Paraoxonase 1 Ameliorates Renal Lipotoxicity by Activating Lipophagy and Inhibiting Pyroptosis.

Several studies in recent years have shown that lipid overload causes lipotoxic damage to the kidney, and oxidative stress, inflammation, and autophagic arrest are all important mechanisms of renal lipotoxicity. However, effective measures with therapeutic effects on renal lipotoxicity are limited. The present study indicated the protective effect of the paraoxonase 1 (PON1) against renal lipotoxicity in high-fat diet-fed scavenger receptor class B type I-deficient (SR-BI-/-) mice. The results showed that SR-BI-/- mice exhibited significant renal pathologic characteristics, such as oxidative stress, inflammation, and fibrosis, under a normal chow diet, and were accompanied by dyslipidemia and reduced plasma PON1 activity and renal PON1 levels. PON1 overexpression significantly attenuated the above pathologic changes in the kidneys of SR-BI-/- mice fed with a high-fat diet. Mechanistically, PON1 may ameliorate renal oxidative stress by reducing reactive oxygen species production, reduce renal lipid accumulation by inhibiting AKT/mechanistic target of rapamycin kinase pathway to activate lipophagy, and reduce the occurrence of inflammation and cell death by inhibiting Nod-like receptor family protein 3 inflammasome-mediated pyroptosis. The present study is the first to show that PON1 overexpression can effectively alleviate renal lipotoxicity injury, and PON1 may be a promising therapeutic strategy for the treatment of renal lipotoxicity-related diseases.

Palliative care stakeholders in Canada.

BACKGROUND: Improving access to palliative care for Canadians requires a focused collective effort towards palliative and end-of-life care advocacy and policy. However, evolution of modern palliative care in Canada has resulted in stakeholders working in isolation. Identification of stakeholders is an important step to ensure that efforts to improve palliative care are coordinated. The purpose of this analysis is to collectively identify, classify and prioritize stakeholders who made contributions to national palliative care policies in Canada. METHODS: A systematic grey literature search was conducted examining policy documents (i.e. policy reports, legislative bills, judicial court cases) in the field of palliative care, end-of-life care and medical assistance in dying, at the national level, over the last two decades. Organizations' names were extracted directly or derived from individuals' affiliations. We then classified stakeholders using an adapted classification approach and developed an algorithm to prioritize their contributions towards the publication of these documents. RESULTS: Over 800 organizations contributed to 115 documents (41 policy reports, 11 legislative, 63 judicial). Discussions regarding national palliative care policy over the last two decades peaked in 2016. Stakeholder organizations contributing to national palliative care policy conversations throughout this period were classified into six types broadly representative of society. The ranking algorithm identified the top 200 prioritized stakeholder organizations. CONCLUSIONS: Stakeholders from various societal sectors have contributed to national palliative care conversions over the past two decades; however, not all the stakeholder organizations engaged to the same extent. The information is useful when a need arises for increased collaboration between stakeholders and can be a starting point for developing more effective engagement strategies.

Regulators of calcineurin 1 deficiency attenuates tubulointerstitial fibrosis through improving mitochondrial fitness.

Renal fibrosis is the common pathological process of various chronic kidney diseases (CKD). Recent studies indicate that mitochondrial fragmentation is closely associated with renal fibrosis in CKD. However, the molecular mechanisms leading to mitochondrial fragmentation remain to be elucidated. The present study investigated the role of regulators of calcineurin 1 (RCAN1) in mitochondrial fission and renal interstitial fibrosis using conditional knockout mice in which RCAN1 was genetically deleted in tubular epithelial cells (TECs). TEC-specific deletion of RCAN1 attenuated tubulointerstitial fibrosis and epithelial to mesenchymal transition (EMT)-like phenotype change after unilateral ureteral obstruction (UUO) and ischemia reperfusion injury (IRI) through suppressing TGF-ß1/Smad3 signaling pathway. TEC-specific deletion of RCAN1 also reduced the tubular apoptosis after UUO by inhibiting cytochrome c/caspase-9 pathway. Ultrastructure analysis revealed a marked decrease in mitochondrial fragmentation in TECs of RCAN1-deficient mice in experimental CKD models. The expression of mitochondrial profission proteins dynamin-related protein 1 (Drp1) and mitochondrial fission factor (Mff) was also downregulated in obstructed kidney of TEC-specific RCAN1-deficient mice. Furthermore, TEC-specific deletion of RCAN1 attenuated the dysfunctional tubular autophagy by regulating PINK1/Parkin-induced mitophagy in CKD. RCAN1 knockdown and knockout similarly improved the mitochondrial quality control in HK-2 cells and primary cultured mouse tubular cells stimulated by TGF-ß1. Put together, our data indicated that RCAN1 plays an important role in the progression of tubulointerstitial fibrosis through regulating the mitochondrial quality. Therefore, targeting RCAN1 may provide a potential therapeutic approach in CKD.

Relationship between Sarcopenia and mTOR Pathway in Patients with Colorectal Cancer: Preliminary Report.

Sarcopenia is a syndrome characterized by loss of muscle mass and strength that impacts clinical outcomes and mortality in cancer patients. Although the molecular pathways involved in sarcopenia are not fully elucidated, the decrease in protein synthesis rate appears to be one of the most important events. The objective of this study was to investigate the relationship between sarcopenia and mTOR signaling pathway in patients undergoing colorectal resection surgery. Three groups of patients were assessed: 1) the control group (no cancer, no sarcopenia), 2) the cancer non-sarcopenic group and 3) the cancer sarcopenic group. All individuals were evaluated in relation to presence of sarcopenia and mTOR signaling pathway. Sarcopenia was evaluated by the combination of low muscle mass and low muscle strength, measured using computerized tomography images, and hand grip strength, respectively. Rectus abdominis muscle biopsy was performed at the time of surgery. mTOR pathway was analyzed by MILLIPLEX Map Kit Phospho/total mTOR 2-Plex Magnetic Bead Panel. Results were presented by phosphor/total mTOR ratio. Independent T test, Kruskal-Wallis test, and Dunn-Bonferroni post hoc were performed for statistical analysis and P < 0.05 was considered. Thirty-six patients and five controls were evaluated. A total of 13 cancer patients (36.1%) had sarcopenia. The phospho/total mTOR ratio was different between the control group (0.167 MFI) and the cancer non-sarcopenic group (0.055 MFI) (P = 0.026) as well as between the control group (0.167 MFI) and the cancer sarcopenic group (0.0049 MFI) (P = 0.041). No difference was observed on the median phospho/total mTOR ratio between the cancer groups (P > 0.05). More research is needed to extrapolate these results.

Muscle radiodensity and mortality in patients with colorectal cancer.

BACKGROUND: Low skeletal muscle radiodensity (SMD) is related to higher mortality in several cancers, but the association with colorectal cancer (CRC) prognosis is unclear. METHODS: This observational study included 3262 men and women from the Kaiser Permanente Northern California population diagnosed between 2006 and 2011 with AJCC stages I to III CRC. The authors evaluated hazard ratios (HRs) of low SMD for all-cause and CRC-specific mortality, assessed by computed tomography using optimal stratification, compared with patients with normal SMD. They also evaluated the cross-classification of categories of low versus normal SMD and muscle mass (MM) with outcomes. RESULTS: The median follow-up was 6.9 years. Optimal stratification cutpoints for SMD were 32.5 in women and 35.5 in men. In multivariate-adjusted analyses, among patients with CRC, those with low SMD demonstrated higher overall (HR, 1.61; 95% confidence interval [95% CI], 1.36-1.90) and CRC-specific (HR, 1.74; 95% CI, 1.38-2.21) mortality when compared with those with normal SMD levels. Patients with low SMD and low MM (ie, sarcopenia) were found to have the highest overall (HR, 2.02; 95% CI, 1.65-2.47) and CRC-specific (HR, 2.54; 95% CI, 1.91-3.37) mortality rates. CONCLUSIONS: In patients with CRC, those with low SMD were found to have elevated risks of disease-specific and overall mortality, independent of MM or adiposity. Clinical practice should incorporate body composition measures into the evaluation of the health status of patients with CRC. Cancer 2018;124:3008-15. © 2018 American Cancer Society.

Primary Cultivation and Identification of Vascular Smooth Muscle Cells from the Spiral Modiolar Artery of Guinea Pigs.

BACKGROUND This article reports a method to obtain vascular smooth muscle cells (SMCs) from the spiral modiolar artery (SMA) of guinea pigs and provides materials for related experimental studies. MATERIAL AND METHODS SMA was separated from the cochlea of guinea pigs, digested with trypsin (1.25 g/L) and allowed to adhere in a 35-mm culture dish. The morphology of the sample was investigated, and the sample was identified by immunofluorescence analysis, flow cytometry, Western blot, and RT-PCR. Cell viability was calculated using trypan blue and flow cytometry. Whole-cell patch clamp was used to record the membrane input resistance (Rinput), reciprocal membrane input conductance (Ginput), membrane input capacitance (Cinput), and resting membrane potential (RP) of the SMCs. RESULTS Microscopy results showed that the cells had typical peak-valley growth pattern. The cell growth curve was similar to an S curve, and flow cytometry results showed that the cell apoptosis rate was less than 10%. Moreover, flow cytometry, immunofluorescent staining, Western blot and RT-PCR detected the specific and intensely positive expression of cell type-specific markers α-SM-actin, SM22α, calponin and desmin. Furthermore, following properties of the P3 and P6 cells were obtained: Rinput, 2611±356 and 2477±338 MΩ; Ginput, 0.454±0.071 and 0.273±0.037 ns; Cinput, 17.029±0.917 and 18.042±1.051 pF, and RP -20.602±1.503 and -22.192±1.905 mV. CONCLUSIONS Various highly purified SMCs were obtained from the SMA of guinea pigs. We provide an ideal experimental material for the study of the pathogenesis of diseases related to the circulation disturbances in the inner ear in vitro. The results can be used to evaluate the effects of drugs on vascular smooth muscle.

Muscle mass at the time of diagnosis of nonmetastatic colon cancer and early discontinuation of chemotherapy, delays, and dose reductions on adjuvant FOLFOX: The C-SCANS study.

BACKGROUND: For many chemotherapy regimens dosed based on body surface area (BSA), patients experience dose reductions or delays or discontinue treatment, thereby reducing survival. Consideration of body composition may be useful in individualizing chemotherapy dosing, but to the authors' knowledge few studies to date have examined the association of body composition with chemotherapy tolerance in patients with colon cancer. METHODS: The authors identified patients with nonmetastatic colon cancer who were diagnosed from 2006 through 2011 at Kaiser Permanente and who received leucovorin calcium/calcium folinate, 5-fluorouracil, and oxaliplatin (FOLFOX) as initial adjuvant chemotherapy (533 patients). Patients' muscle mass was quantified using clinically acquired computed tomography scans. The authors quantified chemotherapy doses, treatment dates, and related toxicities using the electronic medical record. In logistic regression models adjusting for age, sex, and American Joint Committee on Cancer stage of disease, the authors examined associations of muscle tertiles with early treatment discontinuation (<6 cycles), treatment delay (>3 days off schedule for ≥3 times), and/or dose reduction (relative dose intensity ≤ 0.70, based on planned treatment). RESULTS: The average age of the patients at the time of diagnosis was 58.7 years; BSA was 1.9 m2 and body mass index was 28.7 kg/m2 . Compared with the highest sex-specific tertile of muscle mass, patients in the lowest tertile were more likely to experience toxicities and had twice the risk of adverse outcomes while receiving FOLFOX; for early discontinuation, the odds ratio (OR) was 2.34 (95% confidence interval [95% CI], 1.04-5.24; P for trend = .03), whereas the ORs were 2.24 (95% CI, 1.37-3.66; P for trend = .002) for treatment delay and 2.28 (95% CI, 1.19-4.36; P for trend = .01) for dose reduction. CONCLUSIONS: Lower muscle mass is associated with greater toxicity and poor chemotherapy adherence among patients receiving FOLFOX. Many chemotherapy drugs are dosed based on BSA, but treatment may be better individualized if muscle mass is considered. Cancer 2017;123:4868-77. © 2017 American Cancer Society.

Computed tomography-derived skeletal muscle index: A novel predictor of frailty and hospital length of stay after transcatheter aortic valve replacement.

To determine the prevalence of low skeletal muscle mass in patients undergoing transcatheter aortic valve replacement (TAVR) and whether skeletal muscle mass measured from preoperative computed tomography (CT) images provides value in predicting postoperative length of stay (LOS). BACKGROUND: There are limited data on the use of body composition as a frailty measure in TAVR patients and no studies have determined if this measure predicts LOS. METHODS: We studied 104 consecutive patients who underwent TAVR at Tallahassee Memorial Hospital from 2012 to 2016. Patient demographics, standard frailty measures (hand grip, albumin, and 5-m walk test), clinical comorbidities, echocardiographic data, and Valve Academic Research Consortium II major complications were recorded prospectively. Skeletal muscle index (SMI) [skeletal muscle mass cross-sectional area at L3/height2] was measured from CT images using Slice-O-Matic software (Tomovision, Montreal, Quebec, Canada). Clinical outcomes were assessed and multivariate methods used to determine predictors of LOS. RESULTS: Sarcopenia was prevalent in men (83%) and women (56%). Patients who suffered from a major complication had significantly longer length of stay (13 vs 4.6days, P<.0001). Skeletal muscle index correlated with age, sex, body mass index, handgrip strength, and previous coronary artery bypass graft surgery, but not major complications. A multivariate model including all univariate predictors of LOS showed SMI, major complications, transapical access, atrial fibrillation, and chronic obstructive pulmonary syndrome as independent predictors of LOS. For every 14-cm2/m2 increase in SMI, there was a 1-day reduction in LOS. None of the standard measures of frailty predicted LOS. CONCLUSIONS: Skeletal muscle index, a measure of sarcopenia readily determined from pre-TAVR CT scans, independently predicts TAVR LOS better than standard frailty testing. Further evaluation of SMI as a frailty measure after TAVR and other cardiovascular procedures is warranted.

Inhibition of mitochondrial over-division by (+)-14,15-Dehydrovincamine attenuates cisplatin-induced acute kidney injury via the JNK/Mff pathway.

Cisplatin-induced acute kidney injury (AKI) is characterized by mitochondrial damage and apoptosis, and safe and effective therapeutic agents are urgently needed. Renal tubular epithelial cells, the main site of AKI, are enriched with a large number of mitochondria, which are crucial for the progression of AKI with an impaired energy supply. Vincamine has anti-inflammatory and antioxidant effects in mouse AKI models. As a natural compound derived from Tabernaemontana pandacaqui, (+)-14, 15-Dehydrovincamine and Vincamine differ in structure by only one double bond, and the role and exact mechanism of (+)-14, 15-Dehydrovincamine remains to be elucidated in AKI. The present study demonstrated that (+)-14,15-Dehydrovincamine significantly ameliorated mitochondrial dysfunction and maintained mitochondrial homeostasis in a cisplatin-induced AKI model. Furthermore, (+)-14,15-Dehydrovincamine ameliorates cytochrome C-dependent apoptosis in renal tubular epithelial cells. c-Jun NH2-terminal kinase (JNK) was identified as a potential target protein of (+)-14,15-Dehydrovincamine attenuating AKI by network pharmacological analysis. (+)-14,15-Dehydrovincamine inhibited cisplatin-induced JNK activation, mitochondrial fission factor (Mff) phosphorylation, and dynamin-related protein 1 (Drp1) translocation to the mitochondria in renal tubular epithelial cells. Meanwhile, the JNK activator anisomycin restored Mff phosphorylation and Drp1 translocation, counteracting the protective effect of (+)-14,15-Dehydrovincamine on mitochondrial dysfunction in cisplatin-induced TECs injury. In conclusion, (+)-14,15-Dehydrovincamine reduced mitochondrial fission, maintained mitochondrial homeostasis, and attenuated apoptosis by inhibiting the JNK/Mff/Drp1 pathway, which in turn ameliorated cisplatin-induced AKI.

Scavenger Receptor Class B Type I Deficiency Induces Iron Overload and Ferroptosis in Renal Tubular Epithelial Cells via Hypoxia-Inducible Factor-1α/Transferrin Receptor 1 Signaling Pathway.

Aims: Scavenger receptor class B type I (SRBI) promotes cell cholesterol efflux and the clearance of plasma cholesterol. Thus, SRBI deficiency causes abnormal cholesterol metabolism and hyperlipidemia. Studies have suggested that ferroptosis is involved in lipotoxicity; however, whether SRBI deficiency could induce ferroptosis remains to be investigated. Results: We knocked down or knocked out SRBI in renal HK-2 cells and C57BL/6 mice to determine the expression levels of ferroptosis-related regulators. Our results demonstrated that SRBI deficiency upregulates transferrin receptor 1 (TFR1) expression and downregulates ferroportin expression, which induces iron overload and subsequent ferroptosis in renal tubular epithelial cells. TFR1 is known to be regulated by hypoxia-inducible factor-1α (HIF-1α). Next, we investigated whether SRBI deletion affected HIF-1α. SRBI deletion upregulated the mRNA and protein expression of HIF-1α, and promoted its translocation to the nucleus. To determine whether HIF-1α plays a key role in SRBI-deficiency-induced ferroptosis, we used HIF-1α inhibitor and siHIF-1α in HK-2 cells, and found that downregulation of HIF-1α prevented SRBI-silencing-induced TFR1 upregulation and iron overload, and eventually reduced ferroptosis. The underlying mechanism of HIF-1α activation was explored next, and the results showed that SRBI knockout or knockdown may upregulate the expression of HIF-1α, and promote HIF-1α translocation from the cytoplasm into the nucleus via the PKC-ß/NF-κB signaling pathway. Innovation and Conclusion: Our study showed, for the first time, that SRBI deficiency induces iron overload and subsequent ferroptosis via the HIF-1α/TFR1 pathway.

Muscle abnormalities in patients with liver cirrhosis and its effect on muscle function.

OBJECTIVES: The progression of chronic liver disease is associated with metabolic alterations that compromise the patient's body composition and physical function. Muscle wasting often occurs with pathologic fat accumulation in the muscle (myosteatosis). Unfavorable changes in body composition frequently arise in conjunction with a decrease in muscle strength. These conditions are associated with worse prognoses. The aim of this study was to explore the associations between computed tomography (CT)-derived measures of muscle mass and muscle radiodensity (myosteatosis) and its correlation with muscle strength in patients with advanced chronic liver disease. METHODS: This cross-sectional study was conducted between July 2016 and July 2017. CT images at the third lumbar vertebra level (L3) were analyzed, and skeletal muscle index (SMI) and skeletal muscle radiodensity (SMD) were defined. Handgrip strength (HGS) was assessed by dynamometry. Correlations between CT-assessed body composition and HGS were tested. Multivariable linear regression was used to determine the factors associated with HGS. RESULTS: We evaluated 118 patients with cirrhosis, of whom 64.4% were men. Of those evaluated, the mean age was 57.5 ± 8.5 y. Both SMI and SMD showed a positive correlation with muscle strength (r = 0.46 and 0.25, respectively); and age and Model for End-Stage Liver Disease (MELD)score showed the highest negative correlations (r = -0.37 and -0.34, respectively). In multivariable analyses, the presence of comorbidities (≥1), MELD score, and SMI were significantly associated with HGS. CONCLUSIONS: Low muscle mass and clinical characteristics of disease severity may adversely affect muscle strength in patients with liver cirrhosis.

Empagliflozin attenuates the renal tubular ferroptosis in diabetic kidney disease through AMPK/NRF2 pathway.

Renal tubular damage plays a key role in the pathogenesis of diabetic kidney disease (DKD), and one of the main pathological process associated with DKD in diabetic mice is the ferroptosis, a novel form of cell death caused by iron-dependent lipid peroxidation. Several researches suggested that empagliflozin may treat renal injury, but its effects on diabetic-related ferroptosis and underlying mechanisms were not fully elucidated. In this study, the influence of empagliflozin on renal injury was evaluated in vivo and in vitro in a mouse model and in high-glucose (HG) or Erastin-stimulated renal HK-2 cell line, respectively. Ferroptosis-related markers were assessed, including GSH, labile iron levels, and ferroptosis regulators by Western blot, qRT-PCR, immunohistochemistry, and immunofluorescence. The level of malondialdehyde (MDA) and the fluorescence intensity of BODIPY probe indicated the level of lipid peroxidation. It was demonstrated that solute carrier family 7, member 11 (SLC7A11) and glutathione peroxidase 4 (GPX4) were less expressed in renal biopsy samples from patients affected by DKD than in those from non-diabetic renal disease patients (NDRD), proving the ferroptosis of tubular epithelial cells in case of DKD. Furthermore, empagliflozin markedly decreased the ferroptosis impairment in DKD mice, as well as in HG model of HK-2 cells. Our investigations showed the ability of empagliflozin to suppress ferroptosis was partially countered by AMP-activated protein kinase (AMPK) inhibitor, which led to a reduction of the nuclear translocation of the antioxidant transcription factor NFE2-related factor 2 (NRF2) and downregulation of target genes such as GPX4, ferritin heavy chain 1 (FTH1), and SLC7A11, while AMPK agonists were responsible for the enhancement of the protective effects of empagliflozin. Taken together, our findings showed that empagliflozin may prevent the development of ferroptosis by promoting the AMPK-mediated NRF2 activation pathway, providing important insights for possible novel treatment approaches for DKD.

Computed tomography-determined skeletal muscle density predicts 3-year mortality in initial-dialysis patients in China.

BACKGROUND: Skeletal muscle mass and quality assessed by computed tomography (CT) images of the third lumbar vertebra (L3) level have been established as risk factors for poor clinical outcomes in several illnesses, but the relevance for dialysis patients is unclear. A few studies have suggested a correlation between CT-determined skeletal muscle mass and quality at the first lumbar vertebra (L1) level and adverse outcomes. Generally, chest CT does not reach beyond L1. We aimed to determine whether opportunistic CT scan (chest CT)-determined skeletal muscle mass and quality at L1 are associated with mortality in initial-dialysis patients. METHODS: This 3-year multicentric retrospective study included initial-dialysis patients from four centres between 2014 and 2017 in China. Unenhanced CT images of the L1 and L3 levels were obtained to assess skeletal muscle mass [by skeletal muscle index, (SMI), cm2 /m2 ] and quality [by skeletal muscle density (SMD), HU]. Skeletal muscle measures at L1 were compared with those at L3. The sex-specific optimal cutoff values of L1 SMI and L1 SMD were determined in relation to all-cause mortality. The outcomes were all-cause death and cardiac death. Cox regression models were applied to investigate the risk factors for death. RESULTS: A total of 485 patients were enrolled, of whom 257 had both L1 and L3 images. Pearson's correlation coefficient between L1 and L3 SMI was 0.84 (P < 0.001), and that between L1 and L3 SMD was 0.90 (P < 0.001). No significant association between L1 SMI and mortality was observed (P > 0.05). Low L1 SMD (n = 280, 57.73%) was diagnosed based on the optimal cutoff value (<39.56 HU for males and <33.06 HU for females). Multivariate regression analysis revealed that the low L1 SMD group had higher risks of all-cause death (hazard ratio 1.80; 95% confidence interval 1.05-3.11, P = 0.034) and cardiac death (hazard ratio 3.74; 95% confidence interval 1.43-9.79, P = 0.007). CONCLUSIONS: In initial-dialysis patients, there is high agreement between the L1 and L3 measures for SMI and SMD. Low SMD measured at L1, but not low SMI, is an independent predictor of both all-cause death and cardiac death.

Stakeholder perspectives towards implementing the national framework on palliative care in Canada.

CONTEXT: In 2018 Health Canada developed a national framework and subsequent action plan for palliative care. Collaboration and implementation by stakeholder organizations however continues to take place without coordination. Little is known about their attitudes toward national policy development and motivation to work together. METHODS: We employ a well-known stakeholder analysis framework to identify and understand the attitudes of key stakeholders. Organizations that have contributed to national palliative policy development over the past 25 years were identified and prioritized. In this paper, we survey key stakeholders to understand their attitudes towards collaboration and implementation of the 2018 Framework. A novel method to identify homogeneous stakeholder cohorts was developed. FINDINGS: Fifty-four out of 75 key organizations (72%) completed the survey. Organizations genuinely support the Framework. However, three-quarters of organizations were not confident in their abilities to strongly influence national palliative care policies. Barriers to collaboration include differences in governance models and funding arrangements, a lack of resources and divergent priorities. Homogeneous stakeholder cohorts and in-depth analysis of stakeholder characteristics resulted in recommendations to support targeted engagement strategies. CONCLUSIONS: Implementation of national palliative care policies requires a large-scale coordinated approach involving all stakeholders. Recommendations are centered on the premise that targeted and tailored stakeholder engagement needs to be coordinated and is superior to a one-size fits all approach.

Regulator of calcineurin 1 deletion attenuates mitochondrial dysfunction and apoptosis in acute kidney injury through JNK/Mff signaling pathway.

Ischemia-reperfusion (I/R) induced acute kidney injury (AKI), characterized by excessive mitochondrial damage and cell apoptosis, remains a clinical challenge. Recent studies suggest that regulator of calcineurin 1 (RCAN1) regulates mitochondrial function in different cell types, but the underlying mechanisms require further investigation. Herein, we aim to explore whether RCAN1 involves in mitochondrial dysfunction in AKI and the exact mechanism. In present study, AKI was induced by I/R and cisplatin in RCAN1flox/flox mice and mice with renal tubular epithelial cells (TECs)-specific deletion of RCAN1. The role of RCAN1 in hypoxia-reoxygenation (HR) and cisplatin-induced injury in human renal proximal tubule epithelial cell line HK-2 was also examined by overexpression and knockdown of RCAN1. Mitochondrial function was assessed by transmission electron microscopy, JC-1 staining, MitoSOX staining, ATP production, mitochondrial fission and mitophagy. Apoptosis was detected by TUNEL assay, Annexin V-FITC staining and Western blotting analysis of apoptosis-related proteins. It was found that protein expression of RCAN1 was markedly upregulated in I/R- or cisplatin-induced AKI mouse models, as well as in HR models in HK-2 cells. RCAN1 deficiency significantly reduced kidney damage, mitochondrial dysfunction, and cell apoptosis, whereas RCAN1 overexpression led to the opposite phenotypes. Our in-depth mechanistic exploration demonstrated that RCAN1 increases the phosphorylation of mitochondrial fission factor (Mff) by binding to downstream c-Jun N-terminal kinase (JNK), then promotes dynamin related protein 1 (Drp1) migration to mitochondria, ultimately leads to excessive mitochondrial fission of renal TECs. In conclusion, our study suggests that RCAN1 could induce mitochondrial dysfunction and apoptosis by activating the downstream JNK/Mff signaling pathway. RCAN1 may be a potential therapeutic target for conferring protection against I/R- or cisplatin-AKI.

Ultrasound-assessed diaphragm dysfunction predicts clinical outcomes in hemodialysis patients.

Skeletal muscle atrophy is prevalent and remarkably increases the risk of cardiovascular (CV) events and mortality in hemodialysis (HD) patients. However, whether diaphragm dysfunction predicts clinical outcomes in HD patients is unknown. This was a prospective cohort study of 103 HD patients. After assessment of diaphragm function by ultrasonography and collection of other baseline data, a 36-month follow-up was then initiated. Participants were divided into diaphragm dysfunction (DD+) group and normal diaphragm function (DD-) group, according to cutoff value of thickening ratio (i.e. the change ratio of diaphragm thickness) at force respiration. The primary endpoint was the first nonfatal CV event or all-cause mortality. A secondary endpoint was less serious CV events (LSCEs, a composite of heart failure readmission, cardiac arrhythmia or myocardial ischemia needed pharmacological intervention in hospital). 98 patients were eligible to analysis and 57 (58.16%) were men. 28 of 44 patients(63.64%) in DD+ group and 23 of 54 patients (42.59%) in DD- group had at least one nonfatal CV event or death (p = 0.038). Compared to DD- group, DD+ group had significantly higher incidence of LSCEs (21 vs.14, p = 0.025) and shorter survival time (22.02 ± 12.98 months vs. 26.74 ± 12.59 months, p = 0.046). Kaplan-Meier analysis revealed significantly higher risks of primary endpoint (p = 0.039), and LSCEs (p = 0.040) in DD+ group. Multivariate hazard analysis showed that DD+ group had significantly higher risk of primary endpoint [hazard ratio (HR) 1.59; 95% confident interval (CI) 1.54-1.63], and LSCEs (HR 1.47; 95%CI 1.40-1.55). Ultrasound-assessed diaphragm dysfunction predicts clinical outcomes in HD patients.Trial registration: This study was registered with Chinese Clinical Trials Registry ( www.chictr.org.cn ) as ChiCTR1800016500 on Jun 05, 2018.

Definitions of Palliative Care Terms: A Consensus-Oriented Decision-Making Process.

Background: Lack of consistency in palliative care language can serve as barriers when designing, delivering, and accessing high-quality palliative care services. Objective: To develop a consensus-driven and evidence-based palliative care glossary for the Health Standards Organization Palliative Care Services National Standard of Canada (CAN/HSO 13001:2020). Design: Content analysis of the Palliative Care Services standard was used to refine a list of terms. Environmental scan and rapid review were used for identification of concepts and definitions. Two meetings of consultation based on the modified Delphi approach took place among a working committee consisting of 12 health care providers, administrators, academics, and patient/family representatives. Results: Palliative approach to care, quality of life, pain and symptom management, caregivers, palliative care, life-limiting illness, and serious illness were defined by modification/adoption of existing definitions. Conclusion: A glossary of key palliative care terms was developed and included in the HSO Palliative Care Services standard, which will facilitate communication using consistent language across care settings.

Advance care planning dashboard: quality indicators and usability testing.

OBJECTIVE: Advance care planning (ACP) and goals of care designation (GCD) performance indicators were developed and implemented across Alberta, Canada, and have been used to populate an electronic ACP/GCD dashboard. The study objective was to investigate whether users found the indicators and dashboard usable and acceptable. METHODS: This study employed a survey among a convenience sample of ACP/GCD community of practice members. The survey included questions on demographics, clinical practices and a validated usability questionnaire for the dashboard, System Usability Scale (SUS). RESULTS: Eighteen of 33 community of practice members (54.5%) answered the survey. Half of participants had a leadership or management role for ≥10 years. Most respondents (55.6%) had access to the ACP/GCD dashboard, and various ACP/GCD audit resources were used. Mean SUS was 70.83 (SD 19.72), which was above the threshold for acceptability (68). Approximately three-quarters of respondents (72.7%) found the indicators informative and meaningful for their practice, and over half (54.5%) were willing to use the dashboard and/or indicators to change their ACP/GCD practice. CONCLUSION: The nine indicators and dashboard were acceptable and usable for monitoring ACP/GCD performance. This set of indicators shows promise for describing and evaluating ACP/GCD uptake throughout a complex, multisector healthcare system.

Weight stability masks changes in body composition in colorectal cancer: a retrospective cohort study.

BACKGROUND: There is an emerging viewpoint that change in body weight is not sufficiently sensitive to promptly identify clinically meaningful change in body composition, such as skeletal muscle depletion. OBJECTIVES: We aimed to determine whether body weight stability is associated with skeletal muscle depletion and whether skeletal muscle depletion is prognostic of death independently of change in body weight. METHODS: This retrospective cohort included 1921 patients with stage I-III colorectal cancer. Computed tomography (CT)-based skeletal muscle characteristics and body weight were measured at diagnosis and after a mean 15.0-mo follow-up. Body weight stability was defined as weight change less than ±5% during follow-up. Sarcopenia and myosteatosis were defined using established thresholds for patients with cancer. Multivariable-adjusted logistic and flexible parametric proportional hazards survival models were used to quantify statistical associations. RESULTS: At follow-up, 1026 (53.3%) patients were weight stable. Among patients with weight stability, incident sarcopenia and myosteatosis occurred in 8.5% (95% CI: 6.3%, 10.6%) and 13.5% (95% CI: 11.1%, 15.9%), respectively. Men were more likely to be weight stable than were women (56.7% compared with 49.9%; P = 0.04). Weight-stable men were less likely to develop incident sarcopenia (5.4% compared with 15.4%; P = 0.003) and myosteatosis (9.3% compared with 20.8%; P = 0.001) than weight-stable women. Among all patients, the development of incident sarcopenia (HR: 1.40; 95% CI: 1.02, 1.91) and of myosteatosis (HR: 1.41; 95% CI: 1.05, 1.90) were associated with a higher risk of death, independently of change in body weight. Patient sex did not modify the relation between skeletal muscle depletion and death. CONCLUSIONS: Body weight stability masks clinically meaningful skeletal muscle depletion. Body composition quantified using clinically acquired CT images may provide a vital sign to identify patients at increased risk of death. These data may inform the design of future cachexia trials.

Myokines in treatment-naïve patients with cancer-associated cachexia.

Cancer-associated cachexia is a complex metabolic syndrome characterized by weight loss and systemic inflammation. Muscle loss and fatty infiltration into muscle are associated with poor prognosis in cancer patients. Skeletal muscle secretes myokines, factors with autocrine, paracrine and/or endocrine action, which may be modified by or play a role in cachexia. This study examined myokine content in the plasma, skeletal muscle and tumor homogenates from treatment-naïve patients with gastric or colorectal stages I-IV cancer with cachexia (CC, N = 62), or not (weight stable cancer, WSC, N = 32). Myostatin, interleukin (IL) 15, follistatin-like protein 1 (FSTL-1), fatty acid binding protein 3 (FABP3), irisin and brain-derived neurotrophic factor (BDNF) protein content in samples was measured with Multiplex technology; body composition and muscle lipid infiltration were evaluated in computed tomography, and quantification of triacylglycerol (TAG) in the skeletal muscle. Cachectic patients presented lower muscle FSTL-1 expression (p = 0.047), higher FABP3 plasma content (p = 0.0301) and higher tumor tissue expression of FABP3 (p = 0.0182), IL-15 (p = 0.007) and irisin (p = 0.0110), compared to WSC. Neither muscle TAG content, nor muscle attenuation were different between weight stable and cachectic patients. Lumbar adipose tissue (AT) index, visceral AT index and subcutaneous AT index were lower in CC (p = 0.0149, p = 0.0455 and p = 0.0087, respectively), who also presented lower muscularity in the cohort (69.2% of patients; p = 0.0301), compared to WSC. The results indicate the myokine profile in skeletal muscle, plasma and tumor is impacted by cachexia. These findings show that myokines eventually affecting muscle wasting may not solely derive from the muscle itself (as the tumor also may contribute to the systemic scenario), and put forward new perspectives on cachexia treatment targeting myokines and associated receptors and pathways.