Assessing treatment adherence is crucial to determine adequacy of mineralocorticoid therapy.

Background: There is no consensus strategy for mineralocorticoid (MC) therapy titration in patients with primary adrenal insufficiency (PAI). We aim to measure serum fludrocortisone (sFC) and urine fludrocortisone (uFC) levels and to determine their utility, alongside clinical/biochemical variables and treatment adherence to guide MC replacement dose titration. Methods: Multi-centre, observational, cross-sectional study on 41 patients with PAI on MC replacement therapy. sFC and uFC levels (measured by liquid chromatography-tandem mass spectrometry), plasma renin concentration (PRC), electrolytes (Na+, K+), mean arterial blood pressure (MAP), total daily glucocorticoid (dGC) and MC (dMC) dose, and assessment of treatment adherence were incorporated into statistical models. Results: We observed a close relationship between sFC and uFC (r = 0.434, P = 0.005) and between sFC and the time from the last fludrocortisone dose (r = -0.355, P = 0.023). Total dMC dose was related to dGC dose (r = 0.556, P < 0.001), K+ (r = -0.388, P = 0.013) as well as sFC (r = 0.356, P = 0.022) and uFC (r = 0.531, P < 0.001). PRC was related to Na+ (r = 0.517, P < 0.001) and MAP (r = -0.427, P = 0.006), but not to MC dose, sFC or uFC. Regression analyses did not support a role for sFC, uFC or PRC measurements and confirmed K+ (B = -44.593, P = 0.005) as the most important variable to guide dMC titration. Of the patients, 32% were non-adherent with replacement therapy. When adherence was inserted into the regression model, it was the only factor affecting dMC. Conclusions: sFC and uFC levels are not helpful in guiding dMC titration. Treatment adherence impacts on clinical variables used to assess MC replacement and should be included as part of routine care in patients with PAI.

Random 'spot' urinary metanephrines compared with 24-h-urinary and plasma results in phaeochromocytomas and paragangliomas.

BACKGROUND: In patients with phaeochromocytomas or paragangliomas (PPGLs), 24-h urine collections for metanephrines (uMNs) are cumbersome. OBJECTIVE: To evaluate the diagnostic utility of ratios to creatinine of 'spot' uMNs. METHODS: Concentrations of uMNs and plasma metanephrines (pMNs) were measured by HPLC-mass-spectrometry. We retrospectively compared correlations of 24-h-urine output and ratio to creatinine in historical specimens and prospectively assessed 24-h and contemporaneous spot urines and, where possible, pMNs. Using trimmed log-transformed values, we derived reference intervals based on age and sex for spot urines. We used multiples of upper limit of normal (ULNs) to compare areas under curves (AUCs) for receiver-operator characteristic curves of individual, and sum and product of, components. RESULTS: In 3143 24-h-urine specimens on 2416 patients, the correlation coefficients between the ratios and outputs of metanephrine, normetanephrine and 3-methoxytyramine in 24-h urines were 0.983, 0.905 and 0.875, respectively. In 96 patients, the correlations between plasma concentrations, urine output and ratios in spot specimens were similar to those for raw output or ratios in 24-h specimens. Of the 160 patients with PPGLs, the CIs for AUCs for individual metabolites overlapped for all four types of measurement, as did those for the sum of the multiple ULNs although these were slightly higher (AUC for spot urine: 0.838 (0.529-1), plasma: 0.929 (0.874-0.984) and output: 0.858 (0.764-0.952)). CONCLUSIONS: Ratios of fractionated metanephrines to creatinine in spot urine samples appear to have a similar diagnostic power to other measurements. The ease of spot urine collection may facilitate diagnosis and follow-up of PPGLs through improved patient compliance.

Utility of cardiac biomarkers for the diagnosis of type V myocardial infarction after coronary artery bypass grafting: insights from serial cardiac MRI.

OBJECTIVES: To examine, using cardiac magnetic resonance (CMR), the utility of cardiac biomarkers for the determination of myocyte necrosis and function after coronary artery bypass grafting (CABG), and to test the recently updated guidelines for the diagnosis of postoperative myocardial infarction (type V MI). METHODS AND RESULTS: Forty patients included in a single-centre randomised trial of two surgical techniques for performing CABG underwent serial assessment with CMR biochemical markers. Cine and delayed enhancement CMR (DE-CMR) for assessment of left ventricular (LV) function and irreversible myocyte necrosis was performed and levels of troponin I (TnI) and creatine kinase-MB isoform (CK-MB) were determined. The area under the curve for TnI strongly correlated with the mass of new myocyte necrosis as assessed by DE-CMR (r = 0.83, p<0.001), compared with CK-MB (r=0.39, p=0.06). Furthermore, routine assessment of TnI alone at 24 h (> 6.6 µg/l) predicted type V MI on DE-CMR with a sensitivity of 88% and specificity of 97%, whereas CK-MB predicted type V MI with a sensitivity of 75% and specificity of 87%. CONCLUSIONS: Biomarkers alone (TnI), at an appropriate threshold appear robust for the detection of type V MI, independently of supplementary evidence, as suggested by the ESC/ACCF/AHA/WHF criteria. Clinical trial registration information The study is listed on the Current Controlled Trials Registry: ISRCTN41388968. URL: http://www.controlled-trials.com.

A randomized trial of on-pump beating heart and conventional cardioplegic arrest in coronary artery bypass surgery patients with impaired left ventricular function using cardiac magnetic resonance imaging and biochemical markers.

BACKGROUND: Beating heart coronary artery bypass grafting (CABG) improves early postoperative cardiac function in patients with normal ventricular function, but its effect in patients with impaired function is uncertain. We compared a novel hybrid technique of on-pump beating heart CABG (ONBEAT) with conventional on-pump CABG (ONSTOP) in patients with impaired ventricular function. METHODS AND RESULTS: In a single-center randomized trial, 50 patients with impaired ventricular function were randomly assigned to ONBEAT or ONSTOP. Patients underwent cardiac magnetic resonance imaging for function and delayed hyperenhancement early and later after surgery. Serial assessment of biochemical markers was also undertaken. Preoperative characteristics were well matched; cardiac index was 2.85+/-0.53 (ONBEAT) and 2.62+/-0.59 L x min(-1) x m(-2) (ONSTOP). Early after surgery, there was a trend toward a greater reduction in end-systolic volume index in ONSTOP patients versus ONBEAT (-9+/-8 versus -4+/-11 mL x m(-2); P=0.06). The changes were sustained and significant at 6 months (-14+/-18 versus -2+/-19 mL x m(-2); P=0.04). Furthermore, the incidence of new hyperenhancement at 6 days was higher in ONBEAT patients (P=0.05), with 6 of 17 (35%) sustaining 8.2+/-5.2 g of new hyperenhancement each versus 2 of 23 (9%) in the ONSTOP group, each with 9.8+/-9.0 g (P=0.86). Finally, median area under the curve for troponin was higher in ONBEAT at 461 (interquartile range, 226 to 1141) microg/L versus 160 (interquartile range, 98 to 357) microg/L for ONSTOP (P=0.002). CONCLUSIONS: The incidence of new irreversible myocardial injury was significantly higher in ONBEAT than in ONSTOP patients. Furthermore, at 6 months, only ONSTOP patients demonstrated an improvement in ventricular geometry. The most likely mechanism is inadequate coronary perfusion to distal myocardial territories in patients with severe proximal coronary disease.

A single dose of vitamin D enhances immunity to mycobacteria.

RATIONALE: Vitamin D was used to treat tuberculosis (TB) in the preantibiotic era. Prospective studies to evaluate the effect of vitamin D supplementation on antimycobacterial immunity have not previously been performed. OBJECTIVES: To determine the effect of vitamin D supplementation on antimycobacterial immunity and vitamin D status. METHODS: A double-blind randomized controlled trial was conducted in 192 healthy adult TB contacts in London, United Kingdom. Participants were randomized to receive a single oral dose of 2.5 mg vitamin D or placebo and followed up at 6 weeks. MEASUREMENTS AND MAIN RESULTS: The primary outcome measure was assessed with a functional whole blood assay (BCG-lux assay), which measures the ability of whole blood to restrict luminescence, and thus growth, of recombinant reporter mycobacteria in vitro; the readout is expressed as a luminescence ratio (luminescence postinfection/baseline luminescence). IFN-gamma responses to the Mycobacterium tuberculosis antigens early secretory antigenic target-6 and culture filtrate protein 10 were determined with a second whole blood assay. Vitamin D supplementation significantly enhanced the ability of participants' whole blood to restrict BCG-lux luminescence in vitro compared with placebo (mean luminescence ratio at follow-up, 0.57, vs. 0.71, respectively; 95% confidence interval for difference, 0.01-0.25; p=0.03) but did not affect antigen-stimulated IFN-gamma secretion. CONCLUSIONS: A single oral dose of 2.5 mg vitamin D significantly enhanced the ability of participants' whole blood to restrict BCG-lux luminescence in vitro without affecting antigen-stimulated IFN-gamma responses. Clinical trials should be performed to determine whether vitamin D supplementation prevents reactivation of latent TB infection. Clinical trial registered with www.clinicaltrials.gov (NCT 00157066).

Routine isotope-dilution liquid chromatography-tandem mass spectrometry assay for simultaneous measurement of the 25-hydroxy metabolites of vitamins D2 and D3.

BACKGROUND: Measurement of 25-hydroxyvitamin D2 and D3 (25-OH D2 and D3) is essential for investigating vitamin D deficiency. Competitive binding techniques are unable to distinguish between the 2 metabolites and suffer from interference from other hydroxy metabolites of vitamin D. METHODS: We used isotope-dilution liquid chromatography-tandem mass spectrometry (ID-LC-MS/MS) for routine determination of 25-OH D2 and D3 with a stable-isotope-labeled internal standard (IS). Serum samples (100 microL) were denatured with methanol-propanol containing IS, vortex-mixed, extracted into hexane, and dried under nitrogen. The reconstituted extract was chromatographed on a BDS C8 HPLC column, and the metabolites and IS were detected by electrospray ionization MS/MS in multiple-reaction monitoring mode. RESULTS: 25-OH D2 and D3 and the IS nearly coeluted, whereas 1alpha-hydroxyvitamin D3 was separated; total run time was 8 min. The interassay CVs for 25-OH D2 were 9.5% and 8.4% at 52 and 76 nmol/L, respectively, and for 25-OH D3 were 5.1% and 5.6% at 55 and 87 nmol/L, respectively. The detection limit of the present method was <4 nmol/L for both metabolites. Method comparison with a commercial RIA measuring total 25-hydroxyvitamin D showed good correlation: y=0.97x - 2.7 nmol/L (r=0.91). The analytical system can assay 100 samples in 12.5 h. CONCLUSIONS: This simple robust interference-free LC-MS/MS assay is suitable for routine measurement of the 25-hydroxy metabolites of vitamins D2 and D3 in human serum. The assay has been in use for 9 months and has been used to assay more than 6000 routine samples.