RESUMO
The study of rare families with inherited pain insensitivity can identify new human-validated analgesic drug targets. Here, a 66-yr-old female presented with nil requirement for postoperative analgesia after a normally painful orthopaedic hand surgery (trapeziectomy). Further investigations revealed a lifelong history of painless injuries, such as frequent cuts and burns, which were observed to heal quickly. We report the causative mutations for this new pain insensitivity disorder: the co-inheritance of (i) a microdeletion in dorsal root ganglia and brain-expressed pseudogene, FAAH-OUT, which we cloned from the fatty-acid amide hydrolase (FAAH) chromosomal region; and (ii) a common functional single-nucleotide polymorphism in FAAH conferring reduced expression and activity. Circulating concentrations of anandamide and related fatty-acid amides (palmitoylethanolamide and oleoylethanolamine) that are all normally degraded by FAAH were significantly elevated in peripheral blood compared with normal control carriers of the hypomorphic single-nucleotide polymorphism. The genetic findings and elevated circulating fatty-acid amides are consistent with a phenotype resulting from enhanced endocannabinoid signalling and a loss of function of FAAH. Our results highlight previously unknown complexity at the FAAH genomic locus involving the expression of FAAH-OUT, a novel pseudogene and long non-coding RNA. These data suggest new routes to develop FAAH-based analgesia by targeting of FAAH-OUT, which could significantly improve the treatment of postoperative pain and potentially chronic pain and anxiety disorders.
Assuntos
Amidoidrolases/genética , Ácidos Araquidônicos/sangue , Endocanabinoides/sangue , Insensibilidade Congênita à Dor/sangue , Insensibilidade Congênita à Dor/genética , Alcamidas Poli-Insaturadas/sangue , Pseudogenes/genética , Idoso , Amidoidrolases/sangue , Feminino , Humanos , Polimorfismo de Nucleotídeo Único/genéticaRESUMO
Due to increased convenience and faster test results, interest in point-of-care testing (PoCT) has grown significantly. Though PoCT may improve the speed and convenience of testing, the devices need to be fit for their intended purpose. Our aim was to verify the performance of Roche cobas b 101 and Abbott Afinion 2 for C-reactive protein (CRP), lipid studies and glycated haemoglobin (HbA1c), and Siemens Atellica DCA for HbA1c. For all PoCT analysers and measurands, accuracy was assessed by method comparison with central laboratory analysers. Passing-Bablok linear regression was performed, and Bland-Altman plots were generated. The proportion of samples within the Royal College of Pathologists of Australasia Quality Assurance Programs Analytical Performance Specifications (RCPAQAP APS) was assessed. Within-run and between-day imprecision was assessed and compared with manufacturer claims and biological variation or clinical guidelines for desirable imprecision. For CRP, both evaluated PoCT analysers had all samples within the RCPAQAP APS and had optimal imprecision according to biological variation. For lipid studies, the Roche cobas b 101 had most samples within the RCPAQAP APS, with two of 22 cholesterol, one of 22 high-density-lipoprotein-cholesterol (HDL-C) and zero of 22 triglyceride comparisons outside the RCPAQAP APS. The Abbott Afinion 2 had a positive bias with all three measured parameters, although the effect was more limited in the calculated parameters cholesterol:HDL-C ratio, non-HDL-C and low-density-lipoprotein-cholesterol (LDL-C). For HbA1c, all analysers had acceptable imprecision for monitoring with coefficient of variation (CV) <3% and minimal bias at the treatment target (HbA1c 53 mmol/mol or 7.0%). However, significant biases were apparent at higher or lower HbA1c for all analysers. All evaluated analysers were fit for purpose for CRP and for serial monitoring of HbA1c, although bias in some analysers was present at extremes of HbA1c. For lipid studies, the Roche cobas b 101 had fewer results outside the RCPAQAP allowable limits, and better precision. The Abbott Afinion 2 had a positive bias on both the cholesterol and HDL-C, but there is limited clinical impact when calculating cholesterol:HDL-C, LDL-C and non-HDL-C.
Assuntos
Proteína C-Reativa , Sistemas Automatizados de Assistência Junto ao Leito , Humanos , Hemoglobinas Glicadas , LDL-Colesterol , Testes ImediatosRESUMO
BACKGROUND: The aim of this study was to measure the variability in estimated glomerular filtration rate (eGFR) calculated by laboratories in Northern Ireland where creatinine assays other than the Beckman CX3 assay used to derive the Modification of Diet in Renal Disease (MDRD) are utilized. METHODS: Fifty patient samples were analysed for serum creatinine by kinetic Jaffe assays on the Roche modular P-800 (compensated assay), the Beckman LX20 and the Abbott Aeroset analysers. RESULTS: The median (interquartile range) eGFR calculated by the abbreviated MDRD equation using the creatinine results obtained by each method were 45.4 (31.7-66.6), 49.2 (35.4-78.1) and 50.0 (35.1-71.2) mL/min/1.73 m2 for Beckman, Roche (compensated) and Abbott assays, respectively. Following mathematical alignment of creatinine methods to the Beckman method the median (interquartile range) eGFR for the Roche and Abbott methods were 44.0 (32.0-67.6) and 45.6 (31.2-64.8) mL/min/1.73 m2, respectively. CONCLUSION: The regression equations published in this study can be used to align creatinine methods. However, method-related biases in eGFR of up to 10% are minimal in the context of the magnitude of variance reflected in the 90% confidence intervals.