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1.
Can J Cardiol ; 40(7): 1183-1197, 2024 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-38336003

RESUMEN

Detecting dyslipidemia early is important because atherosclerosis originates in childhood and early treatment can improve outcomes. In 2022, the Canadian Cardiovascular Society (CCS) and Canadian Pediatric Cardiology Association (CPCA) published a clinical practice update to detect, evaluate, and manage pediatric dyslipidemia. However, guidance on its translation into clinical laboratories is lacking. The Canadian Society of Clinical Chemists Working Group on Reference Interval Harmonization Lipid Team aims to assist guideline implementation and promote harmonized pediatric lipid reporting across Canada. The 2022 CCS/CPCA clinical practice update, 2011 National Heart, Lung, and Blood Institute integrated guidelines, and new data analysis (Canadian pediatric reference values from the Canadian Laboratory Initiative on Pediatric Reference Intervals [CALIPER] and retrospective patient data from large community laboratories) were incorporated to develop 5 key recommendations. These include recommendations to: (1) offer nonfasting and fasting lipid testing; (2) offer a lipid panel including total cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), non-HDL-C, and triglycerides, with apolipoprotein B and lipoprotein(a) available as individually orderable tests; (3) flag total cholesterol, LDL-C, and non-HDL-C results ≥ 95th percentile, and HDL-C results < 10th percentile, as recommended by CCS/CPCA/National Heart, Lung, and Blood Institute and validated by CALIPER, and flag apolipoprotein B and nonfasting triglyceride results ≥ 95th percentile on the basis of CALIPER, and do not flag Lp(a) results but mention the adult cutoff in the interpretive comments; (4) implement interpretive comments listed in the current report; and (5) implement the National Institutes of Health LDL-C equation. The Canadian Society of Clinical Chemists Working Group on Reference Interval Harmonization Lipid Team will support clinical laboratories to implement these recommendations using knowledge translation strategies. Harmonizing pediatric lipid reporting across Canadian clinical laboratories will optimize clinical decision-making and improve cardiovascular risk management in youth.


Asunto(s)
Dislipidemias , Lípidos , Humanos , Canadá , Niño , Lípidos/sangre , Dislipidemias/diagnóstico , Dislipidemias/sangre , Sociedades Médicas , Valores de Referencia
2.
Clin Chem ; 69(9): 991-1008, 2023 09 01.
Artículo en Inglés | MEDLINE | ID: mdl-37478022

RESUMEN

BACKGROUND: Harmonization in laboratory medicine is essential for consistent and accurate clinical decision-making. There is significant and unwarranted variation in reference intervals (RIs) used by laboratories for assays with established analytical traceability. The Canadian Society of Clinical Chemists (CSCC) Working Group on Reference Interval Harmonization (hRI-WG) aims to establish harmonized RIs (hRIs) for laboratory tests and support implementation. METHODS: Harnessing the power of big data, laboratory results were collected across populations and testing platforms to derive common adult RIs for 16 biochemical markers. A novel comprehensive approach was established, including: (a) analysis of big data from community laboratories across Canada; (b) statistical evaluation of age, sex, and analytical differences; (c) derivation of hRIs using the refineR method; and (d) verification of proposed hRIs across 9 laboratories with different instrumentation using serum and plasma samples collected from healthy Canadian adults. RESULTS: Harmonized RIs were calculated for all assays using the refineR method, except free thyroxine. Derived hRIs met proposed verification criterion across 9 laboratories and 5 manufacturers for alkaline phosphatase, albumin (bromocresol green), chloride, lactate dehydrogenase, magnesium, phosphate, potassium (serum), and total protein (serum). Further investigation is needed for some analytes due to failure to meet verification criteria in one or more laboratories (albumin [bromocresol purple], calcium, total carbon dioxide, total bilirubin, and sodium) or concern regarding excessively wide hRIs (alanine aminotransferase, creatinine, and thyroid stimulating hormone). CONCLUSIONS: We report a novel data-driven approach for RI harmonization. Findings support feasibility of RI harmonization for several analytes; however, some presented challenges, highlighting limitations that need to be considered in harmonization and big data analytics.


Asunto(s)
Ciencia de los Datos , Laboratorios , Adulto , Humanos , Valores de Referencia , Canadá , Albúminas
3.
Clin Chem Lab Med ; 61(7): 1280-1287, 2023 06 27.
Artículo en Inglés | MEDLINE | ID: mdl-37043622

RESUMEN

OBJECTIVES: Monitoring quality indicators (QIs) is an important part of laboratory quality assurance (QA). Here, the Canadian Society of Clinical Chemists (CSCC) Point of Care Testing (POCT) and QI Special Interest Groups describe a process for establishing and monitoring QIs for POCT glucose testing. METHODS: Key, error prone steps in the POCT glucose testing process were collaboratively mapped out, followed by risk assessment for each step. Steps with the highest risk and ability to detect a non-conformance were chosen for follow-up. These were positive patient identification (PPID) and repeat of critically high glucose measurements. Participating sites were asked to submit aggregate data for these indicators from their site(s) for a one-month period. The PPID QI was also included as part of a national QI monitoring program for which fifty-seven sites submitted data. RESULTS: The percentage of POCT glucose tests performed without valid PPID ranged from 0-87%. Sites without Admission-Discharge-Transfer (ADT) connectivity to POCT meters were among those with the highest percentage of POCT glucose tests performed without valid PPID. The percentage repeated critically high glucose measurements ranged from 0-50%, indicating low compliance with this recommendation. A high rate of discordance was also noted when critically high POCT glucose measurements were repeated, demonstrating the importance of repeat testing prior to insulin administration. CONCLUSIONS: Here, a process for establishing these QIs is described, with preliminary data for two QIs chosen from this process. The findings demonstrate the importance of QIs for identification and comparative performance monitoring of non-conformances to improve POCT quality.


Asunto(s)
Glucosa , Sistemas de Atención de Punto , Indicadores de Calidad de la Atención de Salud , Canadá , Opinión Pública , Glucosa/química , Pruebas en el Punto de Atención , Humanos
4.
Can J Cardiol ; 38(8): 1180-1188, 2022 08.
Artículo en Inglés | MEDLINE | ID: mdl-35378262

RESUMEN

There is limited guidance on laboratory reporting and interpretation of lipids and lipoproteins used in cardiovascular risk stratification. This contributes to inconsistencies in lipid reporting across clinical laboratories. Recently, the Canadian Cardiovascular Society (CCS) published the 2021 CCS guidelines for the management of dyslipidemia for the prevention of cardiovascular disease in the adult. A subcommittee of the Working Group on Reference Interval Harmonization of the Canadian Society of Clinical Chemists has developed harmonized lipid reporting recommendations that are aligned with the 2021 CCS guidelines, to improve the standardization of lipid assessment and clinical decision-making. The proposed harmonized lipid reporting recommendations were critically reviewed by a broad range of laboratory and clinical experts across Canada. Feedback from approximately 30 expert reviewers was reviewed by the Working Group on Reference Interval Harmonization lipid subcommittee, and consensus decisions were incorporated into the 2021 harmonized lipid reporting recommendations. In this position statement, we provide 6 recommendations for laboratory reporting of lipid parameters. These recommendations include implementing the new National Institutes of Health equation to replace the Friedewald equation for calculating low-density lipoprotein cholesterol, offering lipoprotein (a), either as an in-house or send-out test, and using assays that report lipoprotein (a) in molar units (nmol/L). We also developed a harmonized lipid reporting format with interpretive comments that includes flagging results based on screening patients using treatment decision thresholds in a primary prevention setting. Overall, harmonized lipid reporting will help bridge the gap between clinical guideline recommendations and clinical laboratory reporting and interpretation, and will improve cardiovascular risk assessment across Canada.


Asunto(s)
Dislipidemias , Laboratorios Clínicos , Lípidos , Adulto , Canadá/epidemiología , Enfermedades Cardiovasculares/prevención & control , Dislipidemias/diagnóstico , Factores de Riesgo de Enfermedad Cardiaca , Humanos , Laboratorios Clínicos/normas , Lípidos/análisis , Lipoproteína(a)
5.
Clin Biochem ; 94: 62-66, 2021 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-33895125

RESUMEN

BACKGROUND: Parathyroid hormone (PTH) is measured routinely as part of Chronic Kidney Disease Bone and Mineral Disorders (CKD-MBD) assessment. Multiple PTH assays exist with known differences resulting in CKD-MBD guidelines recommending treatment based on assay-specific thresholds. The study objectives are to assess between manufacturer and within manufacturer variability of PTH assays and the impact of assay variability on the assessment of CKD-BMD using both vendor defined and empirically derived thresholds. METHODS: Data were collected from Ontario, Canada's Proficiency Testing Program (24 challenge vials, 115-133 laboratories all using secondary generation PTH assays. Mean PTH and precision by the coefficient of analytical variation (CVa) were calculated. For each vial, whether the manufacturer's mean value exceeded the vendor-defined and empirically-derived upper limit of normal (ULN) was recorded and the concordance between assays was determined. RESULTS: Across all laboratories, the mean PTH range was 12.0 ± 3.9 pmol/L and the mean CVa was 30%. The percent of vials with a mean PTH exceeding manufacturer's specific ULN varied substantially between manufacturers. Only 58% of vials had complete concordance as to whether mean PTH was above assay-specific ULNs. This increased to 83% using the empirically derived ULN. CONCLUSIONS: CKD-BMD assessment and management will depend on the PTH assay. The between-assay variability is reduced but not eliminated when empirically derived reference intervals are used. Improvements in PTH measurement are required in order to ensure consistent patient care.


Asunto(s)
Hormona Paratiroidea/sangre , Insuficiencia Renal Crónica/sangre , Anciano , Trastorno Mineral y Óseo Asociado a la Enfermedad Renal Crónica/sangre , Trastorno Mineral y Óseo Asociado a la Enfermedad Renal Crónica/diagnóstico , Femenino , Humanos , Masculino , Persona de Mediana Edad , Insuficiencia Renal Crónica/diagnóstico
6.
Can J Cardiol ; 37(6): 933-937, 2021 06.
Artículo en Inglés | MEDLINE | ID: mdl-33775880

RESUMEN

To effectively implement the Canadian Cardiovascular Society (CCS) guidelines for dyslipidemia management into clinical laboratories, clear recommendations for lipid reporting are essential. In this study, the Canadian Society of Clinical Chemists Working Group on Reference Interval Harmonisation surveyed Canadian laboratories on adult lipid reporting practices to set a foundation for the development and implementation of harmonised lipid reporting across Canada. Key aspects of the survey asked laboratories: what reporting parameters were in place to assess lipid results; what interpretative comments were provided; whether nonfasting lipids were permitted and, if so, what strategy was used to document fasting status; and whether there was interest in implementing a harmonised lipid report. A total of 101 laboratories were represented by 24 respondents, as many responses were submitted by laboratory networks that included more than 1 laboratory. There was at least 1 response from 9 Canadian provinces and representation across 5 testing platforms. Upper and lower limits for lipid parameters and referenced source of limits varied substantially across laboratories, with only 56% of laboratories (9 respondents) referencing the 2016 CCS guidelines. Eighty-six percent of laboratories (19 respondents) report nonfasting lipids, although the method of documenting nonfasting status varied. Overall, 36% of laboratories (8 respondents) reported interest in implementing a harmonised lipid report. Assessment of current lipid-reporting practices supports the need for harmonised lipid reporting across Canada. Development of a harmonised lipid report for the adult population, consistent with up-to-date Canadian guidelines, will improve continuity of lipid test interpretation across Canada and improve clinical decision making.


Asunto(s)
Servicios de Laboratorio Clínico , Dislipidemias , Lípidos , Manejo de Atención al Paciente , Canadá/epidemiología , Servicios de Laboratorio Clínico/organización & administración , Servicios de Laboratorio Clínico/normas , Dislipidemias/sangre , Dislipidemias/epidemiología , Dislipidemias/terapia , Necesidades y Demandas de Servicios de Salud , Humanos , Lípidos/análisis , Lípidos/sangre , Manejo de Atención al Paciente/métodos , Manejo de Atención al Paciente/normas , Mejoramiento de la Calidad , Estándares de Referencia , Valores de Referencia , Proyectos de Investigación
7.
Clin Chim Acta ; 488: 189-195, 2019 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-30445029

RESUMEN

BACKGROUND: Diagnosis, prognostication and treatment in chronic kidney disease is often informed by an estimate of the glomerular filtration rate (GFR). Commonly used GFR estimation (eGFR) equations are based on serum creatinine (Cr) concentrations and display suboptimal precision and accuracy. Newer equations incorporating additional endogenous markers such as ß-Trace Protein (BTP), ß2-Microglobulin (B2M) and cystatin C (cysC) have been developed but require validation. METHODS: This prospective cohort study evaluated the performance of 6 eGFR equations developed by the chronic kidney disease - epidemiology collaboration group (CKD-EPI) against urinary inulin clearance GFR in patients recruited from outpatient nephrology clinics. RESULTS: Mean biases were negligible and similar between equations. The eGFR-EPI Cr/cysC had the best precision and accuracy of all the equations and the best agreement with inulin mGFR when classifying participants into GFR categories. The BTP and B2M equations displayed the worst precisions and accuracies and showed the least consistent performance across levels of GFR. Thus, the eGFR-EPI Cr/cysC is the least biased, most precise and has the highest accuracy as compared to other eGFR-EPI equations. CONCLUSIONS: The BTP and B2M equations are the worst performing of the eGFR-EPI equations, and no benefit is observed with the addition of BTP or B2M to Cr/cysC.


Asunto(s)
Tasa de Filtración Glomerular , Inulina/orina , Insuficiencia Renal Crónica/epidemiología , Insuficiencia Renal Crónica/orina , Biomarcadores/sangre , Estudios de Cohortes , Creatinina/sangre , Cistatina C/sangre , Femenino , Humanos , Oxidorreductasas Intramoleculares/sangre , Lipocalinas/sangre , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Microglobulina beta-2/sangre
8.
Clin Biochem ; 51: 10-20, 2018 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-29061378

RESUMEN

Protein electrophoresis is commonly used as an aid in the diagnosis of monoclonal gammopathies and is performed in many laboratories in Canada and throughout the world. However, unlike many other diagnostic tests, there is limited guidance for standardization and neither guidance nor specific recommendations for clinical reporting of serum (SPE) or urine (UPE) protein electrophoresis and immunotyping available in the literature. Therefore, a Canadian effort was undertaken to recommend standards that cover all aspects of clinical reporting with an ultimate goal towards reporting standardization. The Canadian Society of Clinical Chemists (CSCC) Monoclonal Gammopathy Interest Group (MGIG), which is composed of CSCC members with an interest in protein electrophoresis, has formed a Monoclonal Gammopathy Working Group (MGWG) to take initial steps towards standardization of SPE, UPE and immunotyping. Candidate standardization recommendations were developed, discussed and voted upon by the MGWG. Candidate recommendations that achieved 90% agreement are presented as consensus recommendations. Recommendations that did not achieve 90% consensus remain candidate recommendations and are presented with accompanying MGWG discussion. Eleven consensus recommendations along with candidate recommendations for nomenclature, protein fraction reporting, test utilization, interference handling and interpretive reporting options are presented.


Asunto(s)
Electroforesis de las Proteínas Sanguíneas/métodos , Guías como Asunto , Paraproteinemias/sangre , Sociedades Médicas , Canadá , Humanos
9.
Clin Biochem ; 50(16-17): 925-935, 2017 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-28647526

RESUMEN

OBJECTIVE: Reference intervals are widely used decision-making tools in laboratory medicine, serving as health-associated standards to interpret laboratory test results. Numerous studies have shown wide variation in reference intervals, even between laboratories using assays from the same manufacturer. Lack of consistency in either sample measurement or reference intervals across laboratories challenges the expectation of standardized patient care regardless of testing location. Here, we present data from a national survey conducted by the Canadian Society of Clinical Chemists (CSCC) Reference Interval Harmonization (hRI) Working Group that examines variation in laboratory reference sample measurements, as well as pediatric and adult reference intervals currently used in clinical practice across Canada. DESIGN AND METHODS: Data on reference intervals currently used by 37 laboratories were collected through a national survey to examine the variation in reference intervals for seven common laboratory tests. Additionally, 40 clinical laboratories participated in a baseline assessment by measuring six analytes in a reference sample. RESULTS: Of the seven analytes examined, alanine aminotransferase (ALT), alkaline phosphatase (ALP), and creatinine reference intervals were most variable. As expected, reference interval variation was more substantial in the pediatric population and varied between laboratories using the same instrumentation. Reference sample results differed between laboratories, particularly for ALT and free thyroxine (FT4). Reference interval variation was greater than test result variation for the majority of analytes. CONCLUSION: It is evident that there is a critical lack of harmonization in laboratory reference intervals, particularly for the pediatric population. Furthermore, the observed variation in reference intervals across instruments cannot be explained by the bias between the results obtained on instruments by different manufacturers.


Asunto(s)
Análisis Químico de la Sangre/normas , Servicios de Laboratorio Clínico , Laboratorios/normas , Adolescente , Adulto , Anciano , Canadá , Preescolar , Femenino , Humanos , Masculino , Persona de Mediana Edad , Control de Calidad , Valores de Referencia , Informe de Investigación
10.
Can J Kidney Health Dis ; 4: 2054358117693353, 2017.
Artículo en Inglés | MEDLINE | ID: mdl-28321322

RESUMEN

BACKGROUND: The international initiative to standardize creatinine (Cr) assays by tracing reference materials to Isotope Dilution Mass Spectrometry (IDMS) assigned values was implemented to reduce interlaboratory variability and improve assay accuracy. OBJECTIVE: The aims of this study were to examine whether IDMS standardization has improved Cr assay accuracy (bias), interlaboratory variability (precision), total error (TE), and attainment of recommended analytical performance goals. METHODS: External Quality Assessment (EQA) data (n = 66 challenge vials) from Ontario, Canada, were analyzed. The bias, precision, TE, and the number of EQA challenge vials meeting performance goals were determined by assay manufacturer before (n = 32) and after (n = 34) IDMS implementation. RESULTS: The challenge vials with the worst bias and precision were spiked with known common interfering substances (glucose and bilirubin). IDMS standardization improved assay bias (10.4%-1.6%, P < .001), but precision remained unchanged (5.0%-4.7%, P = .5) with performance goals not consistently being met. Precision and TE goals based on biologic variation were attained by only 29% to 69% and 32% to 62% of challenge vials. CONCLUSIONS: While IDMS standardization has improved Cr assay accuracy and thus reduced TE, significant interlaboratory variability remains. Contemporary Cr assays do not currently meet the standards required to allow for accurate and consistent estimated glomerular filtration rate assessment and chronic kidney disease diagnosis across laboratories. Further improvements in Cr assay performance are needed.


MISE EN CONTEXTE: L'initiative internationale visant à standardiser les épreuves de dosage de la créatinine par le traçage des substances de référence aux valeurs qui leur sont assignées par spectrométrie de masse à dilution isotopique (IDMS) a été mise en œuvre dans le but de réduire la variabilité inter-laboratoires et d'améliorer la précision de l'essai lui-même. OBJECTIFS DE L'ÉTUDE: Cette étude visait à déterminer si la standardisation par IDMS parvenait à améliorer l'exactitude de l'épreuve de dosage de la créatinine (biais), à réduire la variabilité inter-laboratoires (précision) et si elle contribuait à l'atteinte des objectifs recommandés en matière de performance analytique. MÉTHODOLOGIE: On a analysé les données de l'assurance externe de la qualité (AEQ) provenant de l'Ontario, au Canada. Le biais, l'exactitude, l'erreur totale ainsi que le nombre de fioles d'épreuves provenant du AEQ atteignant les objectifs d'erreurs ont été déterminés par le fabricant de l'épreuve avant et après la mise en œuvre de l'IDMS. RÉSULTATS: Les essais enzymatiques ont obtenu des résultats plus précis et des valeurs d'erreur totale inférieures. Les fioles d'épreuves qui présentaient la plus faible précision et le plus fort biais étaient celles à qui l'on avait ajouté des substances connues pour créer de l'interférence (glucose et bilirubine). La standardisation par IDMS a permis d'améliorer le biais lié à l'épreuve (de 10,4% à 1,6%, P < 0,001), mais n'a pas affecté la précision qui est demeurée faible (5,0 à 4,7%, P = 0,5). De plus, les objectifs de performance n'ont pas toujours été atteints: les objectifs de précision et d'erreur totale établis en tenant compte des variations biologiques ont été atteints par seulement 29 à 69% et 32 à 62% des fioles d'épreuves. CONCLUSIONS: Bien que la standardisation par IDMS ait réduit les valeurs d'erreur totale obtenues lors des épreuves de dosage de la créatinine et ait amélioré la précision de l'essai, une variabilité inter-laboratoires significative subsiste dans les résultats. À ce jour, les épreuves de dosage de la créatinine ne rencontrent toujours pas les standards exigés pour permettre une mesure précise et homogène du débit de filtration glomérulaire estimé et le diagnostic de l'insuffisance rénale chronique dans tous les laboratoires. Par conséquent, des améliorations supplémentaires en ce qui concerne la performance des épreuves de dosage de la créatinine s'avèrent nécessaires.

11.
Clin J Am Soc Nephrol ; 12(1): 29-37, 2017 01 06.
Artículo en Inglés | MEDLINE | ID: mdl-27827312

RESUMEN

BACKGROUND AND OBJECTIVES: The tracing of creatinine (Cr) reference materials to isotope dilution mass spectrometry-assigned values was implemented worldwide to reduce interlaboratory variability and improve assay accuracy. The aims of this study were to examine the current extent of interlaboratory variability and its effect on eGFR. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Leftover plasma from 2-3 consecutive days was obtained from 53 intensive care unit patients with a range of kidney functions. Individual patient samples were pooled and split and sent to 12 different laboratories for Cr measurement. For each patient, the mean Cr and Chronic Kidney Disease Epidemiology Collaboration eGFR (eGFR-EPI), assuming a 65-year-old nonblack woman, were determined. Interlaboratory variability was assessed by the range and SD of Cr and eGFR-EPI. This was repeated after stratifying by assay type and by the median Cr of 1.36 mg/dl. For patients whose eGFR-EPI range included 60 ml/min per 1.73 m2, the percentage of laboratories with eGFR-EPI<60 ml/min per 1.73 m2 was determined. RESULTS: The mean±SD of the Cr and eGFR-EPI ranges were 0.20±0.09 mg/dl and 14±9 ml/min per 1.73 m2 for Cr<1.36 mg/dl. Jaffe Cr results were an average 0.1 mg/dl (Cr≥1.36 mg/dl) and 0.05 mg/dl (Cr<1.36 mg/dl) higher than enzymatic results (P<0.001 for both). Ten patients had an eGFR-EPI range that included 60 ml/min per 1.73 m2. Their median eGFR-EPI range was 15 ml/min per 1.73 m2. There was significant discordance in the diagnosis of CKD (eGFR-EPI<60 ml/min per 1.73 m2), with laboratories using Jaffe Cr methods making the diagnosis more frequently than those using enzymatic Cr methods (60% versus 39%). CONCLUSIONS: Significant interlaboratory variability in Cr measurement still exists. Jaffe assays yield higher Cr values than enzymatic assays, leading to lower eGFR-EPIs and more frequent CKD diagnoses. Further improvements in assay performance are required to standardize patient CKD diagnosis and to facilitate longitudinal Cr monitoring across laboratories.


Asunto(s)
Creatinina/sangre , Tasa de Filtración Glomerular , Insuficiencia Renal Crónica/diagnóstico , Insuficiencia Renal Crónica/fisiopatología , Anciano , Técnicas de Laboratorio Clínico , Pruebas de Enzimas , Femenino , Humanos , Laboratorios , Insuficiencia Renal Crónica/sangre , Reproducibilidad de los Resultados
12.
J Immunol ; 196(2): 823-31, 2016 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-26673142

RESUMEN

Metabolic changes can influence inflammatory responses to bacteria. To examine whether localized manipulation of the mevalonate pathway impacts innate immunity, we exploited a unique mucosal disease model, endometritis, where inflammation is a consequence of innate immunity. IL responses to pathogenic bacteria and LPS were modulated in bovine endometrial cell and organ cultures by small molecules that target the mevalonate pathway. Treatment with multiple statins, bisphosphonates, squalene synthase inhibitors, and small interfering RNA showed that inhibition of farnesyl-diphosphate farnesyl transferase (squalene synthase), but not 3-hydroxy-3-methylglutaryl-CoA reductase or farnesyl diphosphate synthase, reduced endometrial organ and cellular inflammatory responses to pathogenic bacteria and LPS. Although manipulation of the mevalonate pathway reduced cellular cholesterol, impacts on inflammation were independent of cholesterol concentration as cholesterol depletion using cyclodextrins did not alter inflammatory responses. Treatment with the isoprenoid mevalonate pathway-intermediates, farnesyl diphosphate and geranylgeranyl diphosphate, also reduced endometrial cellular inflammatory responses to LPS. These data imply that manipulating the mevalonate pathway regulates innate immunity within the endometrium, and that isoprenoids are regulatory molecules in this process, knowledge that could be exploited for novel therapeutic strategies.


Asunto(s)
Endometritis/inmunología , Endometritis/metabolismo , Inmunidad Innata/fisiología , Ácido Mevalónico/inmunología , Ácido Mevalónico/metabolismo , Animales , Bovinos , Colesterol/biosíntesis , Modelos Animales de Enfermedad , Ensayo de Inmunoadsorción Enzimática , Femenino , Lipopolisacáridos/inmunología , Lipopolisacáridos/toxicidad
14.
PLoS One ; 7(5): e38057, 2012.
Artículo en Inglés | MEDLINE | ID: mdl-22666445

RESUMEN

BACKGROUND: During pregnancy, the demand for folic acid increases since the fetus requires this nutrient for its rapid growth and cell proliferation. The placenta concentrates folic acid into the fetal circulation; as a result the fetal levels are 2 to 4 times higher than the maternal level. Animal and in vitro studies have suggested that alcohol may impair transport of folic acid across the placenta by decreasing expression of transport proteins. We aim to determine if folate transfer to the fetus is altered in human pregnancies with chronic alcohol consumption. METHODOLOGY/PRINCIPAL FINDINGS: Serum folate was measured in maternal blood and umbilical cord blood at the time of delivery in pregnancies with chronic and heavy alcohol exposure (n = 23) and in non-drinking controls (n = 24). In the alcohol-exposed pairs, the fetal:maternal serum folate ratio was ≤ 1.0 in over half (n = 14), whereas all but one of the controls were >1.0. Mean folate in cord samples was lower in the alcohol-exposed group than in the controls (33.15 ± 19.89 vs 45.91 ± 20.73, p = 0.04). CONCLUSIONS/SIGNIFICANCE: Our results demonstrate that chronic and heavy alcohol use in pregnancy impairs folate transport to the fetus. Altered folate concentrations within the placenta and in the fetus may in part contribute to the deficits observed in the fetal alcohol spectrum disorders.


Asunto(s)
Alcoholes/efectos adversos , Exposición a Riesgos Ambientales/efectos adversos , Feto/metabolismo , Ácido Fólico/metabolismo , Intercambio Materno-Fetal/efectos de los fármacos , Adulto , Alcoholismo/sangre , Alcoholismo/metabolismo , Femenino , Enfermedades Fetales/metabolismo , Ácido Fólico/sangre , Humanos , Embarazo , Factores de Tiempo
15.
Can J Urol ; 19(3): 6314-8, 2012 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-22704323

RESUMEN

The biochemical diagnosis of male hypogonadism remains a controversial issue. The problem is compounded by the variety of laboratory assays available to measure serum testosterone (T) and the limited understanding, among clinicians, of their relative diagnostic validity. It is widely accepted that only the testosterone not bound to sex hormone-bounding globulin is metabolically active. Therefore, for diagnostic purposes it is frequent practice to order the measurement of free T (FT) or bioavailable T (BAT). Our objective is to describe the methods available for measuring FT and to review the literature to determine the relevance of ordering FT as a diagnostic laboratory tool in cases of suspected hypogonadism. We also provide our biochemical approach in evaluating men with T deficiency. The limited information available in this regard is frequently confined to the biochemistry literature. The few reliable studies indicate that analog-based measurement of FT offers no diagnostic or financial advantage over automated assay for total T. The manuscript also describes "How we do it." For optimal diagnostic accuracy and financial responsibility, total T and calculated FT (cFT) should be the tests employed for initial and confirmatory diagnosis respectively. Measurement of bioavailable T is an alternative option but not germane to the points to which we are calling attention in this paper. While clinicians should be discouraged from ordering FT assays, laboratories performing it should indicate what method was used and warned about possible reliability concerns. FT assays should no longer be a reimbursable test.


Asunto(s)
Técnicas de Diagnóstico Endocrino/economía , Técnicas de Diagnóstico Endocrino/normas , Hipogonadismo/diagnóstico , Testosterona/sangre , Humanos , Hipogonadismo/economía , Masculino , Testosterona/análisis , Testosterona/economía
16.
Hemodial Int ; 16(1): 53-8, 2012 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-22099949

RESUMEN

Fibroblast growth factor 23 (FGF-23) is elevated in patients with end-stage kidney disease and has been linked with mortality, vascular calcification, markers of bone turnover, and left ventricular hypertrophy. In this cohort study, we determined the correlates of FGF-23 (including cardiac troponin T [cTNT]) and determined its association with mortality over 3.5 years of follow-up in 103 prevalent hemodialysis patients. Mean age was 61.2 (15.5) and the mean dialysis vintage was 4.19 years (4.6). The median (interquartile range) FGF-23 was 1259 (491, 2885) RU/mL. Independent predictors (estimate standard error) of log-transformed FGF-23 concentrations included phosphorus (0.75 [0.237], P = 0.002) and cardiac troponin T (1.04 [0.41], P = 0.01). There were 57 deaths. In the fully adjusted model, the significant predictors of mortality included age and albumin. The independent association between FGF-23 and cTNT is a novel finding. Whether this relationship supports the possibility that a downstream effect of dysregulated phosphorous homeostasis may be enhanced cardiac remodeling requires further study.


Asunto(s)
Factores de Crecimiento de Fibroblastos/fisiología , Diálisis Renal/mortalidad , Troponina T/sangre , Adulto , Anciano , Femenino , Factor-23 de Crecimiento de Fibroblastos , Factores de Crecimiento de Fibroblastos/sangre , Humanos , Masculino , Persona de Mediana Edad , Fósforo/metabolismo
18.
Clin J Am Soc Nephrol ; 6(9): 2150-6, 2011 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-21799146

RESUMEN

BACKGROUND AND OBJECTIVES: Cystatin C (CysC) is a promising marker of GFR. Several equations have been derived to estimate GFR from its serum concentration. Heterogeneity in the performance of these equations exists in validation studies even when the same CysC assay from the same manufacturer is utilized. This study was designed to examine the differences in CysC and GFR estimation (eGFR) using Siemens' nephelometric immunoassay and the Mayo Clinic equation. The ability of the eGFRs to predict measured GFR was also examined. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Ninety-seven split samples were sent to laboratories at Children's Hospital of Eastern Ontario (CHEO) in Ottawa, Canada, and at the Mayo Clinic in Rochester, Minnesota. RESULTS: The mean CHEO CysC was 0.17 mg/L (10%) lower than the mean Mayo Clinic CysC. Using the Mayo Clinic equation, the mean eGFR difference was 7.2 ml/min per 1.73 m(2) (15%). Approximately 36% of the results agreed within 10%, while 13% were discordant by greater than 30%. Larger absolute differences in mean eGFR between the two laboratories were found in the subgroup with CysC less than 1.41 mg/L as compared with the subgroup greater than 1.41 mg/L (9.5 versus 5.0 ml/min per 1.73 m(2)). Correction of CHEO values to the Mayo Clinic did not improve GFR estimation. CONCLUSIONS: Significant differences in CysC measurement exist between laboratories using the same assay by the same manufacturer and these lead to clinically relevant differences in GFR estimation. This interlaboratory variability needs to be recognized when interpreting and comparing CysC and eGFR results.


Asunto(s)
Cistatina C/sangre , Tasa de Filtración Glomerular , Calibración , Humanos , Laboratorios , Modelos Lineales
19.
Reprod Toxicol ; 31(4): 500-6, 2011 May.
Artículo en Inglés | MEDLINE | ID: mdl-21315145

RESUMEN

Chronic ethanol exposure (CEE) can produce developmental abnormalities in the CNS of the embryo and developing fetus. Folic acid (FA) is an important nutrient during pregnancy and low folate status exacerbates ethanol-induced teratogenicity. This study tested the hypotheses that (1) CEE depletes folate stores in the mother and fetus; and (2) maternal FA supplementation maintains folate stores. CEE decreased fetal body, brain, hippocampus weights, and brain to body weight ratio but not hippocampus to body weight ratio. These effects of CEE were not mitigated by maternal FA administration. The FA regimen prevented the CEE-induced decrease of term fetal liver folate. However, it did not affect maternal liver folate or fetal RBC folate at term, and did not mitigate the nutritional deficit-induced decrease of term fetal hippocampus folate. This study suggests that maternal FA supplementation may have differential effects on folate status in the mother and the fetus.


Asunto(s)
Anomalías Inducidas por Medicamentos/prevención & control , Consumo de Bebidas Alcohólicas/efectos adversos , Encéfalo/efectos de los fármacos , Suplementos Dietéticos , Etanol/toxicidad , Ácido Fólico/farmacología , Exposición Materna , Complejo Vitamínico B/toxicidad , Anomalías Inducidas por Medicamentos/etiología , Anomalías Inducidas por Medicamentos/metabolismo , Animales , Encéfalo/anomalías , Encéfalo/metabolismo , Eritrocitos/efectos de los fármacos , Eritrocitos/metabolismo , Femenino , Sangre Fetal/metabolismo , Reabsorción del Feto/inducido químicamente , Reabsorción del Feto/prevención & control , Peso Fetal/efectos de los fármacos , Ácido Fólico/administración & dosificación , Ácido Fólico/metabolismo , Edad Gestacional , Cobayas , Hipocampo/anomalías , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Tamaño de la Camada/efectos de los fármacos , Masculino , Tamaño de los Órganos/efectos de los fármacos , Embarazo , Complejo Vitamínico B/administración & dosificación , Complejo Vitamínico B/metabolismo
20.
J Urol ; 183(6): 2294-9, 2010 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-20400148

RESUMEN

PURPOSE: The diagnosis of testosterone deficiency syndrome is based on clinical manifestations and documentation of low testosterone. Which biochemical tests to use and the importance of morning sampling are still controversial. Biological variation (including interindividual and intraindividual biological variation) must be considered when interpreting individual results as it determines the usefulness of reference intervals and the change (reference change value) necessary for a significant difference between results. MATERIALS AND METHODS: A total of 87 healthy men (50 to 70+ years old) provided blood in the morning of the first day, and 4 weeks later in the morning and afternoon. Samples were frozen (-70C) and analyzed in the same run for serum testosterone, sex hormone-binding globulin and albumin, and bioavailable testosterone and free testosterone were calculated. RESULTS: Serum testosterone was lower in the afternoon by 1.5 nmol/l (43 ng/dl, p <0.05), with larger changes observed with higher morning values. However, this diurnal effect was dwarfed by the normal biological variation observed for repeat morning samples (serum testosterone +/- 4 nmol/l [115 ng/dl]). Between day intra-individual biological variation for morning serum testosterone was 18.7% while within day intra-individual biological variation was 12.9%. A change of 52% (reference change value) is necessary between serial morning results to confirm a significant difference. The biological variation parameters of calculated bioavailable testosterone and calculated free testosterone confer no advantage over total testosterone. CONCLUSIONS: Marked individuality of serum testosterone is evident even in healthy men. Because intraindividual biological variation is less than interindividual biological variation, reference intervals are marginally useful. The homeostatic set point of a patient could decrease by half and still be within the reference interval. Prospective establishment of an individual's baseline over repeated measurements or symptoms regardless of serum testosterone concentration should be used to guide clinical decisions.


Asunto(s)
Testosterona/sangre , Testosterona/deficiencia , Anciano , Humanos , Masculino , Persona de Mediana Edad , Valores de Referencia
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