX2, and POU5F1 (OCT3/4 protein). Some reports suggest that mesenchymal progenitor cells (MPCs) may express increased quantities of these genes, creating the possibility that MPCs are more "pluripotent" than other adult cell types. The objective of this study was to determine whether equine bone marrow-derived MPCs had gene expression or DNA methylation patterns that differed from either early fetal-derived or terminally differentiated adult cells. Specifically, this study compared DNA methylation of the NANOG and SOX2 promoter regions and concurrent gene expression of NANOG, SOX2, and POU5F1 in equine induced pluripotent stem (iPS) cells, fetal fibroblasts, fetal brain cells, adult chondrocytes, and MPCs. Results indicate that NANOG and POU5F1 were not detectable in appreciable quantities in tissues other than the equine iPS cell lines. Equine iPS cells expressed large quantities of all three genes examined. Significantly increased quantities of SOX2 were noted in iPS cells and both fetal-derived cell types compared with adult cells. MPCs and adult chondrocytes expressed equivalent, low quantities of SOX2. Further, NANOG and SOX2 expression inversely correlated with the DNA methylation pattern in the promoter region, such that as gene expression increased, DNA methylation decreased. The equine iPS cell lines examined demonstrated DNA methylation and gene expression patterns that were consistent with pluripotency features described in other species. Results do not support previous reports that NANOG, SOX2, and POU5F1 are poised for increased activity in MPCs compared with other adult cells.