ARTEMISININ RESISTANT MALARIA

MALARIA, ARTEMISININ RESISTANCE - SOUTHEAST ASIA ************************************************ A ProMED-mail post ProMED-mail is a program of the International Society for Infectious Diseases Date: Tue 12 Nov 2013 Source: Firstpost [edited] Rise of drug-resistant malaria in Southeast Asia ------------------------------------------------ US experts are raising the alarm over the spread of drug-resistant malaria in several Southeast Asian countries, endangering major global gains in fighting the mosquito-borne disease that kills more than 600 000 people annually. While the communicable disease wreaks its heaviest toll in Africa, it's in nations along the Mekong River where the most serious threat to treating it has emerged. The availability of therapies using the drug artemisinin has helped cut global malaria deaths by a quarter in the past decade. But resistance to it emerged on the Thai-Cambodia border in 2003, and has since been confirmed in Viet Nam and Myanmar too. It has also been detected in southwest China and suspected as far away as Guyana and Suriname, according to a new report by the Center for Strategic and International Studies think tank. The report warns that could be a health catastrophe in the making, as no alternative anti-malarial drug is on the horizon. The UN World Health Organization, or WHO, is warning that what seems to be a localized threat could easily get out of control and have serious implications for global health. "Absent elimination of the malaria parasite in the Mekong, it is only a matter of time before artemisinin resistance becomes the global norm, reversing the recent gains," writes Dr Christopher Daniel, former commander of the US Naval Medical Research Center, in the report for a conference at the Washington think tank Tuesday [12 Nov 2013]. Mosquitoes have developed resistance [it is the malaria parasite which develops resistance, not the mosquito. - Mod.EP] to antimalarial drugs before. The same happened with the drug chloroquine, which helped eliminate malaria from Europe, North America, the Caribbean, and parts of Asia and South-Central America during the 1950s. Resistance first began appearing on the Thai-Cambodia border, and by the early 1990s it was virtually useless as an antimalarial in much of the world. Nowhere are the challenges in countering the threat to drug-resistance greater than in Myanmar, also known as Burma. Some 70 percent of its 55 million people live in malaria-endemic areas, and as a nation, it accounts for about three-quarters of malaria infections and deaths in the Mekong region, the report says. Myanmar's public health system is ill-equipped to cope, as government spending on health dwindled to the equivalent of just 60 US cents per person under military rule, although it has been increased significantly under the quasi-civilian administration that took power in 2011. In a third of townships, there been virtually no public health presence for years. It's an issue of regional concern as Myanmar has large transient populations in its border regions, including ethnic minorities displaced by fighting and migrant workers who cross borders. "It is clear that this country with its chronically under-resourced health system needs urgent additional attention," Daniel said. Resistance to artemisinin can be driven by various factors: delays in giving treatment, use of counterfeit or substandard drugs, and prescribing artemisinin on its own rather than in combination with another longer-acting drug to ensure that all malaria-carrying parasites in a patient's bloodstream are killed off. Cambodia and Laos have banned the use of such monotherapies, and Myanmar's military, which manufactures pharmaceuticals, announced in June [2013] it would cease production of them by early 2014. That comports with the global push by the UN for proper testing, treating, and tracking of malaria cases to prevent the disease spreading. The Center for Strategic and International Studies is advocating greater US involvement and aid for health and fighting malaria in the Mekong region, particularly in Myanmar, where Washington has been in the vanguard of ramping up international aid, as sanctions have been eased to reward it for democratic reforms. The centrist think tank argues that it can increase America's profile in Southeast Asia in a way that will benefit needy people and not be viewed as threatening to strategic rival, China. But securing more funds won't be easy at a time when Washington is cutting back on programs for its own poor. The US is already a major contributor to international anti-malaria efforts, and in Myanmar, is promising USD 20 million per year in health assistance under its recently resumed bilateral aid program. -- Communicated by: ProMED-mail from HealthMap Alerts [The emergence of artemisinin resistance in Myanmar (Burma) and Cambodia and indeed in the rest of Southeast Asia is a matter of grave concern. This is also where resistance to chloroquine (as pointed out in the message), sulfadoxine/pyrimethamine [Fansidar(R)], and mefloquine [Lariam(R)] first developed. The main driver is probably substandard dosing where purchase of single tablets is possible and counterfeit drugs containing substandard doses are common. We have previously argued that the development of resistance is best contained by providing the population with free malaria drugs ensuring a full course of treatment with drugs which contain the active compounds in the required doses (Schlagenhauf P, Petersen E: Antimalaria drug resistance: the mono-combi-counterfeit triangle. Expert Rev Anti Infect Ther. 2009; 7(9): 1039-42). Free drugs are provided to patients with HIV and tuberculosis and should be provided to malaria patients as well to remove the market for counterfeit and substandard drugs. - Mod.EP

Hep. C transmission by tears.

Hepatitis C and ocular surface disease. AU Jacobi C, Wenkel H, Jacobi A, Korn K, Cursiefen C, Kruse FE SO Am J Ophthalmol. 2007;144(5):705. PURPOSE: To assess the frequency of changes in the ocular surface and the presence of hepatitis C virus (HCV) in tear samples of patients with chronic HCV infection. DESIGN: Prospective, nonrandomized, clinical, interdisciplinary, single-center study. METHODS: Seventy-one patients with previously untreated chronic HCV infection and a control group consisting of 66 patients without systemic HCV infection were enrolled in the trial. The patients with HCV infection were screened for ocular symptoms, visual acuity, and ocular changes. Tear production was measured by the Jones test. Conjunctival impression cytologic analysis was performed. The presence of HCV ribonucleic acid (RNA) in tear and blood samples was determined by quantitative polymerase chain reaction. RESULTS: On examination, systemic HCV infection was present for a median of 30 months. Fifty percent of all HCV patients showed a decrease in tear production measured by the Jones test. Apart from epithelial changes related to dry eye syndrome in 12 patients,two patients presented mild peripheral corneal thinning. Polymerase chain reaction analysis detected HCV RNA in five (10%) of 52 tear samples. HCV RNA levels in tear samples (mean, 1.0 x 10(4) copies/ml) were considerably lower than in blood samples (mean, 5.3 x 10(5) copies/ml). CONCLUSIONS: Dry eye syndrome is the most frequently observed ocular feature in HCV infection. Patients with HCV infection (age range, 21 to 60 years) compared with the controls had a significant lower tear production (P = .05). The presence of HCV RNA in 10% of tear samples emphasizes the potential risk of viral transmission through tears. AD Department of Ophthalmology, University of Erlangen, Erlangen, Germany. christina.jacobi@augen.imed.uni-erlangen.de PMID 17870047

UTRECHT Univ. Hospital: Prof HENK LOKHORST on DARATUMUMAB for Multiple Myeloma

http://myeloma.org/ArticlePage.action?tabId=0&menuId=0&articleId=4118&aTab=-4 VIDEO of Prof LOKHORST on DARATUMUMAB trials.

ProMED:OBITUARY Dr. J.H.STEELE DVM(Mich.) MPH(Harvard)

OBITUARY: JAMES HARLAN STEELE ***************************** A ProMED-mail post ProMED-mail is a program of the International Society for Infectious Diseases Date: 11 Nov 2013 From: Peter Cowan, ProMED-mail Animal Disease Assistant Moderator Yesterday [10 Nov 2013], we all witnessed the exit of a lion. Over his 100-year-plus lifespan, James Harlan Steele was a true pioneer in Public Health and the rebirth of One Health. He was tenacious in his quest to enlarge the role of veterinary medicine in public health, emboldened by the conviction that any avenue that can benefit the health and well-being of people leads to a more progressive, rational and fair state of affairs for his community, country, and the world. Steele set the direction, found the resources, selected and cultivated enough talented people to achieve his dream of One Health, which was manifested as the establishment of vital veterinary public health infrastructure at the state, national, and international levels. He literally built the 1st of many veterinary public health programs in the United States and the world beginning at CDC in 1946. Dr. Steele was a systems thinker, a strategic analyst, and a magnet for bright, young talented veterinarians, physicians, and other health professionals. He took the idea of One Health and implemented it, building a framework for programs such as rabies control, which could showcase what One Health, 1st named by Steele as Veterinary Public Health, could do. Dr. Steele received a doctorate of veterinary medicine from Michigan State University in 1941 and an MPH from Harvard University in 1942. Until yesterday [10 Nov 2013], he was the oldest living graduate of the Harvard School of Public Health. He founded and named the 1st Veterinary Public Health program at CDC and within the United States Public Health Service where he served for many years. Early on, Jim worked closely with Alex Langmuir and was so critical to the implementation and growth of CDC's EIS training program through the 1950s and 1960s that he was inducted as an honorary EIS member in 1976. He served as Assistant Surgeon General for Veterinary Affairs and the 1st Chief Veterinary Officer of the USPHS. He played a critical part at the 1st meeting of the Veterinary Public Health Expert Committee on Zoonosis at WHO. He played an inspirational role in the development of several European Veterinary Public Health Services, particularly in West Germany. Professor Steele was the Editor in Chief of the CRC Handbook of Zoonoses series and a consultant to the Control of Communicable Disease Manual for decades. These accomplishments are only a brief mention of his activities and barely scratch the surface of his impact both nationally and internationally. Jim's honors and awards are almost too numerous to count. In 1971, he joined the University of Texas School of Public Health's Infectious Disease Center, where he served as Professor until his 80th birthday. He then went into "retirement," which consisted of a whirlwind of writing, editing, consulting, and mentoring that would dwarf the output of many younger people. He was incredibly sharp and active right up to the end, engaging at over 100 years of age in an update of his work on tuberculosis, a short history of One Health, and planning for a special symposium entitled the James H. Steele Challenge: A better world through One Health. His video speech last July [2013] to the American Veterinary Medical Association's 150th anniversary was an inspiration, not solely because he had lived through 2/3rds of the existence of that professional organization dating back to the U.S. Civil War, but because of the forwardness of the thoughts in his speech. To have a vision to hand over to others at age 100 is truly remarkable. Jim loved to tell stories related to the history and purpose of Veterinary Public Health. He recalled this experience many times to many of us: "In 1945, at the end of WW II, Joseph Mountin, a physician and chief of the USPHS's Bureau of State Services, met with him to discuss the global origin and importance of zoonotic diseases. He challenged Steele by saying: "What are you veterinarians going to do for public health now that the war is over?" Jim Steele's response was vital to the future of veterinary public health and the rest of his career. Eventually, he suggested the creation of a program within USPHS that would work on zoonotic diseases. He looked down the hall and saw Dental Public Health and Public Health Nursing and decided Veterinary Public Health would do just fine. He further recommended the establishment of a corps of veterinary officers within the USPHS so that veterinarians who became Commissioned Corps members would have a place in the structure. Craig Carter, at the University of Kentucky, has written a very nice biography entitled One Man, One Medicine, One Health: The James H. Steele story. Over his career, Jim had big megaphones at CDC, WHO, USDA, PAHO, APHA and AVMA, which he used to advocate for acceptance of the idea of One Health. He developed programs which served as models the world over and that proved that good animal health meant good human health, which, in turn, translates to good economic health. Steele played a seminal role in the rebirth of the idea of One Health. His efforts finally flowered in full bloom in the 1st decade of the 21st century, embodied by the wide acceptance of One Health and activities worldwide in response to HPAI H5N1 and other emerging disease threats. Notwithstanding his gargantuan accomplishments and his photographic memory, Jim's singular quality was mentoring. He loved people, especially young people, and for the last 2 decades of his life, everyone was young to Jim. He loved to work with people, and so very many of them became friends. He was an optimist with a sense of humor, and the jokes he made on the occasion of his 100th birthday were too rich to repeat here. He had charisma to the maximum extent, but he was also a hard driving realist who knew how to fund and build programs the world over. He was never too busy, and he truly knew how to listen. Whether the problem was epidemiological or personal, Jim would provide sound advice, oftentimes guiding his mentees towards their own solutions. Jim loved to think and do; he loved to listen and comfort. The list of Jim's "students" included not only those for whom he had acted as a professor at the University of Texas School of Public Health but also so many individuals at CDC and the United States Public Health Service as well as veterinary colleges and the United States Department of Agriculture. The width of the swath cut by Jim's mentees was truly impressive. Bill Foege, the former director of CDC, said at Jim's 90th annual birthday lecture that Jim's seminal contribution was that the health of humans and the health of animals are inseparable. This premise was Jim's greatest gift and allowed us to develop a more rational public health future, because you cannot consider the health of people without considering the health of animals. Dr. Foege finished Jim's 90th birthday address with the following paragraph, which bears repeating now: "And so our tribute to a long life well lived as a generalist, specialist, globalist, futurist, moralist, optimist, and gift giver is mixed with gratitude, gratefulness, and the anticipation of the next decade being the best ever. On behalf of countless generations, yet unborn, we say: Thank you Jim, for this greatest gift." Yes, a lion has roared, and we are all the better for it. -- Peter Cowen ProMED-mail Animal Disease Assistant Moderator

DENMARK: GENMAB A/S HuMax-CD38

Daratumumab is a human CD38 monoclonal antibody with broad-spectrum killing activity. Daratumumab is in clinical development for multiple myeloma (MM). Daratumumab targets the CD38 molecule which is highly expressed on the surface of multiple myeloma cells. Daratumumab could also have potential in other hematological tumors on which CD38 is expressed, including diffuse large B-cell lymphoma, chronic lymphocytic leukemia, acute lymphoblastic leukemia, acute myeloid leukemia, follicular lymphoma and mantle cell lymphoma. Daratumumab has received Fast Track Designation and Breakthrough Therapy Designation from the US FDA for the treatment of patients with multiple myeloma who have received at least three prior lines of therapy including a proteasome inhibitor (PI) and an immunomodulatory agent (IMiD) or who are double refractory to a PI and IMiD. Breakthrough Therapy Designation is a program intended to expedite the development and review of drugs to treat serious or life-threatening diseases in cases where preliminary clinical evidence shows that the drug may provide substantial improvements over available therapy. Daratumumab has also received Orphan Drug Designation from the US FDA and the EMA for the treatment of multiple myeloma. Daratumumab has multiple mechanisms of action, including complement-dependent cytotoxicity (CDC), antibody-dependent cell-mediated cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), apoptosis and modulation of CD38 enzymatic activity. In pre-clinical studies, daratumumab has been shown to effectively kill multiple myeloma cells and to enhance the potency of other multiple myeloma treatments. Genmab announced a global license and development agreement for daratumumab with Janssen Biotech, Inc. in August 2012. The agreement become effective in September 2012.

NEW DISEASE:PASLI P110 delta Activating mutation causing Senescent T-cells, Lymphadenopathy, Immunodeficiency

NIH Scientists Identify a New Immunodeficiency Disease Condition May be Treatable with Anti-Rejection Drug The NIAID Primary Immune Deficiency Clinic is located in the NIH Mark O. Hatfield Clinical Research Center. Credit: NIH. Scientists from the National Institute of Allergy and Infectious Diseases (NIAID) and National Human Genome Research Institute at the National Institutes of Health have identified a novel, genetic human immunodeficiency called PASLI disease. People with this disease have impaired immune responses, predisposing them to chronic infections and lymphoma, a form of cancer. After pinpointing the genetic cause of PASLI disease, researchers treated one patient with rapamycin, a drug approved by the Food and Drug Administration (FDA) to prevent transplant rejection. The therapy showed promise and will be further evaluated in other patients. The study appears in the October 28, 2013, online issue of Nature Immunology. Background Primary immune deficiency diseases (PIDDs) are rare, genetic disorders that impair the immune system. Without a functional immune response, people with PIDDs may be subject to chronic, debilitating infections, such as Epstein-Barr virus (EBV), which also can increase the risk of developing cancer. PIDDs may be diagnosed in infancy, childhood, or adulthood, depending on disease severity. They are estimated to affect more than 500,000 people in the United States. PIDDs usually are treated with therapies that broadly boost the immune response, such as regular infusions of antibodies from healthy blood donors. These therapies may not be completely effective or even target the underlying cause of disease. However, identification of the mutated gene responsible for a PIDD allows researchers to address the specific cause and test therapies that directly target the problem. NIAID runs a primary immune deficiency (PID) clinic, which operates on a referral basis. The goal of the clinic is to provide patients with an accurate disease diagnosis, particularly from a genetic standpoint, and help referring specialists improve patient care. Results of Study NIAID researchers and their collaborators identified a novel PIDD called PASLI disease, named after the mutated gene and its symptoms (p110 delta activating mutation causing senescent T cells, lymphadenopathy, and immunodeficiency). PASLI disease was initially detected in 6 patients who were referred to the NIAID PID Clinic. Upon further screening of the patients’ relatives, the disease was confirmed in 14 patients from 7 unrelated families of different ethnic and racial backgrounds. The patients have experienced recurring infections, including bacterial infections of the respiratory system and chronic viral infections with EBV, since childhood, and some have developed EBV-associated lymphoma. By studying this group, the researchers found that the patients have a mutation in their PIK3CD gene, resulting in an overactive protein called PI3K-p110 delta. PI3K proteins are essential for directing the growth and activity of many types of immune cells, and p110 delta is specifically involved in B and T cells, which make antibodies and recognize and eliminate infected cells, respectively. The mutated, overactive p110 delta protein causes a chain reaction of problems. By sending the wrong signals at the wrong times, it disrupts the normal development of B and T cells, increasing susceptibility to infection. The genetic information allowed the researchers to identify and target mTOR, an important signal that is excessively activated by p110 delta in PASLI patients. Drugs that block mTOR are already FDA-approved for the prevention of transplant rejection. One patient was treated with the drug rapamycin daily, which restored T cells to normal levels after 4 months. While the patient is not cured, normalization of T cells was adequate to improve disease symptoms. Significance The study has identified a novel immunodeficiency disease called PASLI, its underlying genetic cause, and a promising, targeted treatment that is already FDA-approved for other purposes. The discovery of PASLI disease also contributes to our understanding of the immune system and highlights the role of PI3K-p110 delta and mTOR in immunity. Next Steps NIAID researchers are currently treating more PASLI patients with rapamycin to better understand the drug’s clinical effects. In the future, patients also may be treated with drugs that target p110 delta, rather than mTOR. However, such drugs are still under development and some are being evaluated in human disease. Researchers also continue to optimize therapy for PASLI patients, who may eventually need to undergo bone-marrow transplantation to reboot their immune systems. Reference Lucas CL, Kuehn HS, Zhao F, Niemela JE, Deenick EK, Palendira U, Avery DT, Moens L, Cannons JL, Biancalana M, Stoddard J, Ouyang W, Frucht DL, Rao VK, Atkinson TP, Agharahimi A, Hussey AA, Folio LR, Olivier KN, Fleisher TA, Pittaluga S, Holland SM, Cohen JI, Oliviera JB, Tangye SG, Schwartzberg PL, Lenardo MJ, and Uzel G. Dominant-activating germ line mutations in the gene encoding the PI3K subunit p110d result in T cell senescence and human immunodeficiency.External Web Site Policy Nature Immunology (2013)

Obituary: Dr.Milton PUZISS developer of ANTHRAX VACCINE.

Date: 26 Oct 2013 Source: Washington Post [edited] Milton Puziss, a microbiologist who helped develop the 1st human vaccine against anthrax in the United States, died on 9 Oct 2013 at the Edenton retirement community in Frederick, Maryland. He was 93. The cause was congestive heart failure, said his daughter, Marla Puziss. Dr. Puziss was working for the Army Department at Fort Detrick, Md. when he developed an anthrax vaccine in the late 1950s with another scientist, George Wright. One purpose of the research was to find a vaccine to use in the case of a biological attack. Earlier anthrax vaccines had been developed in other countries. The Wright-Puziss vaccine was tested in clinical trials, and a version of it is widely used today. After 17 years with the Army Department, Dr. Puziss joined the National Institute of Allergy and Infectious Diseases in 1968. He conducted research on Legionnaire's disease and other bacterial and fungal diseases. He retired as chief of the NIAID bacteriology and virology branch in 1986. He was a recipient of the NIH Director's Award. Milton Puziss was born in Philadelphia and grew up in Shrub Oak, N.Y. After Army service in World War II, he graduated in 1948 from Kansas State University. In 1949, he received a master's degree in bacteriology and biochemistry from the University of Wisconsin, and in 1956, he received a doctorate in the same disciplines from the University of Southern California.