Lenvatinib Suppresses Protein Kinase B Signaling and Induces Apoptosis in Osteosarcoma Cells.

BACKGROUND/AIM: Lenvatinib, an oral multikinase inhibitor, has demonstrated promising activity in patients with osteosarcoma (OS). Therefore, it is worth exploring the inhibitory efficacy and mechanism of action of lenvatinib in osteosarcoma. The primary goal of this study was to examine the inhibitory effectiveness and mechanism of lenvatinib on the growth and invasion of OS cells. MATERIALS AND METHODS: The effects of lenvatinib on cell viability, apoptosis, protein kinase B (AKT) activation, its downstream effector proteins involved in tumor progression, and invasion capability were assessed using MTT assay, flow cytometry, western blotting, and invasion/migration assay on U-2 OS and MG63 cells. RESULTS: Lenvatinib effectively induced cytotoxicity, apoptosis, as well as extrinsic and intrinsic apoptotic signaling in OS cells. Lenvatinib also significantly decreased the invasion/migration capability, AKT activation, and downstream effector proteins. CONCLUSION: The anti-OS effect of lenvatinib may be associated with the induction of apoptosis and the inactivation of AKT.

A Retrospective Comparison of Clinical Efficacy between Multimodal Analgesia and Patient-Controlled Epidural Analgesia in Patients Undergoing Total Knee Arthroplasty.

Background and Objectives: Adequate pain management during early rehabilitation is mandatory for improving the outcomes of patients undergoing total knee arthroplasty (TKA). Conventional pain management, mainly comprising opioids and epidural analgesia, may result in certain adverse effects such as dizziness, nausea, and motor blockade. We proposed a multimodal analgesic (MA) strategy involving the use of peripheral nerve block (NB), periarticular injection (PAI), and intravenous patient-controlled analgesia (IVPCA). This study compared the clinical efficacy and adverse effects of the proposed MA strategy and patient-controlled epidural analgesia (PCEA). Materials and Methods: We enrolled 118 patients who underwent TKA under spinal anesthesia. The patients followed either the MA protocol or received PCEA after surgery. The analgesic effect was examined using a numerical rating scale (NRS). The adverse effects experienced by the patients were recorded. Results: A lower proportion of patients in the MA group experienced motor blockade (6.45% vs. 22.98%) compared to those in the PCEA group on the first postoperative day. Furthermore, a lower proportion of patients in the MA group experienced numbness (18.52% vs. 43.33%) than those in the PCEA group on the first postoperative day. Conclusions: The MA strategy can be recommended for reducing the occurrence of motor blockade and numbness in patients following TKA. Therefore, the MA strategy ensures early rehabilitation while maintaining adequate pain relief.

Prediction of clinically significant prostate cancer through urine metabolomic signatures: A large-scale validated study.

PURPOSE: Currently, there are no accurate markers for predicting potentially lethal prostate cancer (PC) before biopsy. This study aimed to develop urine tests to predict clinically significant PC (sPC) in men at risk. METHODS: Urine samples from 928 men, namely, 660 PC patients and 268 benign subjects, were analyzed by gas chromatography/quadrupole time-of-flight mass spectrophotometry (GC/Q-TOF MS) metabolomic profiling to construct four predictive models. Model I discriminated between PC and benign cases. Models II, III, and GS, respectively, predicted sPC in those classified as having favorable intermediate risk or higher, unfavorable intermediate risk or higher (according to the National Comprehensive Cancer Network risk groupings), and a Gleason sum (GS) of ≥ 7. Multivariable logistic regression was used to evaluate the area under the receiver operating characteristic curves (AUC). RESULTS: In Models I, II, III, and GS, the best AUCs (0.94, 0.85, 0.82, and 0.80, respectively; training cohort, N = 603) involved 26, 24, 26, and 22 metabolites, respectively. The addition of five clinical risk factors (serum prostate-specific antigen, patient age, previous negative biopsy, digital rectal examination, and family history) significantly improved the AUCs of the models (0.95, 0.92, 0.92, and 0.87, respectively). At 90% sensitivity, 48%, 47%, 50%, and 36% of unnecessary biopsies could be avoided. These models were successfully validated against an independent validation cohort (N = 325). Decision curve analysis showed a significant clinical net benefit with each combined model at low threshold probabilities. Models II and III were more robust and clinically relevant than Model GS. CONCLUSION: This urine test, which combines urine metabolic markers and clinical factors, may be used to predict sPC and thereby inform the necessity of biopsy in men with an elevated PC risk.

A case report of systemic lupus erythematosus combined with central serous chorioretinopathy treated with glucocorticoids.

Glucocorticoids are generally contraindicated for use in central serous chorioretinopathy (CSC) because their use is considered to be an independent risk factor for CSC. There are rare reports regarding the treatment of systemic lupus erythematosus (SLE) combined with CSC. This current case report describes a rare case of a 24-year-old female patient with severely active SLE combined with CSC, whose vision was significantly restored after she was administered 120 mg methylprednisolone intravenously once a day for 3 days. This case report presents the clinical characteristics for the first time in terms of distinguishing between typical CSC and lupus chorioretinopathy. It also provides a review of the relevant literature. In patients with clinically severe active lupus nephritis combined with bilateral lupus chorioretinopathy, timely systemic application of appropriate doses of glucocorticoids is the preferred method to control the primary disease and serious ocular complications.

Improved Mechanical and Corrosion Properties of Powder Metallurgy Austenitic, Ferritic, and Martensitic Stainless Steels by Liquid Phase Sintering.

Powder metallurgy (PM) has been widely used to produce various steels in industry, mainly due to its capabilities for manufacturing nearly net-shaped products and mass production. To improve the performances of PM stainless steels, the roles of 0.6 wt% B additive in the microstructures, mechanical properties, and corrosion resistances of PM 304L austenitic, 410L ferritic, and 410 martensitic stainless steels were investigated. The results showed that adding 0.6 wt% B significantly improved the sintered densities of the three kinds of stainless steels due to the liquid phase sintering (LPS) phenomenon. The borides in 304L + 0.6B, 410L + 0.6B, and 410 + 0.6B were rich in B and Cr atoms but deficient in Fe, Ni, or C atoms, as analyzed by electron probe micro-analysis. Furthermore, the B additive contributed to the improved apparent hardness and corrosion resistance of PM stainless steels. In the 410L stainless steel, the 0.6 wt% B addition increased the corrosion voltage from -0.43 VSCE to -0.24 VSCE and reduced the corrosion current density from 2.27 × 10-6 A/cm2 to 1.93 × 10-7 A/cm2. The effects of several factors, namely: porosity; the generation of boride; the matrix/boride interfacial areas; Cr depletion; and the microstructure on the corrosion performances are discussed. The findings clearly indicate that porosity plays a predominant role in the corrosion resistances of PM austenitic, ferritic, and martensitic stainless steels.

Magnolol Suppresses ERK/NF-κB Signaling and Triggers Apoptosis Through Extrinsic/Intrinsic Pathways in Osteosarcoma.

BACKGROUND/AIM: Osteosarcoma is an aggressive primary malignant bone tumor that occurs in childhood. Although the diagnostic and treatment options have been improved, osteosarcoma confers poor prognosis. Magnolol, an active component of Magnoliae officinalis cortex, has been widely applied in herb medicine and has been shown to have multiple pharmacological activities. However, whether magnolol possesses anti-osteosarcoma capacity remains unknown. MATERIALS AND METHODS: We examined magnolol is cytotoxicity, and whether it regulates apoptosis and oncogene expression using MTT, flow cytometry and Western blotting assays in osteosarcoma cells. RESULTS: Magnolol exerted toxicity towards U-2 OS cells by inducing intrinsic/extrinsic apoptosis pathways. Additionally, treatment of U-2 OS cells with magnolol inhibited MAPK1 mitogen-activated protein kinase 1 (ERK)/Nuclear factor kappa B (NF-B) signaling involved in tumor progression and reduced the expression of anti-apoptotic and metastasis-associated genes. CONCLUSION: Magnolol may induce apoptosis and inactivate ERK/NF-B signal transduction in osteosarcoma cells.

From University to Court: The Reversal of Stahl's Positions on Gold-Making.

Georg Ernst Stahl, an influential chymical-medical author of the late seventeenth and early eighteenth centuries, first believed in alchemical transmutation and reversed his position over the course of his career. This essay begins by placing Stahl's early teaching in alchemy in a larger background in which German princes and academics shared intense interest in gold-making. Then, tracing Stahl's intellectual development, it shows that he developed an increasing reservation about alchemy, though he remained open to the possibility of transmutation during his tenure at Halle. Finally, this essay shows that Stahl's service to King Friedrich Wilhelm I was an important context for his later public denunciation of alchemy. An analysis of Stahl's career shift from a university professor to a royal physician at court thus sheds light on the reversal of his positions.

Association between endometriosis and risk of systemic lupus erythematosus.

To examine the association between endometriosis and the risk of systemic lupus erythematosus (SLE), this nationwide, population-based, retrospective cohort study was conducted based on National Health Insurance Research Database in Taiwan. Endometriosis (N = 16,758) and non-endometriosis (N = 16,758) groups were identified by matching baseline characteristics and comorbidities. Student's t-tests and the Kaplan-Meier estimator were utilized to estimate the hazard ratio (HR) and cumulative probability of SLE in the two groups. The endometriosis group showed a significantly higher incidence density rate (0.3 vs. 0.1 per 1000 person-years) and hazard ratio in SLE group (adjusted HR [aHR], 2.37; 95% confidence interval [CI] 1.35-4.14) compared to the non-endometriosis group. Subgroup analysis revealed that patients with endometriosis between 30 and 45 years of age, or were non-steroidal anti-inflammatory drug users, or were hormonal medications-free participants, had higher risks of SLE. For patients with endometriosis, surgical intervention did not significantly impact on the risk of SLE. Our results demonstrated an increased risk of SLE in patients with endometriosis. Clinicians should be aware of this association when managing patients with endometriosis or SLE.

Efficacy of a Smart Antisnore Pillow in Patients with Obstructive Sleep Apnea Syndrome.

OBJECTIVE: Untreated obstructive sleep apnea syndrome (OSAS) increases the risk of cardiovascular, dementia, and motor vehicle accident events. However, continuous positive airway pressure (CPAP) which is the gold standard treatment is not acceptable for many patients with OSAS. Development of devices for the patients of nonadherence to CPAP is necessary. MATERIALS AND METHODS: We evaluated the effect of the smart antisnore pillow (SAP) in patients with OSAS in a prospective, noncontrolled, nonrandomized, pilot study. According to the apnea-hypopnea index (AHI), they were divided into two groups: mild-to-moderate OSAS group and severe OSAS group. Single-night polysomnography (PSG) with application of a SAP was performed. Thirty patients, 15 males and 15 females, 33-82 years old (mean age, 59.3 ± 12.9 years), completed the smart antisnore pillow therapy test. Among them, 23 patients had mild-to-moderate OSAS. RESULTS: The SAP significantly improved the snore number (p = 0.018), snore index (p = 0.013), oxygen denaturation index (p = 0.001), total AHI (p = 0.002), and supine AHI (p = 0.002) in the mild-to-moderate OSAS group, but there was no significant improvement in the severe OSAS group. CONCLUSIONS: We concluded that the SAP is an effective positional therapy device for patients with OSAS of mild-to-moderate severity.

Seroepidemiology of Hepatitis B Virus Infection in Native and Immigrant Pregnant Women: A 20-Year Retrospective Study in Taiwan.

Universal immunoprophylaxis against hepatitis B virus (HBV) is regarded as a key element to prevent perinatal HBV infection. The aim of the present study was to investigate the changes in the hepatitis B surface antigen (HBsAg)- and hepatitis B envelope antigen (HBeAg)-positive rates in native and immigrant pregnant women, to realize the impact of immigrants, and to identify any weaknesses 30 years after the implementation of hepatitis B vaccination in Taiwan. A total of 20,020 test results of HBsAg and HBeAg in pregnant women-2,915 (14.6%) immigrant women and 17,105 native Taiwanese-from 1996 to 2015 were analyzed for changes during this 20-year retrospective cohort study. Native Taiwanese have a higher HBsAg-positive rate than immigrant women (P < 0.001). However, the HBsAg-positive rates decreased by 0.6% per year among native women, but did not decrease significantly (only by 0.18% per year) among immigrant women. The overall HBsAg-positive rate remained at high levels, 4.8% in the year 2015. The HBeAg-positive rate decreased significantly, by 0.22% per year, in the total women as well as by 0.23% per year in the native women (all P < 0.001); by contrast, the HBeAg-positive rate in immigrants decreased at a slower rate (0.10% per year), without a significant decreasing trend (P = 0.300). Higher HBeAg (+)/HBsAg (+) rate was found for the immigrants than for the native women (P < 0.001). To quickly and effectively lower the risk of vertical transmission, new approaches combined with vaccination may be needed in the post-immunization era.

Sorafenib with Transarterial Chemoembolization Achieves Improved Survival vs. Sorafenib Alone in Advanced Hepatocellular Carcinoma: A Nationwide Population-Based Cohort Study.

We hypothesized that sorafenib plus transarterial chemoembolization (TACE) would confer survival benefits over sorafenib alone for advanced hepatocellular carcinoma (aHCC). We investigated this while using the population-based All-Cancer Dataset to assemble a cohort (n = 3674; median age, 60; 83% men) of patients receiving sorafenib for aHCC (Child-Pugh A) with macro-vascular invasion or nodal/distant metastases. The patients were classified into the sorafenib-TACE group (n = 426) or the propensity score-matched sorafenib-alone group (n = 1686). All of the participants were followed up until death or the end of the study. Time-dependent Cox model and the Mantel-Byar test were used for survival analysis. During the median follow-ups of 221 and 133 days for the sorafenib-TACE and sorafenib-alone groups, 164 (39%) and 916 (54%) deaths occurred, respectively; the corresponding median overall survivals (OS) were 381 and 204 days, respectively (hazard ratio, HR: 0.74; 95% confidence interval, CI, 0.63-0.88; p = 0.021). The one-year and six-month OS were 53.5% and 80.3% in the sorafenib-TACE group and 32.4% and 54.4% in the sorafenib-alone group, respectively. The major complications were comparable between the two groups. The addition of TACE to sorafenib improves survival, with a 26% reduction in mortality. These findings provide strong real-world evidence that supports this combination strategy for eligible Child-Pugh A aHCC patients.

Do rheumatoid arthritis patients have more major complications and length of stay after lower extremities fracture surgery?: A nationwide data with propensity score matching.

Patients with rheumatoid arthritis (RA) have a high risk of cardiovascular diseases and fractures. This retrospective cohort study explored whether patients with RA face higher complication risks or longer hospital stays than other patients when they had a lower limb fracture that required the surgery. Patients aged >45 years who received lower limb fracture surgeries between 2005 and 2012 were selected from the National Health Insurance Research Database, and 10 related variables including sex and age were used in propensity score matching to pair RA patients with non-RA patients in a 1:4 ratio. The final study sample comprised 1109 patients with RA and 4436 non-RA patients. The results indicated that 5.57% of the study sample had postoperative complications, accounting for 5.05% of patients with RA and 5.70% of the control group. After conditional logistic regression analysis was performed, the risk of major complications has no significant differences between patients with RA and the control group (odds ratio [OR] = 0.87; 95% confidence interval [CI]: 0.61-1.24; P > .05). However, the comorbidity severity score exerted a significant effect on complications; patients with scores ≥3 were 2.78 times more likely to experience complications (OR = 2.78; 95% CI 1.52-5.07). When considering different types of complications, patients with RA were less likely to be exposed to the risk of stroke (OR = 0.48). After controlling all related factors, no significant differences were observed in the complication risks or deaths between the 2 groups (P > .05). Regarding hospitalization length, the average stay for all patients was 8.12 days; after controlling related factors, the hospitalization length for patients with RA was 0.97 times that of the control group, which was nonsignificant (P > .05). These results may provide some information to healthcare professionals when providing treatments.

Femoral Component Alignment with a New Extramedullary Femoral Cutting Guide Technique.

BACKGROUND: Intramedullary (IM) or extramedullary (EM) mechanical guides are used as alignment tools during total knee arthroplasty (TKA) surgery. The EM guide is less invasive; however, the IM mechanical guide is the preferred option since it has shown superior outcomes in several studies. Picture archive and communication system (PACS) images, if available, are extensively used for preoperative planning and intraoperative guidance. This retrospective study compared TKA outcomes using the conventional IM guide and a new EM technique which uses PACS image for preoperative and intraoperative assessment bone resection. To the best of our knowledge, this is the first study with the new EM technique. MATERIALS AND METHODS: The study was performed on 205 knees (190 patients) for TKA from 2011 to 2013. The perioperative blood loss and the postoperative alignment angles were assessed for both mechanical guides. The angles were measured on the radiographs of the patient. The blood loss was assessed by the blood accumulated in the hemovac drain during the surgery and until 3 days after the surgery. RESULTS: The new EM guide provided similar postoperative alignment as that obtained with the IM guide. CONCLUSION: The EM-guided method for femoral bone cutting using PACS films in TKA is as good as the IM method. The additional advantages of less injury to the bone and less fat emboli load to the cardiopulmonary system with the EM method makes it an attractive choice for routine, especially in the elderly and/or simultaneous bilateral, TKA in hospitals without modern computer-assisted navigation systems.

Embrittlement Due to Excess Heat Input into Friction Stir Processed 7075 Alloy.

The grain size of high strength 7075 hot-rolled aluminum plates was refined by a friction stir process (FSP) to improve their mechanical properties. The results of the tensile ductility tests, which were conducted at various tool rotational speeds, in the friction stir zone indicate significant tensile ductility loss, which even resulted in a ductile-to-brittle transition (DBT). DBT depends on the tool rotational speed. Our 1450 rpm specimens showed large data fluctuation in the tensile ductility and the location of the fracture controlled the formation of friction stir induced bands (FSIB). The crack initiation site located at FSIB was due to the tool rotational speed (1670 rpm). A higher heat-input causes the formation of FSIB, which is accompanied with micro-voids. This contributes significantly to tensile cracking within the stir zone after the application of the aging treatment. This investigation aimed to determine the dominant factor causing tensile ductility loss at the stir zone, which is the major restriction preventing further applications.

Extra-articular endoscopic excision of symptomatic popliteal cyst with failed initial conservative treatment: A novel technique.

To reduce the damage to posteromedial knee capsule, we developed a direct extra-articular arthroscopic approach for excision of symptomatic popliteal cysts. This study aimed to demonstrate the surgical technique and present the 2-year follow-up results. Cystectomy is performed by extra-articular surgical approach through a high posteromedial portal. Twenty-one consecutive patients diagnosed of symptomatic popliteal cysts with failed initial conservative treatments were included. At a median follow-up of 29.4 months, all knees had improved clinical function assessed by Rauschning and Lindgren knee classification (p<0.001). The cysts were either disappeared (95.2%) or reduced in size (4.8%). Only one (4.8%) patient had recurrent cyst, which was solved after ultrasound-guided aspiration. This direct extra-articular arthroscopic technique could be a feasible alternative for treatment of symptomatic popliteal cysts.

Rotational Shortening of Collateral Ligament in TKR With Severe Deformity.

Instability of the knee joint after total knee replacement (TKR) is one of the most important reasons for revision TKR. Inadequate release or tightening of the collateral ligaments in the knee joint may cause instability and early failure. This study presents a case series study of a new technique for ligament balancing wherein the collateral ligament is detached from its origin and rotated (twisted) around its longitudinal axis to tighten the ligament before the origin is reattached to its original position. The surgical technique for collateral ligament tightening during TKR was performed on 6 patients with a deformed knee caused by osteoarthritis and rheumatoid arthritis. The range of motion, knee society score, and laxity of the patients' knee joint, after 7 months to 13 years of follow-up, were evaluated. The technique was successful, achieving good range of motion and satisfactory stability of the joint. Further evaluation in a larger number of cases and a comparative analysis with different techniques would further support the usefulness of this rotational ligamentoplasty technique.

Treatment and Cost of Hepatocellular Carcinoma: A Population-Based Cohort Study in Taiwan.

Hepatitis B virus vaccination and antiviral therapies reduce the risk of hepatocellular carcinoma (HCC). However, the lifetime healthcare expenditure involved in caring for HCC patients remains unclear. We examined the use and direct costs of healthcare services for a cohort of HCC patients to the healthcare system using Taiwan national health insurance program research database between 1997 and 2012. Total medical cost for all reimbursed patient encounters, including hospitalizations and outpatient care was cumulated from HCC onset to the end of follow-up or death. The mean follow-up time was 2.7 years (standard deviation, SD = 3.3) for the entire HCC cohort. Insurance payments of approximately US$92 million were made to 5522 HCC patients, with a mean cost of US$16,711 per patient (21,350). On average, the total cost per patient per month was US$2143 (5184); it was 50% higher for advanced cirrhosis patients at the baseline but 23% lower for mild-to-moderate cirrhotic patients. In the two-part regression, patients' underlying comorbid conditions, liver transplants, hepatectomy, and transarterial chemoembolization were associated with increased total cost, with liver transplants having the greatest impact over time. Hepatocellular carcinoma imposes substantial burden on the healthcare system. Real-world evidence on treatment and cost outcomes highlighted the needs to expand effective screening strategies and to optimize healthcare delivery to meet HCC patients' clinical needs.

Effects of pay for performance on risk incidence of infection and of revision after total knee arthroplasty in type 2 diabetic patients: A nationwide matched cohort study.

As the world's population ages, the number of people receiving total knee arthroplasty (TKA) has been on the rise. Although patients with diabetes mellitus are known to face greater risks of TKA postoperative infection and revision TKA owing to diabetic complications, studies on whether such patients' participation in pay for performance (P4P) programs influences the incidence rates of TKA postoperative infection or revision TKA are still lacking. This study examined the 2002-2012 data of Taiwan's National Health Insurance Research Database to conduct a retrospective cohort analysis of diabetic patients over 50 years old who have received TKA. To reduce any selection bias between patients joining and not joining the P4P program, propensity score matching was applied. The Cox proportional hazards model was used to examine the influence of the P4P program on TKA postoperative infection and revision TKA, and the results indicate that joining P4P lowered the risk of postoperative infection (HR = 0.91, 95% CI: 0.77-1.08), however, which was not statistically significant, and significantly lowered the risk of revision TKA (HR = 0.53, 95% CI: 0.39-0.72). Being younger and male, having multiple comorbid conditions or greater diabetic severity, receiving care at regional or public hospitals, and not having a diagnosis of degenerative or rheumatoid arthritis were identified as factors for higher risk of TKA postoperative infection for patients with diabetes. As for the risk of revision TKA, postoperative infection and being younger were identified as factors for a significantly higher risk (p < 0.05).