Citations

The purpose of this study was to compare hemodynamic and blood analyte responses to reduced central venous pressure (CVP) and pulse pressure (PP) elicited during graded lower body negative pressure (LBNP) to those observed during graded blood loss (BL) in conscious humans. We hypothesized that the stimulus-response relationships of CVP and PP to hemodynamic responses during LBNP would mimic those observed during BL. We assessed CVP, PP, heart rate, mean arterial pressure (MAP), and other hemodynamic markers in 12 men during LBNP and BL. Blood samples were obtained for analysis of catecholamines, hematocrit, hemoglobin, arginine vasopressin, and blood gases. LBNP consisted of 5-min stages at 0, 15, 30, and 45 mmHg of suction. BL consisted of 5 min at baseline and following three stages of 333 ml of hemorrhage (1,000 ml total). Individual r2 values and linear regression slopes were calculated to determine whether the stimulus (CVP and PP)-hemodynamic response trajectories were similar between protocols. The CVP-MAP trajectory was the only CVP-response slope that was statistically different during LBNP compared with BL (0.93 ± 0.27 vs. 0.13 ± 0.26; P = 0.037). The PP-heart rate trajectory was the only PP-response slope that was statistically different during LBNP compared with BL (−1.85 ± 0.45 vs. −0.46 ± 0.27; P = 0.024). Norepinephrine, hematocrit, and hemoglobin were all lower at termination in the BL protocol compared with LBNP ( P < 0.05). Consistent with our hypothesis, LBNP mimics the hemodynamic stimulus-response trajectories observed during BL across a significant range of CVP in humans.

Abstract Motivation: Exome sequencing (exome-seq) data, which are typically used for calling exonic mutations, have also been utilized in detecting DNA copy number variations (CNVs). Despite the existence of several CNV detection tools, there is still a great need for a sensitive and an accurate CNV-calling algorithm with built-in QC steps, and does not require a paired reference for each sample. Results: We developed a novel method named PatternCNV, which (i) accounts for the read coverage variations between exons while leveraging the consistencies of this variability across different samples; (ii) reduces alignment BAM files to WIG format and therefore greatly accelerates computation; (iii) incorporates multiple QC measures designed to identify outlier samples and batch effects; and (iv) provides a variety of visualization options including chromosome, gene and exon-level views of CNVs, along with a tabular summarization of the exon-level CNVs. Compared with other CNV-calling algorithms using data from a lymphoma exome-seq study, PatternCNV has higher sensitivity and specificity. Availability and implementation: The software for PatternCNV is implemented using Perl and R, and can be used in Mac or Linux environments. Software and user manual are available at http://bioinformaticstools.mayo.edu/research/patterncnv/ , and R package at https://github.com/topsoil/patternCNV/ . Contact: Asmann.Yan@mayo.edu Supplementary information: Supplementary data are available at Bioinformatics online.

Background There is a considerable amount of practice variation in managing migraines in emergency settings, and evidence-based therapies are often not used first line. Methods A peer-reviewed search of databases (MEDLINE, Embase, CENTRAL) was carried out to identify randomized and quasi-randomized controlled trials of interventions for acute pain relief in adults presenting with migraine to emergency settings. Where possible, data were pooled into meta-analyses. Results Two independent reviewers screened 831 titles and abstracts for eligibility. Three independent reviewers subsequently evaluated 120 full text articles for inclusion, of which 44 were included. Individual studies were then assigned a US Preventive Services Task Force quality rating. The GRADE scheme was used to assign a level of evidence and recommendation strength for each intervention. Interpretation We strongly recommend the use of prochlorperazine based on a high level of evidence, lysine acetylsalicylic acid, metoclopramide and sumatriptan, based on a moderate level of evidence, and ketorolac, based on a low level of evidence. We weakly recommend the use of chlorpromazine based on a moderate level of evidence, and ergotamine, dihydroergotamine, lidocaine intranasal and meperidine, based on a low level of evidence. We found evidence to recommend strongly against the use of dexamethasone, based on a moderate level of evidence, and granisetron, haloperidol and trimethobenzamide based on a low level of evidence. Based on moderate-quality evidence, we recommend weakly against the use of acetaminophen and magnesium sulfate. Based on low-quality evidence, we recommend weakly against the use of diclofenac, droperidol, lidocaine intravenous, lysine clonixinate, morphine, propofol, sodium valproate and tramadol.

Abstract Hepatocellular cancer (HCC) is a highly treatment-refractory cancer and is also highly resistant to adverse cellular stress. Although cell behavior can be modulated by noncoding RNAs (ncRNA) within extracellular vesicles (EV), the contributions of long noncoding RNAs (lncRNAs) are largely unknown. To this end, the involvement and functional roles of lncRNAs contained within EVs during chemotherapeutic stress in human HCC were determined. Expression profiling identified a subset of lncRNAs that were enriched in tumor cell–derived vesicles released from two different cell lines. Of these, lincRNA-VLDLR (linc-VLDLR) was significantly upregulated in malignant hepatocytes. Exposure of HCC cells to diverse anticancer agents such as sorafenib, camptothecin, and doxorubicin increased linc-VLDLR expression in cells as well as within EVs released from these cells. Incubation with EVs reduced chemotherapy-induced cell death and also increased linc-VLDLR expression in recipient cells. RNAi-mediated knockdown of linc-VLDLR decreased cell viability and abrogated cell-cycle progression. Moreover, knockdown of VLDLR reduced expression of ABCG2 (ATP-binding cassette, subfamily G member 2), whereas overexpression of this protein reduced the effects of VLDLR knockdown on sorafenib-induced cell death. Here, linc-VLDLR is identified as an EV-enriched lncRNA that contributes to cellular stress responses. Implications: These findings provide new insight into the role of EVs and demonstrate the capacity of lncRNAs to mediate chemotherapeutic stress response in HCC. Mol Cancer Res; 12(10); 1377–87. ©2014 AACR.

Pediatric and Congenital Interventional Cardiology is the practice of catheter‐based techniques that improve cardiac physiology and circulation through the treatment of heart disease in children and adults with congenital or acquired heart defects. Over the last decade, and since last published training guidelines for pediatric cardiac catheterization and interventional cardiology were published in 2005 [1] the field of Pediatric and Congenital Cardiac Catheterization has evolved into a predominantly interventional discipline. As there is no sub‐specialty certification for interventional cardiac catheterization in pediatrics, the Congenital Heart Disease Committee of the Society of Cardiovascular Angiography and Interventions has put together this consensus statement for advanced training in pediatric and congenital interventional cardiac catheterization. The statement puts forth recommendations for program infrastructure in terms of teaching, personnel, equipment, facilities, conferences, patient volume and trainee assessment. This is meant to set a standard for training programs as well as giving applicants a basis on which to judge and compare programs. © 2014 Wiley Periodicals, Inc.

Proposed kinetic mechanism for Mt IMPDH in the presence of K + .

A patient presented with neuromuscular, respiratory and cardiac symptoms and was initially diagnosed with amyotrophic lateral sclerosis (ALS), myocardial ischaemia and pneumonia. He developed unexplained progressive kidney failure over the ensuing week, and his kidney biopsy showed thrombotic microangiopathy that led to the correct diagnosis of normotensive scleroderma renal crisis. His clinical presentation and course were consistent with systemic sclerosis and normotensive scleroderma renal crisis. He was treated with an ACE inhibitor (ACEi) and haemodialysis with significant functional improvement over the next 3 months to his prior baseline with the exception of kidney failure. This case highlights a diagnostic challenge requiring astute history and physical examination skills, and the value of a kidney biopsy in providing the final diagnosis.

Background Heart failure ( HF ) patients experience impaired functional status, diminished quality of life, high utilization of healthcare resources, and poor survival. Yet, the identification of patient‐centered factors that influence prognosis is lacking. Methods and Results We determined the association of 2 measures of self‐rated health with healthcare utilization and skilled nursing facility ( SNF ) admission in a community cohort of 417 HF patients prospectively enrolled between October 2007 and December 2010 from Olmsted County, MN . Patients completed a 12‐item Short Form Health Survey ( SF ‐12). Low self‐reported physical functioning was defined as a score ≤25 on the SF ‐12 physical component. The first question of the SF ‐12 was used as a measure of self‐rated general health. After 2 years, 1033 hospitalizations, 1407 emergency department ( ED ) visits, and 19,780 outpatient office visits were observed; 87 patients were admitted to a SNF . After adjustment for confounding factors, an increased risk of hospitalizations (1.52 [1.17 to 1.99]) and ED visits (1.48 [1.04 to 2.11]) was observed for those with low versus moderate‐high self‐reported physical functioning. Patients with poor and fair self‐rated general health also experienced an increased risk of hospitalizations (poor: 1.73 [1.29 to 2.32]; fair: 1.46 [1.14 to 1.87]) and ED visits (poor: 1.73 [1.16 to 2.56]; fair: 1.48 [1.13 to 1.93]) compared with good‐excellent self‐rated general health. No association between self‐reported physical functioning or self‐rated general health with outpatient visits and SNF admission was observed. Conclusion In community HF patients, self‐reported measures of physical functioning predict hospitalizations and ED visits, indicating that these patient‐reported measures may be useful in risk stratification and management in HF .

Hartsfield syndrome has been recently reported to be associated with mutations in FGFR1 however, to this date; no familial cases have been reported. In this report, we describe two siblings with Hartsfield syndrome and a novel de novo FGFR1 mutation suggesting gonadal mosaicism. The proband presented at our institution at age 6 years with a clinical diagnosis of Hartsfield syndrome and requesting further genetic evaluation. Previous studies included a normal karyotype, oligonucleotide array, and single gene testing for nonsyndromic holoprosencephaly (SHH, SIX3, ZIC2, TGIF). At the age of 6 years, exome sequencing was performed and a de novo novel missense variant was identified in FGFR1 (coding for fibroblast growth factor‐1) on chromosome 8p12: c.1880G>C (p.R627T). Subsequently, a younger sibling was born with the same phenotype (holoprosencephaly, ectrodactyly of bilateral hands and feet and bilateral cleft lip and palate). Targeted sequencing of FGFR1 revealed the identical variant that was previously identified in the proband. To our knowledge this observation is the first documentation of familial recurrence of Hartsfield syndrome. As both parents were negative for the sequence variant in FGFR1 gene by testing peripheral blood samples, this suggests gonadal mosaicism. The frequency of gonadal mosaicism in Hartsfield syndrome is not known however given our case, this possibility should be taken in to consideration for recurrence risk estimation in children of clinically unaffected parents. © 2014 Wiley Periodicals, Inc.

In the era of targeted therapies, patients with gynecologic malignancies have not yet been major beneficiaries of this new class of agents. This may reflect the fact that the main tumor types—ovarian, uterine, and cervical—are a highly heterogeneous group of cancers with variable response to standard chemotherapies and the lack of models in which to study the diversity of these cancers. Cancer-derived cell lines fail to adequately recapitulate molecular hallmarks of specific cancer subsets and complex microenvironments, which may be critical for sensitivity to targeted therapies. Patient-derived xenografts (PDX) generated from fresh human tumor without prior in vitro culture, combined with whole genome expression, gene copy number, and sequencing analyses, could dramatically aid the development of novel therapies for gynecologic malignancies. Gynecologic tumors can be engrafted in immunodeficient mice with a high rate of success and within a reasonable time frame. The resulting PDX accurately recapitulates the patient's tumor with respect to histologic, molecular, and in vivo treatment response characteristics. Orthotopic PDX develop complications relevant to the clinic, such as ascites and bowel obstruction, providing opportunities to understand the biology of these clinical problems. Thus, PDX have great promise for improved understanding of gynecologic malignancies, serve as better models for designing novel therapies and clinical trials, and could underpin individualized, directed therapy for patients from whom such models have been established.