Autoantibodies against Linear Epitopes of Myeloperoxidase in Anti–Glomerular Basement Membrane Disease

Background and objectives

Approximately 20%–30% of patients with anti–glomerular basement membrane disease present coexisting anti-myeloperoxidase (MPO) autoantibodies. We previously showed the recognition of a linear fragment of the MPO heavy chain N-terminus (¹H, MPO_279–409) in plasma from most double-positive patients. Herein, we investigated the frequency of autoantibodies against overlapping ¹H-derived linear peptides in plasma from patients with anti–glomerular basement membrane disease.

Design, setting, participants, & measurements

We synthesized 13 overlapping linear peptides (¹H–1 to ¹H–13) covering MPO_279–409. We retrospectively collected plasma samples from 67 patients with anti–glomerular basement membrane disease from 1996 to 2012, and we screened them for IgG autoantibodies by ELISA using intact human MPO and the overlapping peptides as antigens, and we further investigated the clinical significance. Autoantibody binding to the linear MPO structure was confirmed by Western blotting.

Results

We followed up the 67 patients until 2015, with a median follow-up time of 10.0 (2.3–36.0) months, and 56 ESRD events occurred among the 67 patients with follow-up data. Plasma from 23.9% (16) of the patients recognized intact human MPO, whereas 62.7% (42) plasma samples recognized MPO_279–409 linear peptides. Of the 13 linear peptides, ¹H–4 (44.8%, 30 patients) and ¹H–12 (40.3%, 27 patients) exhibited the highest recognition frequencies. Patients with autoantibodies against ¹H–11 or ¹H–12 (MPO_371–400) were older (46.1±18.8 versus 34.1±16.6 years; P<0.01), had higher serum creatinine upon diagnosis (median 7.8 mg/dl, interquartile range 4.9–12.6 mg/dl versus median 5.4 mg/dl, interquartile range 2.4–7.3 mg/dl; P=0.02), and had a higher probability of progressing to ESRD; however, multivariate Cox regression analysis showed that ¹H–11 or 12 reaction was not an independent risk factor for renal failure (hazard ratio, 1.2; 95% confidence interval, 0.8 to 2.8; P=0.19).

Conclusions

Autoantibodies against linear peptides of MPO can be detected in the majority of patients with anti–glomerular basement membrane disease, and several are associated with disease severity. The potential common pathogenic mechanism between anti–glomerular basement membrane antibodies and anti-MPO autoantibodies in anti–glomerular basement membrane disease requires further investigation.     

Prognostic Impact of Mild Hypokalemia in Terms of Death and Stroke in the General Population—A Prospective Population Study

Background

Potassium supplementation reduces the risk of cardiovascular mortality and stroke in population studies; however, the prognostic impact of mild hypokalemia in the general population has not been thoroughly investigated. We aimed to investigate associations between mild hypokalemia and endpoints in the general population.

Prevention of Recurrent Thrombosis in Antiphospholipid Syndrome: Different from the General Population?

Antiphospholipid syndrome (APS) is characterized by arterial and/or venous thrombosis with or without pregnancy morbidity in the presence of autoantibodies targeting proteins that associate with membrane phospholipids, termed “antiphospholipid antibodies” (aPL). Management of arterial and venous thromboses shares some similarities with management of arterial and venous thromboses in the general population; however, there are key differences. The majority of studies addressing management of thrombotic APS focus on secondary prevention. Vitamin K antagonists (VKA) are typically used for secondary prevention of venous thromboembolism in APS. Optimal management of isolated arterial thrombosis, in particular ischemic stroke, in patients with APS is controversial, and proposed therapeutic options have included antiplatelet agents and VKA. Primary prophylaxis in aPL-positive patients should be an individualized decision taking into account patient-specific risks. There may be a role for adjuvant therapies such as hydroxychloroquine, vitamin D, statins, or novel therapeutics in specific patient populations.     

Prevalence of Anticardiolipin and Anti-β<Subscript>2</Subscript>-Glycoprotein I Antibodies in Celiac Disease

The aim of this study was to evaluate the prevalence of anticardiolipin antibodies (aCL) and anti-β₂-glycoprotein I antibodies (aβ2GPI) in patients with celiac disease and to analyze the clinical features of antiphospholipid syndrome in these patients. We conducted a prospective case-control study based on the evaluation of IgG, IgM and IgA aCL, and IgG and IgA aβ2GPI in celiac disease patients and in controls. All patients were asked about any occurrence of thrombotic manifestations. In addition, women were asked about pregnancy morbidity. Fifty celiac disease patients and 50 healthy controls were studied. IgM aCL were not detected in study group or in controls. IgG aCL were found in two patients and in one control. IgA aCL were significantly more frequent in celiac disease patients compared with controls (13/50 (26%) vs. 2/50 (4%), p=0.004, OR [95% CI]=9.09 [1.81–50]). There was no statistically significant difference for the prevalence of IgG and IgA aβ2GPI between patients and controls. Clinical features of antiphospholipid syndrome were noted in two patients with negative antibodies. Prevalence of IgM and IgG aCL and of aβ2GPI were not increased in celiac disease. IgA aCL were more frequently detected in celiac disease. However, no clinical features of antiphospholipid syndrome were noted.     

Performance Comparison of Al–Ti Master Alloys with Different Microstructures in Grain Refinement of Commercial Purity Aluminum

Three types of Al–5Ti master alloys were synthesized by a method of thermal explosion reaction in pure molten aluminum. Performance comparison of Al–5Ti master alloy in grain refinement of commercial purity Al with different additions (0.6%, 1.0%, 1.6%, 2.0%, and 3.0%) and holding time (10, 30, 60 and 120 min) were investigated. The results show that Al–5Ti master alloy with blocky TiAl₃ particles clearly has better refining efficiency than the master alloy with mixed TiAl₃ particles and the master alloy with needle-like TiAl₃ particles. The structures of master alloys, differing by sizes, morphologies and quantities of TiAl₃ crystals, were found to affect the pattern of the grain refining properties with the holding time. The grain refinement effect was revealed to reduce markedly for master alloys with needle–like TiAl₃ crystals and to show the further significant improvement at a longer holding time for the master alloy containing both larger needle–like and blocky TiAl₃ particles. For the master alloy with finer blocky particles, the grain refining effect did not obviously decrease during the whole studied range of the holding time.     

Computer-Assisted Brush-Biopsy Analysis for the Detection of Dysplasia in a High-Risk Barrett’s Esophagus Surveillance Population

Background  

Barrett’s epithelial dysplasia, the direct precursor to esophageal adenocarcinoma, is often unapparent and frequently missed during surveillance of Barrett’s esophagus with four-quadrant forceps biopsy protocol.     

Performance of the revised ‘175’ Modification of Diet in Renal Disease equation in patients with type 2 diabetes

AIMS/HYPOTHESIS: Estimation of GFR (eGFR) is recommended for the assessment of kidney function in all patients with diabetes. We studied performance of the traditional '186' Modification of Diet in Renal Disease (MDRD) equation, and the 2005 revised '175' MDRD equation in patients with type 2 diabetes. METHODS: Two hundred and ninety-three mainly normoalbuminuric (267/293) patients were recruited. Patients were classified as having mild renal impairment (group 1, GFR <90 ml min(-1) 1.73 m(-2)) or normal renal function (group 2, GFR >or=90 ml min(-1) 1.73 m(-2)). eGFR was calculated by the traditional 186 MDRD equation using traditional creatinine values and the revised 175 MDRD equation using isotope dilution mass spectrometry-standardised creatinine values. Isotopic GFR was measured by the four-sample plasma clearance of (51)Cr-EDTA. RESULTS: For patients in group 1, mean +/- SD isotopic (51)Cr-EDTA GFR (iGFR) was 83.8 +/- 4.3 ml min(-1) 1.73 m(-2), and eGFR was 73.2 +/- 11.9 and 75.8 +/- 13.7 ml min(-1) 1.73 m(-2) using the 186 and 175 MDRD equations, respectively. Method bias was -10.6 with the 186 MDRD and -7.9 ml min(-1) 1.73 m(-2) (p < 0.05) with the 175 MDRD equation. In group 2, iGFR was 119.4 +/- 20.2 ml min(-1) 1.73 m(-2), and eGFR was 92.3 +/- 18.6 and 97.5 +/- 21.6 ml min(-1) 1.73 m(-2) using the 186 and 175 MDRD equations, respectively. Method bias was -27.1 with the 186 MDRD equation and -21.9 ml min(-1) 1.73 m(-2) (p < 0.05) with the 175 MDRD equation. CONCLUSIONS/INTERPRETATION: In patients newly diagnosed with type 2 diabetes, the revised 175 MDRD equation was less biased than the traditional 186 MDRD equation. Despite a continued tendency to underestimate isotopically measured GFR, use of standardised creatinine values is a positive step towards improved estimation of GFR.     

Diagnostic Accuracy of the Modified Evan’s Blue Dye Test in Detecting Aspiration in Patients with Tracheostomy: A Systematic Review of the Evidence

Oropharyngeal aspiration (OPA) is a common occurrence in patients with tracheostomy. The modified Evan’s blue dye test (MEBDT) is an easily administered bedside procedure for the assessment of tracheostomised patients. However, studies evaluating the diagnostic accuracy of the MEBDT reach conflicting results. Therefore, we conducted a systematic review to determine the overall accuracy of the MEBDT in detecting OPA in adults with tracheostomy. The search strategy incorporated searching electronic databases, checking reference lists and citations and retrieving unpublished data. Data of primary studies were extracted and examined by three independent reviewers. The assessment of the methodological quality of included studies was performed using the QUADAS-2 tool. Six studies met the inclusion criteria for this systematic review. The studies presented significant disparities in study design and patient characteristics. Furthermore, high discrepancies in the administration of MEBDT across studies were noted. Therefore, a meta-analysis was not considered appropriate. Sensitivity estimates varied widely across the studies (38–95 %), indicating that the MEBDT is unreliable in detecting OPA. However, the studies emerge with overall high specificity values, ranging from 79 to 100 %. This true negative rate suggests that the MEBDT correctly identifies patients without OPA. This review highlights the need for further research studies assessing the accuracy of the MEBDT in detecting aspiration in patients with tracheostomy, using a standardised and reliable procedure. Outcomes from such studies will update the current level of evidence in relation to the MEBDT and consequently define best clinical practice.