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Autoimmune hemolytic anemia (AIHA) is a heterogeneous group of diseases mediated by autoantibody directed against RBCs causing hemolysis and anemia. AIHA develops rapidly or over time, depending on the triggering factor. Desidustat is a prolyl hydroxylase inhibitor clinically used for the treatment of chronic kidney disease (CKD)-induced anemia. In this study, we investigated the effect of desidustat in preclinical model of AIHA. We used rat RBC for induction of AIHA in mice. These mice were then treated with desidustat (15 mg/kg, PO, once a day) for eight weeks. Desidustat treatment increased hemoglobin, RBC and hematocrit and decreased WBC and lymphocytes. This treatment suppressed serum LDH, oxidative stress in RBCs, antibody titer and antibody deposition on RBC surface, and increased RBC lifespan. Serum and spleen iron along with spleen mass and oxidative stress were decreased by desidustat. Bone marrow iron was increased and expression of CD71 (cell surface marker for early erythroid progenitor) and TER-119 (cell surface marker for late erythroid progenitor) in bone marrow were found to be elevated by desidustat by treatment. This treatment also suppressed deposition of membrane-bound antibody in late erythroid cells. The treatment showed reduction in total splenic cells, CD71 and TER-119 positive cells in the spleen. Thus, desidustat treatment increased erythropoiesis, early maturation of bone marrow erythroid cells having longer RBC life span due to decrease in the antibody-mediated lysis of RBCs and its progenitors leading to reduced oxidative stress. Thus, desidustat can be a good therapeutic option for treatment of AIHA.
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Complement cascade is a defence mechanism useful for eliminating pathogenic microorganisms and damaged cells. However, activation of alternative complement system can also cause inflammation and promote kidney and retinal disease progression. Inflammation causes tissue hypoxia, which induces hypoxia-inducible factor (HIF) and HIF helps the body to adapt to inflammation. In this study, we investigated the effect of HIF stabilizer desidustat in complement-mediated diseases. Oral administration of desidustat (15 mg/kg) was effective to reduce the kidney injury in mice that was induced by either lipopolysaccharide (LPS), doxorubicin or bovine serum albumin (BSA)-overload. Complement activation-induced membrane attack complex (MAC) formation and factor B activity were also reduced by desidustat treatment. In addition, desidustat was effective against membranous nephropathy caused by cationic BSA and retinal degeneration induced by sodium iodate in mice. C3-deposition, proteinuria, malondialdehyde, and interleukin-1ß were decreased and superoxide dismutase was increased by desidustat treatment in cBSA-induced membranous nephropathy. Desidustat specifically inhibited alternative complement system, without affecting the lectin-, or classical complement pathway. This effect appears to be mediated by inhibition of factor B. These data demonstrate the potential therapeutic value of HIF stabilization by desidustat in treatment of complement-mediated diseases.
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Activación de Complemento , Animales , Ratones , Activación de Complemento/efectos de los fármacos , Glomerulonefritis Membranosa/tratamiento farmacológico , Glomerulonefritis Membranosa/metabolismo , Glomerulonefritis Membranosa/patología , Masculino , Lipopolisacáridos , Degeneración Retiniana/tratamiento farmacológico , Degeneración Retiniana/prevención & control , Degeneración Retiniana/metabolismo , Degeneración Retiniana/patología , Albúmina Sérica Bovina , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Complejo de Ataque a Membrana del Sistema Complemento/metabolismo , Modelos Animales de Enfermedad , Riñón/efectos de los fármacos , Riñón/metabolismo , Riñón/patología , Interleucina-1beta/metabolismo , Sustancias Protectoras/farmacologíaRESUMEN
With so much data available, health system leaders are challenged with sifting through it all to find the most useful information for decision-making. Meritus Health implemented effective approaches to understand, use, and communicate large amounts of data to alleviate some of this burden. These processes include system-wide daily huddles, dashboards, and standardized communication write-ups.
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Estudios de Casos Organizacionales , Humanos , Toma de Decisiones , Toma de Decisiones en la Organización , Sistemas MultiinstitucionalesRESUMEN
Iron deficiency anemia is caused by many pathological conditions like chronic kidney disease (CKD), inflammation, malnutrition and gastrointestinal abnormality. Current treatments that are erythropoiesis stimulating agents (ESAs) and iron supplementation are inadequate and often lead to tolerance and/or toxicity. Desidustat, a prolyl hydroxylase (PHD) inhibitor, is clinically used for the treatment of anemia with CKD. In this study, we investigated the effect of desidustat on iron deficiency anemia (IDA). IDA was induced in C57BL6/J mice by iron deficient diet feeding. These mice were then treated with desidustat (15 mg/kg, PO) and FeSO4 (20 mg/kg) for five weeks and effect of the treatment on hematology, iron homeostasis, and bone marrow histology was observed. Effect of desidustat on iron metabolism in inflammation (LPS)-induced iron deficiency was also assessed. Both, Desidustat and FeSO4, increased MCV (mean corpuscular volume), MCH (mean corpuscular hemoglobin), hemoglobin, and HCT (hematocrit) in blood and increased iron in serum, liver, and spleen. Desidustat increased MCHC (mean corpuscular hemoglobin concentration) while FeSO4 treatment did not alter it. FeSO4 treatment significantly increased iron deposition in liver, and spleen, while desidustat increased iron in circulation and demonstrated efficient iron utilization. Desidustat increased iron absorption, serum iron and decreased hepcidin without altering tissue iron, while FeSO4 increased serum and tissue iron by increasing hepcidin in LPS-induced iron deficiency. Desidustat increased erythroid population, especially iron-dependent polychromatic normoblasts and orthochromatic normoblasts, while FeSO4 did not improve cell architecture. PHD inhibition by desidustat improved iron utilization in iron deficiency anemia, by efficient erythropoiesis.
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Anemia Ferropénica , Inhibidores de Prolil-Hidroxilasa , Quinolonas , Insuficiencia Renal Crónica , Ratones , Animales , Anemia Ferropénica/tratamiento farmacológico , Hepcidinas/metabolismo , Inhibidores de Prolil-Hidroxilasa/farmacología , Inhibidores de Prolil-Hidroxilasa/uso terapéutico , Lipopolisacáridos , Hierro/metabolismo , Inflamación/metabolismo , Hemoglobinas/análisisRESUMEN
INTRODUCTION: Currently available treatments for chronic lower back pain (CLBP) do not adequately address both nociceptive and neuropathic components of pain. We evaluated efficacy and safety of fixed-dose combination (FDC) of low-dose pregabalin prolonged release 75 mg-etoricoxib 60 mg to address both pain components. METHODS: This randomized phase 3 trial conducted at 12 centres across India evaluated efficacy (based on mean change in numeric rating scale [NRS], Roland-Morris disability questionnaire [RDQ], visual analogue scale [VAS], patient global impression of improvement [PGI-I], clinical global impression of improvement [CGI-I] and rescue medication consumption) and safety of FDC in comparison to etoricoxib alone in adult patients with CLBP. Treatment duration was 8 weeks. RESULTS: Of the 371 patients screened, 319 were randomized and considered for efficacy and safety analysis. Both treatment groups had no significant difference in terms of demography and baseline disease characteristics. Significantly better outcomes with FDC compared to etoricoxib were observed at week 4 onwards. At week 8, both groups showed significant reduction in mean NRS score from baseline (- 4.00 ± 1.65 in FDC; - 2.92 ± 1.59 in etoricoxib) with mean NRS score being significantly less in the FDC group compared to etoricoxib group (3.26 ± 1.56 vs 4.31 ± 1.56; p < 0.0001). The FDC was more effective than etoricoxib in terms of significantly greater reduction in RDQ score (- 9.28 ± 4.48 vs - 6.78 ± 4.34; p < 0.0001) and VAS score (- 37.66 ± 18.7 vs - 28.50 ± 16.31; p < 0.0001) at week 8. The FDC was also better in terms of significantly more patients reporting their condition as 'very much better' (36.9% vs 5.0%; p < 0.0001) and clinicians reporting patient's condition as 'very much improved' (36.3% vs 5.7%; p < 0.0001). Overall, study medications were well tolerated. CONCLUSION: FDC of pregabalin and etoricoxib provided significant benefits in reducing pain and improving functional status compared with etoricoxib alone in patients with CLBP. Pregabalin prolonged release-etoricoxib FDC could be one of the treatment options for early and sustained pain relief and improvement in quality-of-life in treating CLBP as it addresses both neuropathic and nociceptive components of pain. TRIAL REGISTRATION: CTRI/2018/10/015886.
Low back pain is one of the most common causes of loss of productivity worldwide. About 60% of Indians suffer from low back pain at some point. Low back pain that persists for more than 3 months is classified as chronic low back pain which mostly includes both nociceptive and neuropathic components. Monotherapies, if prescribed, are not completely effective, as they generally only target either nociceptive or neuropathic components of pain. Multiple drugs are usually needed at multiple times a day, at higher doses for optimal effectiveness, and in most cases they have significant side effects if taken over prolonged periods and also add to the pill burden. To minimize treatment-associated adverse effects, and to increase treatment compliance, while addressing both the components of pain, we developed a fixed-dose combination of low-dose pregabalin prolonged release and etoricoxib. A phase 3 trial was designed to assess the efficacy and safety of the fixed-dose combination in comparison with etoricoxib alone in treating chronic low back pain. The combination demonstrated statistically and clinically significant improvement in patient-reported outcomespain, functionality and quality of lifeas early as 4 weeks after starting the medication. No severe or serious adverse effects were reported. Thus, the combination of low-dose pregabalin prolonged release and etoricoxib could provide an option for optimal management of chronic low back pain. This would provide multiple benefits, such as addressing both nociceptive and neuropathic components of chronic low back pain, reducing drug-related adverse effects because of low dose, reducing pill burden and thereby increasing drug compliance.
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Many anemic chronic kidney disease (CKD) patients are refractory to erythropoietin (EPO) effects due to inflammation, deranged iron utilization, and generation of EPO antibodies. This work assessed the effect of desidustat, an inhibitor of hypoxia inducible factor (HIF) prolyl hydroxylase (PHD), on EPO-refractory renal anemia. Sprague Dawley rats were made anemic by cisplatin (5 âmg/kg, IP, single dose) and turpentine oil (5 âmL/kg, SC, once a week). These rats were given recombinant human EPO (rhEPO, 1 âµg/kg) and desidustat (15 or 30 âmg/kg) for eight weeks. Separately, rhEPO (1-5 âµg/kg) was given to anemic rats to sustain the normal hemoglobin levels and desidustat (15 âmg/kg) for eight weeks. In another experiment, the anemic rats were treated rhEPO (5 âµg/kg) for two weeks and then desidustat (15 âmg/kg) for the next two weeks. Dosing of rhEPO was thrice a week, and for desidustat, it was on alternate days. Desidustat inhibited EPO-resistance caused by rhEPO treatment, decreased hepcidin, IL-6, IL-1ß, and increased iron and liver ferroportin. Desidustat reduced EPO requirement and anti-EPO antibodies. Desidustat also maintained normal hemoglobin levels after cessation of rhEPO treatment. Thus, novel prolyl hydroxylase inhibitor desidustat can treat EPO resistance via improved iron utilization and decreased inflammation.
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AIMS: There is a paucity of long-term data on outcomes of high-risk prostatic adenocarcinoma after moderately hypofractionated radiotherapy with elective nodal treatment and long-term androgen deprivation therapy (ADT). We report long-term control and toxicity outcomes and analyse the predictors of failure and toxicity. MATERIALS AND METHODS: The records of 120 consecutive high-risk prostate cancer patients treated in a single institution between February 2012 and December 2016 were retrospectively analysed. A moderately hypofractionted radiotherapy (HypoRT) regimen of 60 Gy in 20 fractions over 4 weeks with simultaneous elective pelvic irradiation to 44 Gy in 20 fractions with intensity-modulated radiotherapy was used, together with long-term ADT with either orchiectomy or medical castration for a total duration of 2-3 years. We analysed biochemical control, metastasis-free survival and late toxicities and their predictive factors using survival analysis. RESULTS: Patients had locally advanced cancers (cT3 77.5%, median pretreatment prostate-specific antigen 30 ng/ml, Gleason score 8-10 in 45.8%). The median follow-up time was 70 months. The 3- and 5-year probability of freedom from biochemical progression was 93% and 80%, respectively. The 5-year probability of freedom from local relapse/intra-pelvic nodal relapse/distant metastases as the site of first failure was 96%/97%/86%, respectively. Gleason score 8-10 and medical ADT for 2-3 years (as opposed to orchidectomy) were independent risk factors for distant metastases. A total of 18 grade 2 and above late gastrointestinal toxicity events and a total of 23 grade 2 and above late genitourinary toxicity events were documented. Patients who underwent a transurethral resection of prostate prior to radiotherapy had worse urological toxicity. CONCLUSIONS: HypoRT with elective nodal treatment results in excellent pelvic control. Distant metastases are the primary mode of failure. Risk of metastases is associated with Gleason score and the duration of ADT. Late urinary toxicities are more common in those with prior transurethral resection of prostate.
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Neoplasias de la Próstata , Radioterapia de Intensidad Modulada , Resección Transuretral de la Próstata , Antagonistas de Andrógenos/efectos adversos , Andrógenos , Humanos , Masculino , Recurrencia Local de Neoplasia , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/radioterapia , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
Diabetic retinopathy is a serious complication of diabetes, marked by retinal vascular damage, inflammation, and angiogenesis. This study's objective was to assess the potential benefits of saroglitazar, a peroxisome proliferator-activated receptor-alpha/gamma (PPAR-α/γ) agonist in diabetic retinopathy. Diabetic retinopathy was induced by streptozotocin in Sprague Dawley rats. The effect of saroglitazar was also assessed in the oxygen-induced retinopathy model in newborn rats and VEGF-induced angiogenesis in the chick chorioallantoic membrane (CAM) assay. Treatment of saroglitazar (1 and 4 mg/kg, oral) for 12 weeks significantly ameliorated retinal vascular leakage and leukostasis in the diabetic rats. Saroglitazar decreased oxidative stress, VEGF receptor signalling, NF-κBp65, and ICAM-1 in the retina of diabetic rats. The beneficial effects of saroglitazar (1 and 4 mg/kg, oral) were also observed on the neovascularization in oxygen-induced retinopathy in newborn rats. Saroglitazar also reduced VEGF-induced angiogenesis in CAM assay. This study reveals that saroglitazar has the potential to prevent the progression of retinopathy in diabetic patients.
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Inhibidores de la Angiogénesis/farmacología , Retinopatía Diabética/tratamiento farmacológico , PPAR alfa/agonistas , PPAR gamma/agonistas , Fenilpropionatos/farmacología , Pirroles/farmacología , Retina/efectos de los fármacos , Neovascularización Retiniana/tratamiento farmacológico , Vasos Retinianos/efectos de los fármacos , Animales , Animales Recién Nacidos , Embrión de Pollo , Diabetes Mellitus Experimental/inducido químicamente , Retinopatía Diabética/etiología , Retinopatía Diabética/metabolismo , Retinopatía Diabética/patología , Femenino , Hiperoxia/complicaciones , Molécula 1 de Adhesión Intercelular/metabolismo , Masculino , Neovascularización Fisiológica/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , PPAR alfa/metabolismo , PPAR gamma/metabolismo , Ratas Sprague-Dawley , Receptores de Factores de Crecimiento Endotelial Vascular/metabolismo , Retina/metabolismo , Retina/patología , Neovascularización Retiniana/etiología , Neovascularización Retiniana/metabolismo , Neovascularización Retiniana/patología , Vasos Retinianos/metabolismo , Vasos Retinianos/patología , Transducción de Señal , Estreptozocina , Factor de Transcripción ReIA/metabolismoRESUMEN
Chronic kidney disease (CKD) is associated with activated inflammatory responses. Desidustat, a prolyl hydroxylase (PHD) inhibitor is useful for treatment of anemia associated with CKD, but its effect on the inflammatory and fibrotic changes in CKD is not evaluated. In this study, we investigated the effect of desidustat on the inflammatory and fibrotic changes in preclinical models of acute and chronic kidney injury. Acute kidney injury was induced in male Sprague Dawley rats by ischemia-reperfusion, in which effect of desidustat (15 mg/kg, PO) was estimated. In a separate experiment, male C57 mice were treated with adenine for 14 days to induce CKD. These mice were treated with desidustat (15 mg/kg, PO, alternate day) treatment for 14 days, with adenine continued. Desidustat prevented elevation of serum creatinine, urea, IL-1ß, IL-6, and kidney injury molecule-1 (KIM-1), and elevated the erythropoietin levels in rats that were subjected to acute kidney injury. Mice treated with adenine developed CKD and anemia, and desidustat treatment caused improvement in serum creatinine, urea, and also improved hemoglobin and reduced hepatic and serum hepcidin. A significant reduction in IL-1ß, IL-6, myeloperoxidase (MPO) and oxidative stress was observed by desidustat treatment. Desidustat treatment also reduced renal fibrosis as observed by histological analysis and hydroxyproline content. Desidustat treatment reduced the renal fibrosis and inflammation along with a reduction in anemia in preclinical models of kidney injury, which may translate to protective effects in CKD patients.
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Inhibidores de Prolil-Hidroxilasa , Quinolonas , Daño por Reperfusión , Animales , Citocinas/metabolismo , Riñón , Masculino , Ratones , Ratones Endogámicos C57BL , Estrés Oxidativo , Inhibidores de Prolil-Hidroxilasa/farmacología , Quinolonas/farmacología , Ratas , Ratas Sprague-Dawley , Daño por Reperfusión/patologíaRESUMEN
Biochemical reactions in eukaryotic cells occur in subcellular, membrane-bound compartments called organelles. Each kind of organelle is characterized by a unique lumenal chemical composition whose stringent regulation is vital to proper organelle function. Disruption of the lumenal ionic content of organelles is inextricably linked to disease. Despite their vital roles in cellular homeostasis, there are large gaps in our knowledge of organellar chemical composition largely from a lack of suitable probes. In this Outlook, we describe how, using organelle-targeted ratiometric probes, one can quantitatively image the lumenal chemical composition and biochemical activity inside organelles. We discuss how excellent fluorescent detection chemistries applied largely to the cytosol may be expanded to study organelles by chemical imaging at subcellular resolution in live cells. DNA-based reporters are a new and versatile platform to enable such approaches because the resultant probes have precise ratiometry and accurate subcellular targeting and are able to map multiple chemicals simultaneously. Quantitatively mapping lumenal ions and biochemical activity can drive the discovery of new biology and biomedical applications.
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Innate immune cells destroy pathogens within a transient organelle called the phagosome. When pathogen-associated molecular patterns (PAMPs) displayed on the pathogen are recognized by Toll-like receptors (TLRs) on the host cell, it activates inducible nitric oxide synthase (NOS2) which instantly fills the phagosome with nitric oxide (NO) to clear the pathogen. Selected pathogens avoid activating NOS2 by concealing key PAMPs from their cognate TLRs. Thus, the ability to map NOS2 activity triggered by PAMPs can reveal critical mechanisms underlying pathogen susceptibility. Here, we describe DNA-based probes that ratiometrically report phagosomal and endosomal NO, and can be molecularly programmed to display precise stoichiometries of any desired PAMP. By mapping phagosomal NO produced in microglia of live zebrafish brains, we found that single-stranded RNA of bacterial origin acts as a PAMP and activates NOS2 by engaging TLR-7. This technology can be applied to study PAMP-TLR interactions in diverse organisms.
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Encéfalo/enzimología , ADN/química , Colorantes Fluorescentes/química , Óxido Nítrico Sintasa de Tipo II , Animales , Encéfalo/metabolismo , Química Encefálica , ADN/metabolismo , Colorantes Fluorescentes/metabolismo , Técnicas de Inactivación de Genes , Ratones , Microglía/química , Microglía/enzimología , Microglía/metabolismo , Microscopía Fluorescente , Sondas Moleculares/química , Sondas Moleculares/metabolismo , Óxido Nítrico Sintasa de Tipo II/análisis , Óxido Nítrico Sintasa de Tipo II/química , Óxido Nítrico Sintasa de Tipo II/metabolismo , Fagosomas/química , Fagosomas/metabolismo , Pez CebraRESUMEN
Membrane-initiated steroid signaling (MISS) involves rapid second messenger based intracellular signaling without coupling to transcription or translation. MISS activates important cellular signaling cascades such as mitogen-activated protein kinase (MAPK) or adenylate cyclase pathways. Despite its vital role in signaling, the downstream second messengers involved in MISS and their temporal dynamics remain elusive. A technology which can offer pristine spatiotemporal control over the release of the steroid initiator could pave the way to understand these rapid and ultrasensitive signaling processes. Toward this, we describe a DNA-nanocapsule based technology to chemically release steroids and study MISS in endothelial cells. Here we discuss the synthesis and cellular protocols for investigators who seek to utilize DNA-nanocapsules for the chemically triggered release of small molecules.
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Células Endoteliales , Transducción de Señal , Preparaciones de Acción Retardada , Células Endoteliales/metabolismo , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Sistemas de Mensajero SecundarioRESUMEN
Nitric oxide synthase 3 (NOS3) produces the gasotransmitter nitric oxide (NO), which drives critical cellular signaling pathways by S-nitrosylating target proteins. Endogenous NOS3 resides at two distinct subcellular locations: the plasma membrane and the trans-Golgi network (TGN). However, NO generation arising from the activities of both these pools of NOS3 and its relative contribution to physiology or disease is not yet resolvable. We describe a fluorescent DNA-based probe technology, NOckout, that can be targeted either to the plasma membrane or the TGN, where it can quantitatively map the activities of endogenous NOS3 at these locations in live cells. We found that, although NOS3 at the Golgi is tenfold less active than at the plasma membrane, its activity is essential for the structural integrity of the Golgi. The newfound ability to spatially map NOS3 activity provides a platform to discover selective regulators of the distinct pools of NOS3.
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ADN/química , Colorantes Fluorescentes/química , Óxido Nítrico Sintasa de Tipo III/metabolismo , Carbamatos/química , Línea Celular Tumoral , Membrana Celular/metabolismo , Humanos , Cinética , Óxido Nítrico/metabolismo , Imagen Óptica , Polietilenglicoles/química , Imagen Individual de Molécula , Red trans-Golgi/metabolismoAsunto(s)
Salud Pública , Determinantes Sociales de la Salud , Socialismo , Especialización , HumanosRESUMEN
BACKGROUND: Balanced coagonists of glucagon-like peptide-1 (GLP-1) and glucagon receptors are emerging therapies for the treatment of obesity and diabetes. Such coagonists also regulate lipid metabolism, independent of their body weight lowering effects. Many actions of the coagonists are partly mediated by fibroblast growth factor 21 (FGF21) signaling, with the major exception of bile homeostasis. Since thyroid hormone is an important regulator of bile homeostasis, we studied the involvement of thyroid hormone in coagonist-induced changes in lipid and bile metabolism. METHODS: We evaluated the effect of a single dose of coagonist Aib2 C24 chimera2 at 150 to 10000 µg/kg on tetraiodothyronine (T4) and triiodothyronine (T3) in high-fat diet-induced obese (DIO) mice and chow-fed mice. Repeated dose treatment of coagonist (150 µg/kg, subcutaneously) was assessed in four mice models namely, on lipid and bile homeostasis in DIO mice, propylthiouracil (PTU)-treated DIO mice, methimazole (MTM)-treated DIO mice and choline-deficient, L-amino acid-defined, highfat diet (CDAHFD)-induced nonalcoholic steatohepatitis (NASH). RESULTS: Single dose treatment of coagonist did not alter serum T3 and T4 in chow-fed mice and DIO mice. Coagonist treatment improved lipid metabolism and biliary cholesterol excretion. Chronic treatment of GLP-1 and glucagon coagonist did not alter serum T3 in hypothyroid DIO mice and CDAHFDinduced NASH. Coagonist increased serum T4 in DIO mice after 4 and 40 weeks of treatment, though no change in T4 levels was observed in hypothyroid mice or mice with NASH. CONCLUSION: Our data demonstrate that coagonist of GLP-1 and glucagon receptors does not modulate bile homeostasis via thyroid signaling.
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Bilis/metabolismo , Péptido 1 Similar al Glucagón/agonistas , Receptores de Glucagón/agonistas , Tiroxina/sangre , Triyodotironina/sangre , Animales , Dieta Alta en Grasa , Péptido 1 Similar al Glucagón/metabolismo , Hígado/efectos de los fármacos , Hígado/metabolismo , Masculino , Metimazol/farmacología , Ratones , Ratones Endogámicos C57BL , Enfermedad del Hígado Graso no Alcohólico/etiología , Obesidad/etiología , Obesidad/metabolismo , Propiltiouracilo/farmacología , Receptores de Glucagón/metabolismo , Triglicéridos/análisisRESUMEN
BACKGROUND: Racial disparities in healthcare utilization and outcomes have been reported and have wide-reaching implications for individual patient and healthcare system; as providers we bear an ethical burden to address this disparity and provide culturally competent care. This study will examine the influence of race on length of stay, discharge disposition, and complications requiring reoperation following total joint arthroplasty (TJA). METHODS: Single institution retrospective analysis of a consecutive series of 7208 primary TJA procedures performed between July 2013 and June 2017 was conducted. Chi-squared and t-tests were used to quantify differences between the groups and multiple logistic regression was used to identify race as an independent risk factor. RESULTS: In total, 6182 (84.3%) white and 1026 (14.0%) African American (AA) patients were included. AA patients were younger (63.62 vs 66.84 years, P < .001), more likely female (68.8% vs 57.0%, P < .001), had a longer length of stay (2.19 vs 2.00 days, P < .001), more likely to experience septic complications (1.3% vs 0.5%, P = .002) and manipulation under anesthesia (3.9% vs 1.8%, P < .001), and less likely to discharge home (67.1% vs 81.1%, P < .001). Multiple logistic regression showed that AA patients were more likely to discharge to a facility (adjusted odds ratio 2.63, 95% confidence interval 2.19-3.16, P < .001) and experience a manipulation under anesthesia (adjusted odds ratio 1.90, 95% confidence interval 1.26-2.85, P = .002). CONCLUSION: AA patients undergoing TJA were younger with longer length of stay and a higher rate of nonhome discharge; AA race was identified as an independent risk factor. Further study is required to understand the differences identified in this study. Targeted interventions should be developed to attempt to eliminate the disparity.
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Artroplastia de Reemplazo de Cadera/estadística & datos numéricos , Artroplastia de Reemplazo de Rodilla/estadística & datos numéricos , Negro o Afroamericano/estadística & datos numéricos , Complicaciones Posoperatorias/epidemiología , Población Blanca/estadística & datos numéricos , Anciano , Artroplastia de Reemplazo de Cadera/efectos adversos , Artroplastia de Reemplazo de Rodilla/efectos adversos , Femenino , Humanos , Modelos Logísticos , Masculino , Maryland/epidemiología , Persona de Mediana Edad , Análisis Multivariante , Oportunidad Relativa , Alta del Paciente , Complicaciones Posoperatorias/etiología , Reoperación , Estudios Retrospectivos , Factores de RiesgoRESUMEN
Phagocytes destroy pathogens by trapping them in a transient organelle called the phagosome, where they are bombarded with reactive oxygen species (ROS) and reactive nitrogen species (RNS). Imaging reactive species within the phagosome would directly reveal the chemical dynamics underlying pathogen destruction. Here we introduce a fluorescent, DNA-based combination reporter, cHOClate, which simultaneously images hypochlorous acid (HOCl) and pH quantitatively. Using cHOClate targeted to phagosomes in live cells, we successfully map phagosomal production of a specific ROS, HOCl, as a function of phagosome maturation. We found that phagosomal acidification was gradual in macrophages and upon completion, HOCl was released in a burst. This revealed that phagosome-lysosome fusion was essential not only for phagosome acidification, but also for providing the chloride necessary for myeloperoxidase activity. This method can be expanded to image several kinds of ROS and RNS and be readily applied to identify how resistant pathogens evade phagosomal killing.
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ADN/química , Colorantes Fluorescentes/química , Ácido Hipocloroso/química , Fagosomas/química , Concentración de Iones de Hidrógeno , Oxidación-ReducciónRESUMEN
AIM: To investigate the role of glucagon-like peptide-1 (GLP-1)/glucagon receptors coagonist on renal dysfunction associated with diabetes and obesity. METHODS: Chronic high-fat diet fed C57BL/6J mice, streptozotocin-treated high-fat diet fed C57BL/6J mice and diabetic C57BLKS/J db/db mice were used as models of diabetes-induced renal dysfunction. The streptozotocin-treated high-fat diet fed mice and db/db mice were treated with the GLP-1 and glucagon receptors coagonist (Aib2 C24 Chimera2, 150 µg/kg, sc) for twelve weeks, while in chronic high-fat diet fed mice, coagonist (Aib2 C24 Chimera2, 150 µg/kg, sc) treatment was continued for forty weeks. Kidney function, histology, fibrosis, inflammation, and plasma biochemistry were assessed at the end of the treatment. RESULTS: Coagonist treatment decreased body weight, plasma lipids, insulin resistance, creatinine, blood urea nitrogen, urinary albumin excretion rate and renal lipids. In kidney, expression of lipogenic genes (SREBP-1C, FAS, and SCD-1) was decreased, and expression of genes involved in ß-oxidation (CPT-1 and PPAR-α) was increased due to coagonist treatment. In plasma, coagonist treatment increased adiponectin and FGF21 and decreased IL-6 and TNF-α. Coagonist treatment reduced expression of inflammatory (TNF-α, MCP-1, and MMP-9) and pro-fibrotic (TGF-ß, COL1A1, and α-SMA) genes and also improved histological derangement in renal tissue. CONCLUSION: Coagonist of GLP-1 and glucagon receptors alleviated diabetes and obesity-induced renal dysfunction by reducing glucose intolerance, obesity, and hyperlipidemia.
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AIMS: Stereotactic body radiotherapy (SBRT) in low- and intermediate-risk prostate cancer has shown encouraging results. However, its use in high-risk patients is limited due to lack of data regarding adequate radiotherapy dose, need for pelvic nodal treatment and androgen deprivation therapy. Herein we report our experience of SBRT in this subgroup. MATERIALS AND METHODS: Analysis of a prospectively maintained database of 68 consecutive patients of the National Comprehensive Cancer Network (NCCN) high-risk, very high-risk and node-positive adenocarcinoma prostate treated with SBRT was undertaken. All patients were treated with rotational intensity-modulated radiotherapy with daily image guidance. The dose delivered to the prostate and gross node was 35-37.5 Gy in 5 alternate day fractions. Node-positive patients received 25 Gy to pelvic nodal regions until the common iliac nodes. Treatment was delivered in 7-10 days. All patients received long-term androgen deprivation therapy (79% medical and 21% surgical). RESULTS: Most patients (65%) had a Gleason score ≥ 8. The median prostate-specific antigen was 42. Twenty patients were high risk (30%), 11 (16%) very high risk and 37 (54%) node positive. No acute Radiation Therapy Oncology Group grade ≥ 3 genitourinary or gastrointestinal toxicity was noted. Acute grade 2 genitourinary and gastrointestinal toxicity were 12% and 3%, respectively. Late grade 3 genitourinary and gastrointestinal toxicity was 3% and 0%, respectively. There was no increase in acute or late gastrointestinal toxicity with prophylactic pelvic nodal radiotherapy. Prior transurethral resection of prostate (n = 11) did not increase toxicity. At a median follow-up of 18 months, 97% patients were alive and 94% were biochemically controlled. CONCLUSION: SBRT is safe in the treatment of high-risk, very high-risk and node-positive prostate cancer, even with prophylactic pelvic radiotherapy or prior transurethral resection of prostate. Longer follow-up is required to determine efficacy.