The lta4h Locus Modulates Susceptibility to Mycobacterial Infection in Zebrafish and Humans
Last Updated ( Tuesday, 16 March 2010 08:00 )
David M. Tobin, Jay C. Vary, John P. Ray, Gregory S. Walsh, Sarah J. Dunstan, Nguyen D. Bang, Deanna A. Hagge, Saraswoti Khadge, Mary-Claire King, Thomas R. Hawn, Cecilia B. Moens, Lalita Ramakrishnan
Exposure to Mycobacterium tuberculosis produces varied early outcomes, ranging from resistance to infection to progressive disease. Here we report results from a forward genetic screen in zebrafish larvae that identify multiple mutant classes with distinct patterns of innate susceptibility to Mycobacterium marinum. A hypersusceptible mutant maps to the lta4h locus encoding leukotriene A4 hydrolase, which catalyzes the final step in the synthesis of leukotriene B4 (LTB4), a potent chemoattractant and proinflammatory eicosanoid. lta4h mutations confer hypersusceptibility independent of LTB4 reduction, by redirecting eicosanoid substrates to anti-inflammatory lipoxins. The resultant anti-inflammatory state permits increased mycobacterial proliferation by limiting production of tumor necrosis factor. In humans, we find that protection from both tuberculosis and multibacillary leprosy is associated with heterozygosity for LTA4H polymorphisms that have previously been correlated with differential LTB4 production. Our results suggest conserved roles for balanced eicosanoid production in vertebrate resistance to mycobacterial infection.
Link : http://www.cell.com/abstract/S0092-8674(10)00128-5
Research report: CD4 dynamics and the initiation of antiretroviral therapy in HIV-infected patients
More than 30 million people are currently infected with the human immunodeficiency virus (HIV), the cause of acquired immunodeficiency syndrome (AIDS). HIV slowly destroys immune system cells (including CD4 cells). Without treatment, the immune system loses the ability to fight off infections by other disease-causing organisms and HIV-positive people then develop so-called opportunistic infections, Kaposi sarcoma (a skin cancer), or non-Hodgkin lymphoma (a cancer of the lymph nodes) that determine the diagnosis of AIDS. Although HIV-positive people used to die within 10 years of infection on average, the development in 1996 of combination antiretroviral therapy (cART; cocktails of powerful antiretroviral drugs) means that, at least for people living in developed countries, HIV/AIDS is now a chronic, treatable condition.
The number of CD4 cells in the blood is a strong predictor of the likelihood of AIDS or death in untreated HIV-positive individuals and in people starting cART. Current guidelines recommend, therefore, that cART is started in HIV-positive patients without symptoms when their CD4 cell count drops below a specified cutoff level (typically 350 cells/ml.) In addition, several guidelines suggest that clinicians should also consider cART in symptom-free HIV-positive patients with a CD4 cell count above the cutoff level if their CD4 cell count has rapidly declined. However, it is not actually known whether the rate of CD4 cell decline before initiating cART is related to a patient’s outcome, so should clinicians consider this measurement when deciding whether to initiate cART?
A team lead by Marcel Wolbers (formerly at the Basel Institute for Clinical Epidemiology and Biostatistics (CEB), Switzerland, now biostatistician at OUCRU Vietnam) and Heiner C. Bucher (CEB) investigated this question based on data from CASCADE (Concerted Action on SeroConversion to AIDS and Death in Europe), a large collaborative study of 23 groups of HIV-positive individuals. The results have just been published in Plos Medicine.
The researchers found that individual CD4 cell count decline does not improve the prediction of future AIDS events or deaths in HIV-positive patients with a CD4 cell count above 350 cells/ml. They conclude that knowledge of the current CD4 cell count and an assessment of established risk factors are sufficient when deciding whether to initiate cART in asymptomatic HIV patients. Moreover, they found that that the rate of CD4 cell decline in individual patients is highly variable over time. Consequently, a rate measured at one time cannot be used to reliably predict a patient’s future CD4 cell count.
See the Plos Medicine website for the whole article:
The story of a young Vietnamese woman awarded a PhD fellowship in BioEthics at Oxford University, UK.
Last Updated ( Tuesday, 26 January 2010 07:32 )
One of my friends once said to me that there were three things in our life that belongs to our destiny rather than our decision. Those are: job, marriage, and house. It seems true because success is not only a combination of one’s intelligence and effort, but it is also created by many factors coming together at once such as opportunities, time, support and accumulated experiences. So it is with my success in getting a scholarship to Oxford University to do a DPhil in Bioethics.
Cam BinhI have been questioned as to how an administrator was able to get a scholarship to do a DPhil at Oxford University! And my simple answer to it is “It is all because of luck”. It was definitely good luck that I had a chance to take the post of administrator of the OUCRU Clinical Trials Unit which provided me a lot of wide range experiences, especially an opportunity to approach and deal with problems and ethical dilemmas in research. It has also given me the opportunity to work and communicate with excellent scientists, doctors and managers of all departments. They have told me about their lessons in career and life, their passion in pursuing life targets, taught me about working methods, the way to stand up from failures, and given me chances to try and advance. Three years in the role of an administrator has been an eventful period for me, with the work at the beginning being only to maintain study files and PhD student files, later stepping up with more important and specialized tasks which I could utilize my knowledge in law school. There I saw the connection between theory and practice and the flexibility in our application. And so the more I worked, the more interesting I found in exploring new perspectives and methods to apply policy to real matters arising in work. Then good luck came again when the Director of the Unit, Professor Jeremy Farrar, asked me whether I would like to do the DPhil about bioethics, which is a very new subject in Vietnam and for which there are few local experts. It was difficult to start in a field without an expert on hand to give me specific instructions. When I struggled to think of a way to broaden the scope of the proposal I expressed this difficulty to Professor Farrar, who answered me “Binh, this is science, and in science no one is an expert”. This encouraged me to come up with my own ideas and complete the proposal within a month. After that, I had to continue by taking the IELTS exam. This was the big challenge to me because at that time I had to work during the day and attend law classes and sit exams in the evenings. When I was exhausted and thought about giving up, then I had to remind myself how far I have come so far, and I was encouraged to continue. Needless to say, when Training Committee allowed me to register with Oxford University and when I received the acceptance letter from Oxford University are amongst the happiest days of my life.
There is still a long road ahead and I know I will have work hard to achieve my goal. However this experience so far has given me a lot of treasured lessons, and especially the confidence to step forward. Do you believe in yourself and have enough passion to pursue your goals? Keep trying and one day, chance and success will shine on you.
An entertaining way to raise awareness of health and scientific issues in HCM city’s young people.
OUCRU is proud to announce an exciting new endeavor: educational Science Theatre. These Science Theatre productions are part of a larger project of Public Engagement in Science or Mang Khoa Hoc Den Cong Dong - a community outreach project produced by the Training and Public Engagement Department of Oxford University Clinical Research Unit Vietnam (OUCRU) and sponsored by the Wellcome Trust.
In collaboration with the famous Thai Duong Theatre Company (IDECAF) in HCM city, WT-OUCRU has developed an educational theatre production to be performed at primary and secondary schools in various districts throughout Ho Chi Minh City. Through high quality theatre and drama we aim to highlight important, often difficult, current health and scientific issues and increase understanding in our audiences of children, young people and adults.
Science TheatreThe first production, entitled “An Amazing Battle” and starring famous Vietnamese actors such as Dinh Toan and Dai Nghia, is due to premiere just before the Vietnamese Lunar New Year. Incorporating famous Vietnamese folklore characters, such as Ong Dia, the round, happy God of the Earth who symbolizes prosperity and Thanh Giong, a famous mythological Vietnamese warrior, the story illuminates the causes and prevention of bacterial infection and raises awareness about antibiotic resistance.
When a young boy discovers Ong Dia has fallen ill, he and Thanh Giong use magical powers to become microscopic and travel in to the abyss of Ong Dia’s round belly to uncover the mystery of his ailment. With the help of an extremely meticulous doctor and a friendly bacterium the child and Thanh Giong learn about the sources and prevention of bacterial infection, as well as safe treatment methods. But, will they absorb enough information in time to conquer the mischievous bad bacteria and restore Ong Dia back to robust health? Captivated young audiences will be waiting in anticipation for that answer.
The first WT-OUCRU Science Theatre production is running from February to April 2010 and will be held in 25 schools in HCMC, reaching an estimated 25,000 students. A second show will be produced in early 2011. Through this work we hope to raise awareness about health and scientific related issues of relevance to people of all ages, and increase the profile of OUCRU Vietnam within the community that we work.
Dengue in Viet Nam: research for improved case management and prevention
2010 promises to be a landmark year for dengue research in Viet Nam. In collaboration with Roche Plc and the Hospital for Tropical Diseases, we will conduct the first ever clinical trial of a small molecule anti-viral drug to treat adult patients with dengue. Although this is the first trial of its kind in dengue, we expect many more to follow as anti-viral drug development for dengue accelerates in the public and private sectors. Separately, a randomised controlled trial of methyl-prednisolone (a corticosteroid drug) in children will complete enrolment at the Hospital for Tropical Diseases. This trial will answer whether methyl-prednisolone is safe to use in dengue patients, and might tell us if early interruption of the host immune response to dengue virus infection can improve clinical outcomes. These two trials will give us critical information on the prospects for anti-viral or immunodulatory therapies in the management of dengue as well as provide important insights into pathogenesis.
Our basic research continues apace. The launch of the “Healthy children” birth cohort study has been a major success thanks to the efforts of Katie Anders and her team. Through this study we aim to better understand risk factors for dengue and other infections in the first year of life of infants living in HCMC and Dong Thap. We continue to make advances in understanding dengue pathogenesis and viral epidemiology. We have now sequenced the genomes of ~1000 dengue viruses from Viet Nam and are using these to understand virus transmission dynamics within and between communities. With the aim of understanding why some children develop severe dengue and others do not, we have commenced a genome wide genetic association study in 2000 children with severe dengue.
A highlight of our work is the success of our students. We have recently celebrated the successful completion of PhD’s by Tran Nguyen Bich Chau and Vu Ty Hang and very soon, from Nguyen Thi Phuong Dung, Hoang Truong Long and Vianney Tricou. All of these students have made major contributions to dengue research in Viet Nam.