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.

Doxorubicin metabolism moderately attributes to putative toxicity in prodigiosin/doxorubicin synergism in vitro cells.

Doxorubicin (Dox) is a widely neoplasm chemotherapeutic drug with high incidences of cardiotoxicity. Prodigiosin (PG), a red bacterial pigment from Serratia marcescens, has been demonstrated to potentiate Dox's cytotoxicity against oral squamous cell carcinoma cells through elevating Dox influx and identified as a Dox enhancer via PG-induced autophagy; however, toxicity of normal cell remains unclear. This study is conducted to evaluate putative cytotoxicity features of PG/Dox synergism in the liver, kidney, and heart cells and further elucidate whether PG augmented Dox's effect via modulating Dox metabolism in normal cells. Murine hepatocytes FL83B, cardio-myoblast h9c2, and human kidney epithelial cells HK-2 were sequentially treated with PG and Dox by measuring cell viability, cell death characteristics, oxidative stress, Dox flux, and Dox metabolism. PG could slightly significant increase Dox cytotoxicity in all tested normal cells whose toxic alteration was less than that of oral squamous carcinoma cells. The augmentation of Dox cytotoxicity might be attributed to the increase of Dox-mediated ROS accumulation that might cause slight reduction of Dox influx and reduction of Dox metabolism. It was noteworthy to notice that sustained cytotoxicity appeared in normal cells after PG and Dox were removed. Taken together, moderately metabolic reduction of Dox might be ascribed to the mechanism of increase Dox cytotoxicity in PG-induced normal cells; nevertheless, the determination of PG/Dox dose with sustained cytotoxicity in normal cells needs to be comprehensively considered.

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.

Arthroscopic excision of ganglion cysts of the posterior cruciate ligaments using posterior trans-septal portal.

PURPOSE: To evaluate clinical outcomes of arthroscopic excision of ganglion cysts involving the posterior cruciate ligament (PCL) using the posterior trans-septal portal in the knee. METHODS: A retrospective study was performed of 15 cases of ganglion cyst involving the PCL treated at our institution over a period of 4 years. All the cysts were diagnosed and had their location confirmed preoperatively by magnetic resonance imaging (MRI). All the cysts were excised arthroscopically through the posterior trans-septal portal. All patients were followed up with MRI evaluation at a mean of 36 months after surgery. In addition, International Knee Documentation Committee (IKDC) scores and range of motion (ROM) were obtained preoperatively and postoperatively simultaneously with MRI to assess the surgical outcomes. RESULTS: Most of the patients were male patients, and the mean age was 32 years. The most common presenting complaint was pain and difficulty in knee flexion. Preoperatively, the mean ROM was 3° to 110° and the mean IKDC score was 53 (range, 38 to 67; SD, 7.9). The location of the main cystic component was posterior to the PCL in 14 patients (93%) and anterior to the PCL in 1 patient (7%). After surgery, MRI evaluation at a mean follow-up time of 36 months showed no cyst recurrence. Postoperatively, the mean IKDC score was 91 (range, 70 to 99; SD, 9.3) and the mean ROM was 3° to 128°. CONCLUSIONS: Ganglion cysts associated with the PCL can cause knee pain and limitation of knee flexion. MRI evaluation is a noninvasive method of diagnosing PCL ganglion cysts. Arthroscopic excision through the posterior trans-septal portal is a good option for relieving pain and preventing cyst recurrence. LEVEL OF EVIDENCE: Level IV, therapeutic case series.

Diterpene promptly executes a non-canonical autophagic cell death in doxorubicin-resistant lung cancer.

16-hydroxycleroda-3,13-dien-15,16-olide (HCD) has antitumor activity reported in numerous types of cancers. However, the efficacy of HCD treatment in non-small-cell lung cancer (NSCLC) cells and doxorubicin-resistant (Dox-R)-NSCLC cells remains to be unraveled. The underlying anti-cancer mechanism of HCD on Dox-R and Dox-sensitive (Dox-S) of A549 cells was also investigated. Cytotoxicity of HCD against two cell lines (Dox-S and Dox-R) were determined via MTT assay, flow cytometry, and Western blot. A further examination of its anti-cancer efficacy was performed in A549-bearing xenograft mice via orthotopic intratrachea (IT) inoculation, which showed that HCD could arrest both Dox-S and Dox-R cells at G2/M phase without altering the sub-G1 cycle along with increasing of cleaved-PARP. HCD downregulated the mTOR/Akt/PI3K-p85 and PI3K-ClassIII/Beclin-1 signals and upregulated p62/LC3-I/II expressions to further confirm that the cell autophagy of NSCLC cells after being HCD-induced. Morphological observations of mouse lung sections illustrated that fewer cancer cells accumulated close to the trachea while less neoplastic activities were found in HCD orthotopic treated mice without liver, kidney, and spleen toxicity. Lastly, Dox, HCD, and target therapy medicines of EGFR and ALK were nicely docked with EGFR, ALK, and mTOR. Conclusively, HCD was demonstrated the chemotherapeutic potential regardless of Dox-R and Dox-S cells, suggesting natural autophagic inducer HCD provides a promising lead compound for new drug discovery and development of lung cancer therapies.

The treatment of propofol induced the TGF-ß1 expression in human endothelial cells to suppress endocytosis activities of monocytes.

Propofol anesthesia and sedation are known to downregulate the functions of many hematopoietic cells, such as macrophages and neutrophils, in vivo. However, the effects of propofol on secretion of the regulatory cytokine transforming growth factor ß1 (TGF-ß1) in vivo are unknown. In this study, the effects of propofol on TGF-ß1 expression in human peripheral blood mononuclear cells, umbilical vein endothelial cells (HUVECs), lymphocytes (Jurkat) and monocytes (THP-1) were tested. Moreover, these sera were also tested for regulatory activity on monocyte endocytosis with or without treatment with the TGF-ß1 pathway inhibitor SB431542. Propofol raised levels of both total and activated TGF-ß1 in propofol-treated patient sera after surgical operations. Furthermore, propofol induced secretion of latent TGF-ß1 in HUVEC cells and enhanced TGF-ß1 activation in THP-1 and Jurkat cells in vitro. Additionally, sera from propofol-treated patients suppressed monocyte endocytosis ex vivo, an effect that was abrogated by the TGF-ß1 pathway inhibitor SB431542.

The production and bioactivity of prodigiosin: quo vadis?

Prodigiosin (PG), a red tripyrrole pigment, belongs to a member of the prodiginine family and is normally secreted by various sources including Serratia marcescens and other Gram-negative bacteria. The studies of PG have received innovative devotion as a result of reported antimicrobial, larvicidal and anti-nematoid immunomodulation and antitumor properties, owing to its antibiotic and cytotoxic activities. This review provides a comprehensive summary of research undertaken toward the isolation and structural elucidation of the prodiginine family of natural products. Additionally, the current evidence-based understanding of the biological activities and medicinal potential of PG is employed to determine the efficacy, with some reports of information related to pharmacokinetics, pharmacodynamics and toxicology.

Clerodane Diterpene Ameliorates Inflammatory Bowel Disease and Potentiates Cell Apoptosis of Colorectal Cancer.

Inflammatory bowel disease (IBD) is general term for ulcerative colitis and Crohn's disease, which is chronic intestinal and colorectal inflammation caused by microbial infiltration or immunocyte attack. IBD is not curable, and is highly susceptible to develop into colorectal cancer. Finding agents to alleviate these symptoms, as well as any progression of IBD, is a critical effort. This study evaluates the anti-inflammation and anti-tumor activity of 16-hydroxycleroda-3,13-dien-15,16-olide (HCD) in in vivo and in vitro assays. The result of an IBD mouse model induced using intraperitoneal chemical azoxymethane (AOM)/dextran sodium sulfate (DSS) injection showed that intraperitoneal HCD adminstration could ameliorate the inflammatory symptoms of IBD mice. In the in vitro assay, cytotoxic characteristics and retained signaling pathways of HCD treatment were analyzed by MTT assay, cell cycle analysis, and Western blotting. From cell viability determination, the IC50 of HCD in Caco-2 was significantly lower in 2.30 µM at 48 h when compared to 5-fluorouracil (5-FU) (66.79 µM). By cell cycle and Western blotting analysis, the cell death characteristics of HCD treatment in Caco-2 exhibited the involvement of extrinsic and intrinsic pathways in cell death, for which intrinsic apoptosis was predominantly activated via the reduction in growth factor signaling. These potential treatments against colon cancer demonstrate that HCD could provide a promising adjuvant as an alternative medicine in combating colorectal cancer and IBD.

Preincisional subcutaneous infiltration of ketamine suppresses postoperative pain after circumcision surgery.

OBJECTIVE: N-methyl-D-aspartate and other glutamate receptors have been shown to present on the peripheral axons of primary afferents, and peripheral injection of N-methyl-D-aspartate-receptor antagonists can suppress hyperalgesia and allodynia. Thus, this study examined postoperative analgesic and adverse effects of local ketamine administered postoperatively. METHODS: Ketamine (0.3%, 3 mL) or saline was subcutaneously infiltrated before incision in a double-blind manner using a sample population of 40 patients undergoing circumcision surgery, equally and randomly assigned to 2 groups based on the treatment. The saline-infiltrated patients also received 9-mg intramuscular ketamine into the upper arm to control for any related systemic analgesic effects. The patients were followed up for 24 hours to determine postoperative analgesia and identify adverse effects. RESULTS: In the ketamine-infiltrated patients, the time interval until first analgesic demand (166 vs. 80 min) was longer and the incidence of pain-free status (pain score=0) during movement (45% vs. 10%) and erection (40% vs. 0%) was significantly higher than for the saline-treated analogs (P<0.05). The dose of ketorolac use and pain score during erection were significant lower in group ketamine patients. No significant differences were noted with respect to the incidence of adverse effects comparing the 2 groups. DISCUSSION: We conclude that preincisional subcutaneous ketamine infiltration can suppress postoperative pain after the circumcision surgery.

Comparison of arthroplasty vs. osteosynthesis for displaced femoral neck fractures: a meta-analysis.

BACKGROUND: This meta-analysis compared clinical outcomes of arthroplasty vs. osteosynthesis for displaced femoral neck fractures. METHODS: Meta-analysis was performed on the difference in revision rate and overall mortality between participants undergoing osteosynthesis vs. total hip arthroplasty (THA), osteosynthesis vs. hemiarthroplasty (HA), or THA vs. HA. RESULTS: Pooled direct and indirect results indicated no significant difference in mortality between THA and HA (pooled OR = 0.87, 95% CI 0.55 to 1.38; P = 0.556), between THA and osteosynthesis (pooled OR = 1.17, 95% CI 0.69 to 1.99; P = 0.553), and between HA and osteosynthesis (pooled OR = 1.21, 95% CI 0.84 to 1.74; P = 0.304). Pooled direct and indirect results indicated no significant difference in revision rates between THA and HA (pooled OR = 0.90, 95% CI 0.26 to 3.19; P = 0.874). But, fewer revisions (OR = 0.19, 95% CI 0.10 to 0.34; P = 0.000) were seen in patients treated with THA than osteosynthesis and also in those treated with HA than osteosynthesis (OR = 0.12, 95% CI 0.07 to 0.20; P = 0.000). After excluding studies without showing normal cognition in inclusion criteria, pooled direct and indirect results also indicated no significant difference in mortality between THA, HA, and osteosynthesis. Similarly, there was no significant difference in revision rates between THA and HA, but HA and THA had significantly lower revision rates compared with osteosynthesis. CONCLUSIONS: There was no significant difference in overall mortality among osteosynthesis, HA, and THA. However, HA and THA had significantly lower revision rates compared with osteosynthesis. Results of the present study provide support for the use of hip arthroplasty to treat displaced fractures of the femoral neck.

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.

A fusion protein composed of receptor binding domain of vascular endothelial growth factor-A and constant region fragment of antibody: angiogenesis antagonistic activity.

Vascular endothelial growth factor (VEGF) promotes the growth of solid tumor mainly via VEGF receptor-1 and receptor-2, which are expressed preferentially in proliferating endothelial cells. Therefore, a strategy for simultaneous blockage of both VEGF receptors may have a useful therapeutic effect in tumor growth. In this study, we utilized a fusion protein which is composed of receptor binding domain of VEGF-A (RBDV) and the constant region fragment (Fc) of a human immunoglobulin G1 (IgG1), to interfere with the growth of human umbilical vein endothelial cells (HUVECs) via VEGF receptors. The results showed that RBDV-IgG1 Fc was able to bind with both VEGF receptor-1 and receptor-2. In addition, RBDV-IgG1 Fc could decrease VEGF-induced proliferation and tube formation among HUVECs. Moreover, the cytotoxic test showed RBDV-IgG1 Fc could also enhance the cytotoxic activity of human natural killing cells. The data are suggesting that the fusion protein, RBDV-IgG1 Fc, may have potential as an angiogenesis antagonist for future tumor therapy.

A fusion protein with the receptor-binding domain of vascular endothelial growth factor-A (VEGF-A) is an antagonist of angiogenesis in cancer treatment: Simultaneous blocking of VEGF receptor-1 and 2.

Vascular endothelial growth factor (VEGF) is an angiogenic factor that signals through VEGFR-1 and VEGFR-2, which are expressed preferentially in proliferating endothelial cells. Thus, simultaneous blockage of both VEGF receptors may provide a more efficient therapeutic response in cancer treatment. We created a recombinant fusion protein (RBDV-IgG1 Fc), which is composed of the receptor binding domain of human VEGF-A (residues 8-109) and the Fc region of human IgG1 immunoglobulin. The recombinant protein can bind to both mouse VEGFR-1 and VEGFR-2 to decrease VEGF-induced proliferation and tube formation of endothelial cells in vitro. In this study, the RBDV-IgG1 Fc fusion protein reduced the effects of proliferation, migration and tube formation induced by VEGF in murine endothelial cells in vitro. In vivo tumor therapy with RBDV-IgG1 Fc resulted in tumor inhibition by reducing angiogenesis. Pathological evidence also shows that RBDV-IgG1 Fc can seriously damage vessels, causing the death of tumor cells. These findings suggest that this chimeric protein has potential as an angiogenesis antagonist in tumor therapy.