OBJECTIVEDespite the clinical importance of an accurate diagnosis in individuals with monogenic forms of diabetes, restricted access to genetic testing leaves many patients with undiagnosed diabetes. Recently, common variation near the HNF1 homeobox A (HNF1A) gene was shown to influence C-reactive protein levels in healthy adults. We hypothesized that serum levels of high-sensitivity C-reactive protein (hs-CRP) could represent a clinically useful biomarker for the identification of HNF1A mutations causing maturity-onset diabetes of the young (MODY).RESEARCH DESIGN AND METHODSSerum hs-CRP was measured in subjects with HNF1A-MODY (n = 31), autoimmune diabetes (n = 316), type 2 diabetes (n = 240), and glucokinase (GCK) MODY (n = 24) and in nondiabetic individuals (n = 198). The discriminative accuracy of hs-CRP was evaluated through receiver operating characteristic (ROC) curve analysis, and performance was compared with standard diagnostic criteria. Our primary analyses excluded ∼11% of subjects in whom the single available hs-CRP measurement was >10 mg/l.RESULTSGeometric mean (SD range) hs-CRP levels were significantly lower (P ≤ 0.009) for HNF1A-MODY individuals, 0.20 (0.03–1.14) mg/l, than for any other group: autoimmune diabetes 0.58 (0.10–2.75) mg/l, type 2 diabetes 1.33 (0.28–6.14) mg/l, GCK-MODY 1.01 (0.19–5.33) mg/l, and nondiabetic 0.48 (0.10–2.42) mg/l. The ROC-derived C-statistic for discriminating HNF1A-MODY and type 2 diabetes was 0.8. Measurement of hs-CRP, either alone or in combination with current diagnostic criteria, was superior to current diagnostic criteria alone. Sensitivity and specificity for the combined criteria approached 80%.CONCLUSIONSSerum hs-CRP levels are markedly lower in HNF1A-MODY than in other forms of diabetes. hs-CRP has potential as a widely available, cost-effective screening test to support more precise targeting of MODY diagnostic testing.

1OBJECTIVE -Assessment and follow-up of early renal dysfunction is important in diabetic nephropathy. Plasma creatinine is insensitive for a glomerular filtration rate (GFR) Ͼ50 ml/min and creatinine clearance is unwieldy and subject to collection inaccuracies. We aimed to assess the reproducibility, reliability, and accuracy of plasma cystatin C as a measure of GFR ranging from normal to moderate impairment due to type 1 diabetes in the presence of a normal plasma creatinine concentration. RESEARCH DESIGN AND METHODS-A sensitive immunoturbidimetric cystatin C assay was examined in 29 subjects with type 1 diabetes and 11 nondiabetic subjects. Duplicate measurements of the following were collected from each subject, 2 weeks apart: cystatin C, enzymatic plasma creatinine, 24-h creatinine clearance, GFR estimated from plasma creatinine by the Cockcroft-Gault equation, and iohexol clearance as a gold standard.RESULTS -Iohexol clearance ranged from 35 to 132 ml ⅐ min -1 ⅐ 1.73 m -2 . Plasma cystatin C compared well with the other clinically used tests. The reliability of cystatin C, as assessed by the discriminant ratio, was superior to creatinine clearance (3.4 vs. 1.5, P Ͻ 0.001) and the correlation of cystatin C with iohexol clearance (Rs -0.80) was similar to that of creatinine clearance (Rs -0.74) and superior to that of plasma creatinine and the Cockcroft-Gault estimate (Rs Ϫ0.54 and 0.66, respectively). Duplicate estimations were used to provide an unbiased equation to convert plasma cystatin C to GFR.CONCLUSIONS -Based on this study, cystatin C is a more reliable measure of GFR than creatinine clearance, is more highly correlated with iohexol clearance than plasma creatinine, and is worthy of further investigation as a clinical measure of GFR in type 1 diabetes. Diabetes Care 25:2004 -2009, 2002R enal failure develops in Յ30% of people with type 1 diabetes; however, our ability to assess renal function is poor in early diabetic nephropathy, when active management is important. Serum creatinine level, the most commonly used surrogate measure of glomerular filtration rate (GFR), does not increase until renal function decreases to ϳ50% of its normal value; its excretion rate varies with age, sex, physical exercise, and lean body mass (1,2). The population variance of serum creatinine level is large, making it a poor measure for comparison with a reference range. Creatinine clearance, measured from a 24-h urine collection and a concurrent plasma creatinine concentration, is unwieldy and often inaccurate but is widely used in clinical practice (3). 'Gold standard' tests such as clearance methods using radioisotopes (such as 51 Cr-labeled EDTA, 99m Tcl a b e l e d D T P A , a n d 1 2 5 I -l a b e l e d iothalamate) or iohexol (4,5) are too cumbersome to use in the clinic setting (3). A more precise and accurate marker of GFR as an assessment of renal function would be clinically useful.Cystatin C has been proposed as a good marker of GFR (6,7), particularly in patients with moderate to severe renal impairment. It i...

We investigated the potential for the biochemical analysis of chronic wound fluid to predict healing using simple and widely available analytes in an out-patient clinic setting. Wound fluid was collected from 12 patients attending a leg ulcer clinic and analyzed for a variety of analytes, including lactate, total protein, and albumin. Twelve weeks after collection the wound was assessed for healing (defined as complete healing or greater than 50% reduction in wound size). The median total protein (44.3 +/- 8.8 g/l) and albumin (25.0 +/- 2.3 g/l) concentrations in exudate collected from four healing wounds were significantly higher (p < 0.05) than in exudate from eight nonhealing wounds (median total protein 29.7 +/- 7.6 g/l, median albumin 17.0 +/- 4.3 g/l). No significant difference was observed for lactate. A second specimen of wound fluid was collected from four of the patients (three nonhealing and one healing). The protein analysis confirmed the pattern observed for the first collection: nonhealing wounds had total protein and albumin which remained low compared to healing wounds. No wound with an exudate albumin of less than 20 g/l healed. Both total protein and albumin are stable analytes which can be easily measured in any laboratory and may offer a simple biomarker of healing in chronic wounds.

Aims/hypothesis An accurate molecular diagnosis of diabetes subtype confers clinical benefits; however, many individuals with monogenic diabetes remain undiagnosed.Biomarkers could help to prioritise patients for genetic investigation. We recently demonstrated that highsensitivity C-reactive protein (hsCRP) levels are lower in UK patients with hepatocyte nuclear factor 1 alpha Diabetologia (2011) 54:2801-2810 DOI 10.1007/s00125-011-2261 (HNF1A)-MODY than in other diabetes subtypes. In this large multi-centre study we aimed to assess the clinical validity of hsCRP as a diagnostic biomarker, examine the genotype-phenotype relationship and compare different hsCRP assays. Methods High-sensitivity CRP levels were analysed in individuals with HNF1A-MODY (n=457), glucokinase (GCK)-MODY (n=404), hepatocyte nuclear factor 4 alpha (HNF4A)-MODY (n=54) and type 2 diabetes (n=582) from seven European centres. Three common assays for hsCRP analysis were evaluated. We excluded 121 participants (8.1%) with hsCRP values >10 mg/l. The discriminative power of hsCRP with respect to diabetes aetiology was assessed by receiver operating characteristic curvederived C-statistic. Results In all centres and irrespective of the assay method, meta-analysis confirmed significantly lower hsCRP levels in those with HNF1A-MODY than in those with other aetiologies (z score −21.8, p<5×10 −105 ). HNF1A-MODY cases with missense mutations had lower hsCRP levels than those with truncating mutations (0.03 vs 0.08 mg/l, p<5× 10 −5 ). High-sensitivity CRP values between assays were strongly correlated (r 2 ≥0.91, p≤1×10 −5 ). Across the seven centres, the C-statistic for distinguishing HNF1A-MODY from young adult-onset type 2 diabetes ranged from 0.79 to 0.97, indicating high discriminative accuracy.

ObjectiveTo evaluate the diagnostic accuracy of a single CEA (carcinoembryonic antigen) blood test in detecting colorectal cancer recurrence.BackgroundPatients who have undergone curative resection for primary colorectal cancer are typically followed up with scheduled CEA testing for 5 years. Decisions to investigate further (usually by CT imaging) are based on single test results, reflecting international guidelines.MethodsA secondary analysis was undertaken of data from the FACS trial (two arms included CEA testing). The composite reference standard applied included CT-CAP imaging, clinical assessment and colonoscopy. Accuracy in detecting recurrence was evaluated in terms of sensitivity, specificity, likelihood ratios, predictive values, time-dependent area under the ROC curves, and operational performance when used prospectively in clinical practice are reported.ResultsOf 582 patients, 104 (17.9%) developed recurrence during the 5 year follow-up period. Applying the recommended threshold of 5μg/L achieves at best 50.0% sensitivity (95% CI: 40.1–59.9%); in prospective use in clinical practice it would lead to 56 missed recurrences (53.8%; 95% CI: 44.2–64.4%) and 89 false alarms (56.7% of 157 patients referred for investigation). Applying a lower threshold of 2.5μg/L would reduce the number of missed recurrences to 36.5% (95% CI: 26.5–46.5%) but would increase the false alarms to 84.2% (924/1097 referred). Some patients are more prone to false alarms than others—at the 5μg/L threshold, the 89 episodes of unnecessary investigation were clustered in 29 individuals.ConclusionOur results demonstrated very low sensitivity for CEA, bringing to question whether it could ever be used as an independent triage test. It is not feasible to improve the diagnostic performance of a single test result by reducing the recommended action threshold because of the workload and false alarms generated. Current national and international guidelines merit re-evaluation and options to improve performance, such as making clinical decisions on the basis of CEA trend, should be further assessed.