RESUMEN
GOAL: The goal of this study was to assess the clinical performance of an investigational in vitro fecal calprotectin immunoassay for differentiating inflammatory bowel disease (IBD) from irritable bowel syndrome (IBS). BACKGROUND: Fecal calprotectin is a stool biomarker that can assist in the detection of intestinal inflammation and is utilized to identify individuals who have a higher chance of having IBD and who require further invasive tests. Current assays exhibit variable performance. MATERIALS AND METHODS: This study was a multicenter, cross-sectional analysis of prospectively collected stool samples from patients 4 years of age or older who presented with gastrointestinal (GI) symptoms and underwent colonoscopy for diagnostic confirmation. IBD was diagnosed based on clinical, endoscopic, and histologic findings. IBS was diagnosed based on Rome III Criteria and negative colonoscopy. Stool samples were extracted and tested on the DiaSorin LIAISON XL using the LIAISON Calprotectin Assay. RESULTS: A total of 240 patients (67% female) were included in the study. In total, 102 patients had IBD (54% ulcerative colitis), 67 had IBS, and 71 had other GI disorders. Median fecal calprotectin levels were significantly higher in patients with IBD [522 µg/g; 95% confidence interval (CI): 354-970 µg/g] compared with IBS (34.5 µg/g; 95% CI: 19.7-44.2 µg/g, P<0.001) and other GI disorders (28.6 µg/g; 95% CI: 18.7-40.3 µg/g, P<0.001). Receiver operating characteristic curve analysis indicated a fecal calprotectin cutoff of 94 µg/g for distinguishing IBD from other GI disorders with an area under the curve of 0.964 (sensitivity=92.2%, specificity=88.4%). CONCLUSION: The automated LIAISON Calprotectin assay brings efficient calprotectin testing to the laboratory with a time to the first result of 35 minutes and is a sensitive marker for distinguishing IBD from IBS with a cutoff of â¼100 µg/g.
Asunto(s)
Colitis Ulcerosa , Enfermedades Inflamatorias del Intestino , Síndrome del Colon Irritable , Biomarcadores , Colitis Ulcerosa/diagnóstico , Estudios Transversales , Heces , Femenino , Humanos , Enfermedades Inflamatorias del Intestino/diagnóstico , Síndrome del Colon Irritable/diagnóstico , Complejo de Antígeno L1 de Leucocito , MasculinoRESUMEN
OBJECTIVES: COVID-19 has brought about tests from many manufacturers. While molecular and rapid antigen tests are targeted for early diagnosis, immunoassays have a larger role in epidemiological studies, understanding longitudinal immunity, and in vaccine development and response. METHODS: The performance of the LIAISON® SARS-CoV-2 TrimericS IgG assay was evaluated against the Beckman ACCESS SARS-CoV-2 IgG assay in New Mexico, and against the Siemens ADVIA Centaur COV2G assay in New York. Discordant samples were parsed using a microneutralization assay. RESULTS: A SARS-CoV-2 antibody positivity rate of 23.8% was observed in the samples tested in New York (September 2020), while in the same month the positivity rate was 1.5% in New Mexico. Positive and negative agreement were 67.6% (95% CI 49.5-82.6%) and 99.8% (95% CI 99.5-99.9%), respectively, with the Beckman test, and 98.0% (95% CI 95.7-99.3%) and 94.8% (95% CI 93.4-96.0%), respectively, with the Siemens test. Receiver operating characteristic analysis for the detection of SARS-CoV-2 antibodies discloses an AUC, area under the curve, of 0.996 (95% CI 0.992-0.999) for the LIAISON® SARS-CoV-2 TrimericS IgG assay. The criterion associated to the Youden Index was determined to be >12.9 kAU/L with a sensitivity of 99.44% and a specificity of 99.82%. CONCLUSIONS: The LIAISON® SARS-CoV-2 TrimericS IgG assay is highly sensitive and specific. The balance of these parameters, without emphasis on high specificity alone, is particularly important when applied to high prevalence populations, where a highly sensitive assay will result in reporting a lower number of false negative subjects.
Asunto(s)
Anticuerpos Antivirales/sangre , COVID-19/diagnóstico , Inmunoensayo/métodos , Inmunoglobulina G/sangre , SARS-CoV-2/metabolismo , Glicoproteína de la Espiga del Coronavirus/inmunología , Área Bajo la Curva , Automatización , COVID-19/virología , Humanos , Curva ROC , Juego de Reactivos para Diagnóstico , SARS-CoV-2/aislamiento & purificación , Sensibilidad y EspecificidadRESUMEN
In the coronavirus (CoV) disease 2019 (COVID-19) pandemic, highly selective serological testing is essential to define exposure to severe acute respiratory syndrome CoV 2 (SARS-CoV-2). Many tests have been developed, yet with variable speeds to first results, and are of unknown quality, particularly when considering the prediction of neutralizing capacity. The LIAISON SARS-CoV-2 S1/S2 IgG assay was designed to measure antibodies against the SARS-CoV-2 native S1/S2 proteins in a standardized automated chemiluminescence assay. The clinical and analytical performances of the test were validated in an observational study using residual samples (>1,500) with a positive or negative COVID-19 diagnosis. The LIAISON SARS-CoV-2 S1/S2 IgG assay proved to be highly selective and specific and offered semiquantitative measures of serum or plasma levels of anti-S1/S2 IgG with neutralizing activity. The assay's diagnostic sensitivities were 91.3% and 95.7% at >5 or ≥15 days from diagnosis, respectively, and 100% when assessed against a neutralizing assay. The assay's specificity ranged between 97% and 98.5%. The average imprecision of the assay was a <5% coefficient of variation. Assay performance at 2 different cutoffs was evaluated to optimize predictive values. The automated LIAISON SARS-CoV-2 S1/S2 IgG assay brings efficient, sensitive, specific, and precise serological testing to the laboratory, with the capacity to test large amounts of samples per day; first results are available within 35 min, with a throughput of 170 tests/hour. The semiquantitative results provided by the test also associate with the presence of neutralizing antibodies and may provide a useful tool for the large-scale screening of convalescent-phase plasma for safe therapeutic use.
Asunto(s)
Anticuerpos Antivirales/sangre , Betacoronavirus/inmunología , Técnicas de Laboratorio Clínico , Infecciones por Coronavirus/diagnóstico , Neumonía Viral/diagnóstico , Pruebas Serológicas , Anticuerpos Neutralizantes/sangre , Automatización de Laboratorios , COVID-19 , Prueba de COVID-19 , Técnicas de Laboratorio Clínico/métodos , Técnicas de Laboratorio Clínico/normas , Técnicas de Laboratorio Clínico/estadística & datos numéricos , Infecciones por Coronavirus/inmunología , Humanos , Inmunoglobulina G/sangre , Pandemias , Neumonía Viral/inmunología , Reproducibilidad de los Resultados , SARS-CoV-2 , Sensibilidad y Especificidad , Pruebas Serológicas/métodos , Pruebas Serológicas/normas , Pruebas Serológicas/estadística & datos numéricos , Glicoproteína de la Espiga del Coronavirus/inmunologíaRESUMEN
BACKGROUND: In the majority of patients with advanced chronic kidney disease (CKD), values of parathyroid hormone (PTH1-84) and fibroblast growth factor 23 (FGF-23) exceed the normal reference range, potentially as an appropriate adaptation to reduced glomerular filtration rate (GFR). We tested whether GFR-specific cutoffs for PTH1-84 and FGF-23 could better identify patients with inappropriately high PTH1-84 and FGF-23 for their degree of CKD and thereby improve prognostication of clinical outcomes compared to a uniform threshold. METHODS: Prospective pan-Canadian cohort of 1,812 patients with mean estimated GFR (eGFR) 28.9 mL/min/1.73 m2 followed for a median of 52 months. Repeated log-rank tests were used to identify optimal cutoffs for PTH1-84 and FGF-23 within eGFR strata (<20, 20-29 and ≥30 mL/min/1.73 m2) that maximally differentiated high- and low-risk populations for (1) cardiovascular (CV) events (fatal or nonfatal myocardial infarction, coronary revascularization, stroke, heart failure) and (2) renal events (initiation of chronic renal replacement therapy). In multivariable models, we examined the association between -GFR-specific cutoffs and outcomes and compared their added prognostic value to existing uniform thresholds. RESULTS: Risk-based cutoffs for PTH1-84 and FGF-23 increased in a graded fashion with decreasing eGFR. Among patients with eGFR <20 mL/min/1.73 m2, CV risk-based cutoffs for PTH1-84 and FGF-23 were 3.4 and 5.5 times the upper limit of normal, respectively, and reclassified 31.9 and 35.1% of patients when added to a multivariable base model for CV events. In contrast, the addition of PTH1-84 and FGF-23 to the base model using uniform cutoffs failed to reclassify such patients. Similar findings were demonstrated for renal outcomes. CONCLUSION: GFR-specific risk-based cutoffs for PTH1-84 and FGF-23 may facilitate more meaningful risk stratification in advanced CKD than current GFR-agnostic reference ranges derived from healthy adults. This may be most applicable in those with severely reduced GFR.
Asunto(s)
Trastorno Mineral y Óseo Asociado a la Enfermedad Renal Crónica/diagnóstico , Factores de Crecimiento de Fibroblastos/sangre , Tasa de Filtración Glomerular/fisiología , Hormona Paratiroidea/sangre , Insuficiencia Renal Crónica/diagnóstico , Anciano , Anciano de 80 o más Años , Canadá , Trastorno Mineral y Óseo Asociado a la Enfermedad Renal Crónica/sangre , Trastorno Mineral y Óseo Asociado a la Enfermedad Renal Crónica/etiología , Trastorno Mineral y Óseo Asociado a la Enfermedad Renal Crónica/fisiopatología , Progresión de la Enfermedad , Femenino , Factor-23 de Crecimiento de Fibroblastos , Humanos , Masculino , Persona de Mediana Edad , Pronóstico , Estudios Prospectivos , Valores de Referencia , Insuficiencia Renal Crónica/sangre , Insuficiencia Renal Crónica/complicaciones , Insuficiencia Renal Crónica/fisiopatología , Medición de Riesgo/métodos , Índice de Severidad de la EnfermedadRESUMEN
Background: Sclerostin, a 22-kDa protein secreted by osteocytes, acts as a potent inhibitor of osteoblast activity. In chronic kidney disease (CKD), sclerostin is a putative driver of the bone-vascular axis. However, large discrepancies between sclerostin assays have been described. Methods: We compared four different assays [Biomedica (BM), TecoMedical (TE), R&D (RD) and MesoScaleDiscovery (MSD)] in an analytical study and addressed the question whether bioassay choice affects the correlation between circulating sclerostin and clinical and biochemical determinants. Circulating sclerostin levels were determined in 39 prevalent dialysis patients and 82 non-dialysis patients referred for glomerular filtration rate measurement. Results: In the 82 non-dialysis patients, we observed large differences in median (interquartile range) sclerostin concentrations (in pg/mL): BM, 984 [interquartile range (IQR) 648]; TE, 629 (IQR 237); RD, 154 (IQR 84) and MSD, 36 (IQR 19). The concordance correlation coefficient between assays was poor (0.1-0.44). The same discrepancies were observed in dialysis patients. A significant negative rank correlation was found between glomerular filtration rate and sclerostin measured by BM and TE but not by MSD and RD. Associations between sclerostin and age, gender, weight or parathormone were also different according to the assay considered. Conclusions: Clinical inference relating sclerostin levels found in the general, CKD and dialysis populations is largely influenced by the assay used to measure this biomarker.
Asunto(s)
Proteínas Morfogenéticas Óseas/sangre , Tasa de Filtración Glomerular/fisiología , Insuficiencia Renal Crónica/sangre , Proteínas Adaptadoras Transductoras de Señales , Anciano , Bioensayo , Biomarcadores/sangre , Femenino , Marcadores Genéticos , Humanos , Masculino , Persona de Mediana Edad , Diálisis Renal , Insuficiencia Renal Crónica/fisiopatología , Insuficiencia Renal Crónica/terapiaRESUMEN
BACKGROUND: Over the past few decades, parathyroid hormone (PTH) immunoassays have progressed through successive generations resulting in increased specificity and accuracy for detecting circulating PTH. With the introduction of third-generation assays, in which the biologically active PTH(1-84) is specifically targeted, the PTH(7-84) and other fragments are not detected. The specific recognition of only PTH(1-84) whole molecule allows for more reliable standardization and calibration than with the existing assays. METHODS: Samples from patients on hemodialysis or with primary hyperparathyroidism and apparently healthy subjects were examined in different collection matrices (EDTA plasma, unspun EDTA plasma and SST) stored for 0, 24 or 72 h at room temperature to reflect the prevailing sample collection methods, shipping and processing conditions of centralized labs in the United States. Samples were analyzed by the LIAISON 1-84 PTH and N-TACT assays, and by three additional commercially available intact PTH assays. RESULTS: Defined samples, prepared using two different standards (WHO 95/646 international standard and the synthetic Bachem PTH(1-84)), show little bias with the LIAISON 1-84 PTH assay, but not with the other intact PTH assays. Furthermore, PTH is stable for up to 72 h in plasma, but less stable in serum beyond 24 h. CONCLUSIONS: The FDA-approved LIAISON 1-84 PTH assay is accurate and reliably measures the biologically active PTH molecule in plasma or serum stored at room temperature for up 72 and 24 h, respectively.
Asunto(s)
Inmunoensayo/métodos , Hormona Paratiroidea/sangre , Humanos , Hiperparatiroidismo Primario/patología , Inmunoensayo/normas , Hormona Paratiroidea/normas , Juego de Reactivos para Diagnóstico , Estándares de Referencia , Insuficiencia Renal Crónica/patología , Reproducibilidad de los Resultados , TemperaturaRESUMEN
BACKGROUND: We sought to investigate the mutual interplay between bone, glucose and lipid metabolism in a wide cohort of community-based subjects. METHODS: We studied 1240 blood donors (F/M ratio 1/3.2, mean age 41.9 ± 11.7 SD). Serum ionized (Ca++), magnesium (Mg++), 25-hydroxy-vitamin D [25(OH)D], PTH-1-84, 1,25-dihydroxyvitamin D [1,25(OH)2D], total cholesterol (C), HDL-C, triglycerides and glucose were measured and LDL-C levels were calculated in all subjects. RESULTS: 25(OH)D negatively correlated with BMI (R = -0.11), PTH (R = -0.16) (p < 0.0001), total C (R = -0.06, p < 0.05) and triglycerides (R = -0.13, p < 0.0001) and positively with 1,25(OH)2D (R = 0.12) and creatinine (R = 0.17) (p < 0.0001). Serum PTH positively correlated with total C (R = 0.08, p < 0.01), LDL-C (R = 0.1, p < 0.001), triglycerides (R = 0.09, p < 0.01) and glucose (R = 0.15, p < 0.0001) and negatively with HDL-C (R = -0.09, p < 0.01). The odds of showing abnormal serum triglycerides and HDL-C increased as 25(OH)D decreased (p < 0.0001 and p < 0.03) and PTH increased (p < 0.03 and p = 0.05), while the odds of showing abnormal LDL-C levels increased in association with elevated PTH (p < 0.01). CONCLUSION: Vitamin D, PTH, glucose and lipid metabolism are mutually influenced. Hypovitaminosis D predisposes toward worsening lipid profiles through the actions of PTH, while serum PTH levels per se associate with higher glucose and LDL-C levels.
Asunto(s)
Glucosa , Deficiencia de Vitamina D , Humanos , Adulto , Persona de Mediana Edad , LDL-Colesterol , Metabolismo de los Lípidos , Hormona Paratiroidea , Vitamina D , Vitaminas , TriglicéridosRESUMEN
Background: Heterogeneous progression of chronic kidney disease (CKD) toward dialysis advocates improving in renal care management. Diagnosis and staging of CKD relies on estimated glomerular filtration rate (eGFR) and albuminuria. Tubular biomarkers emerged as new predictors of worsening renal function (WRF), due to partial inaccuracy of eGFR and existing WRF in non-proteinuric patients. Active vitamin D is synthesized in renal tubules and participates to mineral adaptation in CKD. Circulating 1,25-dihydroxyvitamin D [1,25(OH)2D] was poorly investigated as a biomarker of endocrine tubular function and predictor of WRF. Objective: Investigate capability of 1,25(OH)2D to predict parathormone (PTH) increase and WRF in CKD stage 3-4. Methods: PASCaL-1,25D was an observational, prospective, monocentric study. Primary outcomes were absolute and 20% increase in PTH, and WRF defined as 20% reduction in eGFR or dialysis initiation at 6 months. Results: Seventy-one patients completed follow up. Absolute increase in PTH (1-84) was independently predicted by lower 1,25(OH)2D levels (p = 0.0134). No association was detected between 1,25(OH)2D and iPTH increase. Higher 1,25(OH)2D was associated with reduced risk of WRF at univariate analysis [OR 0.89 (95% CI 0.86-0.93), p = 0.006]. The 1,25(OH)2D/PTH (1-84) ratio was associated with non-significant 84% risk reduction for WRF [OR 0.16 (95% CI 0.06-0.41), p = 0.05]. Low 1,25(OH)2D reached 100% sensitivity in predicting WRF in CKD stage 3 (AUC 9.909, p < 0.0001) and non-elderly patients (AUC 0.883, p < 0.0001). Machine learning models retained 1,25(OH)2D/PTH (1-84) as relevant predictor of WRF together with eGFR and albuminuria. Age influenced interaction between renal and mineral biomarkers. Conclusion: 1,25(OH)2D deserves attention as biomarker of tubular health, and sensible predictor of WRF on the short run among non-elderly patients affected by stage 3 CKD. The 1,25(OH)2D/PTH (1-84) ratio may represent a composite biomarker of tubular reserve/endocrine response to the transition from adaptive to maladaptive equilibrium in CKD-MBD.
RESUMEN
BACKGROUND: Antigens derived from Helicobacter pylori can be used as stool biomarkers to assist in the diagnosis of H. pylori infection. Since current assays have variable performance, we assessed the clinical performance of the automated LIAISON® Meridian H. pylori infection. Since current assays have variable performance, we assessed the clinical performance of the automated LIAISON® Meridian. METHODS: This prospective multisite study enrolled patients undergoing an esophagogastroduodenoscopy with collection of biopsy and stool specimens. Adult patients (≥22 years) participated in the study from February 2017 to August 2018. Specimens of the stomach were tested by three methods, known as the Composite Reference Method: (1) histological evaluation, (2) culture of the organism, and (3) rapid urease detection test. H. pylori infection. Since current assays have variable performance, we assessed the clinical performance of the automated LIAISON® Meridian H. pylori infection. Since current assays have variable performance, we assessed the clinical performance of the automated LIAISON® Meridian. RESULTS: 277 patients (63% female) were included in the study. The prevalence of infected subjects was 24.2% in this study cohort. Clinical performance assessed against the Composite Reference Method showed very good agreement (Cohen's kappa = 0.922), with good sensitivity (95.5%) and specificity (97.6%). Reproducibility study results showed total imprecision ranging from 3.1% to 13.9% CV. CONCLUSION: The automated LIAISON® Meridian H. pylori SA assay brings reliable noninvasive testing for H. pylori to the laboratory that is in very good agreement with the current, more invasive biopsy-based methods such as histology, culture, or rapid urease test. The clinical trial identifiers are NCT03060746 (pretherapy) and NCT03060733 (posttherapy).H. pylori infection. Since current assays have variable performance, we assessed the clinical performance of the automated LIAISON® Meridian H. pylori infection. Since current assays have variable performance, we assessed the clinical performance of the automated LIAISON® Meridian.
Asunto(s)
Antígenos Bacterianos/análisis , Heces/microbiología , Infecciones por Helicobacter/inmunología , Helicobacter pylori/inmunología , Técnicas para Inmunoenzimas/métodos , Adulto , Anciano , Biopsia , Femenino , Infecciones por Helicobacter/diagnóstico , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Reproducibilidad de los Resultados , Sensibilidad y Especificidad , Ureasa , Adulto JovenRESUMEN
BACKGROUND: While the inverse relationship between serum ionized calcium (Ca2+) and PTH is well-established, the relationship between 25(OH)D and PTH showed conflicting results. The study aimed to evaluate the relative contributions of age, sex, serum Ca2+, ionized magnesium (Mg2+), 25(OH)D and 1,25(OH)2D in regulating PTH secretion in healthy subjects. METHODS: This is a secondary analysis of an observational study performed from March 2014 to July 2015 carried out in 2259 blood donors (1652 men and 607 women, age range 18-68â¯years). Subjects with parathyroid disorders and taking drugs that affect mineral metabolism were excluded. RESULTS: Significant correlations [between Ca2+ and PTH (râ¯=â¯-0.223, pâ¯<â¯0.001), 25(OH)D and PTH (râ¯=â¯-0.178, pâ¯<â¯0.001) and between PTH and age (râ¯=â¯0.322, pâ¯<â¯0.001)] were found. As a preliminary step to multivariate analysis, a regression tree analysis was performed using PTH as response variable and age, Ca2+, Mg2+, 25(OH)D, 1,25(OH)2D and sex as explanatory variables to determine the effect of each covariate on the response variable. For subjects <38â¯years, 25(OH)D was the most important parameter in regulating PTH. For subjects ≥38 both 25(OH)D and Ca2+ levels regulated PTH secretion. Subjects with 25(OH)Dâ¯<â¯13â¯ng/mL had average higher PTH; in this group only, subjects with Ca2+â¯≥â¯1.30â¯mmol/L had average lower PTH compared to subjects with Ca2+â¯<â¯1.30. The multivariate analysis showed that all variables had a significant effect (pâ¯<â¯0.001) on PTH. Anova Type III errors c indicated that 25(OH)D accounted for 32.1% of the total variance in PTH, Ca2+ accounted for 18% of the total variance, BMI for 14.3%, and 1,25(OH)2D for 11.1%. The remaining percentage was attributable to age and sex. This was confirmed by the regression tree approach, where 25(OH)D and Ca2+ accounted for the largest variation in the average levels of PTH. DISCUSSION: Under stable conditions 25(OH)D plays a significant role in regulating PTH secretion. Under conditions of relative vitamin D sufficiency, Ca2+ also plays an important role.
Asunto(s)
Calcio/sangre , Hormona Paratiroidea/sangre , Vitamina D/análogos & derivados , Adolescente , Adulto , Anciano , Envejecimiento/fisiología , Femenino , Voluntarios Sanos , Humanos , Masculino , Menopausia/sangre , Persona de Mediana Edad , Osteoporosis/sangre , Vitamina D/sangre , Adulto JovenRESUMEN
BACKGROUND AND AIMS: Vitamin D exists as an inactive 25-hydroxyvitamin D (25(OH)D) in the bloodstream, which is converted to active 1,25-dihydroxyvitaminD (1,25(OH)2D) in target tissues. Cohort studies reporting cardiovascular disease among individuals with low vitamin D are inconsistent and solely measure 25(OH)D. Psoriasis, a chronic inflammatory disease, is a vitamin D deficient state and is associated with increased cardiovascular disease risk. While serum 25(OH)D is routinely measured, we hypothesized that measurement of 1,25(OH)2D in psoriasis may perform better than 25(OH)D in capturing cardiovascular risk. METHODS: Consecutive psoriasis patients (Nâ¯=â¯122) at baseline underwent FDG PET/CT and CCTA scans to measure visceral adipose volume, aortic vascular uptake of FDG, and coronary plaque burden respectively. Blood levels of both 1,25(OH)2D and 25(OH)D were measured by chemiluminescence (LIAISON XL DIaSorin, Stillwater, MN). RESULTS: The psoriasis cohort was middle-aged (mean⯱â¯SD: 49.6⯱â¯13.0), predominantly male (nâ¯=â¯71, 58%), in majority Caucasians (nâ¯=â¯98, 80%), and had moderate-to-severe skin disease [psoriasis area severity index score, PASI score, med. (IQR): 5.5 (3.2-10.7)], with almost one-fourth of the cohort on biologic psoriasis therapy for skin disease management (nâ¯=â¯32, 27%) at baseline. Interestingly, serum levels of 1,25(OH)2D but not 25(OH)D were found to be inversely associated with visceral adipose, a marker of cardiometabolic risk in fully adjusted models (ßâ¯=â¯- 0.43, pâ¯=â¯0.026 and ßâ¯=â¯-0.26 pâ¯=â¯0.13). Similarly, we found an inverse relationship between 1,25(OH)2D, but not 25(OH)D, and aortic vascular uptake of FDG independent of traditional risk factors (ßâ¯=â¯-0.19, pâ¯=â¯0.01). Finally, we found that serum 1,25(OH)2D, but not 25(OH)D, was inversely associated with non-calcified coronary plaque burden, as measured by CCTA independent of traditional risk factors (ßâ¯=â¯-0.18, pâ¯=â¯0.03). CONCLUSIONS: In conclusion, we demonstrate that low 1,25(OH)2D levels were associated with visceral adipose volume, vascular uptake of FDG and coronary plaque burden independent of traditional risk factors, suggesting that 1,25(OH)2D may better capture the cardiometabolic risk associated with vitamin D deficient states.
Asunto(s)
Enfermedades Cardiovasculares/sangre , Enfermedades Cardiovasculares/complicaciones , Psoriasis/sangre , Psoriasis/complicaciones , Vitamina D/análogos & derivados , Adiposidad , Anciano , Angiografía Coronaria , Vasos Coronarios/fisiopatología , Femenino , Fluorodesoxiglucosa F18 , Humanos , Inmunoensayo , Grasa Intraabdominal , Masculino , Persona de Mediana Edad , Placa Aterosclerótica/sangre , Tomografía Computarizada por Tomografía de Emisión de Positrones , Estudios Prospectivos , Riesgo , Vitamina D/sangreRESUMEN
Sclerostin is a 190 amino acid protein secreted primarily by osteocytes. It was initially identified due to mutations in the SOST gene associated with high bone mass phenotypes. Much recent work has sought to determine the importance of sclerostin across an array of conditions which affect the human skeleton. However, accurate measurement of sclerostin from serum and plasma sources remains a significant impediment, with currently available commercial assays showing marked differences in measured sclerostin values. Accordingly, sclerostin assay standardization remains an important but unmet need before sclerostin measurements can be used for the clinical management of bone disease. Here we characterize a novel automated chemiluminescent sclerostin assay (LIAISON®, DiaSorin) which overcomes many of these limitations. Important assay characteristics include: a wide dynamic range (50-6500pg/mL); high intra- (<2.5%) and inter- (<5%) assay precision; matched serum and plasma equivalence (<10% difference); specificity for the intact sclerostin molecule; and rapid assay results. Serum sclerostin levels measured with the LIAISON® assay in a population-based sample of adult men (n=278) and women (n=348) demonstrated that sclerostin levels were significantly higher in men as compared to women and were positively associated with age in both sexes, consistent with previously published work. In postmenopausal women, serum sclerostin levels measured with the LIAISON® assay were reduced in response to treatment with either estrogen or teriparatide, again consistent with previous findings. Collectively, the above data demonstrate that the LIAISON® sclerostin assay provides a reliable tool for more confident assessment of emergent mechanisms wherein sclerostin may impact a number of bone related pathologies.
Asunto(s)
Proteínas Morfogenéticas Óseas/análisis , Proteínas Morfogenéticas Óseas/sangre , Mediciones Luminiscentes/métodos , Proteínas Adaptadoras Transductoras de Señales , Adulto , Anciano , Anciano de 80 o más Años , Densidad Ósea , Femenino , Marcadores Genéticos , Humanos , Mediciones Luminiscentes/normas , Masculino , Persona de Mediana Edad , Osteocitos/citología , Osteocitos/metabolismo , Osteoporosis Posmenopáusica/sangreRESUMEN
While bivalent antibodies can block ligand-receptor interactions, IgM pentamers efficiently cross-link cell surface targets and evoke physiological responses. We have described one such interaction between an IgM antibody (Ab) and the B7-DC costimulatory molecule expressed by dendritic cells that induces strong antitumor immunity and modulates pathogenic responses associated with allergic asthma. Progressive changes in gene expression in dendritic cells activated by an IgM B7-DC cross-linking Ab resulted in the increased expression in 350 genes and decreased expression of more than 200 genes over the course of 24 h following Ab treatment. In particular, up-regulation of the caspase inhibitor FLIP and the chemokine receptor CCR7, and the down-regulation of the CXCR4 receptor provide a mechanistic basis of Ab-induced survival and enhanced migration into draining lymph nodes. Increased expression of both cell surface and secreted molecules known to be mediators of the immunomodulatory properties of dendritic cells was detected at both the levels of RNA and protein expression. This analysis documents the ability of IgM Ab to activate a gene expression cascade leading to important biological changes in cellular function and provides mechanistic insight into the potent immunomodulatory properties attributed to this Ab.
Asunto(s)
Anticuerpos/farmacología , Antígeno B7-1/farmacología , Dendritas/fisiología , Regulación de la Expresión Génica , Inmunoglobulina M/inmunología , Animales , Células de la Médula Ósea/citología , Células de la Médula Ósea/inmunología , Cartilla de ADN , Dendritas/efectos de los fármacos , Dendritas/inmunología , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Ratones , Ratones Endogámicos C57BL , Análisis de Secuencia por Matrices de Oligonucleótidos , Proteína 2 Ligando de Muerte Celular Programada 1 , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Transcripción GenéticaRESUMEN
INTRODUCTION: Mounting evidence indicates that a disturbed Wnt-ß-catenin signaling may be involved in the pathogenesis of chronic kidney disease-mineral and bone and mineral disorder (CKD-MBD). Data on the impact of CKD on circulating levels of the Wnt antagonists sclerostin and Dickkopf related protein 1 (DKK1) and the relationship with laboratory parameters of CKD-MBD are incomplete. METHODS: We analyzed serum sclerostin and DKK1 in 308 patients across the stages of chronic kidney disease (kDOQI stage 1-2 n = 41; CKD stage 3 n = 54; CKD stage 4-5 n = 54; hemodialysis n = 100; peritoneal dialysis n = 59) as well as in 49 healthy controls. We investigated associations with demographics, renal function, parameters of mineral metabolism including 25(OH) vitamin D, 1,25(OH)2 vitamin D, biointact fibroblast growth factor 23 (FGF23), and parathyroid hormone (PTH), and bone turnover markers. RESULTS: Serum sclerostin, but not DKK1, increases in more advanced stages of CKD and associates with PTH, phosphate, and 1,25(OH)2 vitamin D concentrations. Bone turnover markers are highest in hemodialysis patients presenting the combination of high PTH with low sclerostin level. Serum DKK1 levels are lower in CKD patients than in controls and are not associated with laboratory parameters of mineral metabolism. Interestingly, a direct association between DKK1 and platelet count was observed. CONCLUSION: In CKD, serum levels of the Wnt inhibitors DKK1 and sclerostin are unrelated, indicating different sites of origin and/ or different regulatory mechanisms. Sclerostin, as opposed to DKK1, may qualify as a biomarker of CKD-MBD, particularly in dialysis patients. DKK1 serum levels, remarkably, correlate almost uniquely with blood platelet counts.
Asunto(s)
Proteínas Morfogenéticas Óseas/sangre , Trastorno Mineral y Óseo Asociado a la Enfermedad Renal Crónica/sangre , Péptidos y Proteínas de Señalización Intercelular/sangre , Riñón/metabolismo , Proteínas Adaptadoras Transductoras de Señales , Anciano , Plaquetas/metabolismo , Trastorno Mineral y Óseo Asociado a la Enfermedad Renal Crónica/fisiopatología , Femenino , Factor-23 de Crecimiento de Fibroblastos , Factores de Crecimiento de Fibroblastos/sangre , Marcadores Genéticos , Voluntarios Sanos , Humanos , Riñón/patología , Masculino , Persona de Mediana Edad , Hormona Paratiroidea/sangre , Diálisis Peritoneal , Fosfatos/metabolismo , Diálisis Renal , Vitamina D/sangre , Vía de Señalización Wnt/genéticaRESUMEN
OBJECTIVES: Vitamin D deficiency and hyperparathyroidism are common in patients with heart failure (HF). There is a growing body of evidence supporting the role of vitamin D and parathyroid hormone (PTH) in cardiac remodeling and worsening of HF. Lack of reliable automated testing of 1,25-dihydroxyvitamin D (1,25(OH)2D), the biologically active metabolite of vitamin D, has limited its contribution to the prognostic assessment of HF. Here, the association of 1,25(OH)2D and PTH(1-84) levels was evaluated for prediction of cardiovascular death in chronic HF patients. METHODS: We conducted a single center prospective cohort including 170 chronic HF patients (females n = 36; males n = 134; NYHA II-IV; mean age: 67 years; etiology: ischemic n = 119, dilated cardiomyopathy n = 51; mean LVEF: 23%). The primary outcome was cardiovascular death. RESULTS: Serum levels of 1,25(OH)2D decreased markedly with increased HF severity. Medians were 33.3 pg/mL for NYHA-II patients, 23.4 pg/mL for NYHA-III, and 14.0 pg/mL for NYHA-IV patients (p<0.001). Most patients had levels of 25(OH)D below 30ng/mL, and stratification by NYHA functional class did not show significant differences (p = 0.249). The 1,25(OH)2D to PTH(1-84) ratio and the (1,25(OH)2D)2 to PTH(1-84) ratio were found to be the most significantly related to HF severity. After a median follow-up of 4.1 years, 106 out of 170 patients reached the primary endpoint. Cox proportional hazard modeling revealed 1,25(OH)2D and the 1,25(OH)2D to PTH(1-84) ratios to be strongly predictive of outcomes. CONCLUSIONS: 1,25(OH)2D and its ratios to PTH(1-84) strongly and independently predict cardiovascular mortality in chronic HF.
Asunto(s)
Insuficiencia Cardíaca/sangre , Insuficiencia Cardíaca/diagnóstico , Hormona Paratiroidea/sangre , Vitamina D/análogos & derivados , Adulto , Anciano , Anciano de 80 o más Años , Enfermedad Crónica/mortalidad , Femenino , Insuficiencia Cardíaca/mortalidad , Humanos , Masculino , Persona de Mediana Edad , Pronóstico , Vitamina D/sangre , Adulto JovenRESUMEN
OBJECTIVE: To determine the prevalence and degree of 25-hydroxyvitamin D deficiency in a group of Arab-American women in the largest, most-concentrated Arab-American settlement in the United States and to search for correlations with dress, diet, and use of vitamin D-fortified foods and vitamin supplements. METHODS: In this cross-sectional study, Arab-American women, 18 years and older, who attended an ethnic market on April 7 or 14, 2007, were recruited. Participants were interviewed by bilingual English- and Arabic-speaking investigators using a semi-structured interview to assess dress; demographic variables; medical history; medication use; clinical symptoms associated with vitamin D deficiency (eg, joint or bone pain, muscle weakness); and dietary intake of vitamin D from fortified orange juice, milk, and vitamin supplementation. Blood samples were drawn to measure concentrations of serum calcium, creatinine, phosphorus, alkaline phosphatase, parathyroid hormone, and 25-hydroxyvitamin D. Participants were initially divided into 2 groups based on whether the woman was veiled and further subdivided into 3 groups on the basis of vitamin D intake from supplemented food sources (milk or vitamin D-fortified orange juice) and vitamin pills: unveiled, veiled and taking supplements, and veiled and taking no supplements. RESULTS: Eighty-seven women participated. Serum 25-hydroxyvitamin D levels were uniformly low, with the highest levels in the unveiled group (median [interquartile range]) (8.5 ng/mL [5.75-13.5 ng/mL]) followed by the veiled, supplemented group (7 ng/mL [4-11.5 ng/mL]) and the veiled, unsupplemented group (4 ng/mL [2-6.8 ng/mL]). 25-Hydroxyvitamin D levels were lower in women with less experience in the United States and in those with less education. Vitamin D-fortified orange juice consumption had a greater positive predictive effect on serum 25-hydroxyvitamin D levels than either milk or vitamin pills and may possibly serve as a surrogate marker for vitamin D awareness. CONCLUSIONS: Vitamin D deficiency, as assessed by 25-hydroxyvitamin D concentrations, is endemic in a sample of Arab-American women living in Dearborn, Michigan. These findings potentially identify an important health problem in the largest, most-concentrated Arab-American population in the United States.