Chronic liver disease and cirrhosis increase morbidity in geriatric patients treated surgically for hip fractures: analysis of the US Nationwide Inpatient Sample.

BACKGROUND: This study aimed to evaluate the impact of chronic liver disease and cirrhosis on inpatient outcomes of geriatric hip fracture surgery. MATERIALS AND METHODS: Using population-based retrospective study design, this study extracted data from the US Nationwide Inpatient Sample (NIS) database 2005-2014, identifying patients aged ≥ 65 years undergoing hip fracture repair. Main outcomes were in-hospital mortality, any/specific complications, non-routine discharge, extended length of stay (LOS) and hospital costs. Associations between cirrhosis, non-cirrhotic chronic liver disease and outcomes were determined using regression analysis. RESULTS: Data of 347,363 hip fracture patients included 344,035 without liver disease, 1257 with non-cirrhotic chronic liver disease and 2,071 with cirrhosis. After adjustments, non-cirrhotic chronic liver disease was significantly associated with non-routine discharge (OR: 1.247, 95% CI: 1.038-1.498), acute kidney injury (OR: 1.266, 95% CI: 1.039-1.541), extended LOS (OR: 1.285, 95% CI: 1.122-1.473) and hospital costs (beta: 9173.42, 95% CI: 6925.9-11,420.95) compared to no liver disease; while cirrhosis was significantly associated with higher risk of in-hospital mortality (OR: 2.325, 95% CI: 1.849-2.922), any complication (OR: 1.295, 95% CI: 1.143-1.467), acute kidney injury (OR: 1.242, 95% CI: 1.177-1.433), non-routine discharge (OR: 1.650, 95% CI: 1.412-1.928), extended LOS (OR: 1.405, 95% CI: 1.263-1.562) and hospital costs (beta: 6680.24, 95% CI: 4921.53-8438.95) compared to no liver disease. CONCLUSION: In geriatric hip fracture patients undergoing surgical repair, non-cirrhotic chronic liver disease and cirrhosis independently predict non-routine discharge, acute kidney injury, prolonged LOS and greater hospital costs, and cirrhosis is also significantly associated with greater risk of any complication and in-hospital mortality.

Autologous Chondrocyte Implantation Versus Microfracture in the Knee: A Meta-analysis and Systematic Review.

PURPOSE: To compare clinical outcomes among patients with fractures of knee cartilage who were treated with autologous chondrocyte implantation (ACI) or microfracture (MF). METHODS: A systematic review was made of randomized controlled trials of articular cartilage lesions of the knee treated with ACI or MF that were published between January 2000 and November 2018 and catalogued in 4 major databases. The outcomes of clinical score, quality of life (QoL), pain relief score, and failure rate were assessed. RESULTS: A final group of 12 randomized controlled trials were included that enrolled a total of 659 patients with knee cartilage lesions: 332 patients had received ACI and 327 patients had undergone MF. Patients ranged in age from 25 to 41 years, and the majority were male. Lesion size ranged from 2.3 to 10.0 cm2. Pooled analysis found no significant difference in the improvement in International Knee Documentation Committee and Lysholm scores or overall Knee Injury and Osteoarthritis Outcome Score measures between patients in the ACI and MF groups at 1-year, 2-year, and 5-year follow-up examinations or in failure rate at 2-year, 3-year, and 5-year follow-up timepoints. However, patients treated with ACI had a significant benefit in activities of daily living at follow-up of 5 years or less compared with patients treated with MF. ACI treatment also showed better improvement in QoL and pain relief than MF at 5-year and 2-year follow-up examinations, respectively. CONCLUSIONS: The pooled analysis found no significant difference in the improvement in International Knee Documentation Committee or Lysholm scores or overall Knee Injury and Osteoarthritis Outcome Score measures between patients in the ACI and MF groups at 1 to 5 years of follow-up. Patients treated with ACI may have a significant benefit in activities of daily living, QoL, and pain relief compared with patients treated with MF, although clinical relevance may not be achieved. LEVEL OF EVIDENCE: Level II, systematic review of Level I and II investigations.

Nutritional factors associated with femoral neck bone mineral density in children and adolescents.

BACKGROUND: Nutritional factors including vitamin D, magnesium, and fat are known to affect bone mineral accrual. This study aimed to evaluate associations between dietary nutrient intakes (both macronutrients and micronutrients) and bone mineral density (BMD) in children and adolescents. METHODS: Data for this cross-sectional, population-based study were derived from the National Health and Nutrition Examination Survey (NHANES). Participants aged from 8 to 19 years were included. The primary outcome was femoral neck BMD. RESULTS: Multivariate analyses revealed that for participants aged 8 to 11, daily sodium intake was significantly and positively associated with femoral neck BMD (B = 0.9 ×  10- 5, p = 0.031); in particular, subgroup analyses by sex found that in male participants aged 8-11, daily total cholesterol intake (B = 5.3 × 10- 5, p = 0.030) and calcium intake (B = - 2.0 × 10- 5, p < 0.05) were significantly associated with femoral neck BMD in a positive and negative manner, respectively, but neither were observed in female participants of this age group. In contrast, daily intakes of vitamin D and magnesium were significantly and positively associated with femoral neck BMD in female participants aged 8-11 (B = 246.8 × 10- 5 and 16.3 × 10- 5, p = 0.017 and 0.033, respectively). For participants aged 16 to 19, daily total fat intake was significantly and negatively associated with femoral neck BMD (B = - 58 × 10- 5, p = 0.048); further stratification by sex found that magnesium and sodium intakes were significantly and positively associated with femoral neck BMD only in females of this age group (B = 26.9 × 10- 5 and 2.1 × 10- 5, respectively; both p < 0.05). However, no significant associations between daily nutrient intakes and femoral neck BMD were identified in participants aged 12-15 before or after subgroup stratification. CONCLUSION: The study found that associations of specific nutrition-related variables with BMD of the femoral neck is dependent upon age and gender.

Carbon Monoxide Inhibits Receptor Activator of NF-κB (RANKL)-Induced Osteoclastogenesis.

BACKGROUND: Low concentrations of carbon monoxide (CO) have anti-inflammatory effects and can reduce bone erosion in a murine collagen-induced arthritis model. The objective of this study was to assess the effects of CO on receptor activator of NF-κB ligand (RANKL), one of the key stimulators of osteoclastogenesis. METHODS: The in vivo effects of CO on RANKL expression were assessed in a collagen antibody-induced arthritis model in mice. Cell proliferation and apoptosis were assessed in the RAW246.7 cell line stimulated with RANKL and exposed to either air or CO. The number of tartrate resistant acid phosphatase (TRAP)-positive RAW246.7 cells was also examined after treatment with RANKL and the peroxisome proliferator-activated receptor gamma (PPARγ) agonist, Troglitazone. RESULTS: CO reduced RANKL expression in the synovium of arthritic mice. Although CO slightly increased RAW246.7 cell proliferation, no differences in activated caspase 3 levels were detected. In addition, Troglitazone ameliorated the inhibitory effects of CO on RANKL-induced TRAP expression by RAW246.7 cells. CONCLUSIONS: CO suppresses osteoclast differentiation by inhibiting the RANKL-induced activation of PPAR-γ. Given the role of the PPAR-γ/cFos (AP-1) pathway in regulating the transcription factor, NFATc1, the master regulator of osteoclastogenesis, further studies are warranted to explore CO in treating inflammatory bone disorders.

Increased COUP-TFII Expression Mediates the Differentiation Imbalance of Bone Marrow-Derived Mesenchymal Stem Cells in Femoral Head Osteonecrosis.

OBJECTIVE: Bone marrow-derived mesenchymal stem cells (BMSCs) have multilineage differentiation potential, which allows them to progress to osteogenesis, adipogenesis, and chondrogenesis. An imbalance of differentiation between osteogenesis and adipogenesis will result in pathologic conditions inside the bone. This type of imbalance is also one of the pathological findings in osteonecrosis of the femoral head (ONFH). Chicken ovalbumin upstream promoter-transcription factor II (COUP-TFII) was previously reported to mediate the differentiation of mesenchymal stem cells. This study investigated the expression of the osteogenesis regulator Runx2, osteocalcin, the adipogenesis regulator PPARγ, and COUP-TFII in the femoral head tissue harvested from ONFH patients, and characterized the effect of COUP-TFII on the differentiation of primary BMSCs. METHODS: Thirty patients with ONFH were recruited and separated into 3 groups: the trauma-, steroid- and alcohol-induced ONFH groups (10 patients each). Bone specimens were harvested from patients who underwent hip arthroplasty, and another 10 specimens were harvested from femoral neck fracture patients as the control group. Expression of the osteogenesis regulator Runx2, osteocalcin, the adipogenesis regulator PPARγ, C/EBP-α, and COUP-TFII was analyzed by Western blotting. Primary bone marrow mesenchymal cells were harvested from ONFH cells treated with COUP-TFII RNA interference to evaluate the effect of COUP-TFII on MSCs. RESULTS: ONFH patients had significantly increased expression of the adipogenesis regulator PPARγ and C/EBP-α and decreased expression of the osteogenesis regulator osteocalcin. ONFH bone tissue also revealed higher COUP-TFII expression. Immunohistochemical staining displayed strong COUP-TFII immunoreactivity adjacent to osteonecrotic trabecular bone. Increased COUP-TFII expression in the bone tissue correlated with increased PPARγ and decreased osteocalcin expression. Knockdown of COUP-TFII with siRNA in BMSCs reduced adipogenesis and increased osteogenesis in mesenchymal cells. CONCLUSION: Increased COUP-TFII expression mediates the imbalance of BMSC differentiation and progression to ONFH in patients. This study might reveal a new target in the treatment of ONFH.

Simulated Microgravity Disrupts Cytoskeleton Organization and Increases Apoptosis of Rat Neural Crest Stem Cells Via Upregulating CXCR4 Expression and RhoA-ROCK1-p38 MAPK-p53 Signaling.

Neural crest stem cells (NCSCs) are a population of multipotent stem cells that are distributed broadly in many tissues and organs and are capable of differentiating into a variety of cell types that are dispersed throughout three germ layers. We are interested in studying the effects of simulated microgravity on the survival and self-renewal of NCSCs. NCSCs extracted from the hair follicle bulge region of the rat whisker pad were cultured in vitro, respectively, in a 2D adherent environment and a 3D suspension environment using the rotatory cell culture system (RCCS) to simulate microgravity. We found that rat NCSCs (rNCSCs) cultured in the RCCS for 24 h showed disrupted organization of filamentous actin, increased globular actin level, formation of plasma membrane blebbing and neurite-like artifact, as well as decreased levels of cortactin and vimentin. Interestingly, ∼70% of RCCS-cultured rNCSCs co-expressed cleaved (active) caspase-3 and neuronal markers microtubule-associated protein 2 (MAP2) and Tuj1 instead of NCSC markers, suggesting stress-induced formation of neurite-like artifact in rNCSCs. In addition, rNCSCs showed increased C-X-C chemokine receptor 4 (CXCR4) expression, RhoA GTPase activation, Rho-associated kinase 1 (ROCK1) and p38 mitogen-activated protein kinase (MAPK) phosphorylation, and p53 expression in the nucleus. Incubation of rNCSCs with the Gα protein inhibitor pertussis toxin or CXCR4 siRNA during RCCS-culturing prevented cytoskeleton disorganization and plasma membrane blebbing, and it suppressed apoptosis of rNCSCs. Taken together, we demonstrate for the first time that simulated microgravity disrupts cytoskeleton organization and increases apoptosis of rNCSCs via upregulating CXCR4 expression and the RhoA-ROCK1-p38 MAPK-p53 signaling pathway.

Interactomics profiling of the negative regulatory function of carbon monoxide on RANKL-treated RAW 264.7 cells during osteoclastogenesis.

BACKGROUND: During osteoclastogenesis, the maturation of osteoclast (OC) progenitors is stimulated by the receptor activator of nuclear factor-κB ligand (RANKL). Excess OC production plays a critical role in the pathogenesis of inflammatory bone disorders. Conversely, the inhibition of abnormal OC proliferation reduces inflammation-induced bone loss. Low concentrations of carbon monoxide (CO) are known to decrease inflammation and OC-mediated bone erosion but the molecular mechanism is unknown. RESULTS: To obtain insight into the biological function of CO, cultured RANKL-treated RAW 264.7 cells were used in an in vitro experimental model of osteoclastogenesis. The results showed that CO inhibited: 1) tartrate-resistant acid phosphatase (TRAP)-positive cell formation; 2) F-actin ring production; 3) c-fos pathway activation; 4) the expression of cathepsin K, TRAP, calcitonin receptor, and matrix metalloproteinase-9 mRNAs; 5) the expression of nuclear factor of activated T cells, cytoplasmic, calcineurin-dependent 1 in translation. Protein-protein interaction analysis predicted mitogen-activated protein kinase kinase kinase 4 as the controlling hub. CONCLUSIONS: Low-concentrations of CO (250 ppm) may inhibit osteoclastogenesis. Data from STRING- and IPA-based interactome analyses suggested that the expression of proteins with the functions of signal transduction, enzymes, and epigenetic regulation are significantly altered by CO during RANKL-induced osteoclastogenesis. Our study provides the first interactome analysis of osteoclastogenesis, the results of which supported the negative regulation of OC differentiation by CO.