Citations

ObjectiveTo discover biomarkers involved in the pathophysiology of antineutrophil cytoplasmic antibody–associated vasculitis (AAV) and to determine whether low‐density granulocytes (LDGs) contribute to gene expression signatures in AAV.MethodsThe source of clinical data and linked biologic specimens was a randomized controlled treatment trial in AAV. RNA sequencing of whole blood from patients with AAV was performed during active disease at the baseline visit and during remission 6 months later. Gene expression was compared between patients who met versus those who did not meet the primary trial outcome of clinical remission at 6 months (responders versus nonresponders). Measurement of neutrophil‐related gene expression was confirmed in peripheral blood mononuclear cells (PBMCs) to validate the findings in whole blood. A negative‐selection strategy isolated LDGs from PBMC fractions.ResultsDifferential expression between responders (n = 77) and nonresponders (n = 35) was detected in 2,346 transcripts at the baseline visit (P < 0.05). Unsupervised hierarchical clustering demonstrated a cluster of granulocyte‐related genes, including myeloperoxidase (MPO) and proteinase 3 (PR3). A granulocyte multigene composite score was significantly higher in nonresponders than in responders (P < 0.01) and during active disease than during remission (P < 0.01). This signature strongly overlapped an LDG signature identified previously in lupus (false discovery rate by gene set enrichment analysis <0.01). Transcription of PR3 measured in PBMCs was associated with active disease and treatment response (P < 0.01). LDGs isolated from patients with AAV spontaneously formed neutrophil extracellular traps containing PR3 and MPO.ConclusionIn AAV, increased expression of a granulocyte gene signature is associated with disease activity and decreased response to treatment. The source of this signature is likely LDGs, a potentially pathogenic cell type in AAV.

BackgroundWe aimed to determine the long‐term outcomes of percutaneous lead extraction and stent placement in patients with pacemaker‐induced superior vena cava (SVC) syndrome.MethodsThe study retrospectively screened patients who underwent lead extraction followed by central vein stent implantation at Mayo Clinic (Rochester, MN, USA), from January 2005 to December 2012, to identify the patients with pacemaker‐induced SVC syndrome. Demographic, clinical, and follow‐up characteristics of those patients were collected from electronic medical records.ResultsSix cases were identified. The mean (standard deviation) age was 56 (15) years (male, 67%). All patients had permanent dual‐chamber pacemakers, with a mean 11‐year history of pacemaker placement. The entire device system was explanted in five patients; one patient had a 21‐year‐old pacemaker lead that could not be removed. Eight stents were implanted in six patients: five patients had one stent, one patient had three. A new pacemaker system was reimplanted through the stented vein in five patients. Technical success was achieved in all patients, without any complication. Symptoms rapidly resolved in all patients after stent deployment. The mean follow‐up duration was 48 months (range, 10–100 months). Three patients remained symptom free. Reintervention with percutaneous balloon venoplasty was successful in three patients with symptom recurrence.ConclusionPercutaneous stent implantation after lead removal followed by reimplantation of leads is a feasible alternative therapy for pacemaker‐induced SVC syndrome, although some cases may require repeat intervention.

Objectives: To examine multiple chronic conditions and related health care expenditures in children. Methods: Retrospective cohort study of all dependents of Mayo Clinic employees aged 0-17 on Jan 1, 2004 with continuous health benefits coverage for 4 years (N=14,727). Chronic conditions, health care utilization, and associated expenditures were obtained from medical and pharmacy claims. Results: The most prevalent chronic conditions were asthma/chronic obstructive pulmonary disease (12%), allergic rhinitis (11%), and behavior problems (9%). The most costly conditions were congenital anomalies, asthma/chronic obstructive pulmonary disease, and behavior problems ($9602, $4335, and $5378 annual cost per child, respectively). Annual health care expenditures increased substantially with the number of chronic conditions, and a small proportion of children with multiple chronic conditions accounted for a large proportion of health care costs. In addition, those with multiple chronic conditions were more likely to persist in the top 10th percentile spender group in year-to-year spending. Conclusion: Children with multiple chronic conditions accounted for a large proportion of health care expenditures. These children were also likely to persist as high spenders in the 4-year time frame. Further research into effective ways to manage the health care delivery for children with multiple chronic conditions is needed.

Percutaneous Lead Revision for Cardiac PerforationIntroductionCardiac perforation is an infrequent but potentially life‐threatening complication associated with placement of a cardiac implantable electronic device (CIED). The objective of this study was to determine the outcomes of percutaneous lead revision in patients who had lead perforation of the myocardium after CIED placement.Methods and ResultsWe reviewed records of 1,458 patients who underwent CIED lead extraction or repositioning. Of these, 31 (2.1%) had the procedure performed for lead perforation as a complication of CIED placement. Demographic, clinical, and follow‐up characteristics of the patients were analyzed. Mean (SD) patient age was 65 (23) years. Cardiac perforation was detected within 24 hours after implantation in 9 patients, within 1 month in 17, and greater than 1 month in 5. Pericardiocentesis was performed with a pigtail drainage catheter in place before the lead revision in 17 patients (55%) who had pericardial effusion, with or without hemodynamic compromise. All culprit leads were successfully managed with percutaneous lead removal (n = 3 [10%]), new lead placement (n = 12 [38%]), or lead repositioning (n = 16 [52%]). Of the 17 patients with pericardiocentesis before the reoperation, none had tamponade develop; in contrast, 3 of the remaining 14 patients had tamponade develop and required urgent pericardiocentesis. All patients survived without requiring open chest surgery.ConclusionPercutaneous removal or repositioning of the perforating lead is feasible and appears effective. Placement of a prophylactic pericardial drain catheter may reduce the incidence of urgent pericardiocentesis during or after a procedure.

Abstract Adenosine signaling has been implicated in chronic lung diseases such as asthma and chronic obstructive pulmonary disease; however, the specific roles of the various adenosine receptors in processes central to these disorders are not well understood. In this study, we have investigated the role(s) of the A3 adenosine receptor in adenosine-dependent pulmonary inflammation observed in adenosine deaminase (ADA)-deficient mice. The A3 receptor (A3R) was found to be expressed in eosinophils and mucus-producing cells in the airways of ADA-deficient mice. Treatment of ADA-deficient mice with MRS 1523, a selective A3R antagonist, prevented airway eosinophilia and mucus production. Similar findings were seen in the lungs of ADA/A3 double knockout mice. Although eosinophils were decreased in the airways of ADA-deficient mice following antagonism or removal of the A3R, elevations in circulating and lung interstitial eosinophils persisted, suggesting signaling through the A3R is needed for the migration of eosinophils into the airways. These findings identify an important role for the A3R in regulating lung eosinophilia and mucus production in an environment of elevated adenosine.

Abstract Despite the high incidence and mortality of prostate cancer, the etiology of this disease is not fully understood. In this study, we develop functional evidence for CBP and PTEN interaction in prostate cancer based on findings of their correlate expression in the human disease. Cbppc−/−;Ptenpc+/− mice exhibited higher cell proliferation in the prostate and an early onset of high-grade prostatic intraepithelial neoplasia. Levels of EZH2 methyltransferase were increased along with its Thr350 phosphorylation in both mouse Cbp−/−; Pten+/− and human prostate cancer cells. CBP loss and PTEN deficiency cooperated to trigger a switch from K27-acetylated histone H3 to K27-trimethylated bulk histones in a manner associated with decreased expression of the growth inhibitory EZH2 target genes DAB2IP, p27KIP1, and p21CIP1. Conversely, treatment with the histone deacetylase inhibitor panobinostat reversed this switch, in a manner associated with tumor suppression in Cbppc−/−;Ptenpc+/− mice. Our findings show how CBP and PTEN interact to mediate tumor suppression in the prostate, establishing a central role for histone modification in the etiology of prostate cancer and providing a rationale for clinical evaluation of epigenetic-targeted therapy in patients with prostate cancer. Cancer Res; 74(7); 2050–61. ©2014 AACR.

Abstract Overexpression of the histone acetyltransferase p300 is implicated in the proliferation and progression of prostate cancer, but evidence of a causal role is lacking. In this study, we provide genetic evidence that this generic transcriptional coactivator functions as a positive modifier of prostate tumorigenesis. In a mouse model of PTEN deletion–induced prostate cancer, genetic ablation of p300 attenuated expression of the androgen receptor (AR). This finding was confirmed in human prostate cancer cells in which PTEN expression was abolished by RNA interference–mediated attenuation. These results were consistent with clinical evidence that the expression of p300 and AR correlates positively in human prostate cancer specimens. Mechanistically, PTEN inactivation increased AR phosphorylation at serine 81 (Ser81) to promote p300 binding and acetylation of AR, thereby precluding its polyubiquitination and degradation. In support of these findings, in PTEN-deficient prostate cancer in the mouse, we found that p300 was crucial for AR target gene expression. Taken together, our work identifies p300 as a molecular determinant of AR degradation and highlights p300 as a candidate target to manage prostate cancer, especially in cases marked by PTEN loss. Cancer Res; 74(6); 1870–80. ©2014 AACR.