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News Article | May 19, 2017
Site: cerncourier.com

Fifty years ago, physicists in the US established a new laboratory and with it a new approach to carrying out frontier research in high-energy physics. Il y a cinquante ans, des physiciens ont créé aux États-Unis un nouveau laboratoire, et dans la foulée une nouvelle manière de mener des recherches de pointe en physique des hautes énergies. Appelé initialement National Accelerator Laboratory et rebaptisé Fermilab quelques années plus tard, le laboratoire a eu comme première grande installation un accélérateur de 200 GeV, lequel a ouvert la voie au collisionneur Tevatron et aux grandes découvertes telles que celle du quark t. Aujourd’hui, le Fermilab se consacre principalement aux études à la frontière des hautes intensités et à la compréhension des propriétés des neutrinos, perpétuant ainsi les rêves d’exploration et de découverte de son premier directeur, Robert Wilson. In 1960, two high-energy physics laboratories were competing for scientific discoveries. The first was Brookhaven National Laboratory on Long Island in New York, US, with its 33 GeV Alternating Gradient Synchrotron (AGS). The second was CERN in Switzerland, with its 28 GeV Proton Synchrotron (PS). That year, the US Atomic Energy Commission (AEC) received several proposals to boost the country’s research programme focusing on the construction of new accelerators with energies between 100–1000 GeV. A joint panel of president Kennedy’s Presidential Science Advisory Committee and the AEC’s General Advisory Committee was formed to consider the submissions, chaired by Harvard physicist and Manhattan Project veteran Norman Ramsey. By May 1963, the panel had decided to have Ernest Lawrence’s Radiation Laboratory in Berkeley, California, design a several-hundred GeV accelerator. The result was a 200 GeV synchrotron costing approximately $340 million. When Cornell physicist Robert Rathbun Wilson, a student of Lawrence’s who also worked on the Manhattan Project, saw Berkeley’s plans he considered them too conservative, unimaginative and too expensive. Wilson, being a modest yet proud man, thought he could design a better accelerator for less money and let his thoughts be known. By September 1965, Wilson had proposed an alternative, innovative, less costly (approximately $250 million) design for the 200 GeV accelerator to the AEC. The Joint Committee on Atomic Energy, the congressional body responsible for AEC projects and budgets, approved of his plan. During this period, coinciding with the Vietnam war, the US Congress hoped to contain costs. Yet physicists hoped to make breakthrough discoveries, and thought it important to appeal to national interests. The discovery of the Ω– particle at Brookhaven in 1964 led high-energy physicists to conclude that “an accelerator ‘in the range of 200–1000 BeV’ would ‘certainly be crucial’ in exploring the ‘detailed dynamics of this strong SU(3) symmetrical interaction’.” Simultaneously, physicists were expressing frustration with the geographic situation of US high-energy physics facilities. East and West Coast laboratories like Lawrence Berkeley Laboratory and Brookhaven did not offer sufficient opportunity for the nation’s experimental physicists to pursue their research. Managed by regional boards, the programmes at these two labs were directed by and accessible to physicists from nearby universities. Without substantial federal support, other major research universities struggled to compete with these regional laboratories. Against this backdrop arose a major movement to accommodate physicists in the centre of the country and offer more equal access. Columbia University experimental physicist Leon Lederman championed “the truly national laboratory” that would allow any qualifying proposal to be conducted at a national, rather than a regional, facility. In 1965, a consortium of major US research universities, Universities Research Association (URA), Inc., was established to manage and operate the 200 GeV accelerator laboratory for the AEC (and its successor agencies the Energy Research and Development Administration (ERDA) and the Department of Energy (DOE)) and address the need for a more national laboratory. Ramsey was president of URA for most of the period 1966 to 1981. Following a nationwide competition organised by the National Academy of Sciences, in December 1966 a 6800 acre site in Weston, Illinois, around 50 km west of Chicago, was selected. Another suburban Chicago site, north of Weston in affluent South Barrington, had withdrawn when local residents “feared that the influx of physicists would ‘disturb the moral fibre of their community’”. Robert Wilson was selected to direct the new 200 GeV accelerator, named the National Accelerator Laboratory (NAL). Wilson asked Edwin Goldwasser, an experimental physicist from the University of Illinois, Urbana-Champaign, and member of Ramsey’s panel, to be his deputy director and the pair set up temporary offices in Oak Brook, Illinois, on 15 June 1967. They began to recruit physicists from around the country to staff the new facility and design the 200 GeV accelerator, also attracting personnel from Chicago and its suburbs. President Lyndon Johnson signed the bill authorising funding for the National Accelerator Laboratory on 21 November 1967. It wasn’t easy to recruit scientific staff to the new laboratory in open cornfields and farmland with few cultural amenities. That picture lies in stark contrast to today, with the lab encircled by suburban sprawl encouraged by highway construction and development of a high-tech corridor with neighbours including Bell Labs/AT&T and Amoco. Wilson encouraged people to join him in his challenge, promising higher energy and more experimental capability than originally planned. He and his wife, Jane, imbued the new laboratory with enthusiasm and hospitality, just as they had experienced in the isolated setting of wartime-era Los Alamos while Wilson carried out his work on the Manhattan Project. Wilson and Goldwasser worked on the social conscience of the laboratory and in March 1968, a time of racial unrest in the US, they released a policy statement on human rights. They intended to: “seek the achievement of its scientific goals within a framework of equal employment opportunity and of a deep dedication to the fundamental tenets of human rights and dignity…The formation of the Laboratory shall be a positive force…toward open housing…[and] make a real contribution toward providing employment opportunities for minority groups…Special opportunity must be provided to the educationally deprived…to exploit their inherent potential to contribute to and to benefit from the development of our Laboratory. Prejudice has no place in the pursuit of knowledge…It is essential that the Laboratory provide an environment in which both its staff and its visitors can live and work with pride and dignity. In any conflict between technical expediency and human rights we shall stand firmly on the side of human rights. This stand is taken because of, rather than in spite of, a dedication to science.” Wilson and Goldwasser brought inner-city youth out to the suburbs for employment, training them for many technical jobs. Congress supported this effort and was pleased to recognise it during the civil-rights movement of the late 1960s. Its affirmative spirit endures today. When asked by a congressional committee authorising funding for NAL in April 1969 about the value of the research to be conducted at NAL, and if it would contribute to national defence, Wilson famously answered: “It has only to do with the respect with which we regard one another, the dignity of men, our love of culture…It has to do with, are we good painters, good sculptors, great poets? I mean all the things we really venerate and honour in our country and are patriotic about. It has nothing to do directly with defending our country except to help make it worth defending.” Wilson, who had promised to complete his project on time and under budget, perceived of the new laboratory as a beautiful, harmonious whole. He felt that science, technology, and art are importantly connected, and brought a graphic artist, Angela Gonzales, with him from Cornell to give the laboratory site and its publications a distinctive aesthetic. He had his engineers work with a Berkeley colleague, William Brobeck, and an architectural-engineering group, DUSAF, to make designs and cost estimates for early submissions to the AEC, in time for their submissions to the congressional committees that controlled NAL’s budget. Wilson appreciated frugality and minimal design, but also tried to leave room for improvements and innovation. He thought design should be ongoing, with changes implemented as they are demonstrated, before they became conservative. There were many decisions to be made in creating the laboratory Wilson envisioned. Many had to be modified, but this was part of his approach: “I came to understand that a poor decision was usually better than no decision at all, for if a necessary decision was not made, then the whole effort would just wallow – and, after all, a bad decision could be corrected later on,” he wrote in 1987. An example was the magnets in the Main Ring, the first name of the 200 GeV synchrotron accelerator, which had to be redesigned as did the plans for the layout of the experimental areas. Even the design of the distinctive Central Laboratory building, constructed after the accelerator achieved its design energy and renamed Robert Rathbun Wilson Hall in 1980, had to have certain adjustments from its initial concepts. Wilson said that “a building does not have to be ugly to be inexpensive” and he orchestrated a competition among his selected architects to create the final design of this visually striking structure. To save money he set up competitions between contractors so that the fastest to finish a satisfactory project were rewarded with more jobs. Consequently, the Main Ring was completed on time by 30 March 1972 and under the $250 million budget. NAL was dedicated and renamed Fermilab on 11 May 1974. Experimentalists from Europe and Asia flocked to propose research at the new frontier facility in the US, forging larger collaborations with American colleagues. Its forefront position and philosophy attracted the top physicists of the world, with Russian physicists making news working on the first approved experiment at Fermilab in the height of the Cold War. Congress was pleased and the scientists were overjoyed with more experimental areas than originally planned and with higher energy, as the magnets were improved to attain 400 GeV and 500 GeV within two years. The higher energy in a fixed-target accelerator complex allowed more innovative experiments, in particular enabling the discovery of the bottom quark in 1977 (see "Revisiting the b revolution"). Fermilab’s early intellectual environment was influenced by theoretical physicists Robert Serber, Sam Trieman, J D Jackson and Ben Lee, who later brought Chris Quigg and Bill Bardeen, who in turn invited many distinguished visitors to add to the creative milieu of the laboratory. Already on Wilson’s mind was a colliding-beams accelerator he called an “energy doubler”, which would employ superconductivity, and he had established working groups to study the idea. But Wilson encountered budget conflicts with the AEC’s successor, the new Department of Energy, which led to his resignation in 1978. He joined the faculties of the University of Chicago and Columbia University briefly before returning to Cornell in 1982. Fermilab’s future was destined to move forward with Wilson’s ideas of superconducting-magnet technology, and a new director was sought. Lederman, who was spokesperson of the Fermilab study that discovered the bottom quark, accepted the position in late 1978 and immediately set out to win support for Wilson’s energy doubler. An accomplished scientific spokesman, Lederman achieved the necessary funding by 1979 and promoted the energy-enhancing idea of introducing an antiproton source to the accelerator complex to enable proton–antiproton collisions. Experts from Brookhaven and CERN, as well as the former USSR, shared ideas with Fermilab physicists to bring superconducting-magnet technology to fruition at Fermilab. Under the leadership of Helen Edwards, Richard Lundy, Rich Orr and Alvin Tollestrup, the Main Ring evolved into the energy doubler/saver in 1983 with a new ring of superconducting magnets installed below the early Main Ring magnets. This led to a trailblazing era during which Fermilab’s accelerator complex, now called the Tevatron, would lead the world in high-energy physics experiments. By 1985 the Tevatron had achieved 800 GeV in fixed-target experiments and 1.6 TeV in colliding-beam experiments, and by the time of its closure in 2011 it had reached 1.96 TeV in the centre of mass – just shy of its original goal of 2 TeV. Theory also thrived at Fermilab in this period. Lederman had brought James Bjorken to Fermilab’s theoretical physics group in 1980 and a theoretical astrophysics group founded by Rocky Kolb and Michael Turner was added to Fermilab’s research division in 1983 to address research at the intersection of particle physics and cosmology. Lederman also expanded the laboratory’s mission to include science education, offering programmes to local high-school students and teachers, and in 1980 opened the first children’s centre for employees of any DOE facility. He founded the Illinois Mathematics and Science Academy in 1985 and the Chicago Teachers Academy for Mathematics and Science in 1990, and the Lederman Science Education Center on the Fermilab site is named after him. Lederman also reached out to many regions including Latin America and partnered with businesses to support the lab’s research and encourage technology transfer. The latter included Wilson’s early Fermilab initiative of neutron therapy for certain cancers, which later would see Fermilab build the 70–250 MeV proton synchrotron for the Loma Linda Medical Center in California. Scientifically, the target in this period was the top quark. Fermilab and CERN had planned for a decade to detect the elusive top, with Fermilab deploying two large international experimental teams at the Tevatron – CDF (founded by Tollestrup) and DZero (founded by Paul Grannis) – from 1976 to 1995. In 1988 Lederman shared the Nobel prize for the discovery of the muon neutrino at Brookhaven 25 years previously, and in 1989 he stepped down as Fermilab director and joined the faculty of the University of Chicago and later the Illinois Institute of Technology. Lederman was succeeded by John Peoples, a machine builder and Fermilab experimentalist since 1970, and leader of the Fermilab antiproton source from 1981 to 1985. Peoples had his hands full not only with Fermilab and its research programme but also with the Superconducting Super Collider (SSC) laboratory in Texas. In 1993 the SSC was cancelled and Peoples was asked by the DOE to close down the project and its many contracts. The only person to direct two national laboratories at the same time, Peoples successfully managed both tasks and returned to Fermilab to see the discovery of the top quark in 1995. He had also launched the luminosity-enhancing upgrade to the Tevatron, the Main Injector, in 1999. Peoples stepped down as laboratory director that summer and became director of the Sloan Digital Sky Survey (SDSS) – Fermilab’s first astrophysics experiment. He later directed the Dark Energy Survey and in 2010 he retired, continuing to serve as director emeritus of the laboratory. In 1999, experimentalist and former Fermilab user Michael Witherell of the University of California at Santa Barbara became Fermilab’s fourth director. Ongoing fixed-target and colliding-beam experiments continued under Witherell, as did the SDSS and the Pierre Auger cosmic ray experiments, and the neutrino programme with the Main Injector. Mirroring the spirt of US–European competition of the 1960s, this period saw CERN begin construction of the Large Hadron Collider (LHC) to search for the Higgs boson at a lower energy than the cancelled SSC. Accordingly, the luminosity of the Tevatron became a priority, as did discussions about a possible future international linear collider. After launching the Neutrinos at the Main Injector (NuMI) research programme, including sending the underground particle beam off-site to the MINOS detector in Minnesota, Witherell returned to Santa Barbara in 2005 and in 2016 he became director of the Lawrence Berkeley Laboratory. Physicist Piermaria Oddone from Lawrence Berkeley Laboratory became Fermilab’s fifth director in 2005. He pursued the renewal of the Tevatron in order to exploit the intensity frontier and explore new physics with a plan called “Project X”, part of the “Proton Improvement Plan”. Yet the last decade has been a challenging time for Fermilab, with budget cuts, reductions in staff and a redefinition of its mission. The CDF and DZero collaborations continued their search for the Higgs boson, narrowing the region where it could exist, but the more energetic LHC always had the upper hand. In the aftermath of the global economic crisis of 2008, as the LHC approached switch-on, Oddone oversaw the shutdown of the Tevatron in 2011. A Remote Operations Center in Wilson Hall and a special US Observer agreement allowed Fermilab physicists to co-operate with CERN on LHC research and participate in the CMS experiment. The Higgs boson was duly discovered at CERN in 2012 and Oddone retired the following year. Under its sixth director, former Fermilab user and director of TRIUMF laboratory in Vancouver, Nigel Lockyer, Fermilab now looks ahead to shine once more through continued exploration of the intensity frontier and understanding the properties of neutrinos. In the next few years, Fermilab’s Long-Baseline Neutrino Facility (LBNF) will send neutrinos to the underground DUNE experiment 1300 km away in South Dakota, prototype detectors for which are currently being built at CERN. Meanwhile, Fermilab’s Short-Baseline Neutrino programme has just taken delivery of the 760 tonne cryostat for its ICARUS experiment after its recent refurbishment at CERN (see "Search for sterile neutrinos triples up"), while a major experiment called Muon g-2 is about to take its first results. This suite of experiments, with co-operation with CERN and other international labs, puts Fermilab at the leading edge of the intensity frontier and continues Wilson’s dreams of exploration and discovery.

News Article | February 21, 2017
Site: www.businesswire.com

LOS ANGELES--(BUSINESS WIRE)--OneLegacy announced today that it has entered into an exclusive agreement to be the ocular tissue provider for Loma Linda Outpatient Surgery Center. OneLegacy is home to the only organ procurement organization and eye bank in Los Angeles that recovers, processes and distributes ocular tissue for transplant and research. While OneLegacy currently recovers corneas from Loma Linda Medical Center, this agreement “means that we are able to assure that tissue recovered can be placed back into the community, helping local residents receive the gift of sight through a successful corneal transplant,” said Prasad Garimella, chief operating officer of OneLegacy and executive director of the OneLegacy Eye Bank. A corneal transplant is a surgical procedure that replaces a portion of an impaired cornea (brought on by disease, injury, infection or any other causes) with a healthy donor cornea. Since 1961, more than 1.5 million people worldwide have had their sight restored through this procedure, yet millions of people around the world struggle to live with corneal blindness. “The donor cornea is an amazing gift that can be used to replace a cornea that has been injured or diseased. Tissue donation makes corneal blindness a treatable condition,” said Garimella. “We have trained technicians who surgically retrieve the cornea and bring it to our eye bank where we carefully evaluate the tissue to ensure its optimal quality and then distribute it to a corneal surgeon who will transplant this tissue to his or her patient as soon as possible.” The OneLegacy Eye Bank is accredited by the Eye Bank Association of America and regulated the by the FDA. It obtains, medically evaluates, processes, and distributes ocular tissue donated by caring individuals for use in corneal transplantation, research and education. By early spring OneLegacy plans to open a new and expanded eye bank in downtown Los Angeles. The Loma Linda Outpatient Surgery Center is part of Loma Linda University Health – the umbrella organization encompassing Loma Linda University’s eight professional schools, Loma Linda University Medical Center’s six hospitals, and more than 900 faculty physicians located across the Inland Empire in Southern California. OneLegacy is the nonprofit organization dedicated to saving lives through organ, eye and tissue donation in seven counties in Southern California: Los Angeles, Orange, Riverside, San Bernardino, Ventura, Santa Barbara and Kern. Serving more than 200 hospitals, 11 transplant centers, and a diverse population of nearly 20 million, OneLegacy is the largest organ, eye and tissue recovery organization in the world. For more information, call OneLegacy at 800-786-4077 or visit onelegacy.org

Schroeder A.R.,Santa Clara Valley Medical Center | Mansbach J.M.,Harvard University | Stevenson M.,University of Louisville | Macias C.G.,Baylor College of Medicine | And 6 more authors.
Pediatrics | Year: 2013

OBJECTIVE: To identify risk factors for inpatient apnea among children hospitalized with bronchiolitis. METHODS: We enrolled 2207 children, aged ,2 years, hospitalized with bronchiolitis at 16 sites during the winters of 2007 to 2010. Nasopharyngeal aspirates (NPAs) were obtained on all subjects, and real-time polymerase chain reaction was used to test NPA samples for 16 viruses. Inpatient apnea was ascertained by daily chart review, with outcome data in 2156 children (98%). Age was corrected for birth ,37 weeks. Multivariable logistic regression was performed to identify independent risk factors for inpatient apnea. RESULTS: Inpatient apnea was identified in 108 children (5%, 95% confidence interval [CI] 4%-6%). Statistically significant, independent predictors of inpatient apnea included: corrected ages of ,2 weeks (odds ratio [OR] 9.67) and 2 to 8 weeks (OR 4.72), compared with age $6 months; birth weight ,2.3 kg (5 pounds; OR 2.15), compared with $3.2 kg (7 pounds); caretaker report of previous apnea during this bronchiolitis episode (OR 3.63); preadmission respiratory rates of ,30 (OR 4.05), 30 to 39 (OR 2.35) and .70 (OR 2.26), compared with 40 to 49; and having a preadmission room air oxygen saturation ,90% (OR 1.60). Apnea risk was similar across the major viral pathogens. CONCLUSIONS: In this prospective, multicenter study of children hospitalized with bronchiolitis, inpatient apnea was associated with younger corrected age, lower birth weight, history of apnea, and preadmission clinical factors including low or high respiratory rates and low room air oxygen saturation. Several bronchiolitis pathogens were associated with apnea, with similar apnea risk across the major viral pathogens. Pediatrics 2013;132:e1194-e1201. Copyright © 2013 by the American Academy of Pediatrics.

Hou J.,Loma Linda University | Hou J.,Loma Linda Medical Center | Hou J.,Rigshospitalet | Manaenko A.,Loma Linda University | And 5 more authors.
Journal of Cerebral Blood Flow and Metabolism | Year: 2012

The inflammatory response plays a pivotal role in propagating injury of intracerebral hemorrhage (ICH). Glucagon-like-peptide-1 (GLP-1) is a hormone with antidiabetic effect and may also have antiinflammatory properties. Despite consensus that the glucoregulatory action is mediated by the GLP-1 receptor (GLP-1R), mechanisms in the brain remain unclear. We investigated the effect of a long-acting GLP-1 analog, liraglutide, and its truncated metabolite, GLP-1(9-36)a from dipeptidyl peptidase-4 (DPP-4) cleavage in ICH-induced brain injury. Primary outcomes were cerebral edema formation, neurobehavior, and inflammatory parameters. GLP-1(9-36)a, GLP-1R inhibitor, adenosine monophosphate-activated protein kinase (AMPK) phosphorylation inhibitor and DPP-4 inhibitor were administered to examine the mechanisms of action. Liraglutide suppressed neuroinflammation, prevented brain edema and neurologic deficit following ICH, which were partially reversed by GLP-1R inhibitor and AMPK phosphorylation inhibitor. Liraglutide-mediated AMPK phosphorylation was unaffected by GLP-1R inhibitor, and was found to be induced by GLP-1(9-36)a. GLP-1(9-36)a showed salutary effects on primary outcomes that were reversed by AMPK phosphorylation inhibitor but not by GLP-1R inhibitor. Liraglutide and DPP-4 inhibitor co-administration reversed liraglutide-mediated AMPK phosphorylation and antiinflammatory effects. Liraglutide exerted duals actions and the antiinflammatory effects are partially mediated by its metabolite in a phosphorylated AMPK-dependent manner. Therapies that inhibit GLP-1 degradation may weaken the metabolite-mediated effects. © 2012 ISCBFM.

Wirtschafter D.D.,MD Inc. | Padilla G.,Miller Childrens Hospital Long Beach | Suh O.,Miller Childrens Hospital Long Beach | Wan K.,Loma Linda Medical Center | And 2 more authors.
Journal of Perinatology | Year: 2011

Objective:To assess antibiotic use as a complementary neonatal intensive care unit (NICU) infection measure to the central line-associated blood stream infection (CLABSI) rate.Study Design:Patient days (PDs), line days, antibiotic (AB) use, CLABSI and other proven infections were analyzed in consecutive admissions to two NICUs over 3 and 6 months, respectively, from 1 January 2008 until discharge. An antibiotic course (AC) consisted of one or more uninterrupted antibiotic days (AD), classified as perinatal or neonatal, if started ≥3 d or ≥4 d post birth and as rule-out sepsis or presumed infection (PI) if treated ≥4 d or ≥5d, respectively. Events were expressed per 1000 PD and aggregated by conventional treatment categories and by clinical perception of infection certainty: possible, presumed or proven.Result:The cohort included 754 patients, 18 345 PD, 6637 line days, 718 AC and 4553 AD. Of total antibiotic use, neonatal use constituted 39.2% of ACs, and 29.0% of ADs, When analyzed per 1000 PD, antibiotic use to treat PIs vs CLABSIs, was either 14 fold (CI 6.6-30) higher for ACs (5.40 vs 0.38/1000 PD, P<0.0001) or 8.8 fold (CI 7.1-11) higher for ADs (48.3 vs 5.5/1000 PD, P<0.0001).Conclusion:CLABSI rates, present a lower limit of NICU-acquired infections, whereas antibiotic-use measures, about 10-fold higher, may estimate an upper limit of that burden. Antibiotic-use metrics should be evaluated further for their ability to broaden NICU infection assessment and to guide prevention and antibiotic stewardship efforts. © 2011 Nature America, Inc. All rights reserved.

Ma Q.,Loma Linda University | Chen S.,Loma Linda University | Chen S.,Zhejiang University | Hu Q.,Loma Linda University | And 4 more authors.
Annals of Neurology | Year: 2014

Objective The NLRP3 (NALP3, cryopyrin) inflammasome, a key component of the innate immune system, facilitates caspase-1 and interleukin (IL)-1β processing, which amplifies the inflammatory response. Here, we investigated whether NLRP3 knockdown decreases neutrophil infiltration, reduces brain edema, and improves neurological function in an intracerebral hemorrhage (ICH) mouse model. We also determined whether mitochondrial reactive oxygen species (ROS) governed by mitochondrial permeability transition pores (mPTPs) would trigger NLRP3 inflammasome activation following ICH. Methods ICH was induced by injecting autologous arterial blood (30μl) into a mouse brain. NLRP3 small interfering RNAs were administered 24 hours before ICH. A mPTP inhibitor (TRO-19622) or a specific mitochondria ROS scavenger (Mito-TEMPO) was coinjected with the blood. In naive animals, rotenone, which is a respiration chain complex I inhibitor, was applied to induce mitochondrial ROS production, and followed by TRO-19622 or Mito-TEMPO treatment. Neurological deficits, brain edema, enzyme-linked immunosorbent assay, Western blot, in vivo chemical cross-linking, ROS assay, and immunofluorescence were evaluated. Results ICH activated the NLRP3 inflammasome. NLRP3 knockdown reduced brain edema and decreased myeloperoxidase (MPO) levels at 24 hours, and improved neurological functions from 24 to 72 hours following ICH. TRO-19622 or Mito-TEMPO reduced ROS, NLRP3 inflammasome components, and MPO levels following ICH. In naive animals, rotenone administration induced mPTP formation, ROS generation, and NLRP3 inflammasome activation, which were then reduced by TRO-19622 or Mito-TEMPO. Interpretation The NLRP3 inflammasome amplified the inflammatory response by releasing IL-1β and promoting neutrophil infiltration following ICH. Mitochondria ROS may be a major trigger of NLRP3 inflammasome activation. The results of our study suggest that the inhibition of the NLRP3 inflammasome may effectively reduce the inflammatory response following ICH. © 2014 American Neurological Association.

Ma Q.,Loma Linda University | Manaenko A.,Loma Linda University | Khatibi N.H.,Loma Linda Medical Center | Chen W.,Loma Linda University | And 3 more authors.
Journal of Cerebral Blood Flow and Metabolism | Year: 2011

The systemic immune response has a vital role in propagating the damage of an intracerebral hemorrhage (ICH). Vascular adhesion protein-1 (VAP-1), a semicarbazide (SCZ)-sensitive-amine-oxidase, was found in previous studies to have a role in migration of immune cells. In this study, we hypothesize that VAP-1 inhibition may decrease brain injury by attenuating the transmigration of immune cells to the injury site, and by doing so, reduce cerebral edema and improve neurobehavioral function in mice. Two VAP-1 inhibitors, LJP1586 and SCZ were given 1 hour after ICH induction by either collagenase or autologous blood injection. The VAP-1 siRNA, a VAP-1 gene silencer, and human recombinant AOC3 protein, a VAP-1 analogue, were delivered by intracerebroventricular injection. Postassessment included neurobehavioral testing, brain edema measurement, quantification of neutrophil infiltration and microglia/macrophage activation, and measurement of intercellular adhesion molecule-1 (ICAM-1), P-selectin, monocyte chemoattractant protein-1 (MCP-1), and tumor necrosis factor-α (TNF-α) expression 24 hours after ICH. We found that LJP1586 and SCZ reduced brain edema and neurobehavioral deficits 24 hours after ICH induction. These two drugs were also found to decrease levels of ICAM-1, MCP-1, TNF-α, and inhibit neutrophilic infiltration and microglia/macrophage activation. We conclude that VAP-1 inhibition provided antiinflammation effect by reducing adhesion molecule expression and immune cell infiltration after ICH. © 2011 ISCBFM All rights reserved.

Jackson C.S.,Loma Linda Medical Center | Gerson L.B.,California Pacific Medical Center
American Journal of Gastroenterology | Year: 2014

OBJECTIVES:Gastrointestinal angiodysplastic lesions (GIADs) are defined as pathologically dilated communications between veins and capillaries. The objective of this systematic review and meta-analysis was to determine the efficacy of available treatment modalities for GIADs.METHODS:We identified eligible studies by searching through PubMed, SCOPUS, and Cochrane central register of controlled trials. We searched for clinical trials examining the efficacy of endoscopic, pharmacologic, or surgical therapy for GIADs. Data were pooled using a random-effects model, and the effect of response to medical or surgical therapy was reported as odds ratios with 95% confidence intervals (CIs). Data and quality indicators were extracted by two authors from 22 studies, including 831 individuals with GIADs. The analysis included 623 patients treated with endoscopic therapy, 63 with hormonal therapy, 72 patients with octreotide, and 73 status post aortic valve replacement surgery.RESULTS:Hormonal therapy, based on two case-control studies, was not effective for bleeding cessation (odds ratio: 1.0, 95% CI: 0.5-1.96). On the basis of 14 studies including patients with gastric, colonic, and small-bowel GIADs, endoscopic therapy was effective as initial therapy, but the pooled recurrence bleeding rate was 36% (95% CI: 28-44%) over a mean (±s.d.) of 22±13 months. The event rate for re-bleeding increased to 45% (95% CI: 37-52%) when studies including only small-bowel GIADs were included (N=341). In four studies assessing the efficacy of somatostatin analogs, the pooled odds ratio was 14.5 (95% CI: 5.9-36) for bleeding cessation. In two studies assessing the role of aortic valve replacement (AVR) in 73 patients with Heyde's syndrome, the event rate for re-bleeding was 0.19 (95% CI: 0.11-0.30) over a mean follow-up period of 4 years postoperatively.CONCLUSIONS:Over one-third of patients with GIADs experienced re-bleeding after endoscopic therapy. Somatostatin analogs and AVR for Heyde's syndrome appeared to be effective therapy for GIADs. © 2014 by the American College of Gastroenterology.

Pandey P.,Stanford University | Marks M.P.,Stanford University | Harraher C.D.,Stanford University | Westbroek E.M.,Stanford University | And 5 more authors.
Journal of Neurosurgery | Year: 2012

Object. Grade III arteriovenous malformations (AVMs) are diverse because of their variations in size (S), location in eloquent cortex (E), and presence of central venous drainage (V). Because they may have implications for management and outcome, the authors evaluated these variations in the present study. Methods. Between 1984 and 2010, 100 patients with Grade III AVMs were treated. The AVMs were categorized by Spetzler-Martin characteristics as follows: Type 1 = S1E1V1, Type 2 = S2E1V0, Type 3 = S2E0V1, and Type 4 = S3E0V0. The occurrence of a new neurological deficit, functional status (based on modified Rankin Scale [mRS] score) at discharge and follow-up, and radiological obliteration were correlated with demographic and morphological characteristics. Results. One hundred patients (49 female and 51 male; age range 5-68 years, mean 35.8 years) were evaluated. The size of AVMs was less than 3 cm in 28 patients, 3-6 cm in 71, and greater than 6 cm in 1; 86 AVMs were located in eloquent cortex and 38 had central drainage. The AVMs were Type 1 in 28 cases, Type 2 in 60, Type 3 in 11, and Type 4 in 1. The authors performed embolization in 77 patients (175 procedures), surgery in 64 patients (74 surgeries), and radiosurgery in 49 patients (44 primary and 5 postoperative). The mortality rate following the management of these AVMs was 1%. Fourteen patients (14%) had new neurological deficits, with 5 (5%) being disabling (mRS score > 2) and 9 (9%) being nondisabling (mRS score ≤ 2) events. Patients with Type 1 AVMs (small size) had the best outcome, with 1 (3.6%) in 28 having a new neurological deficit, compared with 72 patients with larger AVMs, of whom 13 (18.1%) had a new neurological deficit (p < 0.002). Older age (> 40 years), malformation size > 3 cm, and nonhemorrhagic presentation predicted the occurrence of new deficits (p < 0.002). Sex, eloquent cortex, and venous drainage did not confer any benefit. In 89 cases follow-up was adequate for data to be included in the obliteration analysis. The AVM was obliterated in 78 patients (87.6%), 69 of them (88.5%) demonstrated on angiography and 9 on MRI /MR angiography. There was no difference between obliteration rates between different types of AVMs, size, eloquence, and drainage. Age, sex, and clinical presentation also did not predict obliteration. Conclusions. Multimodality management of Grade III AVMs results in a high rate of obliteration, which was not influenced by size, venous drainage, or eloquent location. However, the development of new neurological deficits did correlate with size, whereas eloquence and venous drainage did not affect the neurological complication rate. The authors propose subclassifying the Grade III AVMs according to their size (< 3 and ≥ 3 cm) to account for treatment risk.

Ma Q.,Loma Linda Medical Center | Huang B.,Loma Linda Medical Center | Khatibi N.,Loma Linda Medical Center | Rolland II W.,Loma Linda Medical Center | And 3 more authors.
Annals of Neurology | Year: 2011

Objective: Perihematomal edema results from disruption of the blood-brain barrier (BBB) by key mediators, such as thrombin, following intracerebral hemorrhage (ICH). Platelet-derived growth factor receptor alpha (PDGFR-α), a tyrosine kinase receptor, was found in previous studies to play a role in orchestrating BBB impairment. In the present study, we investigated the role of PDGFR-α following ICH-induced brain injury in mice, specifically investigating its effect on BBB disruption. Methods: Brain injury was induced by autologous arterial blood (30μl) or thrombin (5U) injection into mice brains. A PDGFR antagonist (Gleevec) or agonist (PDGF-AA) was administered following ICH. PDGF-AA was injected with a thrombin inhibitor, hirudin, in ICH mice. Thrombin-injected mice were given Gleevec or PDGF-AA neutralizing antibody. A p38 mitogen-activated protein kinase (MAPK) inhibitor, SB203580, was delivered with PDGF-AA in naïve animals. Postassessment included neurological function tests, brain edema measurement, Evans blue extravasation, immunoprecipitation, western blot, and immunohistology assay. Results: PDGFR-α suppression prevented neurological deficits, brain edema, and Evans blue extravasation at 24 to 72 hours following ICH. PDGFR-α activation led to BBB impairment and this was reversed by SB203580 in naïve mice. Thrombin inhibition suppressed PDGFR-α activation and exogenous PDGF-AA increased PDGFR-α activation, regardless of thrombin inhibition. Animals receiving a PDGF-AA-neutralizing antibody or Gleevec showed minimized thrombin injection-induced BBB impairment. Interpretation: PDGFR-α signaling may contribute to BBB impairment via p38 MAPK-mediated matrix metalloproteinase (MMP) activation/expression following ICH, and thrombin may be the key upstream orchestrator. The therapeutic interventions targeting the PDGFR-α signaling may be a novel strategy to prevent thrombin-induced BBB impairment following ICH. Copyright © 2011 American Neurological Association.

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