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BACKGROUND: Polymyxins have re-emerged as a last-resort therapeutic option for infections caused by carbapenem-resistant gram-negative bacteria. Nephrotoxicity induced by polymyxins is a significant limitation of its use in the clinic. Polymyxin B and colistin sulfate are two widely used active formulations of polymyxins. However, there is a lack of studies conducting a comparative assessment of nephrotoxicity between the two formulations. This study aimed to compare the nephrotoxicity of polymyxin B and colistin sulfate in critically ill patients. METHODS: We conducted a retrospective cohort study among critically ill patients who received intravenous polymyxin B or colistin sulfate for over 48 h from January 2017 to January 2024. The primary outcome was the incidence of acute kidney injury (AKI) associated with polymyxins, and the secondary outcome was 30-day all-cause mortality. Additionally, the risk factors of polymyxins-induced AKI and 30-day all-cause mortality were identified by Cox proportional hazard regression analysis. RESULTS: A total of 473 patients were included in this study. The overall incidence of AKI was significantly higher in patients who received polymyxin B compared to those who received colistin sulfate in the unmatched cohort (20.8% vs. 9.0%, p = 0.002) and in the propensity score matching cohort (21.1% vs. 7.0%, p = 0.004), respectively. However, there was no significant difference in 30-day all-cause mortality between the two groups. Polymyxin type, septic shock, and concomitant use of vasopressors were identified as independent risk factors for polymyxin-induced AKI. CONCLUSIONS: The prevalence of AKI was higher among patients who received polymyxin B compared to those treated with colistin sulfate. However, there was no significant difference in 30-day all-cause mortality between the two groups. Further prospective, multicenter studies with larger sample sizes are needed to validate these findings.
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Lesión Renal Aguda , Antibacterianos , Colistina , Enfermedad Crítica , Polimixina B , Humanos , Colistina/efectos adversos , Colistina/administración & dosificación , Polimixina B/efectos adversos , Polimixina B/administración & dosificación , Polimixina B/uso terapéutico , Lesión Renal Aguda/inducido químicamente , Lesión Renal Aguda/epidemiología , Estudios Retrospectivos , Masculino , Femenino , Persona de Mediana Edad , Antibacterianos/efectos adversos , Antibacterianos/administración & dosificación , Anciano , Estudios de Cohortes , Administración Intravenosa , Incidencia , Factores de RiesgoRESUMEN
OBJECTIVES: Polymyxin-induced nephrotoxicity (PIN) is a major safety concern and challenge in clinical practice, which limits the clinical use of polymyxins. This study aims to investigate the risk factors and to develop a scoring tool for the early prediction of PIN. METHODS: Data on critically ill patients who received intravenous polymyxin B or colistin sulfate for over 24 h were collected. Logistic regression with the least absolute shrinkage and selection operator (LASSO) was used to identify variables that are associated with outcomes. The eXtreme Gradient Boosting (XGB) classifier algorithm was used to further visualize factors with significant differences. A prediction model for PIN was developed through binary logistic regression analysis and the model was assessed by temporal validation and external validation. Finally, a risk-scoring system was developed based on the prediction model. RESULTS: Of 508 patients, 161 (31.6%) patients developed PIN. Polymyxin type, loading dose, septic shock, concomitant vasopressors and baseline blood urea nitrogen (BUN) level were identified as significant predictors of PIN. All validation exhibited great discrimination, with the AUC of 0.742 (95% CI: 0.696-0.787) for internal validation, of 0.708 (95% CI: 0.605-0.810) for temporal validation and of 0.874 (95% CI: 0.759-0.989) for external validation, respectively. A simple risk-scoring tool was developed with a total risk score ranging from -3 to 4, corresponding to a risk of PIN from 0.79% to 81.24%. CONCLUSIONS: This study established a prediction model for PIN. Before using polymyxins, the simple risk-scoring tool can effectively identify patients at risk of developing PIN within a range of 7% to 65%.
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Antibacterianos , Humanos , Femenino , Masculino , Estudios Retrospectivos , Persona de Mediana Edad , Antibacterianos/efectos adversos , Anciano , Factores de Riesgo , Polimixina B/efectos adversos , Polimixina B/administración & dosificación , Proyectos Piloto , Enfermedad Crítica , Medición de Riesgo/métodos , Polimixinas/efectos adversos , Colistina/efectos adversos , Colistina/administración & dosificación , Modelos Logísticos , Adulto , Enfermedades Renales/inducido químicamenteRESUMEN
Tropical cyclones (TCs) cause severe natural hazards and drive intense upper ocean cooling through a series of oceanic and atmospheric physical processes, including vertical mixing and upwelling. Among these processes, TC-induced warming of near-surface waters in the open ocean has rarely been noted. This study provides a detailed analysis of upper ocean responses to 30 TC events observed by two buoys in the western North Pacific between 2016 and 2021. Supplemented with numerical experiments, we suggest that downwelling frequently occurs at the periphery of upwelling regions (around the radius of the 34 knot wind speed) following the passage of a TC. Downwelling is identified via pronounced warm anomalies under a shallow mixed layer depth, and its dynamics are attributed to negative wind stress curl and current-induced convergence. These findings highlight the important role played by TC-induced downwelling and offer insights for reconsidering the influence of TCs on biogeochemical processes.
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The right and left side of the colon derived from the midgut and hindgut, respectively. Previous studies have reported different characteristics of right-sided colon cancer (RCC) and left-sided colon cancer (LCC), but oncological outcomes remain unclear. This study compared the outcomes of RCC and LCC. This retrospective study included 1017 patients who received curative colectomy for stage I-III colon cancer at a single institute between August 2008 and December 2019. Overall survival (OS) and time to recurrence (TTR) were analyzed as outcome measurements. No significant difference in the OS or TTR of patients with RCC and LCC were observed. In subgroup analysis, RCC was associated with shorter TTR than LCC in stage II colon cancer (HR 2.36, 95% confidence interval 1.24-4.48, p < 0.01). Multivariate analysis demonstrated that right sidedness, R1 resection, low body mass index (BMI) and adjuvant chemotherapy were independent factors for poor prognosis for stage II colon cancer. Low BMI, perineural invasion, higher T stage and N2 stage were independent factors for poor prognosis for stage III colon cancer. The results were confirmed by multivariate analysis after propensity score matching. Our study revealed that RCC was an independent risk factor for recurrence in stage II colon cancer.
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Carcinoma de Células Renales , Neoplasias del Colon , Neoplasias Renales , Neoplasias del Colon/patología , Humanos , Estadificación de Neoplasias , Estudios RetrospectivosRESUMEN
BACKGROUND: Hounsfield Units (HU) values derived from Computerized Tomography (CT) have been used in the diagnosis of osteoporosis in the lumbar spine. OBJECTIVE: This study aimed to identify anatomical dimensions of lumbar vertebrae on CT images, which were different between older normal, osteopenic, and osteoporotic subjects. METHODS: This prospective pilot study enrolled 79 older adults. Based on CT measurements of lumbar vertebrae in HU, participants were classified into three groups: normal (HU > 109), osteopenia (HU: 94-108), and osteoporosis (HU < 93). Altogether, 42 anatomical variables of lumbar vertebrae, L2, L3, L4, and L5, were measured in each participant by CT, including 24 parameters measurable by MRI or plain X-ray and 18 parameters measurable by MRI only. RESULTS: Among the morphological measurements also measurable by MRI and plain X-ray, the length upper curve, 50% and 75% of L5, length upper with the cortex of L4, length center of the cortex of L3, as well as width upper curve 75% of L2, were significantly different between the three groups (p= 0.008, 0.007, 0.035, 0.036, and 0.003 respectively). Among the morphological measurements also measurable by MRI, only the width upper cortex 75% of L5 and the width lower cortex 25% of L3, were significantly different between the three groups (p= 0.031 and 0.020, respectively). CONCLUSION: Seven CT morphological measurements may be used as "reference standard" CT measurements for preliminarily diagnosing osteoporosis and osteopenia in older adults.
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Enfermedades Óseas Metabólicas , Osteoporosis , Absorciometría de Fotón/métodos , Anciano , Densidad Ósea , Enfermedades Óseas Metabólicas/diagnóstico por imagen , Humanos , Vértebras Lumbares/diagnóstico por imagen , Osteoporosis/diagnóstico por imagen , Proyectos Piloto , Estudios Prospectivos , Tomografía Computarizada por Rayos X/métodosRESUMEN
BACKGROUND: Immunoglobulin-related genes are associated with the favorable prognosis of triple-negative breast cancer (TNBC) patients. We aimed to analyze the function and prognostic value of immunoglobulin lambda constant 2 (IGLC2) in TNBC patients. METHODS: We knocked down the gene expression of IGLC2 (IGLC2-KD) in MDA-MB-231 cells to evaluate the proliferation, migration, and invasion of tumors via 3-(4,5-Dimethythiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay, wound healing, and transwell cell migration assay respectively. Relapse-free survival (RFS) and distant metastasis-free survival (DMFS) analyses were conducted using the KM plotter online tool. The GSE76275 data set was used to analyze the association of IGLC2 and clinical characteristics. A pathway enrichment analysis was conducted using the next-generation sequencing data of wild-type and IGLC2-KD MDA-MB-231 cells. RESULTS: The low gene expression of IGLC2 was related to unfavorable RFS, DMFS. The high expression of IGLC2 was exhibited in the basal-like immune-activated (BLIA) TNBC molecular subtype, which was immune-activated and showed excellent response to immune therapy. IGLC2 was positively correlated with programmed death-ligand 1 (PD-L1) as shown by Spearman correlation (r = 0.25, p < 0.0001). IGLC2 had a strong prognostic effect on lymph node-negative TNBC (RFS range: 0.31, q value= 8.2e-05; DMFS = 0.16, q value = 8.2e-05) but had no significance on lymph node-positive ones. The shRNA-mediated silencing of IGLC2 increased the proliferation, migration, and invasion of MDA-MB-231 cells. The results of pathway enrichment analysis showed that IGLC2 is related to the PI3K-Akt signaling pathway, MAPK signaling pathway, and extracellular matrix-receptor interaction. We confirmed that MDA-MB-231 tumor cells expressed IGLC2, subverting the traditional finding of generation by immune cells. CONCLUSIONS: IGLC2 linked with the proliferation, migration, and invasion of MDA-MB-231 cells. A high expression of IGLC2 was related to favorable prognosis for TNBC patients. IGLC2 may serve as a biomarker for the identification of TNBC patients who can benefit the most from immune checkpoint blockade treatment.
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Magnolol (MG) is the main active compound of Magnolia officinalis and exerts a wide range of biological activities. In this study, we investigated the effects of MG using tyloxapol (Tylo)-induced (200 mg/kg, i.p.) hyperlipidemia in rats and palmitic acid (PA)-stimulated (0.3 mM) HepG2 cells. Our results showed that Tylo injection significantly increased plasma levels of triglyceride and cholesterol as well as superoxide anion in the livers, whereas MG pretreatment reversed these changes. MG reduced hepatic lipogenesis by attenuating sterol regulatory element-binding protein-1c (SREBP-1c) and fatty acid synthase (FAS) proteins and Srebp-1, Fas, Acc, and Cd36 mRNA expression as well as upregulated the lipolysis-associated genes Hsl, Mgl, and Atgl. Furthermore, MG reduced plasma interleukin-1ß (IL-1ß) and protein expression of NLR family pyrin domain-containing 3 (NLRP3), apoptosis-associated speck-like protein (ASC), and caspase 1 as well as upregulated nuclear translocation of nuclear factor erythroid 2-related factor 2 (Nrf2) and induction of heme oxygenase-1 (HO-1) in hepatocytes of Tylo-treated rats. Enhanced autophagic flux by elevation of autophagy related protein 5-12 (ATG5-12), ATG7, Beclin1, and microtubule-associated protein light chain 3 B II (LC3BII)/LC3BI ratio, and reduction of sequestosome-1 (SQSTM1/p62) and phosphorylation of mTOR was observed by MG administration. However, autophagy inhibition with 3-methyladenine (3-MA) in HepG2 cells drastically abrogated the MG-mediated suppression of inflammation and lipid metabolism. In conclusion, MG inhibited hepatic steatosis-induced NLRP3 inflammasome activation through the restoration of autophagy to promote HO-1 signaling capable of ameliorating oxidative stress and inflammatory responses.
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BACKGROUND: Loss of ovarian function, as in menopause or after ovariectomy (OVX), is closely associated with obesity and white adipose tissue (WAT) inflammation. Estrogen replacement protects against postmenopausal obesity but increases the risks of carcinogenesis. In the present study, we investigated the effects of long-term treatment of raloxifene (RAL), a selective estrogen receptor modulator, on the features of estrogen deficiency-induced obesity and explored the involvement of canonical and non-canonical Wnt regulation in vivo and in vitro. METHODS: Adult female rats received bilateral OVX and divided into 5 groups: (1) Sham, (2) OVX, (3) OVX + E2: OVX rats were administered with E2 (50 µg/kg, s.c., 3 times/week), (4) OVX + RAL: OVX rats were treated with RAL (gavage, 1 mg/kg/day) suspended in 0.8% carboxymethylcellulose (CMC), (5) OVX + CMC: 0.8% CMC as vehicle control. All treatments were given for 8 weeks beginning at 1 week after OVX. In 3 T3-L1 cells, the effects of RAL on adipogenesis and lipopolysaccharide (LPS)-induced inflammation were evaluated. RESULTS: Treatment with RAL significantly decreased body weight, visceral fat pad mass, adipocyte size and plasma levels of glucose but increased plasma adiponectin. RAL reduced the elevation of HIF-1α, VEGF-A and proinflammatory cytokines (MCP-1 and TNF-α) expression by inhibition of NF-κB p65 and JNK cascades in retroperitoneal WAT. This anti-inflammatory capacity of RAL may result from upregulation of secreted frizzle-related protein 5 (SFRP5), an adipokine that repressed Wnt5a signaling. Furthermore, RAL inhibited adipogenic factors such as PPAR-γ, C/EBP-α, and FABP4, and preserved canonical Wnt10b/ß-catenin protein expression. In 3 T3-L1 adipocytes, RAL (20 µM) diminished lipid accumulation and inhibited adipogenic factors accompanied with the induction of ß-catenin, which were effectively reversed by the ß-catenin inhibitor IWR-1-endo. In addition, RAL reduced LPS-induced NF-κB p65 and p-IκB expression as well as TNF-α secretion. Suppression of SFRP5 by small interfering RNA significantly abrogated the anti-inflammatory effects of RAL. CONCLUSIONS: Distinct activation of canonical ß-catenin on inhibition of adipogenesis and non-canonical SFRP5 on suppression of WAT inflammation may contribute to the beneficial effects of RAL. Therefore, this study provides a rationale for the therapeutic potential of RAL for postmenopausal obesity.
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Adipogénesis/efectos de los fármacos , Tejido Adiposo/efectos de los fármacos , Inflamación/inducido químicamente , Clorhidrato de Raloxifeno/farmacología , Receptores de Estrógenos/antagonistas & inhibidores , Moduladores Selectivos de los Receptores de Estrógeno/farmacología , Proteínas Wnt/genética , Células 3T3-L1 , Tejido Adiposo/inmunología , Animales , Femenino , Regulación de la Expresión Génica , Lipopolisacáridos/farmacología , Ratones , Ovariectomía , Ratas , Ratas Wistar , Proteínas Wnt/metabolismo , Proteína Wnt1RESUMEN
A series of five-membered ring aluminum complexes bearing thiol-Schiff base ligands were synthesized, and their application in the ring-opening polymerization of ε-caprolactone (CL) was investigated. The complexes exhibited dramatically higher catalytic activity than the six-membered ring S2AlMe2 complex (approximately 4- to 10-fold higher) and the five-membered ring L5-PhAlMe2 complex (approximately 7- to 19-fold higher). Moreover, a shorter induction period was observed when the five-membered ring aluminum complexes bearing thiol-Schiff base ligands were used compared with the other types of aluminum complexes bearing Schiff base ligands. The electron-withdrawing groups enhanced the catalytic activity of the Al complexes compared with the electron donating groups. The thiol-Schiff base ligand and the five-membered ring aluminum catalysis had a synergistic effect that was stronger than the combination of their individual effects.
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IMPORTANCE: Allopurinol, a first-line drug used for treating gout, is increasingly prescribed worldwide to patients with asymptomatic hyperuricemia and comorbid renal or cardiovascular diseases. Nevertheless, allopurinol use has been associated with fatal hypersensitivity reactions, including drug rash with eosinophilia and systemic symptoms, Stevens-Johnson syndrome, and toxic epidermal necrolysis. The overall risks of allopurinol use remain unclear. OBJECTIVE: To investigate the incidence of, risk factors for, and mortality associated with allopurinol hypersensitivity in new users of allopurinol. DESIGN, SETTING, AND PARTICIPANTS: A retrospective nationwide population study was conducted using data from the Taiwan National Health Insurance Research Database, which includes detailed medical records of more than 23 million insured enrollees. Data were collected from January 1, 2005, through December 31, 2011, using the Anatomical Therapeutic Chemical classification system and International Classification of Diseases, Ninth Revision, Clinical Modification codes. Among 1,613,719 patients receiving allopurinol prescriptions, 495,863 were identified as new users. MAIN OUTCOMES AND MEASURES: Allopurinol hypersensitivity was identified within 3 months since the first prescription. The period for measuring related hospitalizations was 1 month since the episode, and the period for measuring renal complications or mortality was 2 months since the episode. Poisson regression test and multivariable logistic regression analysis were performed, and P < .01 was considered statistically significant. RESULTS: Among the more than 23 million insured enrollees, the annual incidence rates were 4.68 per 1000 new users for allopurinol hypersensitivity, 2.02 per 1000 new users for related hospitalization, and 0.39 per 1000 new users for related mortality. The annual incidence of allopurinol hypersensitivity rose statistically significantly during the study period (P < .001). Risk factors for allopurinol hypersensitivity included female sex, age 60 years or older, initial allopurinol dosage exceeding 100 mg/d, renal or cardiovascular comorbidities, and use for treating asymptomatic hyperuricemia. Patients with asymptomatic hyperuricemia and renal or cardiovascular diseases had statistically significantly increased risk of allopurinol hypersensitivity (odds ratio [OR], 1.61; 95% CI, 1.33-1.94; P < .001 for renal diseases and OR, 1.52; 95% CI, 1.19-1.93; P < .001 for cardiovascular diseases). They also had statistically significantly increased risk of mortality (OR, 5.59; 95% CI, 2.61-11.94; P < .001 for renal diseases and OR, 3.57; 95% CI, 2.31-5.51; P < .001 for cardiovascular diseases). CONCLUSIONS AND RELEVANCE: The use of allopurinol in patients with asymptomatic hyperuricemia accompanied by renal or cardiovascular diseases statistically significantly increased the risk of hypersensitivity reactions. Physicians should be cautious when prescribing allopurinol to high-risk populations and should consider the potential risks of fatal adverse reactions.