Background A key question in the allergy field is to understand how tissue-specific disease is manifested. Eosinophilic esophagitis (EoE) is an emerging tissue-specific allergic disease with an ...unclear pathogenesis. Objective Herein we tested the hypothesis that a defect in tissue-specific esophageal genes is an integral part of EoE pathogenesis. Methods We interrogated the pattern of expression of esophagus-specific signature genes derived from the Human Protein Atlas in the EoE transcriptome and in EPC2 esophageal epithelial cells. Western blotting and immunofluorescence were used for evaluating expression of esophageal proteins in biopsy specimens from control subjects and patients with active EoE. Whole-exome sequencing was performed to identify mutations in esophagus-specific genes. Results We found that approximately 39% of the esophagus-specific transcripts were altered in patients with EoE, with approximately 90% being downregulated. The majority of transcriptional changes observed in esophagus-specific genes were reproduced in vitro in esophageal epithelial cells differentiated in the presence of IL-13. Functional enrichment analysis revealed keratinization and differentiation as the most affected biological processes and identified IL-1 cytokines and serine peptidase inhibitors as the most dysregulated esophagus-specific protein families in patients with EoE. Accordingly, biopsy specimens from patients with EoE evidenced a profound loss of tissue differentiation, decreased expression of keratin 4 (KRT4) and cornulin (CRNN) , and increased expression of KRT5 and KRT14 . Whole-exome sequencing of 33 unrelated patients with EoE revealed 39 rare mutations in 18 esophagus-specific differentially expressed genes. Conclusions A tissue-centered analysis has revealed a profound loss of esophageal tissue differentiation (identity) as an integral and specific part of the pathophysiology of EoE and implicated protease- and IL-1–related activities as putative central pathways in disease pathogenesis.
Transcriptomic analysis was carried out for the top 70 DA associated SNPs using available transcription factor (TF) datasets from relevant lung-derived tissues and cell lines, including ChIP- seq ...datasets for TFs, regulatory histone marks, and DNase-seq (open chromatin).
Genome-Wide Association Scan of Dupuytren's Disease Ojwang, Joshua O., PhD; Adrianto, Indra, PhD; Gray-McGuire, Courtney, PhD ...
The Journal of hand surgery (American ed.),
12/2010, Letnik:
35, Številka:
12
Journal Article
Recenzirano
Odprti dostop
Purpose Dupuytren's disease (DD) has a strong genetic component that is suggested by population studies and family clustering. Genetic studies have yet to identify the gene(s) involved in DD. The ...purpose of this study was to identify regions of the entire genome (chromosomes 1–23) associated with the disease by performing a genome-wide association scan on DD patients and controls. Methods We isolated genomic DNA from saliva collected from 40 unrelated DD patients and 40 unaffected controls. We conducted the genotyping using CytoSNP-Infinium HD Ultra genotyping assay on the Illumina platform. Using both log regression and mapping by admixture linkage disequilibrium analysis methods, we analyzed the single nucleotide polymorphism genotyping data. Results Single nucleotide polymorphism analysis revealed a significant association in regions for chromosomes 1, 3 through 6, 11, 16, 17, and 23. Mapping by admixture linkage disequilibrium analysis showed ancestry-associated regions in chromosomes 2, 6, 8, 11, 16, and 20, which may harbor DD susceptibility genes. Both analysis methods revealed loci association in chromosomes 6, 11, and 16. Conclusions Our data suggest that chromosomes 6, 11, and 16 may contain the genes for DD and that multiple genes may be involved in DD. Future genetic studies on DD should focus on these areas of the genome.
Abstract Introduction In experimental models, spatial dispersion of repolarization (DOR) due to discordant cellular alternans predisposes to ventricular fibrillation. To test the hypothesis that ...microvolt T-wave alternans (MTWA) in humans causes spatial DOR, we measured Tpeak-Tend interval (Tpe) and Tpe/QT ratio, electrocardiographic indices of spatial DOR. Methods Mean Tpe and Tpe/QT were compared in ischemic cardiomyopathy patients with positive and negative MTWA studies. Results MTWA was positive in 12 and negative in 24 patients. Tpe and Tpe/QT were higher in MTWA + subjects compared to MTWA- subjects during exercise (64.5 ± 6.8 vs. 54.9 ± 8.7 ms, p = 0.001 and 0.218 ± 0.03 vs. 0.177 ± 0.02, p = 0.001) but not at rest. Conclusion Ischemic cardiomyopathy patients have increased Tpe and Tpe/QT when MTWA is induced during exercise, suggesting that MTWA causes increased spatial DOR in humans. Future studies are needed to determine if Tpe and Tpe/QT during exercise might predict increased risk of SCD alone or in combination with measurement of MTWA.
To describe the use of intravascular ultrasound (US) guidance for creation of transjugular intrahepatic portosystemic shunts (TIPSs) in humans.
The initial 25 cases of intravascular US-guided TIPS ...were retrospectively compared versus the last 75 conventional TIPS cases during the same time period at the same institution in terms of the number of needle passes required to establish portal vein (PV) access, fluoroscopy time, and needle pass-related complications.
Intravascular US-guided TIPS creation was successful in all cases, and there was no statistically significant difference in number of needle passes, fluoroscopy time, or needle pass-related complications between TIPS techniques. Intravascular US-guided TIPS creation was successful in cases in which conventional TIPS creation had failed as a result of PV thrombosis or distorted anatomy. Intravascular US guidance for TIPS creation was additionally useful in a patient with Budd-Chiari syndrome and in a patient with intrahepatic tumors.
Intravascular US is a safe and reproducible means of real-time image guidance for TIPS creation, equivalent in efficacy to conventional fluoroscopic guidance. Real-time sonographic guidance with intravascular US may prove advantageous for cases in which there is PV thrombus, distorted anatomy, Budd-Chiari syndrome, or hepatic tumors.
To determine the incidence of venous thromboembolism (VTE) after removal of retrievable inferior vena cava (IVC) filters.
Retrospective study was conducted of 67 patients who underwent 72 consecutive ...filter retrievals at a single institution. Data collected included VTE status at the time of filter placement, anticoagulant medications at the time of filter retrieval and afterward, new or recurrent VTE after filter removal, and insertion of subsequent filters. Patient questionnaires were completed in 50 cases, chart review in all patients.
At the time of filter placement, 30 patients had documented VTE, 19 had a history of treated VTE, and 23 were at risk for but had neither previous nor present VTE. Mean duration of follow-up after filter removal was 20.6 months +/- 10.9. A total of 52 patients (57 filters) received anticoagulation and/or antiplatelet medications after filter removal. There were two documented episodes of recurrent deep vein thrombosis (2.8% of filters removed), both in patients who had VTE at the time of filter placement and underwent therapeutic anticoagulation at the time of filter removal. One of these patients (1.4% of filters removed) also experienced pulmonary embolism. Of the 23 patients without VTE when the filter was placed, none developed VTE after filter removal. Four patients (5.5% of filters removed) required subsequent permanent filters, three for complications of anticoagulation, one for failure of anticoagulation.
VTE was rare after removal of IVC filters, but was most likely to occur in patients who had VTE at the time of filter placement.
Objectives: To examine the extent to which elderly individuals use various skilled care facilities after coronary artery bypass grafting (CABG).
Design: Retrospective cohort study.
Setting: State of ...Michigan from 1997 to 1998.
Participants: Residents aged 65 and older enrolled in Medicare who underwent CABG.
Measurements: Cumulative incidence of admission within 100 days of hospital discharge, relative risk (RR) of admission, readmission or extended stay at a skilled care facility, and length of stay in a skilled care facility.
Results: Fifty percent of patients aged 80 and older used a skilled care facility after CABG, with most requiring admission to a skilled nursing facility (SNF) or readmission to an acute‐care hospital within 100 days after discharge. Patients aged 80 and older had a significantly higher risk of admission to a SNF (adjusted RR=3.3, 95% confidence interval (CI)=2.8–4.0) than did those aged 65 to 69, as did patients aged 75 to 79 (adjusted RR=2.2, 95% CI=1.8–2.6) and those aged 70 to 74 (adjusted RR=1.5, 95% CI=1.3–1.8). The length of time spent in skilled care facilities significantly increased with age (mean days=13.3 for aged 65–69, 16.9 for 70–74, 19.6 for 75–79, and 22.9 for 80 and older; P<.001).
Conclusion: Older patients are more likely to be admitted to a SNF, be readmitted to an acute‐care hospital, and have longer institutional stays after CABG. When balancing the risks and benefits of CABG, physicians, patients, families, and policy‐makers need to carefully consider the likelihood of follow‐up institutional care in elderly patients.
Objective Patients who have had curative surgery for lung cancer are at the highest risk of developing a new lung cancer. Individual studies are usually underpowered to describe the clinical ...characteristics and outcomes in second primary lung cancer. The goal of this study is to determine which therapy is best associated with survival in patients who develop a new primary lung cancer. Methods All pathologically proven stage I lung cancer cases that received cancer-directed surgery included in the Surveillance Epidemiology and End Results (SEER) database between 2004 and 2010 were selected. Cases that received radiation therapy were excluded. Cases which developed a second primary lung cancer 6 or more months after the diagnosis of the first cancer were analyzed. The original data set consisted of 9,564 stage I lung cancer cases treated with surgery; 520 of them developed a second primary and completed data were available for 494 of them. Results Stage I disease was diagnosed in 272 patients with second primary lung cancers (58.5%); 45.8% of these underwent cancer surgery alone, 31.6% received radiation alone. Surgery was performed more frequently in early stages and younger patients. Surgical patients had statistically significant longer survival than patients treated with radiation (log-rank p<0.0001) or not treated with surgery or radiation (log-rank p<0.0001). Conclusions The incidence of second primary lung cancers was 5.4%. Stage I second primaries had improved survival compared to later stage disease and surgery conferred an increased survival benefit as compared to radiation. Ultra-Mini Abstract Previously treated lung cancer patients are at the highest risk of developing a new cancer. Second primary lung cancers are often found in early stage. Surgical resection provides survival benefit to patients with metachronous second primary lung cancer compared to radiation and should be further studied as the treatment of choice.
Objective: The study objective was to determine the relationship between lung resection and the development of postoperative hiatal hernia. Methods: Preoperative and postoperative computed tomography ...imaging from 373 patients from the International Early Lung Cancer Action Program and the Initiative for Early Lung Cancer Research on Treatment were compared at a median of 31.1 months of follow-up after resection of clinical early-stage non–small cell lung cancer. Incidence of new hiatal hernia or changes to preexisting hernias were recorded and evaluated by patient demographics, surgical approach, extent of resection, and resection site. Results: New hiatal hernias were seen in 9.6% of patients after lung resection (5.6% after wedge or segmentectomy and 12.4% after lobectomy; P = .047). The median size of new hernias was 21 mm, and the most commonly associated resection site was the left lower lobe (24.2%; P = .04). In patients with preexisting hernias, 53.5% demonstrated a small but significant increase in size from 21 to 22 mm (P < .0001). All hernias persisted through the latest postoperative computed tomography scan. When 110 surgical patients without preexisting hernia were matched by sex, age, and smoking to nonoperative controls, the incidence of new hernia at follow-up was significantly higher among those who underwent surgery (17.3% vs 2.7%, P = .0003). Conclusions: Both open and minimally invasive lung resection for clinical early-stage lung cancer are associated with new or enlarging postoperative hiatal hernia, especially after resections involving the left lower lobe.
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