Citations

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.

The presence of microbialite structures in a freshwater, dimictic mid-latitudelake and their establishment after the last ice age about 10,000 years ago is puzzling.Freshwater calcite microbialites at Pavilion Lake, British Columbia, Canada, consist of acomplex community of microorganisms that collectively form large, ordered structuredaggregates. This distinctive assemblage of freshwater calcite microbialites was studied through standard microbial methods, morphological observations, phospholipid fatty acid(PLFA) analysis, DNA sequencing and the identification of quorum sensing molecules.Our results suggest that the microbialites may represent a transitional form from theexclusively prokaryotic colonial precursors of stromatolites to the multicellular organismicaggregates that give rise to coral reefs.

For decades, investigators have conducted innovative research on shared decision-making (SDM), helping patients and clinicians to discuss health decisions and balance evidence with patients’ preferences for possible outcomes of options. In addition, investigators have developed and used rigorous methods for conducting comparative effectiveness research (CER), comparing the benefits and risks of different interventions in real-world settings with outcomes that matter to patients and other stakeholders. However, incorporating CER findings into clinical practice presents numerous challenges. In March 2012, we organized a conference at Washington University in St Louis (MO, USA) aimed at developing a network of researchers to collaborate in developing, conducting and disseminating research about the implementation of CER through SDM. Meeting attendees discussed conceptual similarities and differences between CER and SDM, challenges in implementing CER and SDM in practice, specific challenges when engaging SDM with unique populations and examples of ways to overcome these challenges. CER and SDM are related processes that emphasize examining the best clinical evidence and how it applies to real patients in real practice settings. SDM can provide one opportunity for clinicians to discuss CER findings with patients and engage in a dialog about how to manage uncertainty about evidence in order to make decisions on an individual patient level. This meeting highlighted key challenges and suggested avenues to pursue such that CER and SDM can be implemented into routine clinical practice.

AbstractBackground and AimHamartomatous polyposis syndromes (HPS) are a group of rare inherited autosomal dominant disorders. Small bowel polyposis is one of the manifestations of HPS. Double‐balloon enteroscopy (DBE) with polypectomy may obviate repeated small bowel surgeries for polyp intussusception, obstruction, or bleeding. The efficacy and safety of DBE‐assisted polypectomy in HPS patients with clinically significant small bowel polyposis were evaluated.MethodsAll HPS patients who underwent DBE from January 2007 to April 2011 were identified using a prospectively maintained database. Data on patient demographics, pre‐DBE radiological studies, polyp characteristics, procedural outcomes, and complications were abstracted.ResultsTwenty‐two patients underwent a total of 34 DBE procedures. Pre‐DBE imaging included computed tomography enterography (n = 15), computed tomography enteroclysis (n = 5), small bowel follow‐through (n = 1), and magnetic resonance enterography (n = 1). Any small bowel polyp ≥ 1 cm in size on radiological imaging was referred for DBE‐assisted polypectomy. Antegrade and retrograde DBE were successful in reaching and resecting targeted polyps in 90% (18/20) and 71.4% (10/14) of procedures, respectively. The overall success rate for DBE‐assisted polypectomy was 82.3% (95% confidence interval: 66.5–91.6%). The median size of resected polyps was 2 cm (range 1–5 cm) and all were hamartomas. Minor adverse events occurred in four (11.8%) procedures, including abdominal pain (n = 2), immediate post‐polypectomy bleeding (n = 1), and self‐limited hematochezia (n = 1).ConclusionsDBE‐assisted polypectomy was successful in over 80% of HPS patients with an acceptable margin of safety. To the knowledge of the authors, this is one of the largest single‐center studies to report on the performance and safety of DBE‐assisted polypectomy in HPS patients.

AbstractRecently, we showed that increased miR-181a expression was associated with improved outcomes in cytogenetically normal acute myeloid leukemia (CN-AML). Interestingly, miR-181a expression was increased in CN-AML patients harboring CEBPA mutations, which are usually biallelic and associate with better prognosis. CEBPA encodes the C/EBPα transcription factor. We demonstrate here that the presence of N-terminal CEBPA mutations and miR-181a expression are linked. Indeed, the truncated C/EBPα-p30 isoform, which is produced from the N-terminal mutant CEBPA gene or from the differential translation of wild-type CEBPA mRNA and is commonly believed to have no transactivation activity, binds to the miR-181a-1 promoter and up-regulates the microRNA expression. Furthermore, we show that lenalidomide, a drug approved for myelodysplastic syndromes and multiple myeloma, enhances translation of the C/EBPα-p30 isoform, resulting in higher miR-181a levels. In xenograft mouse models, ectopic miR-181a expression inhibits tumor growth. Similarly, lenalidomide exhibits antitumorigenic activity paralleled by increased miR-181a expression. This regulatory pathway may explain an increased sensitivity to apoptosis-inducing chemotherapy in subsets of AML patients. Altogether, our data provide a potential explanation for the improved clinical outcomes observed in CEBPA-mutated CN-AML patients, and suggest that lenalidomide treatment enhancing the C/EBPα-p30 protein levels and in turn miR-181a may sensitize AML blasts to chemotherapy.

Purpose Myeloproliferative neoplasm (MPN) symptoms are troublesome to patients, and alleviation of this burden represents a paramount treatment objective in the development of MPN-directed therapies. We aimed to assess the utility of an abbreviated symptom score for the most pertinent and representative MPN symptoms for subsequent serial use in assessing response to therapy. Patients and Methods The Myeloproliferative Neoplasm Symptom Assessment Form total symptom score (MPN-SAF TSS) was calculated as the mean score for 10 items from two previously validated scoring systems. Questions focus on fatigue, concentration, early satiety, inactivity, night sweats, itching, bone pain, abdominal discomfort, weight loss, and fevers. Results MPN-SAF TSS was calculable for 1,408 of 1,433 patients with MPNs who had a mean score of 21.2 (standard deviation [SD], 16.3). MPN-SAF TSS results significantly differed among MPN disease subtypes (P < .001), with a mean of 18.7 (SD, 15.3), 21.8 (SD, 16.3), and 25.3 (SD, 17.2) for patients with essential thrombocythemia, polycythemia vera, and myelofibrosis, respectively. The MPN-SAF TSS strongly correlated with overall quality of life (QOL; r = 0.59; P < .001) and European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 (EORTC QLQ-C30) functional scales (all P < .001 and absolute r ≥ 0.50 except social functioning r = 0.48). No significant trends were present when comparing therapy subgroups. The MPN-SAF TSS had excellent internal consistency (Cronbach's α = .83). Factor analysis identified a single underlying construct, indicating that the MPN-SAF TSS is an appropriate, unified scoring method. Conclusion The MPN-SAF TSS is a concise, valid, and accurate assessment of MPN symptom burden with demonstrated clinical utility in the largest prospective MPN symptom study to date. This new prospective scoring method may be used to assess MPN symptom burden in both clinical practice and trial settings.