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We recently identified a pathway underlying immune activation in hypertension. Proteins oxidatively modified by reactive isoLG (isolevuglandin) accumulate in dendritic cells (DCs). PGE (Prostaglandin E2) has been implicated in the inflammation associated with hypertension. We hypothesized that PGE via its EP (E prostanoid) 3 receptor contributes to DC activation in hypertension. EP3 mice and wild-type littermates were exposed to sequential hypertensive stimuli involving an initial 2-week exposure to the nitric oxide synthase inhibitor N-nitro-L-arginine methyl ester hydrochloride in drinking water, followed by a 2-week washout period, and a subsequent 4% high-salt diet for 3 weeks. In wild-type mice, this protocol increased systolic pressure from 123±2 to 148±8 mm Hg (<0.05). This was associated with marked renal inflammation and a striking accumulation of isoLG adducts in splenic DCs. However, the increases in blood pressure, renal T-cell infiltration, and DC isoLG formation were completely prevented in EP3 mice. Similar protective effects were also observed in wild-type mice that received intracerebroventricular injection of a lentiviral vector encoding shRNA targeting the EP3 receptor. Further, in vitro experiments indicated that PGE also acts directly on DCs via its EP1 receptors to stimulate intracellular isoLG formation. Together, these findings provide new insight into how EP receptors in both the central nervous system and peripherally on DCs promote inflammation in salt-induced hypertension.
OBJECTIVE - To characterize the phenotype and function of fibroblasts derived from airway scar in idiopathic subglottic stenosis (iSGS) and to explore scar fibroblast response to interleukin 17A (IL-17A).
STUDY DESIGN - Basic science.
SETTING - Laboratory.
SUBJECTS AND METHODS - Primary fibroblast cell lines from iSGS subjects, idiopathic pulmonary fibrosis subjects, and normal control airways were utilized for analysis. Protein, molecular, and flow cytometric techniques were applied in vitro to assess the phenotype and functional response of disease fibroblasts to IL-17A.
RESULTS - Mechanistically, IL-17A drives iSGS scar fibroblast proliferation ( P < .01), synergizes with transforming growth factor ß1 to promote extracellular matrix production (collagen and fibronectin; P = .04), and directly stimulates scar fibroblasts to produce chemokines (chemokine ligand 2) and cytokines (IL-6 and granulocyte-macrophage colony-stimulating factor) critical to the recruitment and differentiation of myeloid cells ( P < .01). Glucocorticoids abrogated IL-17A-dependent iSGS scar fibroblast production of granulocyte-macrophage colony-stimulating factor ( P = .02).
CONCLUSION - IL-17A directly drives iSGS scar fibroblast proliferation, synergizes with transforming growth factor ß1 to promote extracellular matrix production, and amplifies local inflammatory signaling. Glucocorticoids appear to partially abrogate fibroblast-dependent inflammatory signaling. These results offer mechanistic support for future translational study of clinical reagents for manipulation of the IL-17A pathway in iSGS patients.
A 2240 gram boy was born at 33.2 weeks gestation with nonblanching, deeply erythematous plaques and papules on the back, flanks, and scalp (Figure 1). His mother was GBS positive and on antibiotic suppression for prior cutaneous MRSA and urinary tract infections. Intrapartum intravenous Penicillin G was administered, and the amniotic sac was artificially ruptured 4 hours prior to delivery to facilitate labor. The delivery was uncomplicated without concern for chorioamnionitis, but the patient initially required CPAP for respiratory distress with 1-minute and 5-minute Apgar scores of 7 and 8, respectively. A skin punch biopsy is shown (Figure 2).
Image-guided percutaneous biopsy of abdominal masses is a safe, minimally invasive procedure with a high diagnostic yield for a variety of pathologic processes. This article describes the basic technique of percutaneous biopsy, including the different modalities available for imaging guidance. Patient selection and preparation for safe performance of the procedure is emphasized, and the periprocedural management of coagulation status as well as basic indications and contraindications of the procedure are briefly discussed. In particular, the role of biopsy in the diagnosis of liver and renal masses is highlighted.
Copyright © 2015 Elsevier Inc. All rights reserved.
Despite advances in perfusion imaging, burn wound imaging technology continues to lag behind that of other fields. Quantification of blood flow is able to predict time for healing, but clear assessment of burn depth is still questionable. Active dynamic thermography (ADT) is a noncontact imaging modality capable of distinguishing tissue of different thermal conductivities. Utilizing the abnormal heat transfer properties of the burn zones, we examined whether ADT was useful in the determination of burn depth in a model of early burn wound evaluation. Duroc pigs (castrated male; n = 3) were anesthetized, and two burns were created with an aluminum billet at 3 and 12 seconds. These contact times resulted in superficial partial and deep partial thickness burn wounds, respectively. ADT and laser Doppler imaging (LDI) imaging were performed every 30 minutes postburn for a total of five imaging sessions ending 150 minutes postburn. For ADT, imaging excitation was performed for 42-120 seconds with dual quartz-infrared lamps, and subsequent infrared image capture was performed for 300 seconds. MATLAB-assisted image analysis was performed to determine burn zone region of interest thermal relaxation and characteristic patterns. LDI was performed with a moorLDI system, and biopsies were captured for histology following the 150-minute imaging session. Both ADT and LDI imaging modalities are able to detect different physical properties at 30, 60, 90 120, and 150 minutes postburn with statistical significance (P < 0.05). Resultant ADT cooling curves characterize greater differences with greater stimulation and a potentially more identifiable differential cooling characteristic. Histological analysis confirmed burn depth. This preliminary work confirms that ADT can measure burn depth and is deserving of further research either as a stand-alone imaging technology or in combination with a device to assess perfusion.
OBJECTIVES - Immunohistochemical markers have been shown to assist in the stratification of breast papillary lesions. We evaluated the ability of different cytokeratin (CK) and p63 expression profiles on needle biopsy specimens to predict excision diagnoses.
METHODS - A CK5/p63/CK8/18 antibody cocktail was applied to 58 needle biopsy specimens (32 papillomas, 7 atypical papillomas, 19 papillary carcinomas on excision).
RESULTS - p63 expression was greater in papillomas than in atypical papillomas (P = .044) and papillary carcinomas (P< .0001). Papillary carcinomas and atypical papillomas showed greater CK8/18 expression (and conversely less CK5 expression) than did papillomas (P < .0001). Negative or focal p63 expression was 96% sensitive for diagnosing any atypical lesion (atypical papilloma or papillary carcinoma) on excision, whereas CK8/18 predominant expression (≥80% cells) was 100% sensitive. In contrast, the sensitivity of the original diagnosis was only 81%. The greatest accuracy for the diagnosis of atypical papillary lesions (95%) was achieved when both p63 and cytokeratins were used in combination in an algorithmic fashion. This method also correctly identified all cases that had papillary carcinoma (100% sensitivity) on excision.
CONCLUSIONS - Although a single stain or combination cannot independently stratify papillary lesions, a CK5/p63/CK8/18 antibody cocktail is a useful adjunct to morphology for evaluating breast papillary lesions in needle biopsy specimens.
Prostatic adenocarcinoma with aberrant diffuse expression of p63 (p63-PCa) is a recently described variant of prostatic adenocarcinoma. The aim of this study was to investigate the clinical and pathologic features of p63-PCa at radical prostatectomy (RP). We reviewed 21 cases of p63-PCa diagnosed on needle biopsy at subsequent RP. Immunohistochemical analysis for PIN4 and Ki-67 was performed in all RP cases. p63-PCa showed a distinctive morphology consisting of atrophic, poorly formed glands, with multilayered and often spindled nuclei. Gleason grading was 3+3=6 in 28.5%, 3+5=8 in 38%, 3+4=7 in 14.3%, and 4+3=7, 5+3=8, and 5+4=9 in 9.5%. Usual-type acinar carcinoma coexisted in 85.7% with only p63-PCa present in the remaining cases. The usual-type carcinoma was Gleason grade 3+2=5 in 4.7%, 3+3=6 in 57%, 3+4=7 in 19%, and 4+3=7 in 4.3%. Overall, p63-PCa represented 65% of the total cancer volume (median 80%). The tumor was organ-confined in 16 cases (76.2%). In the remaining 5 cases, 2 had p63-PCa extending to the margin in areas of intraprostatic incisions, 2 had usual-type acinar adenocarcinoma extending to the margin and extraprostatic tissue, respectively, and 1 had p63-PCa with an unusual cribriform morphology involving the bladder neck. Ki-67 was low, <5% in all cases of p63-PCa, with similar expression in the coexisting acinar-type carcinoma. In summary, it is recommended that these tumors not be assigned a Gleason score and their favorable findings at RP be noted.
BACKGROUND - Sinonasal undifferentiated carcinoma (SNUC) remains a poorly characterized malignancy at both the clinical and molecular level, and, consequently, the optimal treatment strategy remains undefined.
METHODS - We used a mass spectroscopy-based approach (Sequenom) to evaluate 95 hallmark single nucleotide variations (SNVs) within 12 oncogenes or tumor suppressor genes (AKT, BRAF, CDK4, Beta-catenin, epidermal growth factor receptor [EGFR], FBXW7, JAK2, c-KIT, KRAS, PDGFR, PI3K, and vascular endothelial growth factor [VEGF]) in 13 histologically confirmed SNUC cases.
RESULTS - None of the samples demonstrated activating mutations in any of the 95 SNVs.
CONCLUSION - Select clinically relevant activating genomic mutations were not identified in the 13 patient samples. However, polymorphisms were noted within the promoter region of VEGF. These may merit future studies as predictive biomarkers for treatment response or overall survival. Additionally, future studies focusing on larger tumor sets and utilizing whole genome or exome sequencing may help define genetic aberrations in SNUC that can be clinically targeted with available or emerging biological agents.
Copyright © 2013 Wiley Periodicals, Inc.