in the United States to 37 years ( 2 ). Among the phenotypic manifestations of CF patients are abnormalities in blood and tissue polyunsaturated fatty acid (PUFA) levels that are independent of absorption and nutritional status (reviewed in Refs. [3][4][5]. The most consistent of these abnormalities are decreased linoleate (LA; 18:2n-6) and docosahexaenate (DHA; 22:6n-3). In addition, some studies have shown increased arachidonate (AA; 20:4n-6), palmitoleate (16:1n-7), oleate (18:1n-9), and Mead acid (20:3n-9). Similar fi ndings are seen in animal ( 6-9 ) and cell culture ( 10, 11 ) models of CF. The magnitude of fatty acid alterations in CF patients correlates with disease severity, suggesting a role for fatty acid metabolism in CF pathophysiology ( 12-17 ).There is increasing evidence that these abnormalities are due to differences in fatty acid metabolism in CF. PUFAs of the n-3 and n-6 series are metabolized in a stepwise fashion along parallel pathways (reviewed in Ref. 18 ). A common set of desaturase and elongase enzymes catalyzes the conversion of LA through multiple steps to AA and ultimately to docosapentaenoate (DPA; 22:5n-6). The same enzymes convert linolenate (LNA; 18:3n-3) to eicosapentaenoate (EPA; 20:5n-3) and subsequently to DHA. Multiple studies have demonstrated increased conversion of AA to eicosanoids (19)(20)(21)(22), stimulating increased metabolism of LA to maintain AA ( 7, 10, 11 ) and accounting for the decreased LA and increased AA levels seen in CF.Recent studies in our laboratory have uncovered a potential mechanism accounting for these metabolic changes ( 23 ). In cell culture models of CF, decreased LA and increased AA and EPA levels in CF cells correlated with increased expression and activity of the ⌬ 5-and ⌬ 6-desaturase enzymes that catalyze conversion of LA to AA and LNA to EPA. Similar increases in ⌬ 9-desaturase and elongase-6Abstract Patients and models of cystic fi brosis (CF) exhibit consistent abnormalities of polyunsaturated fatty acid composition, including decreased linoleate (LA) and docosahexaenoate (DHA) and variably increased arachidonate (AA), related in part to increased expression and activity of fatty acid desaturases. These abnormalities and the consequent CF-related pathologic manifestations can be reversed in CF mouse models by dietary supplementation with DHA. However, the mechanism is unknown. This study investigates this mechanism by measuring the effect of exogenous DHA and eicosapentaenoate (EPA) supplementation on fatty acid composition and metabolism, as well as on metabolic enzyme expression, in a cell culture model of CF. We found that both DHA and EPA suppress the expression and activity of ⌬ 5-and ⌬ 6-desaturases, leading to decreased fl ux through the n-3 and n-6 PUFA metabolic pathways and decreased production of AA. The fi ndings also uncover other metabolic abnormalities, including increased fatty acid uptake and markedly increased retroconversion of DHA to EPA, in CF cells. These results indicate that the fatty acid abnormalities of CF are ...

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Clinical laboratory tests play an integral role in medical decision-making and as such must be reliable and accurate. Unfortunately, no laboratory tests or devices are foolproof and errors can occur at pre-analytical, analytical and post-analytical phases of testing. Evaluating possible conditions that could lead to errors and outlining the necessary steps to detect and prevent errors before they cause patient harm is therefore an important part of laboratory testing. This can be achieved through the practice of risk management. EP23-A is a new guideline from the CLSI that introduces risk management principles to the clinical laboratory. This guideline borrows concepts from the manufacturing industry and encourages laboratories to develop risk management plans that address the specific risks inherent to each lab. Once the risks have been identified, the laboratory must implement control processes and continuously monitor and modify them to make certain that risk is maintained at a clinically acceptable level. This review summarizes the principles of risk management in the clinical laboratory and describes various quality control activities employed by the laboratory to achieve the goal of reporting valid, accurate and reliable test results.

Polymorphisms in the SLAM family of leukocyte cell surface regulatory molecules have been associated with lupus-like phenotypes in both humans and mice. The murine Slamf gene cluster lies within the lupus-associated Sle1b region of mouse chromosome 1. Non-autoreactive C57BL/6 (B6) mice that have had this region replaced by syntenic segments from other mouse strains (i.e. 129, NZB and NZW) are B6 congenic strains that spontaneously produce non-nephritogenic lupus-like autoantibodies. We have recently reported that genetic ablation of the SLAM family member CD48 (Slamf2) drives full-blown autoimmune disease with severe proliferative glomerulonephritis (CD48GN) in B6 mice carrying 129 sequences of the Sle1b region (B6.129CD48-/-). We also discovered that BALB/c mice with the same 129-derived CD48-null allele (BALB.129CD48-/-) have neither nephritis nor anti-DNA autoantibodies, indicating that strain specific background genes modulate the effects of CD48 deficiency. Here we further examine this novel model of lupus nephritis in which CD48 deficiency transforms benign autoreactivity into fatal nephritis. CD48GN is characterized by glomerular hypertrophy with mesangial expansion, proliferation and leukocytic infiltration. Immune complexes deposit in mesangium and in sub-endothelial, sub-epithelial and intramembranous sites along the glomerular basement membrane. Afflicted mice have low grade proteinuria, intermittent hematuria and their progressive renal injury manifests with elevated urine NGAL levels and with uremia. In contrast to the lupus-like B6.129CD48-/- animals, neither BALB.129CD48-/- mice nor B6 × BALB/c F1.129CD48-/- progeny have autoimmune traits, indicating that B6-specific background genes modulate the effect of CD48 on lupus nephritis in a recessive manner.