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BACKGROUND: The emergence of carbapenem-resistant and extensively drug-resistant (XDR) Acinetobacter baumannii as well as inadequate effective antibiotics calls for an urgent effort to find new antibacterial agents. The therapeutic efficacy of two human scFvs, EB211 and EB279, showing growth inhibitory activity against A. baumannii in vitro, was investigated in immunocompromised mice with A. baumannii pneumonia. RESULTS: The data revealed that infected mice treated with EB211, EB279, and a combination of the two scFvs showed better survival, reduced bacterial load in the lungs, and no marked pathological abnormalities in the kidneys, liver, and lungs when compared to the control groups receiving normal saline or an irrelevant scFv. CONCLUSIONS: The results from this study suggest that the scFvs with direct growth inhibitory activity could offer promising results in the treatment of pneumonia caused by XDR A. baumannii.
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Infecciones por Acinetobacter , Acinetobacter baumannii , Neumonía , Anticuerpos de Cadena Única , Humanos , Animales , Ratones , Anticuerpos de Cadena Única/farmacología , Anticuerpos de Cadena Única/uso terapéutico , Infecciones por Acinetobacter/tratamiento farmacológico , Infecciones por Acinetobacter/microbiología , Antibacterianos/farmacología , Antibacterianos/uso terapéutico , Neumonía/tratamiento farmacológico , Neumonía/microbiología , Farmacorresistencia Bacteriana Múltiple , Pruebas de Sensibilidad MicrobianaRESUMEN
A new development in photoacoustic (PA) imaging has been the use of compact, portable and low-cost laser diodes (LDs), but LD-based PA imaging suffers from low signal intensity recorded by the conventional transducers. A common method to improve signal strength is temporal averaging, which reduces frame rate and increases laser exposure to patients. To tackle this problem, we propose a deep learning method that will denoise point source PA radio-frequency (RF) data before beamforming with a very few frames, even one. We also present a deep learning method to automatically reconstruct point sources from noisy pre-beamformed data. Finally, we employ a strategy of combined denoising and reconstruction, which can supplement the reconstruction algorithm for very low signal-to-noise ratio inputs.
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BACKGROUND: The aim of the current study was to investigate the frequency of variations of the extensor tendons of the carpus and digits in the domestic dog (Canis lupus familiaris) with a reexamination of their insertions as well as the morphometric measurements of the tendons and the brachioradialis muscle. In total, we investigated 68 paired thoracic limbs of the domestic dog (16 females and 18 males) which were fixed in a 10% formalin solution. RESULTS: The extensor carpi radialis (ECR) tendons showed striking variations in both splitting and insertion sites. In 4.4% of dissections, ECR had three tendons. Of these tendons, the extra tendon either attached independently on the fourth metacarpal bone (one right) or joined its counterpart tendon at the distal end (cross-connections) (one bilateral). It is worth mentioning that one of the ECR tendons split into two or three slips which inserted on the first, second, third, or fourth metacarpal bone in 11 (16.2%) of the specimens. In addition, we found a long tendinous slip originating from the ECR tendons to digit II or III in 7.4% of the distal limbs. The most common type of contribution to digit III was a third tendon of the extensor digiti I et II (ED III) joining the extensor digitorum lateralis (EDL III) with a frequency of 17.6%. In other types of variations, the contribution to digit III was incomplete. A part of the abductor pollicis longus (APL) deep to the superficial part of the flexor retinaculum seemed to continue up to the flexor digitorum superficialis (FDS) tendon. CONCLUSIONS: The rare intraspecific variations of the extensor tendons of the manus described in the current research are valuable from both clinical and phylogenetic perspectives. Nonetheless, their functional importance needs more studies.
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Enfermedades de los Perros , Lobos , Masculino , Femenino , Perros , Animales , Filogenia , Tendones , Músculo Esquelético , CadáverRESUMEN
Wearable sensors are able to monitor physical health in a home environment and detect changes in gait patterns over time. To ensure long-term user engagement, wearable sensors need to be seamlessly integrated into the user's daily life, such as hearing aids or earbuds. Therefore, we present EarGait, an open-source Python toolbox for gait analysis using inertial sensors integrated into hearing aids. This work contributes a validation for gait event detection algorithms and the estimation of temporal parameters using ear-worn sensors. We perform a comparative analysis of two algorithms based on acceleration data and propose a modified version of one of the algorithms. We conducted a study with healthy young and elderly participants to record walking data using the hearing aid's integrated sensors and an optical motion capture system as a reference. All algorithms were able to detect gait events (initial and terminal contacts), and the improved algorithm performed best, detecting 99.8% of initial contacts and obtaining a mean stride time error of 12 ± 32 ms. The existing algorithms faced challenges in determining the laterality of gait events. To address this limitation, we propose modifications that enhance the determination of the step laterality (ipsi- or contralateral), resulting in a 50% reduction in stride time error. Moreover, the improved version is shown to be robust to different study populations and sampling frequencies but is sensitive to walking speed. This work establishes a solid foundation for a comprehensive gait analysis system integrated into hearing aids that will facilitate continuous and long-term home monitoring.
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Audífonos , Humanos , Anciano , Marcha , Caminata , Análisis de la Marcha , Velocidad al Caminar , AlgoritmosRESUMEN
Nephrotic syndrome (NS) is associated with metabolic perturbances including profound dyslipidemia characterized by hypercholesterolemia and hypertriglyceridemia. A major underlying mechanism of hypertriglyceridemia in NS is lipoprotein lipase (LPL) deficiency and dysfunction. There is emerging evidence that elevated angiopoietin-like protein 3 (ANGPTL3), an LPL inhibitor that is primarily expressed and secreted by hepatocytes, may be in part responsible for these findings. Furthermore, there is evidence pointing to the contribution of ANGPTL3 to the pathogenesis of proteinuria in NS. Therefore, we hypothesized that inhibition of hepatic ANGPTL3 by RNA interference will ameliorate dyslipidemia and other symptoms of NS and pave the way for a new therapeutic strategy. To this end, we used a subcutaneously delivered, GalNAc (N-Acetylgalactosamine)-conjugated small interfering RNA (siRNA) to selectively target and suppress liver Angptl3 in rats with puromycin-induced NS, which exhibits clinical features of NS including proteinuria, hypoalbuminemia, hyperlipidemia, and renal histologic abnormalities. The study demonstrated that siRNA-mediated knockdown of the liver Angptl3 relieved its inhibitory effect on LPL and significantly reduced hypertriglyceridemia in nephrotic rats. This was accompanied by diminished proteinuria and hypoalbuminemia, which are the hallmarks of NS, and significant attenuation of renal tissue inflammation and oxidative stress. Taken together, this study confirmed the hypothesis that suppression of Angptl3 is protective in NS and points to the possibility that the use of RNA interference to suppress hepatic Angptl3 can serve as a novel therapeutic strategy for NS. SIGNIFICANCE STATEMENT: The current standard of care for mitigating nephrotic dyslipidemia in nephrotic syndrome is statins therapy. However, the efficacy of statins and its safety in the context of impaired kidney function is not well established. Here, we present an alternate therapeutic approach by using siRNA targeting Angptl3 expressed in hepatocytes. As the liver is the major source of circulating Angptl3, siRNA treatment reduced the profound hypertriglyceridemia in a rat model of nephrotic syndrome and was also effective in improving kidney and cardiac function.
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Hipertrigliceridemia/complicaciones , Hígado/metabolismo , Síndrome Nefrótico/genética , Síndrome Nefrótico/prevención & control , Interferencia de ARN , Animales , Modelos Animales de Enfermedad , Lipoproteína Lipasa/metabolismo , Masculino , Síndrome Nefrótico/complicaciones , Ratas , Ratas Sprague-DawleyRESUMEN
BACKGROUND: Patients with ESRD on maintenance hemodialysis (MHD) are particularly susceptible to dysregulation of energy metabolism, which may manifest as protein energy wasting and cachexia. In recent years, the endocannabinoid system has been shown to play an important role in energy metabolism with potential relevance in ESRD. N-acylethanolamines are a class of fatty acid amides which include the major endocannabinoid ligand, anandamide, and the endogenous peroxisome proliferator-activated receptor-α agonists, oleoylethanolamide (OEA) and palmitoylethanolamide (PEA). METHODS: Serum concentrations of OEA and PEA were measured in MHD patients and their correlations with various clinical/laboratory indices were examined. Secondarily, we evaluated the association of circulating PEA and OEA levels with 12-month all-cause mortality. RESULTS: Both serum OEA and PEA levels positively correlated with high-density lipoprotein-cholesterol levels and negatively correlated with body fat and body anthropometric measures. Serum OEA levels correlated positively with serum interleukin-6 (IL-6) (rho = 0.19; p = 0.004). Serum PEA and IL-6 showed a similar but nonsignificant trend (rho = 0.12; p = 0.07). Restricted cubic spline analyses showed that increasing serum OEA and PEA both trended toward higher mortality risk, and these associations were statistically significant for PEA (PEA ≥4.7 pmol/mL; reference: PEA <4.7 pmol/mL) after adjustments in a Cox model (hazard ratio 2.99; 95% confidence interval 1.04, 8.64). CONCLUSIONS: In MHD patients, OEA and PEA are significantly correlated with variables related to lipid metabolism and body mass. Additionally, higher serum levels of PEA are associated with mortality risk. Future studies are needed to examine the potential mechanisms responsible for these findings and their clinical implications.
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Amidas/sangre , Endocannabinoides/sangre , Etanolaminas/sangre , Fallo Renal Crónico/sangre , Fallo Renal Crónico/terapia , Ácidos Oléicos/sangre , Ácidos Palmíticos/sangre , Diálisis Renal , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
BACKGROUND: Lactate dehydrogenase (LDH) plays a role in the glucose metabolism of the human body. Higher LDH levels have been linked to mortality in various cancer types; however, the relationship between LDH and survival in incident hemodialysis (HD) patients has not yet been examined. We hypothesized that higher LDH level is associated with higher death risk in these patients. METHODS: We examined the association of baseline and time-varying serum LDH with all-cause, cardiovascular and infection-related mortality among 109 632 adult incident HD patients receiving care from a large dialysis organization in the USA during January 2007 to December 2011. Baseline and time-varying survival models were adjusted for demographic variables and available clinical and laboratory surrogates of malnutrition-inflammation complex syndrome. RESULTS: There was a linear association between baseline serum LDH levels and all-cause, cardiovascular and infection-related mortality in both baseline and time-varying models, except for time-varying infection-related mortality. Adjustment for markers of inflammation and malnutrition attenuated the association in all models. In fully adjusted models, baseline LDH levels ≥360 U/L were associated with the highest risk of all-cause mortality (hazard ratios = 1.19, 95% confidence interval 1.14-1.25). In time-varying models, LDH >280 U/L was associated with higher death risk in all three hierarchical models for all-cause and cardiovascular mortality. CONCLUSIONS: Higher LDH level >280 U/L was incrementally associated with higher all-cause and cardiovascular mortality in incident dialysis patients, whereas LDH <240 U/L was associated with better survival. These findings suggest that the assessment of metabolic functions and monitoring for comorbidities may confer survival benefit to dialysis patients.
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Biomarcadores/sangre , Enfermedades Cardiovasculares/mortalidad , Infecciones/mortalidad , L-Lactato Deshidrogenasa/sangre , Diálisis Renal/mortalidad , Adulto , Enfermedades Cardiovasculares/sangre , Enfermedades Cardiovasculares/terapia , Femenino , Humanos , Infecciones/sangre , Infecciones/terapia , Masculino , Persona de Mediana Edad , Pronóstico , Tasa de SupervivenciaRESUMEN
BACKGROUND: Several studies have shown that probiotics have beneficial effects on weight control and metabolic health. In addition to probiotics, recent studies have investigated the effects of paraprobiotics and postbiotics. Therefore, we evaluated the preventive effects of live and pasteurized Akkermansia muciniphila MucT (A. muciniphila) and its extracellular vesicles (EVs) on HFD-induced obesity. RESULTS: The results showed that body weight, metabolic tissues weight, food consumption, and plasma metabolic parameters were increased in the HFD group, whereas A. muciniphila preventive treatments inhibited these HFD. The effects of pasteurized A. muciniphila and its extracellular vesicles were more noticeable than its active form. The HFD led to an increase in the colonic, adipose tissue, and liver inflammations and increased the expression of genes involved in lipid metabolism and homeostasis. Nevertheless, these effects were inhibited in mice that were administered A. muciniphila and its EVs. The assessment of the gut microbiota revealed significant differences in the microbiota composition after feeding with HFD. However, all treatments restored the alterations in some bacterial genera and closely resemble the control group. Also, the correlation analysis indicated that some gut microbiota might be associated with obesity-related indices. CONCLUSIONS: Pasteurized A. muciniphila and its EVs, as paraprobiotic and postbiotic agents, were found to play a key role in the regulation of metabolic functions to prevent obesity, probably by affecting the gut-adipose-liver axis.
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Tejido Adiposo/metabolismo , Vesículas Extracelulares , Obesidad/prevención & control , Probióticos/administración & dosificación , Akkermansia/citología , Akkermansia/fisiología , Animales , Homeostasis/genética , Metabolismo de los Lípidos/genética , Masculino , Ratones , Ratones Endogámicos C57BL , PasteurizaciónRESUMEN
Among different pathological mechanisms, neuronal loss and neurogenesis impairment in the hippocampus play important roles in cognitive decline in Alzheimer's disease (AD). AD is a progressive and complex neurodegenerative diseases, which is very debilitating. The purpose of this paper is to review recent research into neurogenesis and AD and discuss how pharmacological drugs and herbal active components have impacts on neurogenesis and consequently improve cognitive functions. To date, despite huge research, no effective treatment has been approved for AD. Therefore, an avenue for future research and drug discovery is stimulating adult hippocampal neurogenesis (AHN). Evidence suggests that neurogenesis is regulated by the pharmacological treatment that may be recommended as a part of prophylaxis and therapeutic options for AD. However, the underlying mechanisms of regulating neurogenesis in AD are not well understood. To this point, we highlight to achieve an efficient treatment in AD by manipulating neurogenesis, it's necessary to target all steps of neurogenesis.
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Enfermedad de Alzheimer/terapia , Neurogénesis , Enfermedad de Alzheimer/etiología , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Animales , Biomarcadores , Terapia Combinada , Manejo de la Enfermedad , Susceptibilidad a Enfermedades , Desarrollo de Medicamentos , Descubrimiento de Drogas , Humanos , Terapia Molecular Dirigida , Neurogénesis/efectos de los fármacos , Neurogénesis/genética , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Neuronas/patologíaRESUMEN
RATIONALE & OBJECTIVE: Clinical practice guidelines recommend a target blood pressure (BP)<130/80 mm Hg to reduce cardiovascular risk. However, the optimal BP to prevent chronic kidney disease (CKD) is unknown. STUDY DESIGN: Population-based retrospective cohort study. SETTING & PARTICIPANTS: 10.5 million adults who participated in the National Health Insurance Service National Health Checkup Program in South Korea between 2009 and 2015 and had an estimated glomerular filtration rate (GFR) ≥ 60 mL/min/1.73 m2 at the beginning of follow-up. PREDICTORS: Baseline and time-updated systolic BP (SBP) as a continuous variable and categorized as<110, 110 to 119, 120 to 129, 130 to 139, or≥140 mm Hg. OUTCOME: Incident CKD GFR categories 3 to 5 (CKD G3-G5), defined as de novo development of estimated GFR<60 mL/min/1.73 m2 for at least 2 consecutive assessments confirmed at least 90 days apart. ANALYTICAL APPROACH: Cox proportional hazards regression for baseline BP and marginal structural analysis for time-updated BP. RESULTS: During 49,169,311 person-years of follow-up, incident CKD G3-G5 developed in 172,423 (1.64%) individuals with a crude event rate of 3.51 (95% CI, 3.49-3.52) per 1,000 person-years. Compared to a baseline SBP of 120 to 129 mm Hg, HRs for incident CKD G3-G5 for the<110, 110 to 119, 130 to 139, and≥140 mm Hg categories were 0.84 (95% CI, 0.82-0.85), 0.92 (95% CI, 0.91-0.94), 1.11 (95% CI, 1.09-1.12), and 1.30 (95% CI, 1.28-1.31), respectively. For time-updated SBPs, corresponding HRs were 0.57 (95% CI, 0.56-0.59), 0.79 (95% CI, 0.78-0.80), 1.58 (95% CI, 1.55-1.60), and 2.49 (95% CI, 2.45-2.53), respectively. Treated as a continuous exposure, each 10-mm Hg higher SBP was associated with 35% higher risk for incident CKD G3-G5 (95% CI, 1.35-1.36). LIMITATIONS: Use of International Classification of Diseases codes to assess comorbid condition burden; residual confounding, and potential selection bias cannot be excluded. CONCLUSIONS: In this large national cohort study, higher SBPs were associated with higher risk for incident CKD G3-G5. These findings support evaluation of SBP-lowering strategies to reduce the development of CKD.
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Presión Sanguínea , Hipertensión/epidemiología , Insuficiencia Renal Crónica/epidemiología , Adulto , Anciano , Antihipertensivos/uso terapéutico , Estudios de Cohortes , Femenino , Tasa de Filtración Glomerular , Humanos , Hipertensión/tratamiento farmacológico , Incidencia , Masculino , Persona de Mediana Edad , Modelos de Riesgos Proporcionales , República de Corea/epidemiología , Estudios Retrospectivos , Factores de Riesgo , SístoleRESUMEN
BACKGROUND: Mortality in patients with end-stage renal disease (ESRD) on maintenance hemodialysis (MHD) remains exceptionally high. While traditional risk factors such as obesity are paradoxically associated with better survival, nontraditional risk factors including cachexia increase the likelihood of poor outcomes. There is accumulating evidence that the endocannabinoid (ECB) system plays a major role in energy preservation and storage, factors which can prevent the deleterious effects of cachexia. Hence, in this study, we evaluated the association of circulating ECB levels with mortality in MHD patients. METHODS: Serum concentrations of anandamide (AEA) and 2-arachidonoyl-sn-glycerol (2-AG), major ECB ligands, were measured in MHD patients. Their correlation with various clinical/laboratory indices and association with 12-month all-cause mortality were examined. RESULTS: Serum 2-AG levels positively correlated with body mass index, serum triglycerides and body anthropometric measures. Meanwhile, serum AEA levels correlated positively with serum interleukin-6, and negatively with serum very low-density lipoprotein levels. While increased serum 2-AG levels were associated with reduced risk of all-cause mortality (hazard ratio [HR] 0.52, 95% CI 0.28-0.98), there was no clear association between serum AEA levels and mortality (HR 0.91, 95% CI 0.48-1.72). CONCLUSIONS: In MHD patients, the circulating levels of ECB ligand, 2-AG, may play an important role in determining body mass and risk of mortality. These observations were unique to 2-AG as similar findings were not obtained with serum AEA. Future studies need to investigate the mechanisms responsible for these associations and examine the modulation of the ECB system as a potential target for therapy in ESRD.
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Ácidos Araquidónicos/sangre , Endocannabinoides/sangre , Glicéridos/sangre , Fallo Renal Crónico/sangre , Fallo Renal Crónico/mortalidad , Alcamidas Poliinsaturadas/sangre , Diálisis Renal , Adulto , Anciano , Correlación de Datos , Femenino , Humanos , Fallo Renal Crónico/terapia , Masculino , Persona de Mediana Edad , Estudios ProspectivosRESUMEN
Alzheimer's disease (AD) is described as cognitive and memory impairments with a sex-related epidemiological profile, affecting two times more women than men. There is emerging evidence that alternations in the hippocampal neurogenesis occur at the early stage of AD. Therapies that may effectively slow, stop, or regenerate the dying neurons in AD are being extensively investigated in the last few decades, but none has yet been found to be effective. The regulation of endogenous neurogenesis is one of the main therapeutic targets for AD. Mounting evidence indicates that the neurosteroid estradiol (17ß-estradiol) plays a supporting role in neurogenesis, neuronal activity, and synaptic plasticity of AD. This effect may provide preventive and/or therapeutic approaches for AD. In this article, we discuss the molecular mechanism of potential estradiol modulatory action on endogenous neurogenesis, synaptic plasticity, and cognitive function in AD.
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Enfermedad de Alzheimer/fisiopatología , Enfermedad de Alzheimer/psicología , Cognición/efectos de los fármacos , Estradiol/farmacología , Neurogénesis/efectos de los fármacos , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/patología , Animales , Modelos Animales de Enfermedad , Hipocampo/efectos de los fármacos , Hipocampo/fisiología , Humanos , Neurogénesis/fisiología , Plasticidad Neuronal/efectos de los fármacos , Plasticidad Neuronal/genética , Neuronas/efectos de los fármacos , Neuronas/fisiologíaRESUMEN
OBJECTIVE: Serum albumin is a marker of malnutrition and inflammation and has been demonstrated as a strong predictor of mortality in chronic kidney disease (CKD) and end-stage renal disease (ESRD) patients. Yet, whether serum albumin levels in late-stage CKD are associated with adverse outcomes after the transition to ESRD is unknown. We hypothesize that lower levels and a decline in serum albumin in late-stage CKD are associated with higher risk of mortality and hospitalization rates 1 year after transition to ESRD. DESIGN AND METHODS: This retrospective cohort study included 29,124 US veterans with advanced CKD transitioning to ESRD between 2007 and 2015. We evaluated the association of pre-ESRD (91 days before transition) serum albumin with 12-month post-ESRD all-cause, cardiovascular, and infection-related mortalities and hospitalization rates as well as the association of 1-year pre-ESRD albumin slope and 12-month post-ESRD mortality using hierarchical multivariable adjustments. RESULTS: There was a negative linear association between serum albumin and all-cause mortality, such that risk doubled (hazard ratio [HR]: 2.07, 95% confidence interval [CI]: 1.87, 2.28) for patients with the lowest serum albumin <2.8 g/dL (ref: ≥4.0 g/dL) after full adjustment. A consistent relationship was observed between serum albumin and cardiovascular and infection-related mortality, and hospitalization outcomes. An increase in serum albumin of >0.25 g/dL/year was associated with reduced mortality risk (HR: 0.76, 95% CI: 0.63, 0.91) compared with a slight decline in albumin (ref: >-0.25 to 0 g/dL/year), whereas a decline more than 0.5 g/dL/year was associated with a 55% higher risk in mortality (HR: 1.55, 95% CI: 1.43, 1.68) in fully adjusted models. CONCLUSIONS: Lower pre-ESRD serum albumin was associated with higher post-ESRD all-cause, cardiovascular, and infection-related mortalities and hospitalization rates. Declining serum albumin levels in the pre-ESRD period were also associated with worse 12-month post-ESRD mortality.
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Diálisis Renal/métodos , Insuficiencia Renal Crónica/sangre , Insuficiencia Renal Crónica/terapia , Albúmina Sérica/metabolismo , Anciano , Biomarcadores/sangre , Estudios de Cohortes , Progresión de la Enfermedad , Femenino , Humanos , Fallo Renal Crónico/sangre , Fallo Renal Crónico/terapia , Masculino , Estudios Retrospectivos , Estados Unidos , VeteranosRESUMEN
Ascorbic acid (AA) accumulation in intestinal epithelial cells is an active transport process mainly mediated by two sodium-dependent vitamin C transporters (SVCT-1 and SVCT-2). To date, little is known about the effect of gut microbiota generated lipopolysaccharide (LPS) on intestinal absorption of water-soluble vitamins. Therefore, the objective of this study was to investigate the effects of bacterially-derived LPS on AA homeostasis in enterocytes using Caco-2 cells, mouse intestine and intestinal enteroids models. Pre-treating Caco-2 cells and mice with LPS led to a significant decrease in carrier-mediated AA uptake. This inhibition was associated with a significant reduction in SVCT-1 and SVCT-2 protein, mRNA, and hnRNA expression. Furthermore, pre-treating enteroids with LPS also led to a marked decrease in SVCT-1 and SVCT-2 protein and mRNA expression. Inhibition of SVCT-1 and SVCT-2 occurred at least in part at the transcriptional level as promoter activity of SLC23A1 and SLC23A2 was attenuated following LPS treatment. Subsequently, we examined the protein and mRNA expression levels of HNF1α and Sp1 transcription factors, which are needed for basal SLC23A1 and SLC23A2 promoter activity, and found that they were significantly decreased in the LPS treated Caco-2 cells and mouse jejunum; this was reflected on level of the observed reduction in the interaction of these transcription factors with their respective promoters in Caco-2 cells treated with LPS. Our findings indicate that LPS inhibits intestinal carrier- mediated AA uptake by down regulating the expression of both vitamin C transporters and transcriptional regulation of SLC23A1 and SLC23A2 genes.
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Ácido Ascórbico/metabolismo , Regulación de la Expresión Génica/efectos de los fármacos , Absorción Intestinal/efectos de los fármacos , Intestinos/efectos de los fármacos , Lipopolisacáridos/farmacología , Animales , Ácido Ascórbico/farmacocinética , Transporte Biológico/efectos de los fármacos , Células CACO-2 , Células Cultivadas , Enterocitos/citología , Enterocitos/efectos de los fármacos , Enterocitos/metabolismo , Humanos , Mucosa Intestinal/metabolismo , Intestinos/citología , Masculino , Ratones Endogámicos C57BL , Transportadores de Sodio Acoplados a la Vitamina C/genética , Transportadores de Sodio Acoplados a la Vitamina C/metabolismo , Vitaminas/metabolismo , Vitaminas/farmacocinéticaRESUMEN
Obesity is a major risk factor for cardiovascular disease and worse survival in the general population. However, in patients with end-stage renal disease (ESRD), higher body mass index and indexes of body fat and muscle are associated with better survival. Furthermore, these associations, which some have described as the obesity paradox, are more consistent in African American patients being treated with hemodialysis when compared with other racial-ethnic groups. This is in view of data indicating that although the rate of progression to ESRD is faster in African American patients, they have a survival advantage after transition to ESRD when compared with their white counterparts. These observations indicate that there may be significant interaction between race/ethnicity and association of body mass index with outcomes in patients with ESRD. In addition, it is possible that mechanisms underlying improved survival in African American hemodialysis patients are partly related to the association of body mass index with outcomes observed in this patient population. Some of these potential mechanisms may include comparatively reduced risk for protein-energy wasting and malnutrition, possible salutary effects of factors that play a role in energy preservation, resistance to deleterious effects of inflammation, and enhanced muscle mass and body composition. Given that ESRD is associated with significantly increased risk for morbidity and mortality, understanding the pathophysiologic mechanisms responsible for the obesity paradox across race-ethnic populations might help identify potential therapeutic targets that can be used to improve survival in this patient population.
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Etnicidad , Fallo Renal Crónico/etnología , Obesidad/etnología , Grupos Raciales , Medición de Riesgo , Índice de Masa Corporal , Salud Global , Humanos , Incidencia , Fallo Renal Crónico/etiología , Obesidad/complicaciones , Pronóstico , Factores de Riesgo , Tasa de Supervivencia/tendenciasRESUMEN
BACKGROUND: Chronic kidney disease (CKD) is associated with cardiac hypertrophy, fibrosis, and increased risk of cardiovascular mortality. LCZ696 (sacubitril/valsartan) is a promising agent that has shown significant potential in treatment of heart failure. We hypothesized that LCZ696 is more effective than valsartan alone in the treatment of cardiovascular abnormalities associated with experimental CKD. METHODS AND RESULTS: Male Sprague-Dawley rats underwent 5/6 nephrectomy and were subsequently randomized to no treatment (CKD), 30 mg/kg valsartan (VAL), or 60 mg/kg LCZ696 (LCZ). After 8 weeks, cardiovascular parameters, including markers of inflammation, oxidative stress, mitochondrial abundance/function, hypertrophy, and fibrosis, were measured. Treatment with LCZ resulted in significant improvements in the heart-body weight ratio and serum concentrations of N-terminal pro-B-type natriuretic peptide and fibroblast growth factor 23 along with improvement of kidney function. In addition, LCZ ameliorated aortic fibrosis and cardiac hypertrophy and fibrosis, reduced markers of cardiac oxidative stress and inflammation, and improved indicators of mitochondrial mass/function. Although VAL also improved some of these indices, treatment with LCZ was more effective than VAL alone. CONCLUSIONS: CKD-associated cardiovascular abnormalities, including myocardial hypertrophy, fibrosis, inflammation, oxidative stress, and mitochondrial depletion/dysfunction, were more effectively attenuated by LCZ treatment than by VAL alone.
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Aminobutiratos , Cardiomegalia , Insuficiencia Cardíaca , Volumen Sistólico , Tetrazoles , Animales , Masculino , Ratas , Aminobutiratos/uso terapéutico , Antagonistas de Receptores de Angiotensina/uso terapéutico , Compuestos de Bifenilo , Cardiomegalia/complicaciones , Cardiomegalia/tratamiento farmacológico , Cardiomegalia/fisiopatología , Modelos Animales de Enfermedad , Combinación de Medicamentos , Fibrosis/complicaciones , Fibrosis/tratamiento farmacológico , Insuficiencia Cardíaca/etiología , Insuficiencia Cardíaca/fisiopatología , Insuficiencia Cardíaca/prevención & control , Neprilisina/antagonistas & inhibidores , Distribución Aleatoria , Ratas Sprague-Dawley , Volumen Sistólico/efectos de los fármacos , Volumen Sistólico/fisiología , Tetrazoles/uso terapéutico , ValsartánRESUMEN
BACKGROUND: Incident hemodialysis patients have a high mortality risk within the first months after dialysis initiation. Pre-end-stage renal disease (ESRD) factors like anemia management may impact early post-ESRD outcomes. Therefore, we evaluated the impact of pre-ESRD hemoglobin (Hgb) and pre-ESRD Hgb slope on post-ESRD mortality and hospitalization outcomes. METHODS: The study included 31,472 veterans transitioning to ESRD. Using Cox and negative binomial regression models, we evaluated the association of pre-ESRD Hgb and Hgb slope with 12-month post-ESRD all-cause and cardiovascular mortality and hospitalization rates using 4 levels of hierarchical multivariable adjustment, including erythropoietin use and kidney decline in slope models. RESULTS: The cohort was 2% female, 30% African-American, and on average 68 ± 11 years old. Compared to Hgb 10-< 11 g/dL, both low (< 10 g/dL) and high (≥12 g/dL) levels were associated with higher all-cause mortality after full adjustment (HR 1.25 [95% CI 1.15-1.35] and 1.09 [95% CI 1.02-1.18], respectively). Similarly, Hgb exhibited a U-shaped association with CV mortality, while only lower Hgb was associated with a higher hospitalization rate. Neither an annual pre-ESRD decline in Hgb nor increase was associated with higher post-ESRD mortality risk after adjustment for kidney decline. However, we observed a modest J-shaped association between pre-ESRD Hgb slope and post-ESRD hospitalization rate. CONCLUSIONS: Lower and higher pre-ESRD Hgb levels are associated with a higher risk of early post-ESRD mortality, while there was no association between the pre-ESRD slope and mortality. An increase in pre-ESRD Hgb slope was associated with higher risk of post-ESRD hospitalization. Additional studies aimed at anemia management prior to ESRD transition are warranted.
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Anemia/epidemiología , Hemoglobinas/análisis , Fallo Renal Crónico/terapia , Diálisis Renal , Anciano , Anemia/sangre , Anemia/etiología , Progresión de la Enfermedad , Femenino , Hospitalización/estadística & datos numéricos , Humanos , Incidencia , Fallo Renal Crónico/complicaciones , Fallo Renal Crónico/mortalidad , Masculino , Persona de Mediana Edad , Medición de Riesgo/métodos , Análisis de Supervivencia , Resultado del Tratamiento , Estados Unidos/epidemiología , Veteranos/estadística & datos numéricosRESUMEN
Cardiovascular disease (CVD) is a major cause of morbidity and mortality worldwide. Although numerous modifiable risk factors in the pathogenesis of CVD and its associated mortality have been identified, dyslipidemia remains to be a key focus for therapy. In this regard, significant progress has been made in reducing cardiovascular mortality via the use of lipid-lowering agents such as HMG CoA reductase inhibitors (statins). Yet, despite the disproportionate risk of CVD and mortality in patients with advanced chronic and end stage renal disease (ESRD), treatment of dyslipidemia in this patient population has not been associated with a notable improvement in outcomes. Furthermore, observational studies have not consistently found an association between dyslipidemia and poor outcomes in patients with ESRD. However, it is imperative that examination of dyslipidemia and its association with outcomes take place in the context of the many factors that are unique to kidney disease and may contribute to the abnormalities in lipid metabolism in patients with ESRD. Understanding these intricacies and distinct features will be vital not only to the interpretation of the available clinical data in regards to outcomes, but also to the individualization of lipid therapy in ESRD. In this review, we will examine the nature and underlying mechanisms responsible for dyslipidemia, the association of serum lipids and lipoprotein concentrations with outcomes and the results of major trials targeting cholesterol (mainly statins) in patients with ESRD.
Asunto(s)
Dislipidemias/tratamiento farmacológico , Dislipidemias/etiología , Fallo Renal Crónico/complicaciones , Fallo Renal Crónico/terapia , Diálisis Renal , Dislipidemias/diagnóstico , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéuticoRESUMEN
Consumption of cannabis and various related products (cannabinoids) for both medicinal and recreational use is gaining popularity. Furthermore, regulatory changes are fostering a cultural shift toward increasing liberalization of cannabis use, thereby increasing the likelihood of even larger numbers of individuals being exposed in the future. The two different types of receptors (CB1 and CB2) that are activated by the pharmacologically active ingredients of cannabis are found in numerous tissues, including the kidneys. Experimental studies suggest that stimulation of these receptors using pharmacologic agents or their naturally occurring ligands could have both deleterious and beneficial effects on the kidneys, depending on receptor distribution, type of renal insult, or the timing of the activation during acute or chronic states of kidney injury. To date, the mechanisms by which the CB1 or CB2 receptors are involved in the pathology of these renal conditions remain to be fully described. Furthermore, a better understanding of the impact of exocannabinoids and endocannabinoids on the renal system may lead to the development of new drugs to treat kidney disease and its complications. Given the increasing public health relevance of cannabis exposure, it is clear that more research is necessary to clarify the various physiological and pathophysiological effects of cannabis and related analogs on the kidney. This will help limit the deleterious effects of these substances while promoting their potential beneficial impact on renal function in various types of kidney diseases.
Asunto(s)
Cannabinoides/farmacología , Endocannabinoides/farmacología , Enfermedades Renales/tratamiento farmacológico , Riñón/efectos de los fármacos , Animales , Humanos , Riñón/metabolismo , Enfermedades Renales/metabolismo , Receptor Cannabinoide CB1/metabolismo , Receptor Cannabinoide CB2/metabolismoRESUMEN
BACKGROUND: Vitamin B12 (B12) and folate are essential vitamins that play important roles in physiological processes. In the general population, many studies have evaluated the association of these vitamins with clinical outcomes, yet this association in hemodialysis (HD) patients remains unclear. METHODS: We examined the association of serum folate and B12 with mortality in a 5-year cohort of 9517 (folate) and 12 968 (B12) HD patients using Cox models with hierarchical adjustment for sociodemographics, comorbidities, and laboratory variables associated with the malnutrition and inflammation complex syndrome. The associations of baseline B12 and folate (separately) with all-cause mortality were evaluated across five categories of B12 [<400 (reference), 400-<550, 550-<650, 650-<750 and ≥750 pg/mL] and folate [<6.2, 6.2-<8.4, 8.4-<11 (reference), 11-<14.3 and ≥14.3 ng/mL]. RESULTS: The study cohort with B12 measurements had a mean ± standard deviation age of 63 ± 15 years, among whom 43% were female, 33% were African-American, and 57% were diabetic. Higher B12 concentrations ≥550 pg/mL were associated with a higher risk of mortality after adjusting for sociodemographic and laboratory variables. However, only lower serum folate concentrations <6.2 ng/mL were associated with a higher risk of all-cause mortality when adjusted for sociodemographic variables [adjusted hazard ratio (95% confidence-interval): 1.18 (1.03-1.35)]. CONCLUSIONS: Higher B12 concentrations are associated with higher all-cause mortality in HD patients independent of sociodemographics and laboratory variables, whereas lower folate concentrations were associated with higher all-cause mortality after accounting for sociodemographic variables. Further studies are warranted to determine the optimal B12 and folate level targets in this population.