News Article | April 17, 2017
Steve Inskeep talks to VA Inspector General Michael Missal about an investigation into the D.C. Veterans Affairs Medical Center. It found serious issues regarding the handling of medical equipment.
News Article | April 18, 2017
"Our research team set out to determine whether phages can be effective at killing a large group of bacteria that have become resistant to antibiotics and cause deadly diseases in people," said corresponding author Dr. Anthony Maresso, associate professor of molecular virology and microbiology at Baylor. "We are running out of available options to treat patients who have these deadly bacterial infections; we need new ideas." When bacteria grow out of control, they can enter the blood stream and infect vital organs in the body. The body's immune system, an army of cells and molecules that fights back infections and other diseases, responds to the bacterial attack, defending the body from the infection. However, the immune response sometimes is excessive and can lead to tissue damage, organ failure and death, a process called sepsis. To end sepsis, bacterial growth has to stop. Antibiotic treatment usually can control bacterial growth and prevent the deadly consequences of sepsis, but increasing number of bacteria is becoming resistant to antibiotics. According to the National Institute of General Medical Sciences, sepsis affects more than 1 million people in the United States every year. About 50 percent of patients with sepsis die; this outnumbers the U.S. deaths caused by prostate cancer, breast cancer and AIDS combined. The number of sepsis cases per year is increasing, which underscores the need for new strategies to fight bacterial infections. In this study, the researchers investigated the possibility of recruiting phages in the fight against antibiotic-resistant bacteria, reviving the original idea of Felix d'Herelle, proposed in 1926. "The driving force behind this project was to find phages that would kill 12 strains of antibiotic-resistant bacteria that were isolated from patients," said co-author Dr. Robert Ramig, professor of molecular virology and microbiology at Baylor. "As the virologist on the team, my first contribution was to go phage hunting." "I have a number of phages in my lab, but none of them killed the antibiotic-resistant E. coli we were working on - the sequence type 131 currently pandemic across the globe," Ramig said. Birds and dogs often carry the bacteria the researchers were interested in, and may be one environmental reservoir of these pathogens. They also carry phages specific for those bacteria. Ramig, Maresso and Sabrina Green, a graduate student in the Molecular Virology Program at Baylor, went phage hunting in local parks and bird refuges to collect avian and canine feces. "We isolated a number of phages from animal feces," said Ramig. "No single phage would kill all the 12 bacterial strains, but collectively two or three of those phages would be able to kill all of those bacteria in cultures in the lab." This good news allowed the researchers to move on to the next step - determining whether the phages also would be able to kill the antibiotic-resistant bacteria in an animal model of sepsis. One of the animal models the researchers worked with mimics how cancer patients develop potentially life-threatening infections during their cancer treatment. "A number of cancer patients who undergo chemotherapy sometimes develop infections that come from bacteria that normally live in their own gut, usually without causing any symptoms," Green said. "Chemotherapy is intended to kill cancer cells, but one of the side effects is that it suppresses the immune system. A suppressed immune system is a major risk factor for infections with these bacteria, which sometimes also are multi-drug resistant." Working in Maresso's lab, Green developed a mouse model in which healthy mice received antibiotic-resistant bacteria that colonize their intestinal tract. "These mice showed no sign of disease," Maresso said. "But when the mice received chemotherapy," Green said, "the bacteria moved from their intestine to major organs - this led to a fatal sepsis-like infection." In this animal model in which the immune system cannot keep in check antibiotic-resistant bacteria, Green tested whether the phages were able to do so. "When the phages are delivered into the animals, their efficacy in reducing the levels of bacteria and improving health is dramatic," Maresso said. "But that is not what is truly remarkable," he continued. "What is remarkable is that these 'drugs' were discovered, isolated, identified and tested in a matter of weeks, and for less money than most of us probably spend in a month on groceries." Phages are very specific for certain species or strains of bacteria, but can be made broadly acting via cocktails, if desired. Thus, unlike antibiotics, using phages may not be associated with some of the side effects observed, such as clearing beneficial intestinal microbiota. They also don't infect human cells. Another advantage over antibiotics is that phages can evolve. Should resistance develop against one set of phages, new phages can be identified in the environment or evolved in the laboratory in a matter days. "On the other hand, an antibiotic is a chemical; it cannot change in real time," Maresso said. "It may take years to develop a new antibiotic and at costs that can run in the billions. But a phage can evolve to efficiently kill a resistant strain and then be propagated. It gives me great personal satisfaction when I think of the irony of this - the next anti-bacterial treatment may use the very same mechanisms bacteria have been using against us for 60-plus years now." Co-author Dr. Barbara Trautner, associate professor and director of clinical research in the Department of Surgery, associate professor of medicine at Baylor and also a researcher with Center for Innovations in Quality, Effectiveness and Safety at the Michael E. DeBakey Veterans Affairs Medical Center in Houston, and Ramig previously published a paper in which they showed that it is possible to take advantage of the phages' ability to change to fight bacterial infections. "In summary, we took four phages that specifically attacked bacteria of the group Pseudomonas, and they would kill four of 26 of these bacterial strains. Then, we evolved the phages in the lab, and in a month the new ones could kill 22 of the 26," Ramig said. "Envision the following possible future clinical scenario: a patient presents with antibiotic-resistant bacterial infection that is untreatable or only treatable with the most toxic of antibiotics. During the 48 hours it takes to identify the bacterial species and strain, physicians and scientists can go to a library of phages at hand, select those that are effective against this antibiotic-resistant bacterial strain and make a personalized cocktail of phages to treat the patient. Should resistance develop again, we will evolve another phage - right back at them!" Maresso said. "There are many ways to kill bacteria, but I know of no other way that has the potential to evolve in real time like phages do. And it's the best 'green' medicine - it's natural, safe thus far, relatively cheap and can be harnessed with the technical skills of a college biology major." Whereas the upside may be high, there is still some caution. "Phages are not infallible medicines," reflects Maresso. "The host's immune system sometimes can neutralize their activity and some phages just don't work well in animals. But we understand very little about any of these dynamics compared to those of other classes of drugs. At the very least, I think the evidence supports the notion that we should be giving phages some experimental attention." More information: Sabrina I. Green et al, Bacteriophages from ExPEC Reservoirs Kill Pandemic Multidrug-Resistant Strains of Clonal Group ST131 in Animal Models of Bacteremia, Scientific Reports (2017). DOI: 10.1038/srep46151
Niewoehner D.E.,Veterans Affairs Medical Center
New England Journal of Medicine | Year: 2010
A 67-year-old man presents with a history of dyspnea, which has progressed for the past several years. He began smoking cigarettes at 15 years of age and continues to smoke one pack per day. Worsening breathlessness forced him to retire as a laborer, and he has sought emergency care for what he calls bronchitis twice in the past year. His physical examination is notable for diminished breath sounds on auscultation, with a prolonged expiratory phase. Spirometry reveals severe airflow obstruction (ratio of forced expiratory volume in 1 second [FEV1] to forced vital capacity [FVC], 0.43; FEV 1, 34% of the predicted value). How should this case be managed? Copyright © 2010 Massachusetts Medical Society.
Lanska D.J.,Veterans Affairs Medical Center
Neurology | Year: 2013
Objective: To analyze the contributions of American photographer Eadweard Muybridge (1830-1904) and Philadelphia neurologist Francis Dercum (1856-1931) toward creating the first motion-picture sequences of patients with neurologic disorders. Background: In the late 1870s and 1880s, prior to the development of movie cameras or projectors, Muybridge photographed sequential images of people and animals in motion, using arrays of sequentially triggered single-image cameras and multilens cameras. Methods: Examination of published writings and photographic sequences by Muybridge and Dercum, and primary source documents, including letters from Dercum. Results: In 1885, Philadelphia neurologist Francis Dercum (1856-1931) collaborated with Muybridge at the University of Pennsylvania to photograph sequential images of patients with various neurologic disorders involving abnormal movements. Subjects were recruited from the neurology services of the University Hospital and the Philadelphia Hospital. Muybridge and Dercum photographed patients with tabes dorsalis, hemiparesis, paraparesis, athetotic cerebral palsy, lead encephalopathy, congenital hydrocephalus with diparesis, poliomyelitis, pseudoseizures, psychogenic movement disorder, and other conditions. Conclusions: These are the first motion-picture sequences of neurologic disorders ever filmed, and provide an important visual archive and teaching resource for neurologic disorders that were prevalent in the late 19th century. © 2013 American Academy of Neurology.
Lederle F.A.,Veterans Affairs Medical Center
New England Journal of Medicine | Year: 2012
BACKGROUND: Whether elective endovascular repair of abdominal aortic aneurysm reduces long-term morbidity and mortality, as compared with traditional open repair, remains uncertain. METHODS: We randomly assigned 881 patients with asymptomatic abdominal aortic aneurysms who were candidates for both procedures to either endovascular repair (444) or open repair (437) and followed them for up to 9 years (mean, 5.2). Patients were selected from 42 Veterans Affairs medical centers and were 49 years of age or older at the time of registration. RESULTS: More than 95% of the patients underwent the assigned repair. For the primary outcome of all-cause mortality, 146 deaths occurred in each group (hazard ratio with endovascular repair versus open repair, 0.97; 95% confidence interval [CI], 0.77 to 1.22; P = 0.81). The previously reported reduction in perioperative mortality with endovascular repair was sustained at 2 years (hazard ratio, 0.63; 95% CI, 0.40 to 0.98; P = 0.04) and at 3 years (hazard ratio, 0.72; 95% CI, 0.51 to 1.00; P = 0.05) but not thereafter. There were 10 aneurysm-related deaths in the endovascular-repair group (2.3%) versus 16 in the open-repair group (3.7%) (P = 0.22). Six aneurysm ruptures were confirmed in the endovascular-repair group versus none in the open-repair group (P = 0.03). A significant interaction was observed between age and type of treatment (P = 0.006); survival was increased among patients under 70 years of age in the endovascular-repair group but tended to be better among those 70 years of age or older in the open-repair group. CONCLUSIONS: Endovascular repair and open repair resulted in similar long-term survival. The perioperative survival advantage with endovascular repair was sustained for several years, but rupture after repair remained a concern. Endovascular repair led to increased long-term survival among younger patients but not among older patients, for whom a greater benefit from the endovascular approach had been expected. (Funded by the Department of Veterans Affairs Office of Research and Development; OVER ClinicalTrials.gov number, NCT00094575). Copyright © 2012 Massachusetts Medical Society.
Lederle F.A.,Veterans Affairs Medical Center
European Journal of Vascular and Endovascular Surgery | Year: 2012
In a 1997 report of a large abdominal aortic aneurysm (AAA) screening study, we observed a negative association between diabetes and AAA. Although this was not previously described and negative associations between diseases are rare, the credibility of the finding was supported by consistent results in several previous studies and by the absence of an obvious artifactual explanation. Since that time, a variety of studies of AAA diagnosis, both by screening and prospective clinical follow-up, have confirmed the finding. Other studies have reported slower aneurysm enlargement and fewer repairs for rupture in diabetics. The seeming protective effect of diabetes for AAA contrasts with its causal role in occlusive vascular disease and so provides a strong challenge to the traditional view of AAA as a manifestation of atherosclerosis. Research focused on a protective effect of diabetes has already increased our understanding of the etiology of AAA, and might eventually pave the way for new therapies to slow AAA progression. © 2011 European Society for Vascular Surgery. Published by Elsevier Ltd. All rights reserved.
Carabello B.A.,Veterans Affairs Medical Center
Circulation Research | Year: 2013
Aortic stenosis is perhaps the most common of all valvular heart diseases in the developed nations of the world. Once primarily caused by rheumatic fever, the most common pathogenesis today is an active inflammatory process with some features that are similar to atherosclerosis. Because of this shift, the age at onset of severe obstruction has changed from the sixth decade 50 years ago to the eighth decade in most individuals today. The onset of symptoms remains a key determinant of outcome, although the later age at onset may make it difficult to discern if aortic stenosis or other age-related comorbidities is the cause of the symptoms. Once symptoms of aortic stenosis develop, life expectancy is shortened to ≈3 years unless the mechanical obstruction to left ventricular outflow is relieved by aortic valve replacement. Traditionally performed during cardiac surgery, aortic valve replacement now may be performed safely and effectively using transcatheter techniques, potentially revolutionizing the approach to this potentially fatal disease. © 2013 American Heart Association, Inc.
Unemo M.,Örebro University |
Shafer W.M.,Emory University |
Shafer W.M.,Veterans Affairs Medical Center
Clinical Microbiology Reviews | Year: 2014
Neisseria gonorrhoeae is evolving into a superbug with resistance to previously and currently recommended antimicrobials for treatment of gonorrhea, which is a major public health concern globally. Given the global nature of gonorrhea, the high rate of usage of antimicrobials, suboptimal control and monitoring of antimicrobial resistance (AMR) and treatment failures, slow update of treatment guidelines in most geographical settings, and the extraordinary capacity of the gonococci to develop and retain AMR, it is likely that the global problem of gonococcal AMR will worsen in the foreseeable future and that the severe complications of gonorrhea will emerge as a silent epidemic. By understanding the evolution, emergence, and spread of AMR in N. gonorrhoeae, including its molecular and phenotypic mechanisms, resistance to antimicrobials used clinically can be anticipated, future methods for genetic testing for AMR might permit region-specific and tailor- made antimicrobial therapy, and the design of novel antimicrobials to circumvent the resistance problems can be undertaken more rationally. This review focuses on the history and evolution of gonorrhea treatment regimens and emerging resistance to them, on genetic and phenotypic determinants of gonococcal resistance to previously and currently recommended antimicrobials, including biological costs or benefits; and on crucial actions and future advances necessary to detect and treat resistant gonococcal strains and, ultimately, retain gonorrhea as a treatable infection. © 2014, American Society for Microbiology. All Rights Reserved.
Samuel V.T.,Yale University |
Samuel V.T.,Veterans Affairs Medical Center |
Shulman G.I.,Yale University |
Shulman G.I.,Howard Hughes Medical Institute
Cell | Year: 2012
Insulin resistance is a complex metabolic disorder that defies explanation by a single etiological pathway. Accumulation of ectopic lipid metabolites, activation of the unfolded protein response (UPR) pathway, and innate immune pathways have all been implicated in the pathogenesis of insulin resistance. However, these pathways are also closely linked to changes in fatty acid uptake, lipogenesis, and energy expenditure that can impact ectopic lipid deposition. Ultimately, these cellular changes may converge to promote the accumulation of specific lipid metabolites (diacylglycerols and/or ceramides) in liver and skeletal muscle, a common final pathway leading to impaired insulin signaling and insulin resistance. © 2012 Elsevier Inc.
Robey R.B.,Veterans Affairs Medical Center
Kidney International | Year: 2014
Severe cyclical dehydration induces chronic renal injury in rodents. This effect is attenuated by global fructokinase deficiency, suggesting possible roles for fructokinase and fructose metabolism in mediating or promoting dehydration-induced injury. Clinical and pathological similarities between this injury model and endemic Mesoamerican nephropathy (MeN) have fueled speculation that dehydration-induced injury and MeN may share common mechanistic underpinnings involving fructokinase that can be targeted to mitigate disease development, progression, and/or severity. © 2014 International Society of Nephrology.