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Revisions of total elbow arthroplasties (TEAs) are commonly performed because of prosthetic loosening. UK National Joint Registry data show that TEA revisions are becoming increasingly common, with 123 TEA revisions performed in 2018 and 76 performed in 2017. TEA radiologic assessment is based on subjective interpretation with no published criteria. We defined TEA loosening by the presence of at least one of the following criteria (1) progressive widening of the bone-cement, bone-prosthesis, or cement-prosthesis interface; (2) fragmentation or fracture of cement; (3) prosthetic component migration; and (4) bead shedding in porous-coated prostheses. Using this definition, we looked at interobserver and intraobserver agreement on radiologic loosening and compared this assessment with intraoperative findings.<br /><br /> In our tertiary care center, we conducted a retrospective review to identify TEA revisions performed between November 2008 and July 2018. Radiologic implant loosening was independently assessed by 5 ort perform a dual-implant exchange.<br /><br />Our definition of loosening provides reproducible interobserver and intraobserver agreement on radiographic component loosening. In our center's experience, radiologic findings may not translate to intraoperative findings, and we would advise that surgical strategies for TEA revision include the possibility of needing to perform a dual-implant exchange.A major goal of human neuroscience is to relate differences in brain function to differences in behavior across people. Recent work has established that whole-brain functional connectivity patterns are relatively stable within individuals and unique across individuals, and that features of these patterns predict various traits. However, while functional connectivity is most often measured at rest, certain tasks may enhance individual signals and improve sensitivity to behavior differences. Here, we show that compared to the resting state, functional connectivity measured during naturalistic viewing-i.e., movie watching-yields more accurate predictions of trait-like phenotypes in the domains of both cognition and emotion. Traits could be predicted using less than three minutes of data from single video clips, and clips with highly social content gave the most accurate predictions. Results suggest that naturalistic stimuli amplify individual differences in behaviorally relevant brain networks.Requirements for safety pharmacology testing have been in place since the issue of initial regulatory guidance over 20 years ago. An evaluation of such testing, supporting first clinical entry of 105 small molecule drug candidates over the last decade, showed that a "core battery" of in vitro electrophysiological (hERG), conscious non-rodent telemetry cardiovascular, rodent central nervous system (CNS) (modified Irwin's or functional observational battery [FOB] test) and respiratory function (plethysmography) studies was performed. Routine use of the latter 2 studies appears to have limited utility, with only 21% and 28% of studies, respectively, giving findings of which none were identified as of obvious concern to moving the affected drugs into the clinic. The use of a stand-alone hERG assay does not appear to be particular sensitive in predicting proarrythmic risk as a tool by itself. Telemetry study testing had utility especially for identifying effects on QTc interval (about 10% of studies), resulting on some occasions in a lower clinical starting dose and/or increased awareness for potential effects on the cardiovascular system in the Phase I study. Overall, this investigation provides information supporting an overhaul of the current "box ticking" core battery approach used for safety pharmacology testing. However, in order to achieve a more focused examination to investigate potential undesirable pharmacodynamic effects of a new candidate drug and also support 3Rs (Replacement, Reduction and Refinement) thinking in performing unnecessary studies, there will not only need to be a sea change by drug developers but also a change in current regulatory guidance.The perturbation of intestinal microbes may serve as a mechanism by which arsenic exposure causes or exacerbates diseases in humans. However, the changes in the intestinal microbiome and metabolome induced by long-term exposure to high concentrations of arsenic have not been extensively studied. In this study, C57BL/6 mice were exposed to sodium arsenite (As) (50 ppm) for 6 months. Our results show that long-term exposure to high As concentrations changed the structure of intestinal tissues and the expression of As resistance related genes in intestinal microbes. In addition, 16S rRNA gene sequencing revealed that As exposure significantly affected the Beta diversity of intestinal flora but had no significant effect on the Alpha diversity (except ACE index). Moreover, As exposure altered the composition of the intestinal microbiota from phylum to species. Non-targeted metabolomics profiling revealed that As exposure significantly changed the composition of metabolites, specifically those related to phenylalanine metabolism. Correlation analysis demonstrated that the changes in microbial communities and metabolites were highly correlated under As exposure. Overall, this study demonstrates that long-term exposure to high As concentrations disrupted the intestinal microbiome and metabolome, which may indicate the role of As exposure at inducing human diseases under similar conditions.Cadmium (Cd) is a nephrotoxicant that primarily damages renal proximal tubular cells. Endoplasmic reticulum (ER) stress is mechanistically linked to Cd-induced renal injury. Inositol-requiring enzyme 1 (IRE-1α) is the most conserved ER stress transducer protein, which has both kinase and endonuclease activities. This study aimed to investigate whether the two enzymatic activities of IRE-1α have different effects in its regulation of Cd-induced apoptosis. Human proximal tubular (HK-2) cells were treated with 20 μM CdCl2 for 0-24 h, and mice were fed with Cd-containing drinking water (100-400 mg/L) for 24 weeks. We found that Cd increased cell apoptosis in HK-2 cells and mouse kidneys in a time-dependent manner. [https://www.selleckchem.com/products/pirfenidone.html Pirfenidone datasheet] Such cytotoxicity was correlated with activation of ER stress, evidenced by upregulation of IRE-1α and its target protein spliced X-box binding protein-1 (XBP-1 s). Interestingly, inhibition of IRE-1α kinase activity by KIRA6 was more protective against Cd-induced apoptosis than inhibition of its RNase activity by STF-083010. Mechanistically, Cd promoted the binding of IRE-1α with signal transducer and activator of transcription-3 (STAT3) leading to elevated phosphorylation of STAT3 at Ser727 and thus inactivation of STAT3 signaling, which resulted in aggravation of Cd-induced apoptosis in HK-2 cells. Collectively, our findings indicate that IRE-1α coordinate ER stress and STAT3 signaling in mediating Cd-induced renal toxicity, suggesting that targeting IRE-1α might be a potential therapeutic approach for Cd-induced renal dysfunction and disease.Human fatty acid synthase (FASN) is the sole cytosolic enzyme responsible for de novo lipid synthesis. FASN is essential for cancer cell survival and contributes to drug and radiation resistance by up-regulating DNA damage repair but not required for most non-lipogenic tissues. Thus, FASN is an attractive target for drug discovery. However, despite decades of effort in targeting FASN, no FASN inhibitors have been approved due to poor pharmacokinetics or toxicities. Here, we show that the FDA-approved proton pump inhibitors (PPIs) effectively inhibit FASN and suppress breast cancer cell survival. PPI inhibition of FASN leads to suppression of non-homologous end joining repair of DNA damages by reducing FASN-mediated PARP1 expression, resulting in apoptosis from oxidative DNA damages and sensitization of cellular resistance to doxorubicin and ionizing radiation. Mining electronic medical records of 6754 breast cancer patients showed that PPI usage significantly increased overall survival and reduced disease recurrence of these patients. Hence, PPIs may be repurposed as anticancer drugs for breast cancer treatments by targeting FASN to overcome drug and radiation resistance.Five new compounds (xuejieins A-E), including three new phenolic glycosides (1, 2, and 5) and two new flavonoids (10 and 11), together with six known compounds were isolated from the resins of Dracaena cochinchinensis (Chinese dragon's blood). The structures of the new compounds were confirmed by extensive spectroscopic methods and electronic circular dichroism (ECD) data analysis. Especially, the absolute configurations of the sugar moieties in compounds 1, 2, and 5 were clarified by GC analysis after acid hydrolysis. All isolated compounds have been tested for antifungal and wound healing promoting activities, The results showed that compound 9 shows significant antifungal activities against Botrytis cinerea, Magnaporthe grisea, Penicillium digitatum, and Sclerotinia sclerotiorum. link2 In addition, compound 4 could significantly stimulate human keratinocytes (HaCAT) proliferation, mobility, and human umbilical vein vascular endothelial cells (HUVECs) tube formation at 40 μM.New flavonoid glycoside, kaempferol 3-O-α-[(6-P-coumaroyl galactopyranosyl-O-β-(→4)-O-α-rhamnopyranosyl-(1→4)]-O-α-rhamnopyranoside 1, in addition to five known flavonoid glycosides (2-6) kaempferol 3-O-[α-rhamnopyranosyl-(1→4)-O-α-rhamnopyranosyl-(1→6)-O]-β-galactopyranoside (kaempferol 3-O-β-isorhamninoside) 2, quercetin 3-O-[(2,3,4-triacetyl-α-rhamnopyranosyl)-(1 → 6)-β-galactopyranoside 3, quercetin 3-O-[(2,4-diacetyl-α-rhamnopyranosyl)-(1 → 6)]-3,4-diacetyl-β-galactopyranoside 4, quercetin 3-O-[(2,4-diacetyl-α-rhamnopyranosyl)-(1→6)]-2,4-diacetyl-β-galactopyranoside 5, quercetin 3-O-[(2,3,4-triacetyl-α-rhamnopyranosyl)-(1 → 6)-3-acetyl-β-galactopyranoside 6 were isolated from bell pepper (Capsicum annum L.) fruits and tested for both anti-inflammatory activity through cytokine production (TNF-α and IL-1β) and antioxidant activity through scavenging effect on 1,1-diphenyl-2-picrylhydrazyl (DPPH) assay. Compounds 1-3 significantly suppressed production of TNF-α / IL-1β in cultured THP-1 cells previously co-stimulated by LPS in a dose-dependent manner (10.2/49.1, 28.1/55.7, and 35.2/57.5 μM respectively) whereas compounds 4-6 have relatively weaker inhibitory activity. (45.3/73.5, 48.2/65.6, and 42.2/67.4 μM respectively). link3 All compounds 1-6 showed no cytotoxic activity against the growth of THP-1where the percentage of cell viability was (127.4, 108.5, 105.4, 103.9, 103.4, and 104.2 μM respectively). All isolated compounds exhibited higher radical scavenging activity than ascorbic acid in (DPPH) assay. These results indicated that bell pepper fruits could be an effective candidate for ameliorating inflammatory-associated complications.Chronic obstructive pulmonary disease (COPD) is estimated to be the sixth major cause of disability, and the third main cause of death in the world by 2020. Although both inflammation and oxidative stress are well known to be the key predisposing factors in the pathogenesis of COPD, other elements, including metabolism, may also contribute to the exacerbation of the disease. However, the therapeutic approach which alters metabolism against COPD has yet been fully developed. Therefore, here we provide a novel therapeutic strategy for COPD patients. We first screened out the known nuclear factor erythroid-2-related factor 2 (Nrf2) activators, CPUY192018, which inhibits glycolysis, boosts antioxidative stress simultaneously and delivers satisfying therapeutic effect in macrophages from COPD patients and cigarette smoke extract induced COPD mice. Furthermore, we clarify that CPUY192018 not only disrupts the interaction between Kelch-like ECH-associated protein 1 (Keap1) and Nrf2, which liberates Nrf2 to activate the antioxidative pathway but also disrupt the interaction between Keap1 and actin which downregulates glycolysis, boosting the phagocytic function of alveolar macrophage in lung tissue.