In Situ Ambient Pressure X-ray Photoelectron Spectroscopy Studies of Lithium-Oxygen Redox Reactions

The lack of fundamental understanding of the oxygen reduction and oxygen evolution in nonaqueous electrolytes significantly hinders the development of rechargeable lithium-air batteries. Here we employ a solid-state Li4+xTi5O12/LiPON/LixV2O5 cell and examine in situ the chemistry of Li-O2 reaction products on LixV2O5 as a function of applied voltage under ultra high vacuum (UHV) and at 500 mtorr of oxygen pressure using ambient pressure X-ray photoelectron spectroscopy (APXPS). Under UHV, lithium intercalated into LixV2O5 while molecular oxygen was reduced to form lithium peroxide on LixV2O5 in the presence of oxygen upon discharge. Interestingly, the oxidation of Li2O2 began at much lower overpotentials (~240 mV) than the charge overpotentials of conventional Li-O2 cells with aprotic electrolytes (~1000 mV). Our study provides the first evidence of reversible lithium peroxide formation and decomposition in situ on an oxide surface using a solid-state cell, and new insights into the reaction mechanism of Li-O2 chemistry.National Science Foundation (U.S.) (Materials Research Science and Engineering Center (MRSEC) Program, Award DMR-0819762)United States. Dept. of Energy (Assistant Secretary for Energy Efficiency and Renewable Energy, Office of FreedomCAR and Vehicle Technologies of the U. S. Department of Energy under contract no. DE-AC03-76SF00098)Lawrence Berkeley National LaboratoryUnited States. Dept. of Energy (Office of Basic Energy Sciences, Materials Sciences and Engineering

The effect of weight loss on lameness in obese dogs with osteoarthritis

This paper describes the effect of weight loss on lameness in obese dogs with osteoarthritis (OA). Fourteen obese client-owned dogs with clinical and radiographic signs of OA participated in an open prospective clinical trial. After a screening visit and a visit for collection of baseline data, the dogs were fed a restricted-calorie diet over a study period of 16 weeks that incorporated six follow-up visits. At each visit, body weight and pelvic circumference were measured and severity of lameness was assessed using a numeric rating scale (NRS), a visual analogue scale (VAS) and kinetic gait analysis. This is the first study to assess both subjectively and objectively, the effect of weight loss alone on lameness in obese dogs with OA. The results indicate that body weight reduction causes a significant decrease in lameness from a weight loss of 6.10% onwards. Kinetic gait analysis supported the results from a body weight reduction of 8.85% onwards. These results confirm that weight loss should be presented as an important treatment modality to owners of obese dogs with OA and that noticeable improvement may be seen after modest weight loss in the region of 6.10 – 8.85% body weight

Intraarticular location predicts cartilage filling and subchondral bone changes in a chondral defect: A randomized, blind, long-term follow-up trial involving 82 rabbit knees

Open Access - This article is distributed under the terms of the Creative Commons Attribution Noncommercial License which permits any noncommercial use, distribution, and reproduction in any medium, provided the source is credited.Background and purpose: The natural history of, and predictive factors for outcome of cartilage restoration in chondral defects are poorly understood. We investigated the natural history of cartilage filling subchondral bone changes, comparing defects at two locations in the rabbit knee. Animals and methods: In New Zealand rabbits aged 22 weeks, a 4-mm pure chondral defect (ICRS grade 3b) was created in the patella of one knee and in the medial femoral condyle of the other. A stereo microscope was used to optimize the preparation of the defects. The animals were killed 12, 24, and 36 weeks after surgery. Defect filling and the density of subchondral mineralized tissue was estimated using Analysis Pro software on micrographed histological sections. Results: The mean filling of the patellar defects was more than twice that of the medial femoral condylar defects at 24 and 36 weeks of follow-up. There was a statistically significant increase in filling from 24 to 36 weeks after surgery at both locations. The density of subchondral mineralized tissue beneath the defects subsided with time in the patellas, in contrast to the density in the medial femoral condyles, which remained unchanged. Interpretation: The intraarticular location is a predictive factor for spontaneous filling and subchondral bone changes of chondral defects corresponding to ICRS grade 3b. Disregarding location, the spontaneous filling increased with long-term follow-up. This should be considered when evaluating aspects of cartilage restoration

Mitochondrially targeted ceramide LCL-30 inhibits colorectal cancer in mice

The sphingolipid ceramide is intimately involved in the growth, differentiation, senescence, and death of normal and cancerous cells. Mitochondria are increasingly appreciated to play a key role in ceramide-induced cell death. Recent work showed the C16-pyridinium ceramide analogue LCL-30 to induce cell death in vitro by mitochondrial targeting. The aim of the current study was to translate these results to an in vivo model. We found that LCL-30 accumulated in mitochondria in the murine colorectal cancer cell line CT-26 and reduced cellular ATP content, leading to dose- and time-dependent cytotoxicity. Although the mitochondrial levels of sphingosine-1-phosphate (S1P) became elevated, transcription levels of ceramide-metabolising enzymes were not affected. In mice, LCL-30 was rapidly absorbed from the peritoneal cavity and cleared from the circulation within 24 h, but local peritoneal toxicity was dose-limiting. In a model of subcutaneous tumour inoculation, LCL-30 significantly reduced the proliferative activity and the growth rate of established tumours. Sphingolipid profiles in tumour tissue also showed increased levels of S1P. In summary, we present the first in vivo application of a long-chain pyridinium ceramide for the treatment of experimental metastatic colorectal cancer, together with its pharmacokinetic parameters. LCL-30 was an efficacious and safe agent. Future studies should identify an improved application route and effective partners for combination treatment

Oestrogen is important for maintenance of cartilage and subchondral bone in a murine model of knee osteoarthritis

Introduction: Oestrogen depletion may influence onset and/or progression of osteoarthritis. We investigated in an ovariectomized mouse model the impact of oestrogen loss and oestrogen supplementation on articular cartilage and subchondral bone in tibia and patella, and assessed bone changes in osteoarthritis development.Methods: C3H/HeJ mice were divided into four groups: sham-operated, oestrogen depletion by ovariectomy (OVX), OVX with estradiol supplementation (OVX+E) and OVX with bisphosphonate (OVX+BP). Each mouse had one knee injected with low-dose iodoacetate (IA), and the contralateral knee was injected with saline. Cartilage was analysed histologically 12 weeks postsurgery; bone changes were monitored over time using in vivo micro-computed tomography.Results: In tibiae, OVX alone failed to induce cartilage damage, but OVX and IA combination significantly induced cartilage damage. In patellae, OVX alone induced significant cartilage damage, whic

Basic Science Considerations in Primary Total Hip Replacement Arthroplasty

Total Hip Replacement is one of the most common operations performed in the developed world today. An increasingly ageing population means that the numbers of people undergoing this operation is set to rise. There are a numerous number of prosthesis on the market and it is often difficult to choose between them. It is therefore necessary to have a good understanding of the basic scientific principles in Total Hip Replacement and the evidence base underpinning them. This paper reviews the relevant anatomical and biomechanical principles in THA. It goes on to elaborate on the structural properties of materials used in modern implants and looks at the evidence base for different types of fixation including cemented and uncemented components. Modern bearing surfaces are discussed in addition to the scientific basis of various surface engineering modifications in THA prostheses. The basic science considerations in component alignment and abductor tension are also discussed. A brief discussion on modular and custom designs of THR is also included. This article reviews basic science concepts and the rationale underpinning the use of the femoral and acetabular component in total hip replacement

Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease

Background: Experimental and clinical data suggest that reducing inflammation without affecting lipid levels may reduce the risk of cardiovascular disease. Yet, the inflammatory hypothesis of atherothrombosis has remained unproved. Methods: We conducted a randomized, double-blind trial of canakinumab, a therapeutic monoclonal antibody targeting interleukin-1β, involving 10,061 patients with previous myocardial infarction and a high-sensitivity C-reactive protein level of 2 mg or more per liter. The trial compared three doses of canakinumab (50 mg, 150 mg, and 300 mg, administered subcutaneously every 3 months) with placebo. The primary efficacy end point was nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. RESULTS: At 48 months, the median reduction from baseline in the high-sensitivity C-reactive protein level was 26 percentage points greater in the group that received the 50-mg dose of canakinumab, 37 percentage points greater in the 150-mg group, and 41 percentage points greater in the 300-mg group than in the placebo group. Canakinumab did not reduce lipid levels from baseline. At a median follow-up of 3.7 years, the incidence rate for the primary end point was 4.50 events per 100 person-years in the placebo group, 4.11 events per 100 person-years in the 50-mg group, 3.86 events per 100 person-years in the 150-mg group, and 3.90 events per 100 person-years in the 300-mg group. The hazard ratios as compared with placebo were as follows: in the 50-mg group, 0.93 (95% confidence interval [CI], 0.80 to 1.07; P = 0.30); in the 150-mg group, 0.85 (95% CI, 0.74 to 0.98; P = 0.021); and in the 300-mg group, 0.86 (95% CI, 0.75 to 0.99; P = 0.031). The 150-mg dose, but not the other doses, met the prespecified multiplicity-adjusted threshold for statistical significance for the primary end point and the secondary end point that additionally included hospitalization for unstable angina that led to urgent revascularization (hazard ratio vs. placebo, 0.83; 95% CI, 0.73 to 0.95; P = 0.005). Canakinumab was associated with a higher incidence of fatal infection than was placebo. There was no significant difference in all-cause mortality (hazard ratio for all canakinumab doses vs. placebo, 0.94; 95% CI, 0.83 to 1.06; P = 0.31). Conclusions: Antiinflammatory therapy targeting the interleukin-1β innate immunity pathway with canakinumab at a dose of 150 mg every 3 months led to a significantly lower rate of recurrent cardiovascular events than placebo, independent of lipid-level lowering. (Funded by Novartis; CANTOS ClinicalTrials.gov number, NCT01327846.

Effects of alirocumab on types of myocardial infarction: insights from the ODYSSEY OUTCOMES trial

Aims  The third Universal Definition of Myocardial Infarction (MI) Task Force classified MIs into five types: Type 1, spontaneous; Type 2, related to oxygen supply/demand imbalance; Type 3, fatal without ascertainment of cardiac biomarkers; Type 4, related to percutaneous coronary intervention; and Type 5, related to coronary artery bypass surgery. Low-density lipoprotein cholesterol (LDL-C) reduction with statins and proprotein convertase subtilisin–kexin Type 9 (PCSK9) inhibitors reduces risk of MI, but less is known about effects on types of MI. ODYSSEY OUTCOMES compared the PCSK9 inhibitor alirocumab with placebo in 18 924 patients with recent acute coronary syndrome (ACS) and elevated LDL-C (≥1.8 mmol/L) despite intensive statin therapy. In a pre-specified analysis, we assessed the effects of alirocumab on types of MI. Methods and results  Median follow-up was 2.8 years. Myocardial infarction types were prospectively adjudicated and classified. Of 1860 total MIs, 1223 (65.8%) were adjudicated as Type 1, 386 (20.8%) as Type 2, and 244 (13.1%) as Type 4. Few events were Type 3 (n = 2) or Type 5 (n = 5). Alirocumab reduced first MIs [hazard ratio (HR) 0.85, 95% confidence interval (CI) 0.77–0.95; P = 0.003], with reductions in both Type 1 (HR 0.87, 95% CI 0.77–0.99; P = 0.032) and Type 2 (0.77, 0.61–0.97; P = 0.025), but not Type 4 MI. Conclusion  After ACS, alirocumab added to intensive statin therapy favourably impacted on Type 1 and 2 MIs. The data indicate for the first time that a lipid-lowering therapy can attenuate the risk of Type 2 MI. Low-density lipoprotein cholesterol reduction below levels achievable with statins is an effective preventive strategy for both MI types.For complete list of authors see http://dx.doi.org/10.1093/eurheartj/ehz299</p

Expression and pharmacological inhibition of TrkB and EGFR in glioblastoma

A member of the Trk family of neurotrophin receptors, tropomyosin receptor kinase B (TrkB, encoded by the NTRK2 gene) is an increasingly important target in various cancer types, including glioblastoma (GBM). EGFR is among the most frequently altered oncogenes in GBM, and EGFR inhibition has been tested as an experimental therapy. Functional interactions between EGFR and TrkB have been demonstrated. In the present study, we investigated the role of TrkB and EGFR, and their interactions, in GBM. Analyses of NTRK2 and EGFR gene expression from The Cancer Genome Atlas (TCGA) datasets showed an increase in NTRK2 expression in the proneural subtype of GBM, and a strong correlation between NTRK2 and EGFR expression in glioma CpG island methylator phenotype (G-CIMP+) samples. We showed that when TrkB and EGFR inhibitors were combined, the inhibitory effect on A172 human GBM cells was more pronounced than when either inhibitor was given alone. When U87MG GBM cells were xenografted into the flank of nude mice, tumor growth was delayed by treatment with TrkB and EGFR inhibitors, given alone or combined, only at specific time points. Intracranial GBM growth in mice was not significantly affected by drug treatments. Our findings indicate that correlations between NTRK2 and EGFR expression occur in specific GBM subgroups. Also, our results using cultured cells suggest for the first time the potential of combining TrkB and EGFR inhibition for the treatment of GBM