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OBJECTIVES:: Both oxygenation and peak inspiratory pressure are associated with mortality in pediatric acute respiratory distress syndrome. Since oxygenation and respiratory mechanics are linked, it is difficult to identify which variables, pressure or oxygenation, are independently associated with outcome. We aimed to determine whether respiratory mechanics (peak inspiratory pressure, positive end-expiratory pressure, ΔP [PIP minus PEEP], tidal volume, dynamic compliance [Cdyn]) or oxygenation (PaO2/FIO2) was associated with mortality. DESIGN:: Prospective, observational, cohort study. SETTING:: University affiliated PICU. PATIENTS:: Mechanically ventilated children with acute respiratory distress syndrome (Berlin). INTERVENTIONS:: None. MEASUREMENTS AND MAIN RESULTS:: Peak inspiratory pressure, positive end-expiratory pressure, ΔP, tidal volume, Cdyn, and PaO2/FIO2 were collected at acute respiratory distress syndrome onset and at 24 hours in 352 children between 2011 and 2016. At acute respiratory distress syndrome onset, neither mechanical variables nor PaO2/FIO2 were associated with mortality. At 24 hours, peak inspiratory pressure, positive end-expiratory pressure, ΔP were higher, and Cdyn and PaO2/FIO2 lower, in nonsurvivors. In multivariable logistic regression, PaO2/FIO2 at 24 hours and ΔPaO2/FIO2 (change in PaO2/FIO2 over the first 24 hr) were associated with mortality, whereas pressure variables were not. Both oxygenation and pressure variables were associated with duration of ventilation in multivariable competing risk regression. CONCLUSIONS:: Improvements in oxygenation, but not in respiratory mechanics, were associated with lower mortality in pediatric acute respiratory distress syndrome. Future trials of mechanical ventilation in children should focus on oxygenation (higher PaO2/FIO2) rather than lower peak inspiratory pressure or ΔP, as oxygenation was more consistently associated with outcome. Copyright © by 2017 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.


Multicenter study shows AF ablation is safe and just as effective in patients with CHD compared to those with normal hearts PHILADELPHIA--Congenital heart disease (CHD) includes a range of defects that occur in the heart which patients are born with, such as a hole in the heart's wall, a leaky valve or even an inversion in the heart's orientation. CHD was once a severe condition often resulting in early death, but now, more and more CHD patients are living long and healthy lives. Therefore, as this population grows, so does the number of patients who are treated for other complications of their disease, such as early onset atrial fibrillation (AF), a quivering or irregular heartbeat that can lead to blood clots, stroke, heart failure and other complications. AF is often treated with a catheter ablation, a minimally invasive procedure in which the areas of the heart causing the irregularity are cauterized, but until now, there was limited data to support the safety and efficacy of treating CHD patients with an AF ablation. In a new study presented today at the Heart Rhythm Society's 38th Annual Scientific Session in Chicago, researchers from the Perelman School of Medicine at the University of Pennsylvania have found that CHD patients--even with complex defects--can safely undergo ablation for AF, with similar success rates as patients with normal hearts. "Treatment for atrial fibrillation is critical, whether the patient has a normal heart or whether they have complex congenital heart disease," said the study's presenter Jackson J. Liang, DO, a third-year cardiovascular disease fellow in the Perelman School of Medicine at the University of Pennsylvania. "In fact, atrial fibrillation can be especially detrimental in patients with complex congenital heart disease since they may be more reliant on the "atrial kick" provided during sinus rhythm. Unfortunately for some CHD patients, AF ablation may be more challenging due to the presence of complex anatomy, and the optimal ablation strategy for these patients remains to be defined." In this multicenter study, researchers performed a retrospective analysis of 69 CHD patients who underwent AF ablation, by collecting data from Penn, University of Colorado, University of California San Francisco, and Texas Cardiac Arrhythmia Institute at St. David's Medical Center. Researchers looked at those who underwent AF ablation for paroxysmal (intermittent) or persistent AF between 2008 and 2016. They identified the type of CHD, and tracked the ablation strategy - pulmonary vein isolation (PVI), PVI with additional ablation, or non-PV ablation only. "Some physicians may not be aware that catheter ablation can be performed to treat atrial fibrillation in patients with congenital heart disease, and instead they may prescribe anti-arrhythmic medications," said David Frankel, MD, an assistant professor of Cardiovascular Medicine at Penn. "We hope this study will increase awareness of catheter ablation as a viable treatment option for atrial fibrillation in these patients." Of the 69 patients, 34 had paroxysmal AF and 25 had complex CHD. The team defined complete success as freedom from recurrent AF for one year off antiarrhythmic medications, and partial success as freedom from AF recurrences for one year on previously ineffective anti-arrhythmic medications. At one year, researchers concluded that 53 percent of the patients had complete success with an additional 13 percent experiencing partial success. 92 percent of patients underwent a PVI approach, while seven percent had a non-PVI ablation alone. "We also found that 12 patients needed a repeat ablation within the first year, but most notably, there were no major procedural complications identified and only five minor complications, which is on par with rates in non-CHD patients," said Liang. "While PVI should remain the cornerstone of ablation, an individualized approach utilizing pre-procedural imaging to help to define the anatomy is necessary to improve outcomes in patients with CHD." Researchers conclude that AF ablation in this complex population was safe and effective, with similar outcomes to those seen in non-CHD patients, despite anatomical differences. However, they noted that more research is needed to further define the challenges and optimal ablation strategies in CHD patients. Penn Medicine is one of the world's leading academic medical centers, dedicated to the related missions of medical education, biomedical research, and excellence in patient care. Penn Medicine consists of the Raymond and Ruth Perelman School of Medicine at the University of Pennsylvania (founded in 1765 as the nation's first medical school) and the University of Pennsylvania Health System, which together form a $6.7 billion enterprise. The Perelman School of Medicine has been ranked among the top five medical schools in the United States for the past 20 years, according to U.S. News & World Report's survey of research-oriented medical schools. The School is consistently among the nation's top recipients of funding from the National Institutes of Health, with $392 million awarded in the 2016 fiscal year. The University of Pennsylvania Health System's patient care facilities include: The Hospital of the University of Pennsylvania and Penn Presbyterian Medical Center -- which are recognized as one of the nation's top "Honor Roll" hospitals by U.S. News & World Report -- Chester County Hospital; Lancaster General Health; Penn Wissahickon Hospice; and Pennsylvania Hospital -- the nation's first hospital, founded in 1751. Additional affiliated inpatient care facilities and services throughout the Philadelphia region include Good Shepherd Penn Partners, a partnership between Good Shepherd Rehabilitation Network and Penn Medicine. Penn Medicine is committed to improving lives and health through a variety of community-based programs and activities. In fiscal year 2016, Penn Medicine provided $393 million to benefit our community.


News Article | May 10, 2017
Site: www.eurekalert.org

PHILADELPHIA - Studies have shown that loss of the sense of smell can be among the first warning signs of diseases such as Alzheimer's and Parkinson's. Now a researcher at the Perelman School of Medicine at the University of Pennsylvania wants to shift the search for clues about this process back even further, to find out if there is a common factor responsible for the loss of smell that may also serve as an early warning signal for a number of neurodegenerative diseases. In a review published online in Lancet Neurology, Richard L. Doty, PhD, a professor of Otorhinolaryngology and director of the Smell and Taste Center, cites evidence that the common link could be damage to neurotransmitter and neuromodulator receptors in the forebrain - the front part of the brain. "We need to retrace the steps of the development of these diseases," Doty said. "We know loss of smell is an early sign of their onset, so finding common factors associated with the smell loss could provide clues as to the pre-existing processes that initiate the first stages of a number of neurodegenerative diseases. An understanding of such processes could provide novel approaches to their treatment, including ways to slow down or stop their development before irreversible damage has occurred." Currently, it's is generally believed that the smell loss of various neurodegenerative diseases is caused by disease-specific pathology. In other words, different diseases can bring about the same loss of smell for different reasons. Doty's review - the first of its kind - looked at many neurodegenerative diseases with varying degrees of smell loss and sought to find a common link that may explain such losses. He considered physiological factors as well as environmental factors like air pollution, viruses, and exposure to pesticides. "Ultimately, as each possibility was evaluated, there were cases where these factors didn't show up, which ruled them out as potential universal biomarkers." Doty did find compelling evidence for a neurological solution: Damage to the neurotransmitter and neuromodulator receptors in the forebrain - most notably, a system employing the neurochemical acetylcholine. Neurotransmitters are the chemicals that send signals throughout the brain. Neuromodulators influence the activity of neurons in the brain. The receptors receive the signals, and if they are damaged, it hurts the brain's ability to process smells normally. "The good news is we can assess damage to some of the systems by evaluating their function in living humans using radioactive neurochemicals and brain imaging processes such as positron emission tomography (PET)," Doty said. "Unfortunately, few data are currently available, and the historical data of damage to neurotransmitter/neuromodulator systems, including cell counts from autopsy studies, are limited to just a few diseases. Moreover, quantitative data on a patient's olfactory status is rarely available, especially prior to disease diagnosis." Doty said the lack of early data is a problem across the board in the search for factors that may explain smell loss. "Smell testing isn't part of a standard check-up, and people don't recognize a smell problem themselves until it's already severe," Doty said. "Research now starting in Japan will be testing thousands of people over the course of the next few years that will better define associations between changes in smell and a wide variety of physiological measures in older populations." "If a universal factor does exist, the benefits for patients would be obvious," Doty said. "Damage to the neurotransmitter and neuromodulator receptors shows promise as one possibility, but we need more research in this area to truly answer the question. It could be the key to unlocking better understanding of neurological disease." Editor's Note: Doty receives funding from the Michael J. Fox Foundation for Parkinson's Research. He is a consultant to Acorda Therapeutics, Eisai Co., Ltd., and Johnson & Johnson. He is president of and major shareholder in Sensonics International, which manufactures and distributes smell and taste tests. Penn Medicine is one of the world's leading academic medical centers, dedicated to the related missions of medical education, biomedical research, and excellence in patient care. Penn Medicine consists of the Raymond and Ruth Perelman School of Medicine at the University of Pennsylvania (founded in 1765 as the nation's first medical school) and the University of Pennsylvania Health System, which together form a $6.7 billion enterprise. The Perelman School of Medicine has been ranked among the top five medical schools in the United States for the past 20 years, according to U.S. News & World Report's survey of research-oriented medical schools. The School is consistently among the nation's top recipients of funding from the National Institutes of Health, with $392 million awarded in the 2016 fiscal year. The University of Pennsylvania Health System's patient care facilities include: The Hospital of the University of Pennsylvania and Penn Presbyterian Medical Center -- which are recognized as one of the nation's top "Honor Roll" hospitals by U.S. News & World Report -- Chester County Hospital; Lancaster General Health; Penn Wissahickon Hospice; and Pennsylvania Hospital -- the nation's first hospital, founded in 1751. Additional affiliated inpatient care facilities and services throughout the Philadelphia region include Good Shepherd Penn Partners, a partnership between Good Shepherd Rehabilitation Network and Penn Medicine. Penn Medicine is committed to improving lives and health through a variety of community-based programs and activities. In fiscal year 2016, Penn Medicine provided $393 million to benefit our community.


News Article | May 10, 2017
Site: www.eurekalert.org

PHILADELPHIA - Bacteria in the gut microbiome drive the formation of cerebral cavernous malformations (CCMs), clusters of dilated, thin-walled blood vessels in the brain that can cause stroke and seizures, according to new research published this week in Nature by researchers from the Perelman School of Medicine at the University of Pennsylvania. Led by Mark Kahn, MD, a professor of Cardiovascular Medicine, the team's research suggests that altering the microbiome in CCM patients may be an effective therapy for this cerebrovascular disease. CCM disease, which occurs in about one in 100 to 200 people, can present in two forms. One is sporadic, accounting for 80 percent of cases, and is most frequent in older individuals. The remaining 20 percent are familial, inherited cases. In 2016, the Kahn lab discovered the molecular mechanism in endothelial cells that underlies the formation of CCMs. In the current Nature study, the team discovered that this molecular pathway is activated by TLR4, a receptor for the bacterial molecule lipopolysaccharide (LPS). Activation of TLR4 on brain endothelial cells by LPS vastly accelerated CCM formation. Conversely, if TLR4 was removed from endothelial cells genetically, or if the mice were treated with drugs that block TLR4 function, CCM formation is prevented. Since TLR4 primarily responds to LPS from Gram-negative bacteria, Alan Tang, an MD-PhD student in the Kahn lab, proposed that bacteria from the animal's gut microbiome may drive CCM formation. To test this theory, he examined CCM formation in mice that were housed under germ-free conditions (in collaboration with the Children's Hospital of Philadelphia through the PennCHOP Microbiome Program Core Facility) or treated with antibiotics to reduce the number of bacteria living in the gut. In both cases, CCM formation was dramatically reduced, demonstrating a key role for bacteria in the pathology of CCM disease. The team next sought evidence that bacterial LPS-TLR4 signaling might also support CCM formation in human patients. They worked with researchers at the University of New Mexico (UNM) and the University of California, San Francisco (UCSF) who have studied several hundred patients who carry an identical mutation in one CCM gene but display a widely variable disease course. "Some of these patients experience severe stroke by the age of two and others have no symptoms over their lifetime," Kahn said. "What makes the disease outcome so variable?" Working with the team from UNM and UCSF, they discovered that genetic variations that raise the amount of TLR4 that is produced are associated with higher numbers of CCM lesions, suggesting that the key role for LPS-TLR4 signaling identified in mice is also present in humans. These studies identify an unexpected, direct link between the microbiome and a common cerebrovascular disease. "This suggests that treatments designed to block TLR4 signaling or alter the microbiome may be used to treat this disease," Kahn said. These studies were in part supported by the National Institutes of Health (R01HL094326, P01NS092521) and a PennCHOP Microbiome Program Pilot & Feasibility Award Grant. Penn Medicine is one of the world's leading academic medical centers, dedicated to the related missions of medical education, biomedical research, and excellence in patient care. Penn Medicine consists of the Raymond and Ruth Perelman School of Medicine at the University of Pennsylvania (founded in 1765 as the nation's first medical school) and the University of Pennsylvania Health System, which together form a $6.7 billion enterprise. The Perelman School of Medicine has been ranked among the top five medical schools in the United States for the past 20 years, according to U.S. News & World Report's survey of research-oriented medical schools. The School is consistently among the nation's top recipients of funding from the National Institutes of Health, with $392 million awarded in the 2016 fiscal year. The University of Pennsylvania Health System's patient care facilities include: The Hospital of the University of Pennsylvania and Penn Presbyterian Medical Center -- which are recognized as one of the nation's top "Honor Roll" hospitals by U.S. News & World Report -- Chester County Hospital; Lancaster General Health; Penn Wissahickon Hospice; and Pennsylvania Hospital -- the nation's first hospital, founded in 1751. Additional affiliated inpatient care facilities and services throughout the Philadelphia region include Good Shepherd Penn Partners, a partnership between Good Shepherd Rehabilitation Network and Penn Medicine. Penn Medicine is committed to improving lives and health through a variety of community-based programs and activities. In fiscal year 2016, Penn Medicine provided $393 million to benefit our community.


News Article | May 11, 2017
Site: www.techrepublic.com

Shiny new smartphones may cause gadget envy, but when it comes to real work you still need a dependable PC. PCs have a tough few years: sales have hit the skids as consumers and businesses have been tempted away by smartphones and tablets. But this year the PC has been making a bit of a comeback, especially the tablet-cum-notebook hybrids such as the Lenovo Yoga range and Microsoft's Surface. And when it comes to business the PC remains the workhouse of choice, according to TechRepublic's exclusive CIO Jury of tech decision makers. When asked: "Is the smartphone now a more important business tool that the PC?" members voted no by a margin on ten to two, showing that while smartphones may be making headlines, the PC remains the enterprise workhorse - at least for now. "Do you want to try and assemble a sixty page monthly board of directors report on a smartphone?" asked John Gracyalny, VP of IT at SafeAmerica Credit Union, adding that while smartphones have a role to play, without a much more comfortable and efficient user interface "better speech recognition? Direct brain plug in?" it will be limited. Tim Stiles, CIO at the Bremerton Housing Authority, made a similar point: "Our particular business will rely on the PC long into the future. Smartphones augment, however [they] will not replace the PC anytime soon for us." Shawn Beighle, CIO at the International Republican Institute, said that while the ability to work on the go is incredibly helpful "whether it be a desktop, laptop, tablet, virtual reality or holographic device, at some point people are going to want to sit down and crank out research papers, contracts, proposals and the like, to which having a full sized keyboard and large monitors is still preferable," while David Wilson, IT manager at VectorCSP, said "the PC is where the work and deliverables are created". Derrick Wood, CIO at Wood Group, saw the device split slightly differently, with smartphones and tablets on one side, and traditional PCs on the other. He said PCs would decline in importance over the next two years "as we leverage VDI technologies, agnostic to the end device". But he added: "One definite is we will not go through another mass PC upgrade project dictated by an operating system upgrade (Windows 7 to Windows 10)." While few CIOs would rank the smartphone as more important than the notebook, a number saw it being more important - alongside tablets - over the next few years. Matt Mielke, director of IT at Innovations Federal Credit Union, felt that while the smartphone has been a welcome supplementary device "the core of our business still utilizes PCs". But he added: "Going forward, I can see this strategy slowly evolving to tablets and smartphones." Mike McGavock, CIO of NeoHealth, said that though the PC still has its place, nearly everything you can do on a PC can be done on a smartphone: "The ability to have everything at your fingertips in or out of the office is why I say the smartphone is more important to the average user than the PC." And Keith Golden, CIO, Econolite Group, said the two different devices are now equally important, with the smartphone "coming on strong", adding "I'd guess in a year or two the smartphone will clearly be more important, with the PC increasing relegated to comparatively small 'niche' roles", while others also saw more of a place for tablets and smartphones further in the future. Brian Wells, associate CIO at Penn Medicine, said the smartphone might not be the most important device but is still a necessary accessory for almost all workers. "In healthcare nurses and doctors are very mobile within the hospital facility and need constant access to the electronic medical record to maintain the continuity of care for our patients." Want to be part of TechRepublic's CIO Jury and have your say on the hot issues for IT decision-makers? If you are a CIO, CTO, IT director or equivalent at a large or small company, working in the private sector or in government, and you want to join TechRepublic's CIO Jury pool, or you know an IT chief who should, then get in contact. Either click the Contact link below or email me, steve dot ranger at techrepublic dot com, and send your name, title, company, location, and email address.


News Article | May 29, 2017
Site: www.sciencedaily.com

For years, the common narrative in human developmental neuroimaging has been that gray matter in the brain -- the tissue found in regions of the brain responsible for muscle control, sensory perception such as seeing and hearing, memory, emotions, speech, decision making, and self-control -- declines in adolescence, a finding derived mainly from studies of gray matter volume and cortical thickness (the thickness of the outer layers of brain that contain gray matter). Since it has been well-established that larger brain volume is associated with better cognitive performance, it was puzzling that cognitive performance shows a dramatic improvement from childhood to young adulthood at the same time that brain volume and cortical thickness decline. A new study published by Penn Medicine researchers this month and featured on the cover of the Journal of Neuroscience may help resolve this puzzle, revealing that while volume indeed decreases from childhood to young adulthood, gray matter density actually increases. Their findings also show that while females have lower brain volume, proportionate to their smaller size, they have higher gray matter density than males, which could explain why their cognitive performance is comparable despite having lower brain volume. Thus, while adolescents lose brain volume, and females have lower brain volume than males, this is compensated for by increased density of gray matter. "It is quite rare for a single study to solve a paradox that has been lingering in a field for decades, let alone two paradoxes, as was done by Gennatas in his analysis of data from this large-scale study of a whole cohort of youths," said Ruben Gur. "We now have a richer, fuller concept of what happens during brain development and now better understand the complementary unfolding processes in the brain that describe what happens." The study was led by Ruben Gur, PhD, professor of Psychiatry, Neurology, and Radiology in the Perelman School of Medicine at the University of Pennsylvania, Raquel Gur, MD, PhD, a professor of Psychiatry, Neurology, and Radiology, and Efstathios Gennatas, MBBS, a doctoral student of neuroscience working in the Brain Behavior Laboratory at Penn. According to Gur, the study findings may better explain the extent and intensity of changes in mental life and behavior that occur during the transition from childhood to young adulthood. "If we are puzzled by the behavior of adolescents, it may help to know that they need to adjust to a brain that is changing in its size and composition at the same time that demands on performance and acceptable behavior keep scaling up," Gur added. In the study, the researchers evaluated 1,189 youth between the ages of 8 and 23 who completed magnetic resonance imaging as part of the Philadelphia Neurodevelopmental Cohort, a community-based study of brain development that includes rich neuroimaging and cognitive data, to look at age-related effects on multiple measures of regional gray matter, including gray matter volume, gray matter density, and cortical thickness. Neuroimaging allowed the researchers to derive several measures of human brain structure in a noninvasive way. Observing such measures during development allowed the researchers to study the brain at different ages to characterize how a child's brain differs from an adult's. "This novel characterization of brain development may help us better understand the relationship between brain structure and cognitive performance," Gennatas said. "Our findings also emphasize the need to examine several measures of brain structure at the same time. Volume and cortical thickness have received the most attention in developmental studies in the past, but gray matter density may be as important for understanding how improved performance relates to brain development." Further study is required to fully characterize the biological underpinnings of different MRI-derived measures by combining neuroimaging and brain histology. The study's findings in healthy people can also help researchers understand the effects of brain disorders in males and females as they evolve during adolescence.


News Article | June 26, 2017
Site: www.eurekalert.org

PHILADELPHIA -- Social isolation has been linked to a wide range of health problems, as well as a shorter lifespan in humans and other animals. In fact, during a U.S. Senate hearing on aging issues this spring, a representative for the Gerontological Society of America urged lawmakers to support programs that help older adults stay connected to their communities, stating that social isolation is a "silent killer that places people at higher risk for a variety of poor health outcomes." Now, researchers at the Perelman School of Medicine at the University of Pennsylvania have found a possible explanation for this association. The team observed that in the fruit fly Drosophila melanogaster, social isolation leads to sleep loss, which in turn leads to cellular stress and the activation of a defense mechanism called the unfolded protein response (UPR). Their findings are published online in the journal SLEEP this month. The UPR is found in virtually all animal species. Although its short-term activation helps protect cells from stress, chronic activation can harm cells. Long-term, harmful activation of the UPR is suspected as a contributor to the aging process and to specific age-related diseases such as Alzheimer's and diabetes. Studies also have shown that social isolation is a growing problem in developed countries. In the United States, for example, about half of people older than 85 live alone, and decreased mobility or ability to drive may cut opportunities for other socialization. "A lot of elderly people live alone, and so we suspect that stresses from the combination of aging and social isolation creates a double-whammy at the cellular and molecular level," said senior author Nirinjini Naidoo, PhD, a research associate professor of Sleep Medicine. "If you have an age-related disruption of the UPR response, compounded by sleep disturbances, and then you add social isolation, that may be a very unhealthy cocktail." This line of research stemmed from a surprise finding by the new study's first author, Marishka K. Brown, PhD, who was then a postdoctoral researcher at Penn. She is now Program Director of the National Center on Sleep Disorders Research at the National Heart, Lung, and Blood Institute (NHLBI). While evaluating the effects of aging on the UPR in fruit flies, she noticed that molecular markers of UPR activation were at higher levels in flies kept singly in vials, compared to same-aged flies kept in groups. "Ultimately, she realized that keeping animals isolated induces a cellular stress response and a higher level of UPR activation," Naidoo said. Markers of UPR activation include the protein BiP, a molecular "chaperone" that helps ensure proper protein folding within cells. Proteins, after being synthesized as simple chains of amino acids, are meant to fold into functional shapes, which are often highly complex. This delicate process is easily disturbed when cells are under stress and can lead to the harmful, runaway clumping of unfolded or misfolded proteins. As its name suggests, the UPR is supposed to protect against this cellular catastrophe. But when it fails to work efficiently to restore proper protein-folding conditions, and stays activated, it can trigger harmful inflammation, suppress normal, healthy cellular activity, and ultimately force the death of the cell. Scientists have found evidence that this inefficient, chronic response becomes more likely with aging. "When animals get older, you start to see a more maladaptive UPR," Naidoo said. Why does social isolation trigger the UPR? Naidoo and others have shown in prior studies that sleep loss induces the UPR in multiple animal species. Other studies have shown that social isolation induces sleep loss, again in multiple species, including humans. When Brown forced the isolated flies to sleep more, for example by giving them the sleep drug Ambien (zolpidem), their levels of UPR markers dropped to those seen in grouped flies. Conversely, when she caused sleep loss in otherwise healthy grouped flies, their levels of UPR markers rose towards the levels seen in socially isolated flies. "When you keep animals isolated, it basically induces a disturbance of sleep, which then gives rise to a cellular stress that in turn triggers the UPR," Naidoo said. Naidoo and her colleagues are continuing to study the connections among aging, sleep loss, the UPR, and age-related diseases such as Alzheimer's. "Aging itself seems to make the UPR more defective, but we suspect this is worsened by the fact that aging also tends to cause more fragmented sleep," Naidoo said. The other co-author of the study was Ewa Strus, also from Penn. Support was provided by the NHLBI (T32 HL07713) and the National Institute on Aging (P01 AG17628). Penn Medicine is one of the world's leading academic medical centers, dedicated to the related missions of medical education, biomedical research, and excellence in patient care. Penn Medicine consists of the Raymond and Ruth Perelman School of Medicine at the University of Pennsylvania (founded in 1765 as the nation's first medical school) and the University of Pennsylvania Health System, which together form a $6.7 billion enterprise. The Perelman School of Medicine has been ranked among the top five medical schools in the United States for the past 20 years, according to U.S. News & World Report's survey of research-oriented medical schools. The School is consistently among the nation's top recipients of funding from the National Institutes of Health, with $392 million awarded in the 2016 fiscal year. The University of Pennsylvania Health System's patient care facilities include: The Hospital of the University of Pennsylvania and Penn Presbyterian Medical Center -- which are recognized as one of the nation's top "Honor Roll" hospitals by U.S. News & World Report -- Chester County Hospital; Lancaster General Health; Penn Wissahickon Hospice; and Pennsylvania Hospital -- the nation's first hospital, founded in 1751. Additional affiliated inpatient care facilities and services throughout the Philadelphia region include Good Shepherd Penn Partners, a partnership between Good Shepherd Rehabilitation Network and Penn Medicine. Penn Medicine is committed to improving lives and health through a variety of community-based programs and activities. In fiscal year 2016, Penn Medicine provided $393 million to benefit our community.


PHILADELPHIA - A research group in the division of Gastroenterology in the Perelman School of Medicine at the University of Pennsylvania has received a National Cancer Institute grant to extend a Barrett's Esophagus translational research network with Columbia University and the Mayo Clinic until 2022. The total award is $6.5 million for all three sites. (The group has additional collaborators at MIT, the Dana Farber Cancer Institute, and Munich Technical University.) The new award enables continuation of a research partnership that began in 2011 with an initial $8 million grant that formed a multidisciplinary, translational research program to study the origins and pathogenesis of Barrett's esophagus. The goal of phase two of the partnership is to advance knowledge of the role of the microbiome (microorganisms) and microenvironment in the development of Barrett's esophagus and esophageal adenocarcinoma, the highly lethal cancer associated with Barrett's Esophagus. The researchers propose that the rapid rise in these two conditions is in part due to changes in the microbiome, leading to the development of a microenvironment conducive to the forming of tumors. Characterization of these changes could lead to predictive biomarkers and targets for intervention. The esophagus is a tube that carries food from the mouth to the stomach. In Barrett's esophagus, esophageal tissue is replaced by tissue that looks and behaves more like small intestine tissue. Barrett's esophagus is caused by chronic gastroesophageal reflux disease (GERD). While the Barrett's esophagus itself is well tolerated by patients, it is a significant risk factor for developing esophageal adenocarcinoma, which is of great concern for physicians and patients alike. "We are grateful to the National Cancer Institute for this important continuation of funding," said John Lynch, MD, PhD, an associate professor in the division of Gastroenterology and a member of the research team. "It will enable us to carry on our work with our partners, with the aim of converting our research findings into potential diagnosis, prevention, and treatment applications against this important disease." Co-principal investigators at Penn include Gary W. Falk, MD, MS a professor of medicine; Gregory Ginsberg, MD, a professor of medicine, and Anil K. Rustgi, MD, the T. Grier Miller professor of Medicine and chief of the division of Gastroenterology. The Columbia University Medical Center component of the partnership is led by Timothy Wang, MD, while the Mayo Clinic team is led by Kenneth Wang, MD. In the new phase of the project, the researchers will focus on the role of microbiota (tens of trillions of microorganisms that live in the esophagus and human gut) and the tissue microenvironment in the development of Barrett's esophagus and its progression to esophageal adenocarcinoma. It is built around the hypothesis that the inflammation-dependent tumor microenvironment, modulated by the microbiome of the gastroesophageal (GE) junction (where the esophagus connects to the stomach), is critical for early progression of esophageal carcinogenesis. The three projects will focus on studying the role of microbiota and blood-forming cells of the bone marrow (myeloid cells) in the L2-IL-1β mouse model of Barrett's esophagus and esophageal adenocarcinoma, characterizing microenvironmental factors in Barrett's esophagus and esophageal adenocarcinoma, and identifying novel biomarkers and gene signatures related to the microbiome and microenvironment. "Overall, these three projects, integrated from the laboratory bench to the patient's bedside, will advance the science of the microbiome and microenvironment in Barrett's esophagus," said Lynch. "We expect our observations here will lead to new insights into how the disease develops and progresses to cancer, and likely result in novel translational applications, including new biomarkers and therapies." Esophageal adenocarcinoma is the fastest growing cancer in the United States; its five-year survival rate is 15 percent, yet our understanding of it lags well behind that of other cancers such as colon and breast cancer. The National Cancer Institute recognized this limitation and developed the BETRNet research program in 2011, to support multicenter, translational research into Barrett's esophagus and esophageal adenocarcinoma. Penn Medicine is one of the world's leading academic medical centers, dedicated to the related missions of medical education, biomedical research, and excellence in patient care. Penn Medicine consists of the Raymond and Ruth Perelman School of Medicine at the University of Pennsylvania (founded in 1765 as the nation's first medical school) and the University of Pennsylvania Health System, which together form a $6.7 billion enterprise. The Perelman School of Medicine has been ranked among the top five medical schools in the United States for the past 20 years, according to U.S. News & World Report's survey of research-oriented medical schools. The School is consistently among the nation's top recipients of funding from the National Institutes of Health, with $392 million awarded in the 2016 fiscal year. The University of Pennsylvania Health System's patient care facilities include: The Hospital of the University of Pennsylvania and Penn Presbyterian Medical Center -- which are recognized as one of the nation's top "Honor Roll" hospitals by U.S. News & World Report -- Chester County Hospital; Lancaster General Health; Penn Wissahickon Hospice; and Pennsylvania Hospital -- the nation's first hospital, founded in 1751. Additional affiliated inpatient care facilities and services throughout the Philadelphia region include Good Shepherd Penn Partners, a partnership between Good Shepherd Rehabilitation Network and Penn Medicine. Penn Medicine is committed to improving lives and health through a variety of community-based programs and activities. In fiscal year 2016, Penn Medicine provided $393 million to benefit our community.


News Article | July 10, 2017
Site: www.eurekalert.org

PHILADELPHIA - During the last decade, commercial brain-training programs have risen in popularity, offering people the hope of improving their cognitive abilities through the routine performance of various "brain games" that tap cognitive functions such as memory, attention and cognitive flexibility. But a recent study at the University of Pennsylvania found that, not only did commercial brain training with Lumosity™ have no effect on decision-making, it also had no effect on cognitive function beyond practice effects on the training tasks. The findings were published in the Journal of Neuroscience. Seeking evidence for an intervention that could reduce the likelihood that people will engage in unhealthy behaviors such as smoking or overeating, a team of researchers at Penn, co-led by Joseph Kable, PhD, the Baird Term associate professor in the department of Psychology in the School of Arts & Sciences, and Caryn Lerman, PhD, the vice dean for Strategic Initiatives and the John H. Glick professor in Cancer Research in the Perelman School of Medicine, examined whether, through the claimed beneficial effect on cognitive function, commercial brain training regimes could reduce individuals' propensity to make risky or impulsive choices. Lerman's prior work had shown that engagement of brain circuits involved in self-control predicts whether people can refrain from smoking. This work provided the foundation for examining whether modulating these circuits through brain training could lead to behavior change. "Our motivation," Kable said, "was that there are enough hints in the literature that cognitive training deserved a real, rigorous, full-scale test. Especially given the addiction angle, we're looking for things that will help people make the changes in their lives that they want to make, one of which is being more future-oriented." The researchers knew that people with stronger cognitive abilities tend to make less impulsive decisions on the kinds of tasks that Kable studies, which involve giving people choices between immediate smaller rewards and delayed larger rewards. They also knew that this behavior is likely mediated by a set of brain structures in the dorsolateral prefrontal area of the brain that have been associated with performance on the executive function tasks like the ones in the Lumosity™ battery. "The logic would be that if you can train cognitive abilities and change activity in these brain structures," Kable said, "then that may change your likelihood of impulsive behavior." The researchers recruited two groups, each with 64 healthy young adults. One group was asked to follow the Lumosity™ regimen, performing the executive function games for 30 minutes a day, five days a week for 10 weeks. The other group followed the same schedule but played online video games instead. Both groups were told that the study was investigating whether playing online video games improves cognition and changes one's decision-making. The researchers had two assessments of decision-making that participants completed before and after the training regimen. To assess impulsive decision-making, the participants were asked to choose between smaller rewards now and larger rewards later. To assess risky decision-making, they were asked to choose between larger rewards at a lower probability versus smaller rewards at a higher probability. The researchers found that the training didn't induce any changes in brain activity or decision-making during these tasks. The participants were also asked to complete a series of cognitive tests that were not part of the training to see if the program had any effect on their general cognitive abilities. While both groups showed improvement, the researchers found that commercial brain training didn't lead to any more improvement than online video games. Furthermore, when they asked a no-contact group, which didn't complete commercial brain training or video games, to complete the tests, the researchers found that the participants showed the same level of improvement as the first two groups, indicating that neither brain training nor online video games led to cognitive improvements beyond likely practice effects. Although the cognitive training by itself did not produce the desired benefits, initial findings from Lerman's laboratory show that combining cognitive exercises with non-invasive brain stimulation enhances self-control over smoking behavior. This group is now conducting clinical trials to learn whether this combination approach can alter other risky behaviors such as unhealthy eating or improve attention and impulse control in persons with attention deficit hyperactivity disorder. "Habitual behaviors such as tobacco use and overeating," said Mary Falcone, a senior research investigator at Penn and coauthor on the study, "contribute to preventable deaths from cancer, cardiovascular disease and other public health problems." Lerman said, "As currently available behavioral and medical treatments for these habitual behaviors are ineffective for most people, there is a critical need to develop innovative approaches to behavior change. Changing the brain to change behavior is the approach that we are taking." Kable hopes to use some of the data collected in this study to better understand both within-person differences in decision-making over time, why one person might be more patient at some times and more impulsive at others, and across-person differences, why some people tend to take the immediate reward and others tend to take the delayed reward. If they can better understand the neural basis for those differences, Kable said, it might provide some clues about what kinds of cognitive or neural interventions would be useful to try to intervene and push people to be less or more impulsive. Although, in this study, the researchers found that commercial cognitive training alone would not have an influence on one's decision-making process or cognitive abilities, they believe that it was still an avenue worthy of rigorous investigation. "I think we'd all like to have better cognitive abilities," Kable said. "And we all see ways in which the vagaries of where we grew up and what school we went to and who our parents were had these effects on learning at an early age. The notion that you could do something now that would remediate it was very exciting. I think it was just an idea that really needed to be tested." This research was supported by grants R01-CA170297 and R35-CA197461 from the National Cancer Institute to Kable and Lerman through NCI's Provocative Questions Initiative. Penn Medicine is one of the world's leading academic medical centers, dedicated to the related missions of medical education, biomedical research, and excellence in patient care. Penn Medicine consists of the Raymond and Ruth Perelman School of Medicine at the University of Pennsylvania (founded in 1765 as the nation's first medical school) and the University of Pennsylvania Health System, which together form a $6.7 billion enterprise. The Perelman School of Medicine has been ranked among the top five medical schools in the United States for the past 20 years, according to U.S. News & World Report's survey of research-oriented medical schools. The School is consistently among the nation's top recipients of funding from the National Institutes of Health, with $392 million awarded in the 2016 fiscal year. The University of Pennsylvania Health System's patient care facilities include: The Hospital of the University of Pennsylvania and Penn Presbyterian Medical Center -- which are recognized as one of the nation's top "Honor Roll" hospitals by U.S. News & World Report -- Chester County Hospital; Lancaster General Health; Penn Wissahickon Hospice; and Pennsylvania Hospital -- the nation's first hospital, founded in 1751. Additional affiliated inpatient care facilities and services throughout the Philadelphia region include Good Shepherd Penn Partners, a partnership between Good Shepherd Rehabilitation Network and Penn Medicine. Penn Medicine is committed to improving lives and health through a variety of community-based programs and activities. In fiscal year 2016, Penn Medicine provided $393 million to benefit our community.


Lamont R.J.,University of Louisville | Hajishengallis G.,Penn Medicine
Trends in Molecular Medicine | Year: 2015

Uncontrolled inflammation of the periodontal area may arise when complex microbial communities transition from a commensal to a pathogenic entity. Communication among constituent species leads to polymicrobial synergy between metabolically compatible organisms that acquire functional specialization within the developing community. Keystone pathogens, even at low abundance, elevate community virulence, and the resulting dysbiotic community targets specific aspects of host immunity to further disable immune surveillance while promoting an overall inflammatory response. Inflammophilic organisms benefit from proteinaceous substrates derived from inflammatory tissue breakdown. Inflammation and dysbiosis reinforce each other, and the escalating environmental changes further select for a pathobiotic community. We have synthesized the polymicrobial synergy and dysbiotic components of the process into a new model for inflammatory diseases. © 2014 Elsevier Ltd.

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