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BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic has disproportionately affected socially disadvantaged populations. Whether disparities in COVID-19 incidence related to race/ethnicity and socioeconomic factors exist in the hemodialysis population is unknown. METHODS: Our study involved patients receiving in-center hemodialysis in New York City. We used a validated index of neighborhood social vulnerability, the Social Vulnerability Index (SVI), which comprises 15 census tract-level indicators organized into four themes: socioeconomic status, household composition and disability, minority status and language, and housing type and transportation. We examined the association of race/ethnicity and the SVI with symptomatic COVID-19 between March 1, 2020 and August 3, 2020. COVID-19 cases were ascertained using PCR testing. We performed multivariable logistic regression to adjust for demographics, individual-level social factors, dialysis-related medical history, and dialysis facility factors. RESULTS: Of the 1378 patients on hemodialysis in the study, 247 (17.9%) developed symptomatic COVID-19. In adjusted analyses, non-Hispanic Black and Hispanic patients had significantly increased odds of COVID-19 compared with non-Hispanic White patients. Census tract-level overall SVI, modeled continuously or in quintiles, was not associated with COVID-19 in unadjusted or adjusted analyses. Among non-Hispanic White patients, the socioeconomic status SVI theme, the minority status and language SVI theme, and housing crowding were significantly associated with COVID-19 in unadjusted analyses. CONCLUSIONS: Among patients on hemodialysis in New York City, there were substantial racial/ethnic disparities in COVID-19 incidence not explained by neighborhood-level social vulnerability. Neighborhood-level socioeconomic status, minority status and language, and housing crowding were positively associated with acquiring COVID-19 among non-Hispanic Whites. Our findings suggest that socially vulnerable patients on dialysis face disparate COVID-19-related exposures, requiring targeted risk-mitigation strategies.
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COVID-19/complicaciones , COVID-19/epidemiología , Disparidades en el Estado de Salud , Fallo Renal Crónico/complicaciones , Diálisis Renal , SARS-CoV-2 , Adolescente , Adulto , Negro o Afroamericano , Anciano , Anciano de 80 o más Años , Estudios de Cohortes , Femenino , Hispánicos o Latinos , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Ciudad de Nueva York/epidemiología , Pandemias , Características de la Residencia , Estudios Retrospectivos , Factores de Riesgo , Factores Socioeconómicos , Poblaciones Vulnerables , Población Blanca , Adulto JovenRESUMEN
OBJECTIVE: Increased fructose consumption is a contributor to the burgeoning epidemic of non-alcoholic fatty liver disease (NAFLD). Recent evidence indicates that the metabolic hormone FGF21 is regulated by fructose consumption in humans and rodents and may play a functional role in this nutritional context. Here, we sought to define the mechanism by which fructose ingestion regulates FGF21 and determine whether FGF21 contributes to an adaptive metabolic response to fructose consumption. METHODS: We tested the role of the transcription factor carbohydrate responsive-element binding protein (ChREBP) in fructose-mediated regulation of FGF21 using ChREBP knockout mice. Using FGF21 knockout mice, we investigated whether FGF21 has a metabolic function in the context of fructose consumption. Additionally, we tested whether a ChREBP-FGF21 interaction is likely conserved in human subjects. RESULTS: Hepatic expression of ChREBP-ß and Fgf21 acutely increased 2-fold and 3-fold, respectively, following fructose gavage, and this was accompanied by increased circulating FGF21. The acute increase in circulating FGF21 following fructose gavage was absent in ChREBP knockout mice. Induction of ChREBP-ß and its glycolytic, fructolytic, and lipogenic gene targets were attenuated in FGF21 knockout mice fed high-fructose diets, and this was accompanied by a 50% reduction in de novo lipogenesis a, 30% reduction VLDL secretion, and a 25% reduction in liver fat compared to fructose-fed controls. In human subjects, serum FGF21 correlates with de novo lipogenic rates measured by stable isotopic tracers (R = 0.55, P = 0.04) consistent with conservation of a ChREBP-FGF21 interaction. After 8 weeks of high-fructose diet, livers from FGF21 knockout mice demonstrate atrophy and fibrosis accompanied by molecular markers of inflammation and stellate cell activation; whereas, this did not occur in controls. CONCLUSIONS: In summary, ChREBP and FGF21 constitute a signaling axis likely conserved in humans that mediates an essential adaptive response to fructose ingestion that may participate in the pathogenesis of NAFLD and liver fibrosis.
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Factores de Transcripción Básicos con Cremalleras de Leucinas y Motivos Hélice-Asa-Hélice/metabolismo , Factores de Crecimiento de Fibroblastos/metabolismo , Fructosa/metabolismo , Proteínas Nucleares/metabolismo , Factores de Transcripción/metabolismo , Animales , Femenino , Factores de Crecimiento de Fibroblastos/sangre , Fructosa/administración & dosificación , Glucólisis , Hepatocitos/metabolismo , Humanos , Lipogénesis , Hígado/metabolismo , Masculino , Ratones , Ratones Noqueados , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Transducción de SeñalRESUMEN
OBJECTIVE: South Asians have higher rates of type 2 diabetes and cardiovascular disease compared to most other racial/ethnic groups. Increased hepatic de novo lipogenesis (DNL) in response to dietary sugar may accelerate the development of these chronic diseases in this population. STUDY DESIGN: Hepatic DNL in response to a calorically sweetened beverage was measured in an outpatient setting in 15 South Asians and 15 Caucasians with similar and normal body mass indexes, waist circumferences, glucose tolerance and lipid profiles. Blood was sampled before and hourly for 4 h after the ingestion of a single beverage made with glucose (1·5 g/kg) and fructose (1·5 g/kg). The main outcome, DNL, was measured as the increase in %palmitate (16:0) in very low-density lipoprotein (VLDL) triglyceride (TG) over 4 h. RESULTS: After the sugar dose, the increase in %16:0 in VLDL TG was significantly greater in South Asians vs Caucasians (P = 0·01). VLDL and total TG also increased to a significantly greater extent in South Asians (P = 0·04 and <0·001, respectively). Although the fasting and postsugar levels of insulin and glucose did not differ between groups, the DNL response significantly correlated with the insulin response to sugar in South Asians (r = 0·56, P = 0·03). CONCLUSIONS: Hepatic DNL in response to a sugar challenge was greater in healthy, young South Asians compared to Caucasians despite normal indices of insulin sensitivity, and it correlated with the insulin response. These findings suggest an early, insulin-related, gene-nutrient interaction contributing to the high prevalence of diabetes and coronary disease in this population.
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Pueblo Asiatico , Sacarosa en la Dieta/farmacología , Lipogénesis/efectos de los fármacos , Adulto , Femenino , Fructosa/administración & dosificación , Fructosa/farmacología , Glucosa/administración & dosificación , Glucosa/farmacología , Humanos , Insulina/sangre , Lipoproteínas VLDL/sangre , Hígado/metabolismo , Masculino , Palmitatos/sangre , Triglicéridos/sangre , Población Blanca , Adulto JovenRESUMEN
PURPOSE: Agarose macrobeads containing mouse renal adenocarcinoma cells (RMBs) release factors, suppressing the growth of cancer cells and prolonging survival in spontaneous or induced tumor animals, mediated, in part, by increased levels of myocyte-enhancing factor (MEF2D) via EGFR-and AKT-signaling pathways. The primary objective of this study was to determine the safety of RMBs in advanced, treatment-resistant metastatic cancers, and then its efficacy (survival), which is the secondary objective. METHODS: Thirty-one patients underwent up to four intraperitoneal implantations of RMBs (8 or 16 macrobeads/kg) via laparoscopy in this single-arm trial (FDA BB-IND 10091; NCT 00283075). Serial physical examinations, laboratory testing, and PET-CT imaging were performed before and three months after each implant. RESULTS: RMBs were well tolerated at both dose levels (mean 660.9 per implant). AEs were (Grade 1/2) with no treatment-related SAEs. CONCLUSION: The data support the safety of RMB therapy in advanced-malignancy patients, and the preliminary evidence for their potential efficacy is encouraging. A Phase 2 efficacy trial is ongoing.
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Agarose encapsulation of porcine islets allows extended in vitro culture, providing ample time to determine the functional capacity of the islets and conduct comprehensive microbiological safety testing prior to implantation as a treatment for type 1 diabetes mellitus. However, the effect that agarose encapsulation and long-term culture may have on porcine islet gene expression is unknown. The aim of the present study was to compare the transcriptome of encapsulated porcine islets following long-term in vitro culture against free islets cultured overnight. Global gene expression analysis revealed no significant change in the expression of 98.47% of genes. This indicates that the gene expression profile of free islets is highly conserved following encapsulation and long-term culture. Importantly, the expression levels of genes that code for critical hormones secreted by islets (insulin, glucagon, and somatostatin) as well as transcripts encoding proteins involved in their packaging and secretion are unchanged. While a small number of genes known to play roles in the insulin secretion and insulin signaling pathways are differentially expressed, our results show that overall gene expression is retained following islet isolation, agarose encapsulation, and long-term culture.
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Islotes Pancreáticos/metabolismo , Animales , Femenino , Expresión Génica , Ontología de Genes , Glucagón/metabolismo , Técnicas In Vitro , Insulina/metabolismo , Secreción de Insulina , Sefarosa , Transducción de Señal/genética , Somatostatina/metabolismo , Sus scrofa , Factores de Tiempo , Técnicas de Cultivo de Tejidos , TranscriptomaRESUMEN
BACKGROUND: Digital tonometry is designed to non-invasively screen for endothelial dysfunction by the detection of impaired flow-induced reactive hyperaemia in the fingertip. We determined whether digital reactive hyperaemia correlated with risk factors for atherosclerosis in two groups of children at increased risk for endothelial dysfunction. METHODS: A total of 15 obese children and 23 non-obese, dyslipidaemic children, 8-21 years of age, were enrolled, and their medical histories, anthropometric measurements, carotid wall thickness by means of ultrasonography, and fasting blood samples for cardiovascular risk factors were obtained. The standard endoPAT index of digital reactive hyperaemia was modified to reflect the true peak response or the integrated response of the entire post-occlusion period. In each group, age, sex, pubertal status, carotid wall thickness, and multiple cardiovascular risk factors were tested as predictors of endothelial dysfunction. RESULTS: In the non-obese, dyslipidaemic group, but not in the obese group, both indices strongly correlated with height (r=0.55, p=0.007, by peak response) followed by weight, waist circumference, and age. In both groups, neither index of reactive hyperaemia significantly correlated with any other cardiovascular risk factor. CONCLUSIONS: Contrary to the known age-related increase in atherosclerosis, digital reactive hyperaemia increased with age and its correlates in non-obese, dyslipidaemic children and was not related to other cardiovascular risk factors in either group. The reason for the lack of this relationship with age in obese children is unknown. The age-dependent physiology of digital microvascular reactivity and the endothelium-independent factors controlling the peak hyperaemic response need further study in children with a wide age range.
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Aterosclerosis/etiología , Endotelio Vascular/fisiopatología , Hiperemia/fisiopatología , Hiperlipidemias/fisiopatología , Obesidad Infantil/fisiopatología , Adolescente , Peso Corporal , Niño , Femenino , Humanos , Masculino , Análisis de Regresión , Factores de Riesgo , Circunferencia de la Cintura , Adulto JovenRESUMEN
BACKGROUND: A global tacrolimus proficiency study recently showed clinically significant variability between laboratories, the inability of a common calibrator to harmonize methods, and differences in patient classification depending on the test method. The authors evaluated (1) the effect of a change in methodology on patient classification based on tacrolimus blood concentration and (2) the ability of 2 methods to position the concentration in a given specimen within the correct range. METHODS: A total of 839 consecutive samples were analyzed at The Rogosin Institute and New York Presbyterian Hospital for routine tacrolimus monitoring over 30 days. Concordance analysis between the methods was performed covering dosage target ranges of 8-10, 6-8, 4-6 ng/mL currently used at our center. Six Sigma Metrics were applied to statistically evaluate the discordance rate. RESULTS: Deming regression comparing liquid chromatography-tandem mass spectrometry and immunoassay yielded y = 0.927x - 0.24; 95% confidence interval, 0.903-0.951; R = 0.875; n = 839. There were 310 pairs (37%) discordant by 1, 21 (2.5%) discordant by 2, and 4 (0.5%) discordant by 3 therapeutic ranges. Surprisingly, 40% of patient samples were discordant when therapeutic ranges were 2 ng/mL wide. This discordant rate is equivalent to 1.7 Sigma and falls far below the minimum acceptable threshold of 3 Sigma. CONCLUSIONS: Both methods are capable of measuring tacrolimus in the clinically relevant range between 1 and 10 ng/mL, yet 40% of the samples were discordant with an unacceptable Sigma level. Standardization of tacrolimus assays will mitigate this issue.
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Monitoreo de Drogas/normas , Inmunosupresores/sangre , Tacrolimus/sangre , Receptores de Trasplantes , Cromatografía Liquida/normas , Monitoreo de Drogas/métodos , Humanos , Espectrometría de Masas/normasRESUMEN
CONTEXT: Increased hepatic de novo lipogenesis (DNL) in response to dietary sugar is implicated in dyslipidemia, fatty liver, and insulin resistance. OBJECTIVE: The aim of the study was to develop a simple outpatient tolerance test for lipogenic sensitivity to dietary sugar. DESIGN AND SETTING: In inpatients given repeated doses of fructose, protocol 1 compared the acute increase in DNL determined from the percentage of palmitate ("new palmitate") and the percentage of isotopically labeled palmitate ("%DNL") in very low-density lipoprotein triglyceride (TG). Protocol 2 compared the increase in new palmitate in outpatients given three different sugar beverages in a randomized crossover design. PARTICIPANTS: There were 15 lean and overweight volunteers in protocol 1 and 15 overweight volunteers in protocol 2. INTERVENTIONS: In protocol 1, subjects received 1.4 g/kg fructose in divided oral doses over 6 h; in protocol 2, subjects received 0.5 g/kg fructose, 0.5 g/kg fructose plus 0.5 g/kg glucose, or 1 g/kg fructose plus 1 g/kg glucose each as a single oral bolus. MAIN OUTCOME MEASURES: We measured the increase in DNL by two methods. RESULTS: After repeated doses of fructose, new palmitate was significantly correlated with the increase in %DNL (Δ, r = 0.814; P < 0.001) and with fasting insulin levels (area under the curve, r = 0.754; P = 0.001). After a single sugar dose, new palmitate showed a dose effect and was greater after fructose plus glucose. Very low-density lipoprotein TG and total TG significantly increased in both protocols. CONCLUSIONS: A single oral bolus of fructose and glucose rapidly increases serum TG and TG palmitate in overweight subjects. A dual sugar challenge test could prove useful to identify individuals at risk for carbohydrate-induced dyslipidemia and other adverse effects of increased DNL.
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Carbohidratos de la Dieta/farmacología , Fructosa/farmacología , Metabolismo de los Lípidos/efectos de los fármacos , Tejido Adiposo/anatomía & histología , Adulto , Glucemia/metabolismo , Estudios Cruzados , Dieta , Ácidos Grasos/metabolismo , Femenino , Glucosa/farmacología , Humanos , Marcaje Isotópico , Lipoproteínas VLDL/sangre , Hígado/efectos de los fármacos , Hígado/metabolismo , Masculino , Persona de Mediana Edad , Sobrepeso/metabolismo , Palmitatos/sangre , Triglicéridos/sangre , Adulto JovenRESUMEN
Cancer cells and their associated tumors have long been considered to exhibit unregulated proliferation or growth. However, a substantial body of evidence indicates that tumor growth is subject to both positive and negative regulatory controls. Here, we describe a novel property of tumor growth regulation that is neither species nor tumor-type specific. This property, functionally a type of feedback control, is triggered by the encapsulation of neoplastic cells in a growth-restricting hydrogel composed of an agarose matrix with a second coating of agarose to form 6- to 8-mm diameter macrobeads. In a mouse cell model of renal adenocarcinoma (RENCA cells), this process resulted in selection for a stem cell-like subpopulation which together with at least one other cell subpopulation drove colony formation in the macrobeads. Cells in these colonies produced diffusible substances that markedly inhibited in vitro and in vivo proliferation of epithelial-derived tumor cells outside the macrobeads. RENCA cells in monolayer culture that were exposed to RENCA macrobead-conditioned media exhibited cell-cycle accumulation in S phase due to activation of a G(2)/M checkpoint. At least 10 proteins with known tumor suppression functions were identified by analysis of RENCA macrobead-conditioned media, the properties of which offer opportunities to further dissect the molecular basis for tumor growth control. More generally, macrobead culture may permit the isolation of cancer stem cells and other cells of the stem cell niche, perhaps providing strategies to define more effective biologically based clinical approaches to treat neoplastic disease.
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Carcinoma de Células Renales/patología , Técnicas de Cultivo de Célula/métodos , Neoplasias Renales/patología , Animales , Ciclo Celular/fisiología , Procesos de Crecimiento Celular/fisiología , Línea Celular Tumoral , Técnicas de Cocultivo , Células HCT116 , Humanos , Ratones , Ratones Endogámicos BALB C , Sefarosa , Especificidad de la EspecieRESUMEN
The culture of tumor cell lines in three-dimensional scaffolds is considered to more closely replicate the in vivo tumor microenvironment than the standard method of two-dimensional cell culture. We hypothesized that our method of encapsulating and maintaining viable and functional pancreatic islets in agarose-agarose macrobeads (diameter 6-8 mm) might provide a novel method for the culture of tumor cell lines. In this report we describe and characterize tumor colonies that form within macrobeads seeded with mouse renal adenocarcinoma cells. Approximately 1% of seeded tumor cells survive in the macrobead and over several months form discrete elliptical colonies appearing as tumor cell niches with increasing metabolic activity in parallel to colony size. The tumor colonies demonstrate ongoing cell turnover as shown by BrdU incorporation and activated caspase-3 and TUNEL staining. Genes upregulated in the tumor colonies of the macrobead are likely adaptations to this novel environment, as well as an amplification of G(1)/S cell-cycle checkpoints. The data presented, including SCA-1 and Oct4 positivity and the upregulation of stem cell-like genes such as those associated with the Wnt pathway, support the notion that the macrobead selects for a subpopulation of cells with cancer stem cell or cancer progenitor properties.
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Carcinoma de Células Renales/patología , Técnicas de Cultivo de Célula/métodos , Neoplasias Renales/patología , Células Madre Neoplásicas/patología , Animales , Apoptosis/fisiología , Carcinoma de Células Renales/genética , Carcinoma de Células Renales/metabolismo , Procesos de Crecimiento Celular , Línea Celular Tumoral , Técnicas de Cocultivo , Expresión Génica , Humanos , Neoplasias Renales/genética , Neoplasias Renales/metabolismo , Ratones , Ratones Endogámicos BALB C , Células Madre Neoplásicas/metabolismo , Sefarosa , Células Tumorales CultivadasRESUMEN
OBJECTIVES: To test the hypothesis that long-term survivors of low-risk Kawasaki disease (KD) have ongoing vascular inflammation and dysfunction and a higher risk of accelerated atherosclerosis than healthy control subjects. STUDY DESIGN: Twenty-eight patients with KD (7-20 years after acute illness) and 27 age-matched healthy control subjects were examined for medical and dietary history, serum markers of atherosclerotic risk and inflammation, carotid intimal-medial thickness (CIMT) with vascular ultrasound scanning and arterial stiffness with applanation tonometry. RESULTS: Patients and control subjects were similar in age, sex, body mass index, waist-to-hip ratio, blood pressure, cigarette smoking, family history, diet, high-density lipoprotein cholesterol level, lipoprotein (a) level, homocysteine level, glucose level, insulin level, CIMT, arterial stiffness, C-reactive protein level, and inflammatory cytokine level. Levels of total cholesterol and apolipoprotein B were significantly higher in patients with KD than in control subjects. CONCLUSIONS: There was no evidence of increased atherosclerosis. Small but significant differences in cholesterol and apolipoprotein B levels could suggest increased future risk for atherosclerosis and warrant further study.
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Aterosclerosis/epidemiología , Síndrome Mucocutáneo Linfonodular/metabolismo , Síndrome Mucocutáneo Linfonodular/patología , Proteínas de Fase Aguda/metabolismo , Adolescente , Adulto , Aterosclerosis/diagnóstico , Biomarcadores/metabolismo , Arterias Carótidas/patología , Estudios de Casos y Controles , Citocinas/sangre , Femenino , Humanos , Mediadores de Inflamación/sangre , Lípidos/sangre , Masculino , Síndrome Mucocutáneo Linfonodular/complicaciones , Factores de Riesgo , Adulto JovenRESUMEN
The objective of this study was to evaluate the analytical performance of 2 new tacrolimus immunoassays (Dade Dimension Xpand and Abbott ARCHITECT) for therapeutic drug monitoring as possible replacements for the current method in our laboratory, the Abbott IMx tacrolimus assay. Attending physicians at our institute desire to minimize calcineurin inhibitor therapy in kidney allograft recipients to prolong graft survival and improve the quality of life of their patients. Proposed future target trough levels of tacrolimus in whole blood are in the range of 2-4 ng/mL, which requires an assay with a limit of quantification (LOQ) below this range, ideally around 1 ng/mL (European Consensus Recommendation from the Committee on Tacrolimus Optimization). Method comparison analysis of the Dade and ARCHITECT assays showed good correlation to the IMx assay, with correlation coefficients of 0.94 and 0.96, respectively. Both assays reported tacrolimus concentrations lower on average than IMx as demonstrated by slopes of 0.83 (Dade) and 0.93 (ARCHITECT). LOQ for both Dade instruments tested was >4 ng/mL, whereas the LOQ for the ARCHITECT i2000 and i1000 instruments was 0.8 and 0.5 ng/mL, respectively (upper 95% confidence limit). Values reported from both Dade instruments were observed to shift over time, whereas the values on the IMx and ARCHITECT instruments were stable. The Abbott ARCHITECT Tacrolimus assay is a sensitive and precise assay that meets the new LOQ recommendation, 1 ng/mL, for monitoring tacrolimus in whole blood.
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Inmunosupresores/sangre , Tacrolimus/sangre , Monitoreo de Drogas , Humanos , InmunoensayoRESUMEN
BACKGROUND: Hepatic de novo lipogenesis (DNL) is markedly stimulated in humans by low-fat diets enriched in simple sugars. However, the dietary responsiveness of the key enzyme controlling DNL in human adipose tissue, fatty acid synthase (FAS), is uncertain. HYPOTHESIS: Adipose tissue mRNA for FAS is increased in lean and obese subjects when hepatic DNL is elevated by a eucaloric, low-fat, high-sugar diet. DESIGN: Twelve lean and seven obese volunteers were given two eucaloric diets (10% vs. 30% fat; 75% vs. 55% carbohydrate; sugar/starch 60/40) each for 2 weeks by a random-order cross-over design. FAS mRNA in abdominal and gluteal adipose tissues was compared to hepatic DNL measured in serum by isotopic and nonisotopic methods. Adipose tissue mRNA for tumor necrosis factor-alpha and IL-6, which are inflammatory cytokines that modulate DNL, was also assayed. RESULTS: The low-fat high-sugar diet induced a 4-fold increase in maximum hepatic DNL (P<.001) but only a 1.3-fold increase in adipose tissue FAS mRNA (P=.029) and no change in cytokine mRNA. There was a borderline significant positive correlation between changes in FAS mRNA and hepatic DNL (P=.039). Compared to lean subjects, obese subjects had lower levels of FAS mRNA and higher levels of cytokine mRNA (P<.001). CONCLUSIONS: The results suggest that key elements of human adipose tissue DNL are less responsive to dietary carbohydrate than is hepatic DNL and may be regulated by diet-independent factors. Irrespective of diet, there is reduced expression of the FAS gene and increased expression of cytokine genes in adipose tissues of obese subjects.
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Tejido Adiposo/metabolismo , Citocinas/genética , Carbohidratos de la Dieta/farmacología , Ácido Graso Sintasas/genética , Obesidad/metabolismo , Delgadez/metabolismo , Glucemia/metabolismo , Peso Corporal/efectos de los fármacos , Citocinas/metabolismo , Ácido Graso Sintasas/metabolismo , Femenino , Humanos , Inflamación/metabolismo , Insulina/metabolismo , Interleucina-6/genética , Interleucina-6/metabolismo , Lipogénesis/genética , Masculino , Delgadez/genética , Factor de Necrosis Tumoral alfa/genética , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
The effect of statins on bone mass and fracture rates is uncertain. Therefore, we investigated whether statin therapy acutely altered bone turnover as measured by changes in bone serum markers (bone-specific alkaline phosphatase, osteocalcin, and type I collagen N-telopeptide cross-links). Fasting blood samples were obtained from 55 (M/F 39/16) healthy nonsmoking adults (mean +/- standard deviation: age, 50.4+/-7.5 years; body mass index, 27.8+/-4.9 kg/m(2)) with low-density lipoprotein cholesterol concentrations between 3.38-4.90 mmol/l. Subjects were randomized to four possible 8-week treatment regimens: placebo (n =14), pravastatin 40 mg/daily (n =12), simvastatin 20 mg/daily (n =14) or simvastatin 80 mg/daily (n =15). High-dose simvastatin (80 mg/daily) produced a significant reduction in bone-specific alkaline phosphatase as compared with other treatment regimens (p =0.009). However, there were no changes in urinary N-telopeptide cross-links, a sensitive marker of bone resorption. Short-term use of high-dose simvastatin lowers the level of the serum bone marker bone-specific alkaline phosphatase, which suggests the possibility of reduced bone turnover.
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Remodelación Ósea/efectos de los fármacos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacología , Simvastatina/farmacología , Adulto , Fosfatasa Alcalina/sangre , Biomarcadores/sangre , Biomarcadores/orina , Colágeno/orina , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Femenino , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Hipercolesterolemia/tratamiento farmacológico , Hipercolesterolemia/metabolismo , Hipercolesterolemia/fisiopatología , Lípidos/sangre , Masculino , Persona de Mediana Edad , Osteocalcina/farmacología , Osteocalcina/uso terapéutico , Pravastatina/farmacología , Pravastatina/uso terapéutico , Simvastatina/uso terapéuticoRESUMEN
BACKGROUND: An approach to endotoxin (lipopolysaccharide [LPS]) blockade makes use of the ability of lipoproteins, via surface phospholipids, to bind and neutralize LPS. The aim of the present study was to determine whether the intravenous administration of a protein-free, phospholipid-rich emulsion is an effective method for neutralizing the effects of LPS in healthy persons. METHODS: This was a double-blind, placebo-controlled study in 20 volunteers. Volunteers received Escherichia coli endotoxin (2 ng/kg) intravenously 2 h into a 6-h infusion of either emulsion (210 mg/kg) or placebo (Intralipid diluted 1 : 64). RESULTS: The volunteers who received emulsion had a lower mean clinical score (P<.01), temperature (P<.05), pulse rate (P<.05), neutrophil count (P<.05), tumor necrosis factor- alpha level (P<.05), and interleukin-6 level (P<.05) than did the volunteers who received placebo. Response was related to serum phospholipid level. The greatest effects were observed in the volunteers achieving phospholipid levels of approximately 500 mg/dL or higher. CONCLUSION: Phospholipid emulsion attenuates the clinical and laboratory effects associated with the administration of LPS in humans, suggesting a novel approach to the treatment of endotoxemia.
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Endotoxinas/antagonistas & inhibidores , Fosfolípidos/uso terapéutico , Adulto , Emulsiones , Endotoxinas/efectos adversos , Endotoxinas/sangre , Femenino , Hemodinámica , Humanos , Masculino , Fosfolípidos/administración & dosificación , Fosfolípidos/sangre , Valores de ReferenciaRESUMEN
Monocyte chemoattractant protein-1 (MCP-1) is essential in atherogenesis. Oxidized lipids regulate MCP-1 expression and release from mononuclear cells. In this study we investigated (1) whether statin therapy reduces lipopolysaccharide (LPS)-stimulated MCP-1 production in human whole-blood samples and (2) the relationships between in vitro low-density lipoprotein (LDL) oxidation and MCP-1 production. Fasting blood samples were obtained from 55 healthy nonsmoking adults with moderate hypercholesterolemia who were participating in a randomized double-blind 8-week trial comparing the effects of statin therapy with those of placebo on cytokine production. Samples were analyzed for resistance to copper-mediated LDL oxidation (lag time in minutes), as well as MCP-1- and interleukin-8 (IL-8)-stimulated production. Statin therapy reduced MCP-1 production (mean +/- SD) -161 +/- 399 pg/mL/mm 3 white cells) compared with 267 +/- 985 pg/mL/mm 3 in the placebo group, but changes were not different between active and placebo groups ( P = .13). Statin therapy also increased lag times (median [interquartile range]; 20.5 [7.0-51.2] minutes vs -17.0 [-5.3-16.5] minutes; P = .067 for group difference). Inhibition of MCP-1 production correlated with prolongation of lag time ( r = .46, P = .0056) in statin-treated subjects. Statin therapy reduced MCP-1 production in the whole blood of human subjects and these changes were correlated with improvement in LDL oxidative resistance.
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Quimiocina CCL2/sangre , LDL-Colesterol/sangre , Inhibidores de Hidroximetilglutaril-CoA Reductasas/administración & dosificación , Hipercolesterolemia/tratamiento farmacológico , Lipoproteínas LDL/sangre , Adulto , Anciano , Femenino , Humanos , Hipercolesterolemia/sangre , Leucocitos Mononucleares/metabolismo , Masculino , Persona de Mediana Edad , Oxidación-ReducciónRESUMEN
Adipose tissue expression of tumor necrosis factor-alpha (TNF-alpha) has been implicated in the pathogenesis of obesity-linked insulin resistance and the dyslipoproteinemia of insulin resistance. This study has two aims: (1) to compare select inflammatory mediators in non-smoking, normoglycemic male subjects with and without the atherogenic dyslipoproteinemia (ADL), and (2) to determine the effects of statin therapy on select inflammatory mediators. ADL subjects had higher levels of insulin (16.7 +/- 7.5 versus 11.6 +/- 5.9 microIU/mL, P=0.008), soluble TNF receptor superfamily 1B (sTNFRSF1B) (3.3 +/- 0.7 versus 2.7 +/- 0.5 ng/mL, P=0.005), and interleukin-6 (IL-6) (2.6 +/- 2.2 versus 1.3 +/- 1.8 pg/mL, P=0.006) as compared to those of the non-ADL subjects. After adjustment for age, sTNFRSF1B (P=0.003) was more predictive of ADL than high-sensitivity C-reactive protein (hs-CRP) (P=0.047). Statin therapy did not change sTNFRSF1B, TNF-alpha, IL-6, hs-CRP, whereas soluble TNF receptor superfamily 1A (sTNFRSF1A) increased slightly (P=0.048). A high level of sTNFRSF1B is a strong marker of the pro-inflammatory state in this sample of male ADL subjects.
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Hiperlipoproteinemias/sangre , Receptores del Factor de Necrosis Tumoral/sangre , Arteriosclerosis/etiología , Femenino , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Hiperlipoproteinemias/complicaciones , Hiperlipoproteinemias/tratamiento farmacológico , Masculino , Persona de Mediana Edad , Pravastatina/uso terapéutico , Receptores Tipo I de Factores de Necrosis Tumoral , Receptores Tipo II del Factor de Necrosis Tumoral , Simvastatina/uso terapéutico , Receptores Señuelo del Factor de Necrosis TumoralRESUMEN
OBJECTIVES: To evaluate the effect of proinflammatory cytokines, their receptors, and nutritional indicators (at baseline and after 12 weeks of megestrol acetate (MA) treatment) upon long-term survival in geriatric cachectic patients without active acute infections, inflammation, or cancer. DESIGN: Randomized clinical trial with placebo or MA treatment for 12 weeks and then follow-up for more than 4 years. SETTING: Veterans Affairs nursing home in Northport, New York. PARTICIPANTS: Nursing home patients with weight loss of 5% of usual body weight over the previous 3 months or body weight 20% below ideal body weight. INTERVENTION: Random assignment of placebo or MA oral suspension 800 mg/d to the eligible patients for 12 weeks. MEASUREMENTS: White blood cell counts, prealbumin, plasma cytokine levels (or their receptors), including tumor necrosis factor receptor (TNFR), soluble subunits (TNFR-p55 and TNFR-p75), interleukin (IL)-6, soluble IL-2 receptor, and C-reactive protein at baseline and 12 weeks after treatment. RESULTS: There was no difference in survival between the MA and placebo groups. Considering possible confounders, initial IL-6, initial TNFR-p75 levels, and final neutrophil percentage were associated with elevated mortality, whereas higher initial prealbumin, initial albumin, final prealbumin, final albumin, and final weight gain were associated with decreased death. CONCLUSION: In geriatric weight-loss patients with cachexia, certain cytokines and nutritional indicators were effective in predicting long-term mortality, regardless of treatment with MA. Interventions to modify levels of these cytokines or their receptors and improvement in nutritional status by weight gain might be helpful in ameliorating undetected chronic inflammation and thus might prolong the survival of these nursing home residents.
Asunto(s)
Caquexia/tratamiento farmacológico , Citocinas/sangre , Inflamación/sangre , Acetato de Megestrol/uso terapéutico , Estado Nutricional , Anciano , Caquexia/mortalidad , Intervalos de Confianza , Femenino , Humanos , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Factores de Riesgo , Aumento de PesoRESUMEN
BACKGROUND: Decreased concentrations of total cholesterol, lipoproteins, and lipoprotein cholesterols occur early in the course of critical illness. Low cholesterol concentrations correlate with high concentrations of cytokines such as interleukin (IL)-6 and IL-10, and may be due to decreased synthesis or increased catabolism of cholesterol. Low cholesterol concentrations have been associated clinically with several adverse outcomes, including the development of nosocomial infections. The study was performed to test the hypothesis that a low cholesterol concentration predicts mortality and secondarily predicts the development of organ dysfunction in critical surgical illness. METHODS: A prospective study was undertaken of 215 patients admitted to a university surgical ICU with systemic inflammatory response syndrome (SIRS). Serial blood samples were collected within 24 h of admission, as well as on the morning of days 2, 4, and 7 of the ICU stay for as long as the patients were in the ICU. Demographic data and predetermined outcomes were noted. RESULTS: One hundred nine patients had at least two samples drawn and form the population for analysis. Sixty-two of the patients had three samples obtained, whereas 42 patients had four samples obtained. By univariate analysis, non-survivors were more severely ill on admission (APACHE III), more likely to have been admitted to the ICU as an emergency, more likely to develop a nosocomial infection, and more likely to develop severe organ dysfunction (MODS) (all, p < 0.05). Death was associated on day 1 with increased concentrations of sIL2R, IL-6, IL-10, and sTNFR-p75 (all, p < 0.01), but there were initially no differences in serum lipid concentrations. However, by day 2, concentrations of IL-6, IL-10, and cholesterol had decreased significantly (all, p < 0.05) from day 1 in non-survivors but not in survivors; the difference in serum cholesterol concentration persisted to day 7 (p < 0.05). Persistently elevated concentrations of IL-6 and IL-10 were observed in patients who developed severe MODS. By logistic regression, increased APACHE III score, development of a nosocomial infection, and decreased cholesterol concentration were independently associated with mortality. CONCLUSIONS: Decreased serum cholesterol concentration is an independent predictor of mortality in critically ill surgical patients. Repletion of serum lipids is a feasible therapeutic approach for the management of critical illness.