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PubMed | Cardiovascular Institute, Mount Sinai School of Medicine, University of Pennsylvania, Vanderbilt University and Allergy and Critical Care.
Type: Journal Article | Journal: Human molecular genetics | Year: 2015

Fever predicts clinical outcomes in sepsis, trauma and during cardiovascular stress, yet the genetic determinants are poorly understood. We used an integrative genomics approach to identify novel genomic determinants of the febrile response to experimental endotoxemia. We highlight multiple integrated lines of evidence establishing the clinical relevance of this novel fever locus. Through genome-wide association study (GWAS) of evoked endotoxemia (lipopolysaccharide (LPS) 1 ng/kg IV) in healthy subjects of European ancestry we discovered a locus on chr7p11.2 significantly associated with the peak febrile response to LPS (top single nucleotide polymorphism (SNP) rs7805622, P = 2.4 10(-12)), as well as with temperature fluctuation over time. We replicated this association in a smaller independent LPS study (rs7805622, P = 0.03). In clinical translation, this locus was also associated with temperature and mortality in critically ill patients with trauma or severe sepsis. The top GWAS SNPs are not located within protein-coding genes, but have significant cis-expression quantitative trait loci (eQTL) associations with expression of a cluster of genes 400 kb upstream, several of which (SUMF2, CCT6A, GBAS) are regulated by LPS in vivo in blood cells. LPS- and cold-treatment of adipose stromal cells in vitro suggest genotype-specific modulation of eQTL candidate genes (PSPH). Several eQTL genes were up-regulated in brown and white adipose following cold exposure in mice, highlighting a potential role in thermogenesis. Thus, through genomic interrogation of experimental endotoxemia, we identified and replicated a novel fever locus on chr7p11.2 that modulates clinical responses in trauma and sepsis, and highlight integrated in vivo and in vitro evidence for possible novel cis candidate genes conserved across human and mouse.


Kassutto S.M.,Allergy and Critical Care | Dine C.J.,Allergy and Critical Care | Dine C.J.,University of Pennsylvania | Kreider M.,Allergy and Critical Care | Shah R.J.,University of California at San Francisco
Annals of the American Thoracic Society | Year: 2016

Rationale: The Accreditation Council for Graduate Medical Education has mandated that pulmonary fellows practice evidencebased medicine "across multiple care settings." Currently, most clinical fellowship training is inpatient based, suggesting that more robust fellowship training in outpatient pulmonology is needed. No standardized ambulatory pulmonary curriculum is currently available. Objectives: To design, implement and test the feasibility of a standardized, case-based outpatient curriculum implemented for pulmonary fellows at the Perelman School of Medicine at the University of Pennsylvania. Methods: A list of 20 topics in ambulatory pulmonology was generated and was used to create a series of literature-based teaching scripts, which served as the foundation for twice-monthly small group teaching sessions. Before implementation, the fellows were asked to complete a survey regarding their impressions of their existing outpatient training and their competency in ambulatory patient care. Participants were surveyed again at 6 and 12 months thereafter. Measurements and Main Results: Fellow survey respondents reported that the curriculum improved the overall ambulatory educational experience. Before implementation, only 6 of 12 fellows (50%) agreed that their current instruction on relevant outpatient pulmonary topics was adequate, compared with 100% after the curriculum (P = 0.01, n = 10). In addition, only five fellows (42%) initially agreed or strongly agreed that their current outpatient educational experience had prepared them well for independent pulmonary practice, compared with 90% on the 12-month survey (P = 0.02). Conclusions: We created a standardized outpatient pulmonary curriculum and demonstrated its feasibility in positively influencing fellows' perceived competency in ambulatory pulmonology. Additional assessment of knowledge, performance outcomes, and applicability at other institutions is needed. Copyright © 2016 by the American Thoracic Society.


News Article | November 28, 2016
Site: www.eurekalert.org

PITTSBURGH (November 28, 2016) ... Cystic Fibrosis (CF) causes the accumulation of dehydrated mucus in the lungs which can lead to chronic infection, inflammation and respiratory failure and drastically affect the lives of CF patients. These ever-changing complexities often make it difficult for doctors to decide which therapies will be most effective in treating the disease. To develop better evaluation methods, the National Institutes of Health (NIH) awarded a research team at the University of Pittsburgh's schools of engineering and medicine a highly competitive $1.7 million U01 grant to develop new mathematical models of liquid and ion transport in the human lung. These models could allow doctors to rapidly personalize interventions for patients suffering from CF and other lung diseases and administer the most effective treatment by simply studying a cell culture from the patient's nose. Robert Parker, professor of chemical and petroleum engineering at the Swanson School of Engineering, and Tim Corcoran, associate professor of medicine, bioengineering and chemical engineering at the School of Medicine, in the Division of Pulmonary, Allergy and Critical Care, will lead the study as co-principal investigators. Three co-investigators will join the study: Carol Bertrand from Pediatrics, and Joe Pilewski and Mike Myerburg, both from the Division of Pulmonary, Allergy and Critical Care Medicine. "We know that mucus hydration and clearance are important factors in CF lung disease," said Dr. Corcoran. "We've developed nuclear imaging techniques to measure how mucus and water move in the lungs. This lets us understand the individual lung pathologies of our patients and may allow us to predict what therapies will help them. The techniques we are using were actually developed here, and we're pretty much the only ones using them." The researchers will begin by collecting data from patients with CF, biological parents of patients with CF who carry the CF mutation and healthy controls. After sampling and culturing of human nasal epithelial (HNE) cells - under the direction of Dr. Myerburg - Dr. Corcoran will use aerosol-based nuclear imaging to measure mucus clearance and airway surface liquid dehydration in the lungs. Once the researchers have collected data from the patients' HNE cell cultures and lung imagining, they will use advanced computational techniques to find the correlation between the nasal cell physiology and lung physiology. Dr. Parker will lead the group's effort to translate the data collected from the test subjects into multi-scale mathematical models that provide cell- and organ-level visualizations of the patients' physiology. "The mathematical models--through a framework of differential equations--describe how basic physiological processes contribute to experimental outcomes," said Parker. "We can link all of the information we've gathered from lab experiments, physiology studies and clinical studies to better predict how a patient will respond to different therapies. By creating millions of simulations over a broad spectrum of patients, we can identify the underlying biological mechanism and understand how the patients will respond to treatment through the painless, non-invasive sampling of the HNE cells." Ultimately, the researchers hope to show that nasal cell sampling and interpretation of the data by the computer models can lead to a highly personalized approach to treating a patient with CF that could begin as early as birth. This would greatly enhance a patient's quality of life, increase life expectancy and limit progress of the disease. "We are always going to be limited by the number of patients we can test," added Parker. "However, we can bridge the gap between the full set of all CF patients and a smaller set of CF patients with similar symptoms who are likely to respond to treatment in a similar way. The mathematical models will help us create those sets and let us predict outcomes and design treatments for individual patients."


Sutliff R.L.,Allergy and Critical Care | Walp E.R.,Allergy and Critical Care | El-Ali A.M.,Allergy and Critical Care | Elkhatib S.,Allergy and Critical Care | And 2 more authors.
American Journal of Physiology - Renal Physiology | Year: 2011

The contribution of medial calcification to vascular dysfunction in renal failure is unknown. Vascular function was measured ex vivo in control, noncalcified uremic, and calcified uremic aortas from rats with adenine-induced renal failure. Plasma urea was 16 ± 4, 93 ± 14, and 110 ± 25 mg/dl, and aortic calcium content was 27 ± 4, 29 ± 2, and 4,946 ± 1,616 nmol/mg dry wt, respectively, in the three groups. Maximal contraction by phenylephrine (PE) or KCl was reduced 53 and 63% in uremic aortas, and sensitivity to KCl but not PE was increased. Maximal relaxation to acetylcholine was impaired in uremic aortas (30 vs. 65%), and sensitivity to nitroprusside was also reduced, indicating some impairment of endothelium-independent relaxation as well. None of these parameters differed between calcified and noncalcified uremic aortas. However, aortic compliance was reduced in calcified aortas, ranging from 17 to 61% depending on the severity of calcification. We conclude that uremic vascular calcification, even when not severe, significantly reduces arterial compliance. Vascular smooth muscle and endothelial function are altered in renal failure but are not affected by medial calcification, even when severe. © 2011 the American Physiological Society.


Simone C.B.,University of Pennsylvania | Friedberg J.S.,University of Pennsylvania | Glatstein E.,University of Pennsylvania | Stevenson J.P.,University of Pennsylvania | And 3 more authors.
Journal of Thoracic Disease | Year: 2012

Photodynamic therapy is increasingly being utilized to treat thoracic malignancies. For patients with early-stage non-small cell lung cancer, photodynamic therapy is primarily employed as an endobronchial therapy to definitely treat endobronchial, roentgenographically occult, or synchronous primary carcinomas. As definitive monotherapy, photodynamic therapy is most effective in treating bronchoscopically visible lung cancers ≤1 cm with no extracartilaginous invasion. For patients with advanced-stage non-small cell lung cancer, photodynamic therapy can be used to palliate obstructing endobronchial lesions, as a component of definitive multi-modality therapy, or to increase operability or reduce the extent of operation required. A review of the available medical literature detailing all published studies utilizing photodynamic therapy to treat at least 10 patients with non-small cell lung cancer is performed, and treatment recommendations and summaries for photodynamic therapy applications are described. © Pioneer Bioscience Publishing Company.


Gaieski D.F.,Allergy and Critical Care | Mikkelsen M.E.,University of Pennsylvania | Band R.A.,Allergy and Critical Care | Pines J.M.,Allergy and Critical Care | And 5 more authors.
Critical Care Medicine | Year: 2010

Objective: To study the association between time to antibiotic administration and survival in patients with severe sepsis or septic shock in whom early goal-directed therapy was initiated in the emergency department. Design: Single-center cohort study. Setting: The emergency department of an academic tertiary care center from 2005 through 2006. Patients: Two hundred sixty-one patients undergoing early goal-directed therapy. Interventions: None. Measurements and Main Results: Effects of different time cutoffs from triage to antibiotic administration, qualification for early goal-directed therapy to antibiotic administration, triage to appropriate antibiotic administration, and qualification for early goal-directed therapy to appropriate antibiotic administration on in-hospital mortality were examined. The mean age of the 261 patients was 59 ± 16 yrs; 41% were female. In-hospital mortality was 31%. Median time from triage to antibiotics was 119 mins (interquartile range, 76-192 mins) and from qualification to antibiotics was 42 mins (interquartile range, 0-93 mins). There was no significant association between time from triage or time from qualification for early goal-directed therapy to antibiotics and mortality when assessed at different hourly cutoffs. When analyzed for time from triage to appropriate antibiotics, there was a significant association at the <1 hr (mortality 19.5 vs. 33.2%; odds ratio, 0.30 [95% confidence interval, 0.11-0.83]; p =.02) time cutoff; similarly, for time from qualification for early goal-directed therapy to appropriate antibiotics, a significant association was seen at the ≤1 hr (mortality 25.0 vs. 38.5%; odds ratio, 0.50 [95% confidence interval, 0.27-0.92]; p =.03) time cutoff. Conclusions: Elapsed times from triage and qualification for early goal-directed therapy to administration of appropriate antimicrobials are primary determinants of mortality in patients with severe sepsis and septic shock treated with early goal-directed therapy. © 2010 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins.


Judy B.F.,University of Pennsylvania | Aliperti L.A.,University of Pennsylvania | Predina J.D.,University of Pennsylvania | Levine D.,University of Pennsylvania | And 4 more authors.
Neoplasia | Year: 2012

Surgery is the most effective therapy for cancer in the United States, but disease still recurs in more than 40% of patients within 5 years after resection. Chemotherapy is given postoperatively to prevent relapses; however, this approach has had marginal success. After surgery, recurrent tumors depend on rapid neovascular proliferation to deliver nutrients and oxygen. Phosphatidylserine (PS) is exposed on the vascular endothelial cells in the tumor microenvironment but is notably absent on blood vessels in normal tissues. Thus, PS is an attractive target for cancer therapy after surgery. Syngeneic mice bearing TC1 lung cancer tumors were treated with mch1N11 (a novel mouse chimeric monoclonal antibody that targets PS), cisplatin (cis), or combination after surgery. Tumor relapses and disease progression were decreased 90% by combination therapy compared with a 50% response rate for cis alone (P =.02). Mice receiving postoperative mch1N11 had no wound-related complications or added systemic toxicity in comparison to control animals. Mechanistic studies demonstrated that the effects of mch1N11 were associated with a dense infiltration of inflammatory cells, particularly granulocytes. This strategy was independent of the adaptive immune system. Together, these data suggest that vascular-targeted strategies directed against exposed PS may be a powerful adjunct to postoperative chemotherapy in preventing relapses after cancer surgery. © 2012 Neoplasia Press, Inc. All rights reserved.


Abrams D.C.,Allergy and Critical Care | Brenner K.,Allergy and Critical Care | Burkart K.M.,Allergy and Critical Care | Agerstrand C.L.,Allergy and Critical Care | And 4 more authors.
Annals of the American Thoracic Society | Year: 2013

Rationale: Acute exacerbations of chronic obstructive pulmonary disease (COPD) requiring invasive mechanical ventilation (IMV) are associated with significant morbidity and mortality. Extracorporeal carbon dioxide removal (ECCO2R) may facilitate extubation and ambulation in these patients and potentially improve outcomes. Objectives:Weassessed the feasibility of achieving early extubation and ambulation in subjects requiring IMV for exacerbations of COPD using single-site ECCO2R. Methods: Five subjects with exacerbations of COPD with uncompensated hypercapnia requiring IMVwere enrolled in this singlecenter, prospective, feasibility trial using a protocol of ECCO2R, extubation, and physical rehabilitation. The primary endpoint was extubation within 72 hours of starting ECCO2R. Measurements and Main Results: Mean preintubation pH and PaCO2 were 7.23 ± 0.05 and 81.6 ±15.9 mm Hg, respectively. All subjects met the primary endpoint (median duration, 4 h; range, 1.5-21.5 h). Mean duration of extracorporeal support was 193. ±76.5 hours. Mean time to ambulation after extracorporeal initiation was 29.4 ± 12.6 hours. Mean maximal ambulation on extracorporeal support was 302 feet (range, 70-600). Four subjects were discharged home, and one underwent planned lung transplantation. Two minor bleeding complications occurred. There were no complications from mobilization on extracorporeal support.Conclusions: ECCO2R facilitates early extubation and ambulation in exacerbations of COPD requiring IMV and has the potential to serve as a new paradigm for the management of a select group of patients. Rigorous clinical trials are needed to corroborate these results and to investigate the effect on longterm outcomes and cost effectiveness over conventional management. © 2013 by the American Thoracic Society.


Rackley C.R.,Allergy and Critical Care | Stripp B.R.,Allergy and Critical Care | Stripp B.R.,Duke University
Journal of Clinical Investigation | Year: 2012

Airspaces of the lung are lined by an epithelium whose cellular composition changes along the proximal-to-distal axis to meet local functional needs for mucociliary clearance, hydration, host defense, and gas exchange. Advances in cell isolation, in vitro culture techniques, and genetic manipulation of animal models have increased our understanding of the development and maintenance of the pulmonary epithelium. This review discusses basic cellular mechanisms that regulate establishment of the conducting airway and gas exchange systems as well as the functional maintenance of the epithelium during postnatal life.


News Article | September 27, 2016
Site: www.rdmag.com

With the help of camera-guided endoscopes, clinicians get a look inside the body's cavities to diagnose and treat many different conditions. In the United States alone, up to 20 million endoscopies are performed on patients every year. But even for the most seasoned endoscope users, the instruments can prove very challenging to use effectively; this is due to the fact that blood and other bodily fluids quite commonly obscure the camera lens in the midst of critical procedures. This problem inspired a team led by Joanna Aizenberg, Amy Smith Berylson Professor of Materials Science and Professor of Chemistry & Chemical Biology at the Harvard John A. Paulson School of Engineering and Applied Sciences (SEAS) and Core Faculty member of the Wyss Institute for Biologically Inspired Engineering at Harvard University, to engineer a transparent surface coating for an endoscope lens that could effortlessly keep blood and other fluids at bay. The idea took roots in conversations Aizenberg had with clinician collaborators, who were quick to lament the propensity for endoscopes to become clouded mid-procedure. Turning to the portfolio of SLIPS (Slippery Liquid-Infused Porous Surfaces) technologies already invented by Aizenberg, they set out to design a specialized SLIPS coating that could prevent bodily fluids from blocking the optical field of view of camera-guided endoscopes. The demonstrated results of their work are published online this week in the Proceedings of the National Academy of Sciences (PNAS) journal. "Endoscopes are used by many physicians around the world for a variety of procedures, and ironically, the moment when bleeding occurs and the optical field is blocked is also precisely when physicians most need to see what's happening," said Aizenberg, who is also the Co-Director of the Kavli Institute for Bionano Science and Technology. Aizenberg's SLIPS technology creates non-wetting and robust self-cleaning surfaces that can resist almost any fouling challenge a surface may face. But to develop the technology for endoscopic use, the team needed to adapt SLIPS specifically to weather the harsh environment of a living body's cavities. "In addition to being entirely transparent and able to coat the curvature of the glass camera lens on the endoscope, the coating also needs to withstand constant contact and abrasion with soft tissues and corrosive bodily fluids," said Steffi Sunny, a co-first author on the study and a graduate student at SEAS and researcher at the Wyss. To achieve this, the team deposited silica nanoparticles layer by layer onto an endoscope's glass camera lens. These silica layers create a porous surface that, at the nanoscale, would be considered "rough" and filled with caverns. They then functionalized this "rough" surface and infused it with a medical-grade silicone oil, filling in the porous cavities and creating a self-replenishing liquid layer. The end result, an entirely biocompatible coating, can endure many procedural uses and standard sterilization protocols, and can be even re-applied with silicone oil intermittently to maintain its extreme repellency. Working with co-first author George Cheng the team tested their antifouling endoscope in vivo, specifically in bronchoscopy. Bronchoscopy is one of the most commonly performed procedures on patients with pathological lung conditions. Cheng, who was an Interventional Pulmonary Fellow at Harvard Combined Training Program (Beth Israel Deaconess Medical Center and Massachusetts General Hospital) at the time of the study, performed bronchoscopy with the modified endoscope on an anesthetized pig to evaluate its effectiveness. "The proof of concept experiment in the pig lung worked beautifully," said Cheng, who today is Assistant Professor of Medicine in the Division of Pulmonary, Allergy and Critical Care at Duke University. "It very easily repelled blood and mucus and dramatically reduced the complexity of the procedure." Conventional scopes generally cause the procedure time to be longer than necessary, due to the need to repeatedly clean and wipe away fluids that obscure the optical field. An antifouling endoscope could, one day, not only improve ease and precision of endoscopies, but could also result in more positive patient outcomes due to a shortened procedural time, significantly reduced side-effects often associated with mid-procedure lens cleaning, less sedation needed, and decreased recovery time. SLIPS-coated endoscopes could even expand our view into new areas of the body that we have not yet been able to access with a camera. Today's endoscopes, which contain irrigation and suction channels to flush away build up from the lens mid-procedure, are limited in how small they can be made due to this important cleansing feature. But the super repellent coating on the lens could potentially eliminate the need for a wash port, leading to more miniaturized endoscopes, which would allow physicians to reach, observe and treat the areas of the body that are off-limits to endoscopes of current sizes. Looking ahead, the team also hopes that their slippery lens coating could have applications in other camera-guided instruments that operate in harsh, contaminated environments and rely on an unobstructed optical field, such as oil exploration, robotics, marine exploration, plumbing and sanitation and drain pipe maintenance.

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