Citations

BackgroundIdentifying antibodies to HLA (anti‐HLA) by solid‐phase assays is used to screen blood donors to mitigate transfusion‐related acute lung injury risk. Various cutoffs for detection assays have been proposed in the literature; however, these do not take into consideration lot‐to‐lot variability of commercially available assays.Study Design and MethodsSamples from 93 nontransfused males were tested using five different lots of a multiplex bead‐based anti‐HLA detection kit. A subset of 17 samples was tested on 5 days using a single lot. An additional 96 samples from donations with varied anti‐HLA levels were tested using kits from two different lots. Results were reported as a normalized background (NBG) ratio.ResultsFor the 93 nontransfused donors, NBG values generated using the reference lot were significantly higher than those obtained with three of the four comparator lots. However, for the 96 samples with low‐, moderate‐, and higher‐level anti‐HLA, Class I (CL‐I) values were 1.4 times lower and Class II (CL‐II) values were 1.2 times lower using the reference versus comparator lot. For CL‐I antibodies the between‐lot standard deviation (SD) was 1.36 (95% confidence interval [CI], 1.19‐1.60), while the between‐day SD was 1.27 (95% CI, 1.08‐1.52). Similarly, for CL‐II antibodies the between‐lot SD was 0.81 (95% CI, 0.70‐0.95), while the between‐day SD was 0.50 (95% CI, 0.43‐0.60).ConclusionsThere is interlot variability in the tested HLA detection assay as well as significant bias between lots. It may be reasonable to develop a new cutoff when a new lot is obtained.

Abstract Goodpasture disease is an autoimmune kidney disease mediated by autoantibodies against noncollagenous domain 1 (NC1) monomers of α3(IV) collagen that bind to the glomerular basement membrane (GBM), usually causing rapidly progressive glomerulonephritis (GN). We identified a novel type of human IgG4-restricted anti–GBM autoantibodies associated with mild nonprogressive GN, which specifically targeted α345NC1 hexamers but not α3NC1 monomers. The mechanisms eliciting these anti–GBM autoantibodies were investigated in mouse models recapitulating this phenotype. Wild-type and FcγRIIB−/− mice immunized with autologous murine GBM NC1 hexamers produced mouse IgG1-restricted autoantibodies specific for α345NC1 hexamers, which bound to the GBM in vivo but did not cause GN. In these mice, intact collagen IV from murine GBM was not immunogenic. However, in Col4a3−/− Alport mice, both intact collagen IV and NC1 hexamers from murine GBM elicited IgG Abs specific for α345NC1 hexamers, which were not subclass restricted. As heterologous Ag in COL4A3-humanized mice, murine GBM NC1 hexamers elicited mouse IgG1, IgG2a, and IgG2b autoantibodies specific for α345NC1 hexamers and induced anti–GBM Ab GN. These findings indicate that tolerance toward autologous intact α345(IV) collagen is established in hosts expressing this Ag, even though autoreactive B cells specific for α345NC1 hexamers are not purged from their repertoire. Proteolysis selectively breaches this tolerance by generating autoimmunogenic α345NC1 hexamers. This provides a mechanism eliciting autoantibodies specific for α345NC1 hexamers, which are restricted to noninflammatory IgG subclasses and are nonnephritogenic. In Alport syndrome, lack of tolerance toward α345(IV) collagen promotes production of alloantibodies to α345NC1 hexamers, including proinflammatory IgG subclasses that mediate posttransplant anti–GBM nephritis.

Cardiac channelopathies are potentially lethal inherited arrhythmia syndromes and an important cause of sudden cardiac death (SCD) in young athletes. Other cardiac rhythm and conduction disturbances also may indicate the presence of an underlying cardiac disorder. The 12-lead ECG is utilised as both a screening and a diagnostic tool for detecting conditions associated with SCD. Fundamental to the appropriate evaluation of athletes undergoing ECG is an understanding of the ECG findings that may indicate the presence of a pathological cardiac disease. This article describes ECG findings present in primary electrical diseases afflicting young athletes and outlines appropriate steps for further evaluation of these ECG abnormalities. The ECG findings defined as abnormal in athletes were established by an international consensus panel of experts in sports cardiology and sports medicine.

Genomewide association studies (GWAS) and candidate‐gene studies have implicated single‐nucleotide polymorphisms (SNPs) in at least 45 different genes as putative glioma risk factors. Attempts to validate these associations have yielded variable results and few genetic risk factors have been consistently replicated. We conducted a case‐control study of Caucasian glioma cases and controls from the University of California San Francisco (810 cases, 512 controls) and the Mayo Clinic (852 cases, 789 controls) in an attempt to replicate previously reported genetic risk factors for glioma. Sixty SNPs selected from the literature (eight from GWAS and 52 from candidate‐gene studies) were successfully genotyped on an Illumina custom genotyping panel. Eight SNPs in/near seven different genes (TERT, EGFR, CCDC26, CDKN2A, PHLDB1, RTEL1, TP53) were significantly associated with glioma risk in the combined dataset (P < 0.05), with all associations in the same direction as in previous reports. Several SNP associations showed considerable differences across histologic subtype. All eight successfully replicated associations were first identified by GWAS, although none of the putative risk SNPs from candidate‐gene studies was associated in the full case‐control sample (all P values > 0.05). Although several confirmed associations are located near genes long known to be involved in gliomagenesis (e.g., EGFR, CDKN2A, TP53), these associations were first discovered by the GWAS approach and are in noncoding regions. These results highlight that the deficiencies of the candidate‐gene approach lay in selecting both appropriate genes and relevant SNPs within these genes.

AbstractBackgroundTo investigate anatomical configuration of ciliary body and iris using ultrasound biomicroscopy as a predictor of malignant glaucoma development.DesignRetrospective study in a tertiary care hospital.ParticipantsCohort of 31 consecutive patients diagnosed with post‐surgical malignant glaucoma.MethodsAnterior chamber angle, iris and ciliary body configuration of involved eyes that had ultrasound biomicroscopy evaluation prior to the malignant glaucoma onset were evaluated. In cases with no presurgical ultrasound biomicroscopy exam of the involved eye, images from the fellow eye (imaged within 6 months) were analysed.Main Outcome MeasuresQualitative parameters.ResultsThirty‐one eyes (31 patients) had confirmed malignant glaucoma between 1996 and 2008. Most patients were women (65%) and had an anatomical narrow angle or angle‐closure glaucoma (77%). Mean intraocular pressure at diagnosis was 30.4 ± 13.5 mmHg. The most common operation was trabeculectomy with mitomycin C (55%, 17/31 eyes), combined (3/17) or not (14/17) with cataract extraction and intraocular lens implantation. Among these 31 cases, we were able to evaluate the ultrasound biomicroscopy images of 13 patients (13 eyes) including involved eyes imaged prior to the malignant glaucoma onset or eligible fellow eyes. A narrow angle with or without iridotrabecular contact was found in all eyes. A large and/or anteriorly positioned ciliary body associated with an iris root angulating forward and centrally, revealing a plateau iris configuration, was noticed in 85% (11/13) of these eyes.ConclusionIdentification of plateau iris configuration by ultrasound biomicroscopy should be considered as a possible predictor of post‐operative malignant glaucoma development.

ObjectivesTo examine the ability of standard and saturation transrectal prostate biopsy techniques to predict appropriate candidates for active surveillance.MethodsBetween 2005 and 2007, 500 consecutive patients underwent transrectal ultrasound‐guided biopsy by a standard template (12 cores) or saturation template (≥18 cores, median 27 cores), with subsequent radical prostatectomy. Using the criteria of Gleason score ≤6, clinical stage T1 or T2a, prostate‐specific antigen <10 and ≤33% of cores involved, 218 patients were potential candidates for active surveillance. Pathology results from the prostatectomy specimens were used to determine the accuracy of each biopsy technique. Biochemical failure after prostatectomy was evaluated using logistic and Cox proportional hazards regression.ResultsA standard biopsy was carried out for 124 patients and saturation biopsy for 94 patients. There was no statistically significant difference between the groups in terms of median age (P = 0.14), preoperative prostate‐specific antigen (P = 0.52) and clinical stage (P = 0.23). Similar rates of Gleason score ≥7 at the time of radical prostatectomy were found, with 14% for standard biopsy and 15% for saturation biopsy (P = 0.70). Upstaging was shown in two standard biopsy patients (1.6%) and no saturation biopsy patients (P = 0.62). A multivariate analysis adjusting for prior prostate biopsy, preoperative prostate‐specific antigen and clinical stage showed no difference in the rate of upgrading based on biopsy technique (P = 0.26). During follow up, 5‐year biochemical failure‐free survival estimates were not significantly different (P = 0.11).ConclusionsIn men with prostate cancer, standard and saturation transrectal prostate biopsies techniques are equally predictive of candidates for active surveillance.

BackgroundTo evaluate the impact of adjuvant hormonal therapy after radical prostatectomy on overall survival in high‐risk prostate cancer patients, stratified by comorbidity status.MethodsWe identified 1247 patients who underwent radical prostatectomy from 1988 to 2004 for high‐risk prostate cancer, as defined by National Comprehensive Cancer Network classification. Comorbidity status was stratified by Charlson Comorbidity Index as 0, 1 or >2, as well as by the presence or absence of cardiovascular disease. Overall survival was estimated by the Kaplan–Meier method, and compared within each comorbidity category/adjuvant hormonal therapy strata with the log–rank test.ResultsMedian patient age was 65 years, and the median postoperative follow up was 11.2 years. In total, 419 patients (34%) received adjuvant hormonal therapy. The distribution of Charlson Comorbidity Index was 0, 1 and ≥2 in 861 (69%), 244 (20%) and 142 (11%) patients, respectively. The 10‐year overall survival for patients who received adjuvant hormonal therapy versus those who did not was 75% versus 82% (P = 0.54) for patients with Charlson Comorbidity Index = 0, 72% versus 76% (P = 0.83) with Charlson Comorbidity Index = 1, and 70% versus 68% (P = 0.33) with Charlson Comorbidity Index ≥2. Meanwhile, 155 (12%) patients had cardiovascular disease, and the 10‐year overall survival for patients with cardiovascular disease who received adjuvant hormonal therapy was 72%, compared with 76% without adjuvant hormonal therapy (P = 0.97). On multivariate analysis, receipt of adjuvant hormonal therapy was not associated with non‐prostate cancer mortality (P = 0.24).ConclusionsAdjuvant hormonal therapy after radical prostatectomy for high‐risk prostate cancer does not increase non‐prostate cancer mortality, even among patients with multiple comorbidities. Additional studies are warranted to determine optimal multimodal treatment approach for high‐risk patients.