Deadly New Virus Kills 3 Organ Transplant Patients 2-6-8
WASHINGTON (Reuters) - A previously unknown virus killed three women who got organ transplants from an Australian donor, and researchers say the technique they used to identify it could lead them to many more new infectious agents.
The as-yet-unnamed virus appears to be related to a bug called lymphocytic choriomeningitis virus, which usually causes only a minor flu-like illness.
But this one killed the three transplant patients by causing encephalitis, a swelling of the brain, the team reported on Wednesday in the New England Journal of Medicine.
The researchers used a relatively new method to find the virus, called high-throughput sequencing. They used powerful machines to get the full genetic sequences from the organs and from the patients, and filtered out everything but the sequences from the virus.
When the three women, ages 63, 64 and 44, all died in the Australian hospital after receiving a liver and two kidneys from the same man, doctors knew something was wrong. But a team at the Victoria Infectious Diseases Reference Laboratory could not find a cause.
"That donor died of a stroke and was not thought to have had an infectious disease at all," said Dr. Ian Lipkin of Columbia University in New York, who led the study.
Traditional methods such as trying to grow a virus or bacteria from samples, and even standard DNA sequencing, failed to turn up anything.
"As a result, the samples were sent to us," Lipkin said in a telephone interview.
HEAVYWEIGHT GENE MACHINE
His team used a new machine -- a high-throughput sequencer made by 454 Life Sciences, a part of Roche Applied Science and Roche AG.
These machines are usually used to mass-sequence entire genomes of large organisms, such as humans. It had never been used on a hunt like this one.
"After 100,000 different sequence analyses we found 14 (suspicious viral genetic sequences)," Lipkin said. "So it was a needle-in-a-haystack problem."
The RNA resembled the RNA from a type of virus known as an arenavirus, specifically lymphocytic choriomeningitis virus or LCMV, known to cause transplant-related disease and birth defects in addition to mild flu-like illness in healthy people.
The 57-year-old organ donor had recently visited the former Yugoslavia before dying of a cerebral hemorrhage in Australia, and Lipkin's team said the virus looked like it was of "Old World" origin.
"The virus is new and was not detected in 100 organ recipients who were not linked to this cluster," they wrote.
Lipkin said the method may be useful for diagnosing mysterious new ailments.
"We have so many diseases where there is no agent implicated," he said. "Over half of pneumonia and over half of encephalitis and over half of diarrheal disease are never diagnosed," he added.
"We need to be able to survey for old and new agents."
Christopher McLeod, president of 454 Life Sciences, said the machine might help identify emerging new infections, like the severe acute respiratory syndrome, or SARS, virus that appeared suddenly in China in 2002 and killed nearly 800 people globally before it was contained two years later.
"Over 30,000 organ transplants are performed in the U.S. each year. Knowledge of the genetic sequence of this virus might enable improvements in screening that will enhance the safety of transplantation," McLeod said in a statement.
(Editing by Will Dunham and Xavier Briand)
Patricia A. Doyle DVM, PhD Bus Admin, Tropical Agricultural Economics Univ of West Indies
"All truth passes through three stages. First, it is ridiculed, second it is violently opposed, and third, it is accepted as self-evident."
Arthur Schopenhauer, Philosopher, 1788-1860
"In the final analysis, our most basic common link is that we all inhabit this small planet, breathe the same air, and we all cherish our children’s future."
By Mary Vorsino Advertiser Staff Writer An O'ahu distributor has voluntarily recalled 11,000 pounds of frozen fish after federal investigators found salmonella while testing a parcel of 'ahi.
"Our main concern is safety," Edmund Choy, owner of Choyce Products, said in a news release. "We unknowingly received a tainted package. We immediately issued a voluntary recall and confirmed that our customers do not have 'ahi from that parcel in their inventory."
The frozen fish is most commonly used in poke.
The recall comes after more than 33 cases of the same strain of salmonella — Salmonella paratyphi B — were reported on O'ahu from October to December 2007. State health officials traced the cases to 'ahi that was consumed raw, but they did not link it to a particular eatery or grocery store, or even one distributor.
That means more tainted fish could still be for sale.
U.S. Food and Drug Administration investigators are testing 'ahi samples at the more than 40 distributors on O'ahu to see whether there are other shipments of tainted fish. Meanwhile, health officials point out the recalled fish is not necessarily related to the outbreak since it is unclear what type of salmonella was found in the frozen parcel.
The recalled fish got to O'ahu from Indonesia in early December.
About half of the recalled shipment has been recovered.
The FDA would not comment on the investigation. But a Choyce Products spokeswoman said the company is cooperating with the FDA. She said the company has never had a similar case of tainted fish.
Carroll Cox, president of EnviroWatch Inc., which has been investigating the salmonella reports, commended Choyce Products for voluntarily recalling the tainted fish, but questioned why state Health Department officials and the FDA are not talking about other distributors, wholesalers and stores that possibly sold tainted fish.
"They need to come out and give the public information on this cluster," he said. "Others could have gotten sick and not know why."
He also questioned why it has taken so long for the fish to be tested.
Janice Okubo, Health Department spokeswoman, said state investigators started to look into the salmonella cases in December, though they had been tracking it since the first reports came in.
Tracing the salmonella to a food source was difficult because residents who got sick did not share a common source — they didn't all eat at the same restaurant or shop at the same grocery store.
Federal investigators were called in last month.
Paul Effler, state epidemiologist with the Health Department, said most of those who got sick after eating raw 'ahi experienced relatively mild symptoms, including diarrhea and vomiting. There were no reports of people getting blood-borne infections, which can require hospitalization.
Hawai'i typically has about 300 cases of salmonella poisoning annually. But the cluster of cases tied to raw fish were from a strain that health officials typically see just 10 times a year. The strain has been associated with smoked white fish, unpasteurized milk and alfalfa.
Effler said although the number of cases of the salmonella strain is higher than usual, the contamination is considered low-level because it did not appear to taint a large portion of the original supply of 'ahi.
He pointed out there are more than 220,000 pounds of 'ahi shipped into Hawai'i monthly."It's not like there have been a tremendous number of illnesses given the 'ahi consumed," Effler said.
Report: Troops Transmitted Mysterious Bacteria That Has Killed 7 And Affected Military And Civilians Alike By JOHN HENDREN
Feb. 8, 2008—
Troops arriving home from Iraq and Afghanistan have been carrying a mysterious, deadly bacteria, according to a new magazine report.
Doctors have linked the bacterium acinetobacter baumannii to at least seven deaths, as well as to loss of limbs and other severe ailments, according to the report, which found the bacterium has spread quickly since the war in Afghanistan began in the fall of 2001
Acinetobacter baumannii has been found in military hospitals in Germany, the Washington, D.C., area and Texas -- the primary destinations of wounded service members from the two war zones. And it has now spread to civilians, according to the report.
"The outbreak began traveling with patients or nonpatients from Iraq all the way back to Walter Reed," said Dr. Rox Anderson at Harvard Medical School.
Dr. Timothy Endy, a retired Army colonel now teaching infectious disease medicine at the Upstate Medical University of the State University of New York, said the outbreak might be the largest of its kind to spread through hospitals in history.
Doctors quoted in the magazine article agreed. "Of the infectious disease problems that come out of the conflict, it is the most important complication we've seen," Dr. Glenn Wortmann, acting chief of infectious disease at Walter Reed Army Medical Center, said in the February issue of Proceedings, published by the U.S. Naval Institute, a professional organization focused on naval issues.
What is Acinetobacter baumannii?: A gram negative bacteria instrinsically resistant to many antibiotics.
Where is it found in the environment? : In water and soil. The bacteria can survive for several days on many surfaces, including those difficult to control such as cell phones and keyboards.
Who gets it?: Generally speaking, only people who have weakened immune systems are at risk. The disease is generally presented as a nosocomial infection only, meaning it affects patients in hospitals. At least 240 US military personnel have had infections from the A. baumannii bacteria since the Iraq war began in 2003. A. baumanni was also seen among soldiers during the Vietnam war.
The disease accounts for only 1.3 per cent of all bloodstream infections in hospitals in the US, but the disease is on the increase in military healthcare facilities where personnel coming from Iraq, Kuwait and Afghanistan are being treated.
Why is A.baumannii a concern?: Treatment options are limited. The already antibiotic resistant bacteria is becoming resistant to more and more antibiotics. A.baumannii infection can lead to complications such as pneumonia, fever and septicaemia. In an article by Steve Mitchell for United Press International, an analyst says that when there is a really serious infectious doctors are left with nothing to fight them. Some A. baumannii strains are resistant to all of the treatments mankind has available today.
How is it treated?: The only drug that works on multi-resistant strains of A.baumannii is colistin (Polymyxin E) a very toxic drug. Colistin is not often administered because of its toxicity and it's not available in the US. Some A.baumannii is also susceptible to treatment with imipenem, also known as cilastatin or Primaxin and other types of carbapenems.
What are the recommendations to prevent A.baumannii infection?: Infection control by good hand hygiene and disease isolation. Groin, axillary and wound cultures in military personnel should be monitored carefully for A.baumannii.
Acinetobacter baumannii Infections Among Patients at Military Medical Facilities Treating Injured U.S. Service Members, 2002--2004
Acinetobacter baumannii is a well known but relatively uncommon cause of health-care--associated infections. Because the organism has developed substantial antimicrobial resistance, treatment of infections attributed to A. baumannii has become increasingly difficult (1). This report describes an increasing number of A. baumannii bloodstream infections in patients at military medical facilities in which service members injured in the Iraq/Kuwait region during Operation Iraqi Freedom (OIF) and in Afghanistan during Operation Enduring Freedom (OEF) were treated. The number of these infections and their resistance to multiple antimicrobial agents underscore 1) the importance of infection control during treatment in combat and health-care settings and 2) the need to develop new antimicrobial drugs to treat these infections.
During January 1, 2002 - August 31, 2004, military health officials identified 102 patients with blood cultures that grew A. baumannii at military medical facilities treating service members injured in Afghanistan and the Iraq/Kuwait region. All of these cases met the criteria for A. baumannii bloodstream infection on the basis of criteria established by CDC's National Nosocomial Infection Surveillance (NNIS) system (2). Of these 102 cases, 85 (83%) were associated with activities during OIF and OEF. Most of the infections were reported from Landstuhl Regional Medical Center (LRMC), Germany (33 patients: 32 OIF/OEF casualties, one non-OIF/OEF), and Walter Reed Army Medical Center (WRAMC), District of Columbia (45 patients: 29 OIF/OEF casualties, 16 non-OIF/OEF). In both facilities, the number of patients with A. baumannii bloodstream infections in 2003 and 2004 exceeded those reported in previous years (one case during 2000--2002 at LRMC; two cases during 2001--2002 at WRAMC).
Of the 33 patients with A. baumannii bloodstream infections at LRMC, 32 (97%) were men; the median age was 30 years (range: 19--72 years). Thirty (91%) patients sustained traumatic injuries in either the Iraq/Kuwait region (25) or in Afghanistan (five). The majority (67%) were active-duty members of the U.S. Armed Forces. Thirty-two (97%) were transferred directly to the LRMC intensive care unit (ICU) from a combat theater military medical facility. In 22 (67%) of these patients, bloodstream infections were detected from blood cultures obtained within 48 hours of ICU admission.
Of the 45 patients with A. baumannii bloodstream infections at WRAMC, 39 (87%) were males; the median age was 39 years (range: 6--86 years). Twenty-nine (64%) patients sustained traumatic injuries in the Iraq/Kuwait region. Of these, 18 (62%) had bloodstream infections detected from blood cultures obtained within 48 hours of hospital admission after transfer from a combat theater medical or other military medical facility.
Antimicrobial susceptibility testing (AST) was performed by using microdilution. Results of 33 A. baumannii isolates from LRMC and 45 isolates from WRAMC indicated widespread resistance to antimicrobial agents commonly used to treat infections with this organism. AST results, expressed as a percentage of susceptible isolates, were as follows: imipenem (LRMC: 87%; WRAMC: 82%), amikacin (LRMC: 80%; WRAMC: 48%), ampicillin/sulbactam (LRMC: 8%; WRAMC: 35%), piperacillin/tazobactam (LRMC: 0%; WRAMC: 27%), cefepime (LRMC: 0%; WRAMC: 22%), and ciprofloxacin (LRMC: 3%; WRAMC: 20%).
Among the WRAMC isolates, 13 (35%) were susceptible to imipenem only, and two (4%) were resistant to all drugs tested. One antimicrobial agent, colistin (polymyxin E), has been used to treat infections with multidrug-resistant A. baumannii; however, AST for colistin was not performed on isolates described in this report.
In addition to LRMC and WRAMC, three other military treatment facilities have identified A. baumannii bloodstream infections in service members injured in Iraq, Kuwait, and Afghanistan: U.S. Navy hospital ship (USNS) Comfort (11 patients), National Naval Medical Center (NNMC), Bethesda, Maryland (eight), and Brooke Army Medical Center (BAMC), San Antonio, Texas (five).
Reported by: PT Scott, MD, Army Medical Surveillance Activity, District of Columbia. K Petersen, DO, National Naval Medical Center, Bethesda, Maryland. J Fishbain, MD, DW Craft, PhD, AJ Ewell, PhD, K Moran, MD, DC Hack, MD, Walter Reed Army Medical Center, District of Columbia. GA Deye, MD, S Riddell, PhD, G Christopher, MD, Landstuhl Regional Medical Center, Landstuhl, Germany. JD Mancuso, MD, BP Petruccelli, MD, US Army Center for Health Promotion and Preventive Medicine. T Endy, MD, L Lindler, PhD, Walter Reed Army Institute of Research, Silver Spring, Maryland. K Davis, MD, Brooke Army Medical Center, San Antonio, Texas. EG Milstrey, PhD, US Army 30th Medical Brigade. L Brosch, MD, Uniformed Svcs Univ of the Health Sciences, Bethesda, Maryland. J Pool, MS, Office of the Surgeon General of the Army. CL Blankenship, MD, Office of the Surgeon General of the Navy. CJ Witt, DVM, JL Malone, MD, Global Emerging Infections Surveillance and Response System; DN Tornberg, MD, Office of Health Affairs, US Dept of Defense. A Srinivasan, MD, Div of Healthcare Quality Promotion, National Center for Infectious Diseases, CDC. Editorial Note:
A. baumannii are a species of gram-negative bacteria commonly found in water and soil. During 1963--2003, A. baumannii became an increasingly important cause of nosocomial infections, particularly in ICUs (3). Treatment of infections attributed to A. baumannii can be difficult because the organism has intrinsic resistance to certain antimicrobial agents and has acquired resistance to many others (3). In health-care settings, colonized and infected patients are often the sources of A. baumannii infections; however, the ability of the organism to survive for prolonged periods on environmental surfaces also has contributed to protracted outbreaks in these settings (1).
In a recent national survey of hospital laboratories, A. baumannii infections accounted for only 1.3% of health-care--associated bloodstream infections (4). However, the findings in this report indicate an increase in the number of reported A. baumannii bloodstream infections in patients at military medical facilities in which service members injured in Iraq, Kuwait, and Afghanistan are treated.
The sources of the A. baumannii that led to the infections described in this report are under investigation. During the Vietnam War, A. baumannii was reported to be the most common gram-negative bacillus recovered from traumatic injuries to extremities, and more recent reports have identified A. baumannii infections in patients who suffered traumatic injuries, suggesting environmental contamination of wounds as a potential source (5--8). Although some of the patients identified in this report had evidence of bloodstream infections at the time of admission to military medical facilities, whether the infections were acquired from environmental sources in the field or during treatment at (or evacuation from) other military medical facilities (e.g., field hospitals) is unknown. Information on patients described in this report is being reviewed to examine potential risk factors for A. baumannii bloodstream infection. In addition to exploring traditionally reported risk factors such as antimicrobial exposure, ICU admission, vascular access, and mechanical ventilation, this investigation will involve detailed reviews of geographic locations where injuries occurred and reviews of the movement of injured patients through treatment facilities. An environmental microbiology survey of both indigenous soil samples and treatment facilities is also under way to explore the potential contribution of environmental contamination to this outbreak. Molecular analysis with pulsed-field gel electrophoresis of patient and environmental isolates will be performed to further characterize the potential contribution of environmental contamination.
The bacterial isolates described in this report demonstrated antimicrobial-resistance patterns similar to multidrug-resistant A. baumannii from ICUs in the United States and Europe (3,4). Data from the NNIS system also indicate that resistance among Acinetobacter isolates is increasing (CDC, unpublished data, 2004). The high level of antimicrobial resistance is a challenge to clinicians treating A. baumannii infections. In some cases, the only effective antimicrobial agent is colistin (polymyxin E); however, this agent is seldom used because of its high toxicity (9). Use of colistin, possibly in combination with other agents, might be effective; however, new agents active against multidrug-resistant A. baumannii are needed. Treatment of patients infected with A. baumannii is being monitored to determine factors predictive of success and failure, to better understand the impact of antimicrobial resistance on therapy, and to monitor the potential toxicities of treatment regimens that include colistin.
Identification of colonized and infected patients, combined with implementation of infection-control measures such as hand-hygiene and contact-isolation precautions, might help prevent transmission of this organism within medical facilities (1). Interventions recommended by military medical officials have included 1) institution of active surveillance of groin, axillary, and/or wound cultures for A. baumannii for all patients; 2) use of contact precautions for colonized or infected patients; and 3) increased availability and use of alcohol-based hand rubs. Laboratory surveillance for A. baumannii has been initiated at LRMC, NNMC, WRAMC, and BAMC, and, as much as possible, at each forward-deployed combat support hospital and medical treatment facility in Iraq, Kuwait, and Afghanistan.
Clinicians who treat patients who have recently been hospitalized (especially in ICUs) at the military hospitals described in this report should be aware of the potential for colonization and infection with A. baumannii. Additional information on A. baumannii is available at www.cdc.gov/ncidod/hip. Clinical management and wound-care guidelines have been developed to help prevent and mitigate A. baumannii infections in military treatment facilities (10). Clinicians with specific questions about A. baumannii among U.S. service members should contact the U.S. Army Center for Health Promotion and Preventive Medicine, telephone 800-222-9698.
This report is based, in part, on contributions by E Gourdine, MS, 31st Combat Support Hospital; A O'Brien, MPH, MultiNational Corps, Baghdad, Iraq. W Wortman, Kadix Systems, Aberdeen Proving Ground, Maryland. M Pe, K Snow, MS, EA Hulten, MD, M Buddle, AF Shorr, MD, Walter Reed Army Medical Center, District of Columbia. M Dobson, PhD, Armed Forces Institute of Pathology, District of Columbia. C Gaddy, MS, LA Pacha, MD, RL Mott, MD, T Hamilton, S Lee, MS, Y Liu, MD, PJ Weina, MD, PhD, M Krauss, MD, Walter Reed Army Institute of Research, Silver Spring, Maryland. P Gray, MSN, DP Dooley, MD, Brooke Army Medical Center, San Antonio, Texas. RD Bradshaw, MD, Uniformed Svcs Univ of the Health Sciences, Bethesda, Maryland. R Gibson, PhD, US Armed Forces Epidemiological Board. M Dorf, PhD, US Army 804th Medical Brigade. SA Tasker, MD, E Campbell, National Naval Medical Center; EM Kilbane, MD, Office of the Surgeon General of the US Navy. S Zobel, RL Erickson, MD, US Army Center for Health Promotion and Preventive Medicine; JM Rusnak, US Army Research Institute of Infectious Diseases. K Woodward, MD, Air Force Medical Support Agency; PA Mondloh, MA, Air Mobility Command; TL DiFato, MPH, Office of the Surgeon General of the US Air Force. EC McDonald, MD, GR Cox, MD, US Marine Corps. J Mansfield, MAS, V MacIntosh, MD, Global Emerging Infections Surveillance and Response System; K Cox, MD, Office of Health Affairs, US Dept of Defense. K Kubota, MPH, Div of Vector-Borne Infectious Diseases, National Center for Infectious Diseases, CDC.
1. Urban C, Maurer-Segal, Rahal JJ. Considerations in control and transmission of nosocomial infections due to multi-drug resistant Acinetobacter baumannii. Clin Infect Dis 2003;36:1268--74. 2. Horan TC, Gaynes RP. Surveillance of nosocomial infections. In: Mayhall CG, ed. Hospital epidemiology and infection control. 3rd ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2004:1659--702. 3. Van Looveren M, Goossens H, ARPAC Steering Group. Antimicrobial resistance of Acinetobacter spp. in Europe. Clin Microbiol Infect 2004;10:684--704. 4. Wisplinghoff H, Bischoff T, Tallent SM, Seifert H, Wenzel RP, Edmond MB. Nosocomial bloodstream infections in US hospitals: analysis of 24,179 cases from a prospective nationwide surveillance study. Clin Infect Dis 2004;39:309--17. 5. Tong MJ. Septic complications of war wounds. JAMA 1972;219:1044--7. 6. Oncul O, Keskin O, Acar HV, et al. Hospital-acquired infections following the 1999 Marmara earthquake. J Hosp Infect 2002;51:47--51. 7. Heath CH, Orrell CT, Lee RC, Pearman JW, McCullough C, Christiansen KJ. A review of the Royal Perth Hospital Bali experience: an infection control perspective. Australian Infection Control 2003;2: 43--54. 8. Aarabi B. Comparative study of bacteriological contamination between primary and secondary exploration of missile head wounds. Neurosurgery 1987;20:610--6. 9. Levin AS, Barone AA, Penco J, et al. Intravenous colistin as therapy for nosocomial infections caused by multidrug-resistant Pseudomonas aeruginosa and Acinetobacter baumannii. Clin Infect Dis 1999;28:1008--11. 10. Blankenship CL. Guidelines for care of open combat casualty wounds. Available at www.geis.fhp.osd.mil
Botox Linked to Children's Deaths By LAURAN NEERGAARD, AP Posted: 2008-02-08 19:08:22
WASHINGTON (Feb. 8) - The popular anti-wrinkle drug Botox and a competitor have been linked to dangerous botulism symptoms in some users, cases so bad that a few children given the drugs for muscle spasms have died, the government warned Friday.
The Food and Drug Administration's warning includes both Botox, a wrinkle-specific version called Botox Cosmetic, and its competitor, Myobloc, drugs that all use botulinum toxin to block nerve impulses, causing them to relax.
patient receives Botox injections Andreas Rentz / Getty Images
Botox and another anti-wrinkle drug, Myobloc, have been linked to some deaths and other side effects suggestive of botulism, the FDA warned. Both drugs use botulinum toxin and in rare cases, the toxin may spread beyond the injection site. In rare cases, the toxin can spread beyond the injection site to other parts of the body, paralyzing or weakening the muscles used for breathing and swallowing, a potentially fatal side effect, the FDA said.
Botox is best known for minimizing wrinkles by paralyzing facial muscles — but botulinum toxin also is widely used for a variety of muscle-spasm conditions, such as cervical dystonia or severe neck spasms.
The FDA said the deaths it is investigating so far all involve children, mostly cerebral palsy patients being treated for spasticity in their legs. The FDA has never formally approved that use for the drugs, but some other countries have.
However, the FDA warned that it also is probing reports of illnesses in people of all ages who used the drugs for a variety of conditions, including at least one hospitalization of a woman given Botox for forehead wrinkles.
The FDA wouldn't say exactly how many reports it is probing.
"We're not talking hundreds. It's a relative handful," said Dr. Russell Katz, FDA's neurology chief.
But the agency warned that patients receiving a botulinum toxin injection for any reason — cosmetic or medical — should be told to seek immediate care if they suffer symptoms of botulism, including: difficulty swallowing or breathing, slurred speech, muscle weakness, or difficulty holding up their head.
"I think people should be aware there's a potential for this to happen," Katz said. "People should be on the lookout for it."
Friday's warning came two weeks after the consumer advocacy group Public Citizen petitioned the FDA to strengthen warnings to users of Botox and Myobloc — citing 180 reports of U.S. patients suffering fluid in the lungs, difficulty swallowing or pneumonia, including 16 deaths.
Nor is it the first warning. The drugs' labels do warn about the potential for botulinum toxin to spread beyond the injection site and occasionally kill, but the warnings link that side effect to patients with certain neuromuscular diseases, such as myasthenia gravis.
That's what's different about these latest cases, said FDA's Katz: The botulism toxin seems to be harming people who don't have that particular risk factor. (Cerebral palsy involves a brain injury, not a disease.)
Still, the FDA cautioned that its investigation is in the early stages. It has asked Botox maker Allergan Inc. and Myobloc maker Solstice Neurosciences Inc. to provide additional safety records.
Allergan spokeswoman Caroline Van Hove said children with cerebral palsy receive far larger doses injected into their leg muscles than the doses given adults seeking wrinkle care.
In a statement, Solstice said it supports FDA's probe but stressed that the agency hasn't concluded the drug poses any new risk.
While the FDA said the problems may be related to overdoses, it also has reports of side effects with a variety of doses.
Public Citizen's Dr. Sidney Wolfe criticized FDA's warning as falling short. He asked that the agency order a black-box warning, the FDA's strongest type, be put on the drugs' labels and require that every patient receive a pamphlet outlining the risk before each injection.
"Every doctor needs to notified about this, every patient needs to be notified," Wolfe said. "Children are showing the way, unfortunately some dead children."
He said drug regulators in Britain and Germany last year required that sterner warnings be sent to every doctor in those countries.
Iron Banded Worms Drying Out Of Blood Could Be Linked To Parkinson's And Alzheimer's
Professor Sadler with diagram of iron banded fibril. (Credit: University of Warwick)
ScienceDaily (Feb. 12, 2008) — Researchers at the University of Warwick and the Indian Institute of Technology Kanpur have discovered that the mechanism that we rely on to transport iron safely through our blood stream can, in certain circumstances, collapse into a state which grows long worm-like "fibrils" banded by lines of iron rust. This process could provide the first insight into how iron gets deposited in the brain to cause some forms of Parkinson's & Alzheimer's and Huntington's diseases.
Human blood relies on a protein called transferrin to safely transport iron through the bloodstream to points were it can be usefully and safely used in the body. In most other circumstances exposed iron contains many dangers for human cells. When deposited in such a state in the brain it can play a role in neurodegenerative diseases such as Parkinson's, Huntington's and Alzheimer's
Transferrin takes up iron out of bloodstream and transports it by a method that combines it with carbonate to bind to two sites on the surface of the transferrin protein. It then curls around the iron and seals it in, almost like a Venus flytrap plant, to prevent it from interacting with anything else until it reaches where it is needed and can safely be used.
The research team led by Professor Peter Sadler from the University of Warwick, and Professor Sandeep Verma from the Indian Institute of Technology, found that if they took transferrin and left it to dry out on a surface, molecules of the safe transporter of iron assembled themselves into tendril - or worm-like fibrils.
Even more interestingly the iron that was once safely wrapped up inside the transferrin now appeared to be settling along the length of these fibrils plating them in a series of spots or bands along the length of the tendril shape. This leaves the iron dangerously exposed and available to interact in ways that could cause cell damage.
Deposits of iron exposed in this way and found in the brain are a possible cause of some forms of Parkinson's, Alzheimer's and Huntington's diseases. Until now there has been no real idea as to how iron becomes deposited there in such a dangerous way. As it is essential for the brain to have iron safely delivered to it, this observation could provide the first real clue as to how that iron comes to be deposited there in such a dangerous way. The research chemists who led this study hope that neurology researchers will be able to build on this work to gain more understanding of how these forms of Parkinson's, Huntington's and Alzheimer's occur and how they can be countered.
The full research paper entitled Periodic Iron Nanomineralization in Human Serum Transferrin Fibrils, by Surajit Ghosh, Arindam Mukherjee, Peter J. Sadler, Sandeep Verma, has just been published in the online edition of Angewandte Chemie. The lead authors are Professor Peter Sadler from the University of Warwick, and Professor Sandeep Verma from the Indian Institute of Technology.
Prenatal Exposure To Maternal Antibodies Linked To Autistic Behaviors In Offspring
ScienceDaily (Feb. 12, 2008) — New research from the UC Davis M.I.N.D. Institute shows that an interaction between fetal brain cells and maternal antibodies could be linked with the repetitive behavior — also called stereotypies — that is characteristic of autism. While additional studies are needed to confirm the outcome, this result leads investigators to suspect that brain-directed antibodies during the prenatal period could be a causal factor for the disorder. The study appears online now and will be published in a future issue of Brain, Behavior and Immunity.
The study builds on recent research led by UC Davis immunologist Judy Van de Water* showing that IgG antibodies from the blood of mothers of children with autism react against fetal brain proteins. The outcome was predominant with IgG samples from mothers of children with the regressive form, rather than the early onset form, of the disorder. Her outcome raised the possibility that some cases of autism may be linked to antibody transplacental transfer during pregnancy which, in turn, affects the growing brain.
"Dr. Van de Water's result implicated maternal immune system factors with at least one form of autism," said neuroscientist David Amaral, research director of the M.I.N.D. Institute and senior author of the current study. "We wanted to take that important finding a step further and find out if IgG exposure during pregnancy could cause the kinds of changes in social interactions or behavior we see in children with autism."
To test this hypothesis, Amaral and his research team at the California National Primate Research Center exposed eight rhesus monkeys to human IgG at three times during the end of the first trimester of pregnancy. Four monkeys received IgG from mothers of children with autism, while four received antibody isolated from the blood of mothers of typically developing children to ensure that any potential outcomes were not due to human IgG exposure. Five monkeys received no treatment whatsoever and were included as study controls. The behavior and social interactions of all 13 offspring were then carefully observed and recorded over the course of a year-and-a-half in a variety of familiar and novel settings.
The team identified only mild social alterations in the four monkeys treated with IgG from mothers of children with autism. The monkeys' behavior, however, was notably distinct, since all of them exhibited repetitive activities such as pacing, backflipping, twirling and swinging with much greater frequency and for longer periods of time than other monkeys in the study. The stereotypies were most pronounced after weaning and were even more striking in unfamiliar settings.
"The major significance of this study is that it links exposure to abnormal immune system factors during pregnancy with specific behavioral outcomes in offpsring," said Amaral. "The monkeys' behavior is profoundly changed from normal, and those changes are similar to impairments that we see in children with autism. The study adds to increasing evidence that immune system factors of mothers could contribute to the development of some forms of autism."
While the finding is remarkable, the results must be replicated in a larger, more comprehensive study before prenatal IgG exposure can be confirmed as a risk factor for autism. At that point, the researchers are hopeful that clinical protocols can be developed to identify this risk factor during pregnancy.
"We started with a small study to see if our assumptions had merit, and that definitely proved to be true," said Amaral. "If a more exhaustive study has the same results, we will be able to say with confidence that we've identified a causal factor for some cases of autism. The goal after that will be to define blood tests that isolate IgG as a diagnostic marker."
One of many forms of antibodies in blood serum, IgG typically crosses the placenta as a protective agent for the growing fetus and newborn child. However, antibodies formed against one's own body (autoantibodies) are implicated in disorders such as lupus, multiple sclerosis and arthritis. The known links between IgG and the prenatal environment and autoimmune-mediated disorders is what originally persuaded Van de Water to test the potential role of fetal-brain-specific IgG in autism.
The presence of stereotypies is part of one major symptom category — in addition to social deficits and language impairments — of the autism diagnosis. Clinicians do not know for certain why children with autism tend to repeatedly, for instance, rock, flap their hands, twirl objects or walk on their toes. It has been surmised that the repetition might help reduce anxiety or could be related to damage in specific parts of the brain. This new research provides evidence that brain-directed antibodies in the immune systems of mothers may provide part of the answer.
"If we confirm that these antibodies are a risk factor for autism, it's possible that they could be removed through treatments much like those used for autoimmune and inflammatory diseases," said study lead author Martin, who is now an assistant professor in the Department of Psychology at Azusa Pacific University and was a postdoctoral fellow in the Amaral lab when the study was conducted. "It's early in the research process to consider specific therapies, but it is clear that our result should lead to a much greater emphasis in autism science on immune system links to the disorder."
This research was supported by grants from the National Institute of Mental Health, the National Institute of Environmental Health Sciences, the M.I.N.D. Institute, Visceral and the Ted Lindsay Foundation. It was conducted in association with the UC Davis Children's Center for Environmental Health and made possible by serum samples made available by the Autism Genetic Resource Exchange.
Immunosuppressant Further Linked To Birth Defects, Case Study Suggests
ScienceDaily (Feb. 12, 2008) — A new study documents malformations seen in an infant born to a kidney transplant recipient who had taken mycophenolate mofetil (MMF), a widely used immunosuppressant available commercially as Cellcept®. The findings suggest a specific birth defect pattern particular to this drug, reinforcing its potential to harm to the fetus.
Approximately 14,000 births to organ transplant recipients, primarily kidney transplant patients, have been reported worldwide. Although pregnancy was initially ill-advised for these women, the American Society of Transplantation concluded in 2003 that pregnancy is usually safe following the first year of a transplant, provided that organ rejection or other complications have not occurred. The fetal side-effects of several immunosuppressant drugs have been studied, though not for widely used newer medications, such as (MMF).
The use of immunosuppressant drugs is a required, life-long treatment for solid organ transplant recipients. They are used to prevent, inhibit or reduce the natural reaction of the immune system against foreign tissues. However, these drugs have important side effects that sometimes preclude their use. The FDA divides immunosuppressants into four categories (A, B, C and D) regarding toxicity to the fetus. MMF has recently been upgraded to class D during pregnancy, meaning that its use is precluded for the high risk of fetal malformations. Immunosupressants are also given to women with severe autoimmune diseases, such as generalized lupus. In fact, 3 out of 10 babies described in the literature regarding these defects had mothers on MMF because of lupus nephritis.
Led by Dr. Antonio Perez-Aytes and Dr. Maximo Vento of the Newborn Research Unit at the Hospital Universitario Materno-Infantil La Fe, in Valencia, Spain, the study describes a 25-year-old Spanish woman who had undergone two kidney transplants. Following the second transplant she took the immunosuppressant drugs tacrolimus and MMF. Two years later she became pregnant and MMF was discontinued at 10 weeks gestation, while tacrolimus, one of the drugs that has been studied in pregnant women, was maintained. She delivered a female infant who had cleft lip and palate, as well as defects of the jaw, eyes and ears, including no external ear canals. At nine months her child was developing normally, although she needed hearing aids.
The pattern of defects seen in this infant is very similar to previous reports of birth defects in infants who were exposed to MMF in utero. The study describes these infants, noting that the pattern of cleft lip/palate and ear malformations was seen in every case but one. Although defects of the eye had not been seen in humans before, studies in rats and rabbits have shown ocular malformations following exposure to MMF. The authors suggest that the pattern of defects seen with MMF establishes a possible link between use of this drug during pregnancy and a specific malformation pattern in structures derived from the frontal-nasal prominence (which develops into the forehead, nose, upper lip and palate) and the first pharyngeal arch (which develops into the jaw and ear).
It should be noted, however, that if a transplant recipient is of fertile age, she can give birth to a healthy baby. “The patient needs to be adequately counseled, and withdraw from immunosuppressants that may be deleterious to the baby within sufficient of becoming pregnant to avoid any interference during the first 12 weeks of gestation,” says Dr. Maximo Vento, co-author of the study.
Article: “In Utero Exposure to Mycophenolate Mofetil: A Characteristic Phenotype?” Antonio Perez-Aytes, Ana Ledo, Virginia boso, Pilar Sáenez, Eva Roma, José Luis Poveda, Maximo Vento, American Journal of Medical Genetics Part A; January 2008.
ScienceDaily (Feb. 12, 2008) — Prion infection of neurons increases the free cholesterol content in cell membranes. A new study suggests that disturbances in membrane cholesterol may be the mechanism by which prions cause neurodegeneration and could point to a role for cholesterol in other neurodegenerative diseases.
It is widely believed that prions (protein only infectious material) are the cause of rare progressive neurodegenerative disorders that affect both humans and animals. A prion is an infectious agent made solely of protein. However what is not known is how the prions damage brain cells (neurons).
Dr Clive Bate and colleagues from the Royal Veterinary College in the UK compared the amounts of protein and cholesterol in prion-infected neuronal cell lines and primary cortical neurons with uninfected controls. Protein levels were similar but the amount of total cholesterol (a mixture of free and esterified cholesterol) was significantly higher in the infected cell lines.
The cholesterol balance was also affected: the amount of free cholesterol increased but that of cholesterol esters reduced, suggesting that prion infection affects cholesterol regulation. The team attempted to reproduce the effects of prions on cholesterol levels, by stimulating cholesterol biosynthesis or by adding exogenous cholesterol. Both approaches resulted in increased amounts of cholesterol esters but not of free cholesterol.
The free cholesterol is thought to affect the function of the cell membranes and to lead to abnormal activation of phospholipase A2, an enzyme implicated in the depletion of neurons in prion and Alzheimer's disease.
Studies have recently shown that the controlling cholesterol levels within the brain is critical in limiting the development of neurodegenerative diseases such as Alzheimer's, Parkinson's and prion diseases, multiple sclerosis, and senile dementia. This study now gives far more specific insight into the kind of mechanisms at work. Dr Bate stated: "Our observations raise the possibility that disturbances in membrane cholesterol induced by prions are major triggering events in the neuropathogenesis of prion diseases".
Journal reference: Sequestration of free cholesterol in cell membranes by prions correlates with cytoplasmic phospholipase A2 activation. Clive Bate, Mourad Tayebi and Alun Williams. BMC Biology (in press).
ScienceDaily (Feb. 12, 2008) — A cellular protein that helps guide immune cells to the gut has been newly identified as a target of HIV when the virus begins its assault on the body's immune system, according to researchers from the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health (NIH).
"The identification of this new receptor opens up new avenues of investigation that may help further elucidate the complex mechanisms of the pathogenesis of HIV infection," says NIAID Director Anthony S. Fauci, M.D., chief of the Institute's Laboratory of Immunoregulation (LIR) and senior author of the new study.
Several other immune cell receptors bind to HIV. Most important among these, the CD4 molecule, identified as an HIV receptor in 1984, functions as the principal receptor for HIV. The CCR5 and CXCR4 molecules, discovered in 1996, serve as co-receptors that HIV uses to enter its target cells. In the new study, which appears online Feb. 10, 2008 in Nature Immunology, NIAID scientists identify a cell adhesion molecule known as integrin alpha 4 beta 7 as another potentially important receptor for HIV.
Early in the course of HIV infection, the virus rapidly invades and replicates in gut-associated lymphoid tissue (GALT), the immune cells of the gut. Once seeded with HIV, the gut is rapidly depleted of CD4+ T cells, the main target of HIV, triggering the process that ultimately leads to AIDS.
"In the very early days of infection, it is in the GALT where most of the damage caused by HIV occurs," says Elena Martinelli, Ph.D., a lead author of the paper and a fellow in Dr. Fauci's laboratory. "The gut is where the virus really takes hold. We found that integrin alpha 4 beta 7, whose natural function is to direct T cells to the GALT, is also a receptor for HIV. It is very unlikely that this is a coincidence."
Dr. Martinelli, along with Claudia Cicala, Ph.D., James Arthos, Ph.D., and their colleagues found that the gp120 protein, part of the HIV envelope, binds to integrin alpha 4 beta 7 on CD4+ T cells, which promotes the formation of a stable junction, or synapse, between neighboring cells.
"A synapse is a junction that allows two cells to adhere in a stable way," says Dr. Arthos. "Many viruses have found a way to trick cells into forming these stable junctions. Now it appears that HIV can also trigger synapse formation."
Specifically, a short piece of the HIV gp120 protein in a region known as the V2 loop recognizes the alpha 4 chain of the integrin molecule on host cells. This stretch of the V2 loop is similar to part of the naturally occurring molecules that bind integrin alpha 4 beta 7. Thus, it appears that HIV is mimicking the natural molecular partners, or ligands, that normally bind to the receptor. The authors note, however, that some HIV isolates react more strongly to integrin alpha 4 beta 7 than others.
"The ability of a particular virus to bind to integrin alpha 4 beta 7 may determine whether it will have a major impact in targeting the gut lymphoid tissue," says Dr. Fauci. "This finding could be a significant determinant in the pathogenic mechanisms that lead to AIDS."
As part of the natural homing process, integrin alpha 4 beta 7 binds to its natural ligands and activates a protein known as LFA-1. According to Dr. Arthos, HIV can co-opt this process by mimicking the cells' alpha 4 beta 7 receptor natural ligands. When HIV gp120 protein binds to the alpha 4 beta 7 receptor it facilitates the formation of a synapse. Thus, HIV tricks an infected cell into binding to an uninfected cell, enabling HIV to readily gain access to the uninfected cell.
"While this study provides important new information concerning the various mechanisms by which HIV debilitates the human immune system, it also raises new questions and challenges that our laboratory and others will pursue," notes Dr. Cicala.
Reference: J Arthos et al. HIV-1 envelope protein binds to and signals through integrin alpha 4 beta 7, the gut mucosal homing receptor for peripheral T cells. Nature Immunology DOI: 10.1038/ni1566 (2008).
Moss Protein Plays Role In Alzheimer's Disease, Researchers Believe
A twenty-eight-day old Physcomitrella (left) moss gametophyte has a surprising link to an amyloid plaque, (right) found in brains that have Alzheimer's disease. (Credit: Moss Image courtesy of Washington University in St. Louis; Plaque image, NIH)
ScienceDaily (Feb. 12, 2008) — Preventing Alzheimer's disease is a goal of Raphael Kopan, Ph.D., professor of molecular biology and pharmacology at the Washington University School of Medicine. The moss plant Physcomitrella patens studied in the laboratory of Ralph S. Quatrano, Ph.D., the Spencer T. Olin Professor and chair of the biology department on WUSTL's Danforth Campus, might inch Kopan toward that goal. Here's how.
The gene presenilin (PS) in mammals provides the catalytic activity for an enzyme called gamma secretase, which cleaves, or cuts, important proteins Notch, Erb4 and the amyloid precursor protein (APP), all key components of communication channels that cells use to arbitrate functions during development. There are two mammalian genes that occur in mammals for which mutations cause an earlier onset of Alzheimer's. One is APP, where a fragment of the protein accumulates in amyloid plaques associated with the disease. Another common site for mutations is found in PS proteins. The enzyme gamma secretase contains PS and works to dispose of proteins stuck in the cellular membrane.
This enzyme, with PS at its core, mediates two cellular decisions. One is to cut APP and, as a byproduct, generate the bad peptide associated with Alzheimer's; the other is to cut the Notch protein in response to specific stimuli. Notch is then free to enter the nucleus of cells where it partakes in regulating normal gene expression. Without Notch activity, a mammal has no chance of living.
Notch is a part of a short-range mammalian communication channel, and for years it has been known to have a working relationship with PS. However, Notch is absent in plant cells, and PS function in plants remained mysterious until Quatrano's post-doctoral researcher, Abha Khandelwal, Ph.D., arrived at WUSTL and was interested in understanding signal transduction in plants.
"When I searched the literature, the plant signal transduction pathways were not very well documented compared to the mammalian counterparts such as Notch," said Khandelwal. "Meanwhile, my husband, Dilip Chandu, Ph.D., was working in the Kopan lab on ways to study functions of PS without interference from its predominant substrate Notch."
This encouraged Khandelwal to search for the PS gene in the genomes of plants including the recently sequenced Physcomitrella patens genome, to which the Quatrano lab had access. In addition to the known Arabidopsis PS, she found the gene in Physcomitrella and asked, "What is PS doing in moss? Is it acting as an enzyme or does it have a different function?"
"Moss, like yeast, has this great ability where you can actually select a gene and remove it, mutate it, or replace it with another gene from any source. This approach allows us to discern a gene's value and function in moss," said Quatrano, who was a world leader in the sequencing of the moss genome. "It is an excellent system to experimentally discern gene function because of this property as well as others that we and a worldwide consortium have developed over the last several years."
Thus, a collaboration was born. By engaging the expertise of the team in the Kopan lab, the Quatrano lab proceeded to experiment with PS in moss, which finally resulted in a fruitful collaboration recently reported in the Proceedings of the National Academy of Science. Khandelwal proceeded to remove PS, and the result was an obvious change — a phenotype. Moss lacking PS looked different, growing with straight, rigid filaments instead of curved and bent filaments like the parent moss with the PS gene intact.
"That showed the gene has an obvious function that clearly did not require Notch. We just don't know exactly what it is yet, but we have proposed a hypothesis to be tested," Quatrano said.
The phenotype piqued Kopan's interest: He saw the potential of looking at the role of PS independent of Notch. Khandelwal and Chandu took the phenotype, switched out a mammalian form of PS into the phenotype and rescued it. Similarly, inserting the moss gene in mammalian cells resulted in reversing some of the losses experienced by animal cells lacking PS function, testifying that the human and moss proteins had an evolutionary conserved function.
"In the moss, the proteins were very nearly interchangeable," Quatrano said. "This suggested that PS has a role outside the Notch pathway and may provide clues in mammalian systems as to its primary role, independent of its substrate in mammalian cells."
"We were amazed to realize that genes from moss and humans were not only structurally conserved but also shared similar functions," Khandelwal said.
Moonlighting protein in mammals
"We spent a lot of time trying to find an activity of PS to circumvent cleavage of APP, which has been very difficult, "Kopan said. "Importantly, the human protein acted in plant cells even if its enzymatic activity was removed by mutation. We stumbled upon an observation that PS proteins in mammals can perform other functions besides the enzymatic ones, that is, outside its role as gamma secretase. We're now looking closely to define these moonlighting functions and determine their contribution to disease."
In moss, the mutant phenotypes suggest PS might play a role in signal gathering, cytoskeleton organization and/or cell wall composition and organization. Quatrano and Khandelwal are investigating. Kopan, Chandu and others are searching for PS's moonlighting activities in mammalian cells.
"As a developmental biologist, my job is to translate the genetic code as if it were a manufacturer's manual, and that is accomplished by gaining detailed understanding of genes and protein function," Kopan said. "Unfortunately, we're doing it one gene at a time, slowly building networks, figuring out what the context is. We can't think of all of it at once. We have to look at a small subset of genes and how they work with their 'friends', and hope that our observations will fit together in one coherent network."
Quatrano said the collaboration between the two labs is a reflection of what the Genomic Age can do.
"Today, sitting at your computer, you can data mine genomes from hundreds of microorganisms, animals, fungi, insects and plants, and you're seeing more evidence of genes being conserved in widely different organisms," Quatrano said. "This collaboration is a perfect example of bringing two labs together that on the surface have nothing in common other than one protein and two people who were aware of the interests of the other. It's led to a significant contribution that hopefully will lead to further clues as to the function of PS."
With this study, the Kopan and Quatrano labs and others could use this outstanding plant model not only to understand some of the off-target affects during Alzheimer's Disease therapy, but also to unravel novel interactions and pathways in plants.
QBI neuroscientists are using a molecule derived from bee venom (Tertiapin) to help them to understand why some nerve cells die. (Credit: Image courtesy of University of Queensland)
ScienceDaily (Feb. 12, 2008) — Queensland Brain Institute (QBI) scientists have found another important clue to why nerve cells die in neurodegenerative diseases, based on studies of the developing brain.
Neuroscientists at The University of Queensland have just published findings, which add more weight to the "use it or lose it" model for brain function.
QBI's Dr Elizabeth Coulson said a baby's brain generates roughly double the number of nerve cells it needs to function; with those cells that receive both chemical and electrical stimuli surviving, and the remaining cells dying.
In research published in the Journal of Neuroscience, Dr Coulson and her colleagues have identified a crucial step in the cell-death process.
"It appears that if a cell is not appropriately stimulated by other cells, it self-destructs," Dr Coulson said. This self-destruct process is also known to be an important factor in stroke, Alzheimer's and motor neuron diseases, leading to the loss of essential nerve cells from the adult brain.
"We know that a lack of both chemical and electrical stimuli causes the cells to self-destruct," Dr Coulson said. "But we believe that nerve cells will survive if appropriate electrical stimuli are produced to block the self-destruct process that we have identified."
The researchers' next step is to test whether dying cells receiving only electrical stimulation can be rescued.
More than three years' research has gone into understanding these crucial factors regulating nerve cell survival, but it is a major step in the long process of discovery needed to combat neurodegeneration.
QBI Director, Professor Perry Bartlett said the research is an extremely exciting finding because it also provides the missing piece of information as to how the brain likely keeps alive the new neurons it generates in some brain areas as an adult.
"Combining this with our knowledge of how to stimulate new neurons in the brain of adults following to disease processes such as stroke, it provides new mechanisms for the treatment of a variety of diseases from depression to dementia," he said.
Changing Patterns Of Stroke And Heart Disease-related Deaths In Europe Revealed
ScienceDaily (Feb. 11, 2008) — New figures show there are still large variations between and within European countries in the numbers of stroke and heart disease-related deaths. Several countries, particularly in northern and eastern Europe, have rates of death that are as much as 7-14 times higher than other countries, while countries such as Poland, Spain, Portugal, Germany and the UK have large regional variations.
Published in the European Heart Journal, the study looked at deaths from ischaemic heart disease (IHD) -- a form of heart disease characterised by a reduced blood supply to the heart -- and cerebrovascular disease (CVD) -- defects in the blood vessels supplying the brain which can result in events such as stroke -- for the year 2000.
The researchers found that mortality rates for IHD were lower in countries to the south and west, while for CVD, mortality was reduced in the centre of western Europe, with higher rates in the countries surrounding this circle, including some Mediterranean countries such as Greece, Portugal and regions in southern Spain and Italy.
The lead author of the study, Dr Jacqueline Müller-Nordhorn, said: "These latest figures show a changing pattern of cardiovascular mortality within Europe, which needs to be taken into account in the definition of countries as high- or low-risk when primary prevention strategies are being designed for heart disease. In addition, there needs to be further research into the underlying reasons for the observed differences in cardiovascular mortality in Europe, both between and within countries. Preventive strategies could then focus on specific risk factors."
Dr Müller-Nordhorn, a senior scientist at the Institute of Social Medicine, Epidemiology and Health Economics, Charité University Medical Center, Berlin, Germany, and her colleagues calculated age-standardised mortality rates for IHD and CVD from data provided by the statistical office of the European Communities (Eurostat) and the national statistics offices of all the countries. They concentrated on the 45-74 age group, as mortality in younger age groups is very low. They divided the rates per 100,000 of the population into five groups: the quintile (or group) with the lowest mortality was indicated by dark green on their published maps of Europe, the second lowest quintile by light green, the middle quintile by yellow, the second highest quintile by orange, and the highest quintile by red.
She said: "In Latvia there was a more than seven-fold higher rate of IHD mortality among men than in France and there was a nearly 10-fold higher rate for women in Estonia than in France. For CVD, there was a 14.5-fold higher rate for men and a 12-fold higher rate for women in Estonia than in Switzerland.
"With regard to IHD, there is a clear north-east to south-west gradient in mortality. In particular, countries from central and eastern Europe have high mortality rates compared with other European countries. The lowest mortality rates are found in France, Portugal, Italy and Spain. There is a considerable within-country variation in IHD in Germany, the UK and Poland.
"With regard to CVD, there is a different pattern of regional variation compared with IHD. CVD mortality is reduced in the centre of western Europe with the lowest national mortality rates in Switzerland, France, Norway and Spain. There is a considerable within-country variation in Italy, Spain, Portugal and the UK."
Dr Müller-Nordhorn said that mortality from both IHD and CVD had decreased continually in most western European countries over the past decades, with public health interventions in countries such as Finland making a big difference to the mortality rates.
"In most central and eastern European countries, on the other hand, cardiovascular mortality increased during the 1970s and 1980s and only started to decline in the 1990s. Despite this recent decrease, mortality rates are still considerably higher in these countries compared to western European countries. Some countries, such as the Ukraine, reach almost top levels in a worldwide comparison. Although most central and eastern European counties appear to have reached their peak in cardiovascular mortality, the majority of them can clearly still be classified as high risk countries."
She said a number of risk factors could account for the large variations between countries; these included classic risk factors such as hypertension or diabetes, income or employment status, psychosocial factors such as stress or the prevalence of depression, lifestyle variables such as physical activity, smoking and diet, environmental factors, or the quality of medical care available.
"For example, in Poland, changes in dietary fat intake during the 1990s, leading to a more favourable ratio of polyunsaturated to saturated fat, were associated with a drop in mortality from IHD by approximately one quarter. Other factors such as the consumption of fruit and vegetables, smoking, or alcohol consumption have been linked to the east-west gradient in mortality."
Regional variations within countries seemed to depend on varying risk factors, depending on the location. "For example, regional differences in Israel, Bavaria and the Czech Republic were found to be associated particularly with differences in blood pressure levels. Within England, on the other hand, the regional variation was associated to a large extent with differences in smoking prevalence," she said.
At present, guidelines for the treatment and prevention of cardiovascular disease divide Europe into high- and low-risk countries, and physicians treat their patients according to the block in which their country falls. However, Dr Müller-Nordhorn said that her research showed that many countries had changed from being high- to low-risk, and, in addition, the current classifications didn't take account of the considerable regional variations.
"Misclassification may have a huge impact at the population level with regard to the number of people over- or under-treated. Regular updates on the complex pattern of regional variation within Europe are needed to make efficient prevention possible," she said.
"It seems that former high-risk western European countries now have similar mortality rates compared with those of the low-risk countries at the time of previous cohort studies conducted in the 1980s and 1990s. For example, Finland had an average of 587 IHD deaths among men per 100,000 in the years 1990-1992, but in 2000 it had dropped to 372 per 100,000, putting it on a par with countries that are currently classified as low-risk. This suggests that the current classification needs to be reconsidered for accurate risk assessment in primary prevention of cardiovascular disease. For example, it may be more appropriate and practical to generally classify western European countries as low-risk and central and eastern European countries as high-risk. Otherwise, there may be an overestimation of current cardiovascular risk in certain populations leading to unnecessary therapies and costs."
Journal reference: An update on regional variation in cardiovascular mortality within Europe. European Heart Journal, doi:10.1093/eurheartj/ehm604
Night-time noise from aircraft or traffic raises blood pressure even while people sleep, a study suggests.
Researchers monitored 140 sleeping volunteers in their homes near Heathrow and three other big European airports.
Volunteers' blood pressure increased after exposure to a noise louder than 35 decibels - whether it came from overhead aircraft, or snoring.
In response to the European Heart Journal study, the UK government said noise at Heathrow was improving.
Also, night-time flights at the London airport were strictly controlled the Department for Transport said.
"However, we are aware of people's concerns which is why the government has set out strict local noise conditions on expansion at Heathrow," a spokesman added.
Restrictions apply at Heathrow between 11pm and 7am.
Measures need to be taken to reduce noise levels from aircraft, in particular during night-time, in order to protect the health of people living near airports Dr Lars Jarup Imperial College London
The researchers measured the volunteers' blood pressure remotely at 15-minute intervals.
Aircraft noise caused an average increase in systolic blood pressure of 6.2 mmHg and an average increase in diastolic blood pressure of 7.4 mmHg.
Similar increases in blood pressure were seen also for other noise sources such as road traffic.
One resident who lives near Heathrow, Margaret Thorburn, told the BBC how noise due to the airport affected her.
There was "no point" trying to sleep before 11pm, she said.
"And that's standard because background noise has died down and any aircraft that goes over when everything else is quiet you notice an awful lot more and it's disturbing in a particular way," she said.
"If it's in the summer when the windows are open then you're going to wake up... and what's more you don't go back to sleep because you're waiting for the next one to come over."
Louder noises worse
The study also found the louder the noise, the greater the increase in blood pressure.
For every five decibel increase in aircraft noise at its loudest point, there was an increase of 0.66 mmHg in systolic blood pressure.
The researchers had previously shown that people who have been living for at least five years under a flight path near an international airport are at greater risk of developing high blood pressure than people living in quieter areas.
Taken together, the two studies suggest that living under a flight path could almost double the risk of hypertension.
The researchers have calculated that for every extra 10 decibels of aircraft noise the risk of hypertension is increased by 14%.
The mechanism by which aircraft noise acts to raise blood pressure is unknown, but the researchers plan further tests to examine the theory that the brain reacts to noise by ramping up levels of the stress hormone cortisol.
HIGH BLOOD PRESSURE Associated with a raised risk of heart disease, stroke, kidney disease and dementia Defined by World Health Organisation as being 140/90mmHg or more
Researcher Dr Lars Jarup, from Imperial College London, said: "We know that noise from air traffic can be a source of irritation, but our research shows that it can also be damaging for people's health - which is particularly significant in light of plans to expand international airports."
Ellen Mason, a cardiac nurse at the British Heart Foundation, said: "Noise pollution may be the latest in a long line of issues that the airline industry needs to tackle."
But she added: "High blood pressure is far more likely to be influenced by the fact that many of us eat far too much salt, don't take enough exercise and are fast becoming overweight."
Professor Graham McGregor, an expert in blood pressure, said the study was interesting, but more work would have to be done to confirm the link.
He said people who lived close to airports tended to be poor, and high blood pressure was associated with poverty.