A University of Illinois at Chicago study has been stopped early due to preliminary results indicating that medical circumcision of men reduces their risk of acquiring HIV during heterosexual intercourse by 53 percent.
The study’s independent Data Safety and Monitoring Board met Dec. 12 to review the interim data. Based on the board’s review, the National Institutes of Health halted the trial and recommended that all men enrolled in the study who remain uncircumcised be offered circumcision.
“Circumcision is now a proven, effective prevention strategy to reduce HIV infections in men,” said Robert Bailey, professor of epidemiology in the UIC School of Public Health and principal investigator of the study.
The clinical trial, funded by the National Institute of Allergy and Infectious Diseases and the Canadian Institute of Health Research, enrolled 2,784 HIV negative, uncircumcised men between 18 and 24 years old in Kisumu, Kenya.
Half the men were randomly assigned to circumcision, half remained uncircumcised. All men enrolled in the study received free HIV testing and counseling, medical care, tests and treatment for sexually transmitted infections, condoms and behavioral risk counseling for 24 months.
Study results show that 22 of the 1,393 circumcised men in the study contracted HIV, compared to 47 of the 1,391 uncircumcised men. In other words, circumcised men had 53 percent fewer HIV infections than uncircumcised men.
Until now, public health organizations have not supported circumcision as a method of HIV prevention due to a lack of randomized controlled trials.
“With these findings, the evidence is now available for donor and normative agencies, like WHO and UNAIDS, to actively promote circumcision in a safe context and along with other HIV prevention strategies,” Bailey said.
“Circumcision cannot be a stand-alone intervention. It has to be integrated with all the other things that we do to prevent new HIV infections, such as treating sexual transmitted diseases and providing condoms and behavioral counseling,” Bailey said. “We can’t expect to just cut off a foreskin and have the guy go on his merry way without additional tools to fight against getting infected.”
Opponents of circumcision have speculated that circumcised men may feel they are not at risk of contracting HIV and may be more likely to engage in risky behavior. The Kenya study suggests that circumcision did not increase risky behavior among circumcised or uncircumcised men, according to Bailey.
“Both uncircumcised and circumcised men are reducing their sexual risk behavior,” he said, “which indicates that our counseling is doing some good.”
The study also evaluated the safety of circumcision in a community health clinic with specially trained practitioners. There were no severe or lasting complications from circumcision. However, 1.7 percent of surgeries resulted in mild complications, such as bleeding or infection.
Bailey said that promoting circumcision in Africa must be done in conjunction with proper technical training and medical tools, equipment and supplies necessary to perform large numbers of circumcisions safely.
“Already, there are large numbers of boys and young men who are seeking circumcision in areas of Africa where men are not traditionally circumcised,” he said. “The danger is that unqualified practitioners will fill a niche by providing circumcision, but with much higher complication rates.”
An estimated 30 million people in Africa are infected with HIV/AIDS and more than 90 percent of HIV infections in adults result from heterosexual intercourse. In Kisumu, the third-largest city in Kenya, an estimated 26 percent of uncircumcised men are HIV infected by age 25.
“This study will likely not have a large impact on the incidence of HIV/AIDS in the United States or Europe where heterosexual transmission of HIV is low compared with areas like sub-Saharan Africa and parts of Asia,” Bailey said. “However, there are other proven health benefits of circumcision, including better hygiene, fewer urinary tract infections, and less risk of cervical cancer in the partners of circumcised men.”
The armamentarium of HIV prevention strategies is very small, according to Bailey. The only other strategy proven effective is the use of antiretroviral drugs to reduce transmission from mother to child.
If a significant proportion of men in a population get circumcised, it will have an enormous impact on preventing HIV infection in men, as well as reducing infections in women, Bailey said.
Co-investigators of the study include Stephen Moses and Ian Maclean at the University of Manitoba, Jekoniah Ndinya-Achola at the University of Nairobi, Corette Parker at Research Triangle International, Kawango Agot at UNIM Project, John Krieger at University of Washington, and Richard Campbell at UIC.
During the past two decades, more than 40 observational epidemiological studies and one previous clinical trial have reported an association between male circumcision and a reduced risk of HIV infection.
On Dec. 12, the NIH stopped another clinical trial of male circumcision undertaken by investigators in Uganda and at Johns Hopkins University, after the study’s Data Safety Monitoring Board reviewed the preliminary results and found a protective effect similar to that found in Bailey’s study.
Source: University of Illinois at Chicago
Tuesday 19 December 2006
Painkillers May Threaten Power Of Vaccines
With flu-shot season in full swing and widespread anticipation of the HPV vaccine to prevent cervical cancer, a new University of Rochester study suggests that using common painkillers around the time of vaccination might not be a good ideaResearchers showed that certain nonsteroidal anti-inflammatory drugs (NSAIDs), also known as cyclooxygenase inhibitors, react with the immune system in such a way that might reduce the effectiveness of vaccines.
The research has widespread implications: study authors report that an estimated 50 to 70 percent of Americans use NSAIDs for relief from pain and inflammation, even though NSAIDs blunt the body’s natural response to infection and may prolong it.
“For years we have known that elderly people are poor responders to the influenza vaccine and vaccines in general,” said principal investigator Richard P. Phipps, Ph.D., a professor of Environmental Medicine, and of Microbiology and Immunology, Oncology and Pediatrics. “And we also know that elderly people tend to be heavy users of inhibitors of cyclooxygenase such as Advil, aspirin, or Celebrex. This study could help explain the immune response problem.”
The study is available online in the Dec. 1, 2006, Journal of Immunology, and was funded in part by the National Institutes of Health.
When a person is vaccinated, the goal is to produce as many antibodies as possible to effectively neutralize the infection. To do this, white blood cells called B-lymphocytes, or B cells, spring into action to produce those antibodies. B cells also serve as the immune system’s memory for future protection against the illness.
But Phipps and colleagues discovered that human B cells also highly express the cyclooxygenase-2 (cox-2) enzyme, which is not intrinsically bad unless it is overproduced, causing pain and fever. So, when a person takes a drug to block the cox-2 enzyme — and thereby reduce pain and fever — the drug also reduces the ability of B cells to make antibodies.
“The next step is to figure out the worst time to take drugs that inhibit cox-2 in the context of getting vaccinated. Is it the day before, the day of, or the day after” The timing is likely to be very important,” Phipps said. “But meanwhile, we believe that when you reach for the medicine cabinet to reduce pain at the injection site, that is probably the wrong thing to do.”
The findings are based on laboratory studies of blood samples from people who participated in early clinical trials for the HPV vaccine, and on studies of mice.
For the animal portion of the study, researchers vaccinated normal mice and mice engineered to be cox-2 deficient with a component form of the HPV vaccine. They analyzed the amount of antibodies the animals produced, focusing on the critical virus-neutralizing antibodies. The cox-2 deficient mice made 50 to 70 percent less of these key antibodies.
The same experiment was done on preserved blood samples from people who had been vaccinated against HPV-16, the strain linked to cervical cancer. Scientists reactivated the B cells in the blood samples and watched them churn out antibodies, as expected. But when researchers treated the B cells with a cox-2 inhibiting drug, the cells significantly diminished their production of antibodies — showing that cox-2 is essential for an optimal immune response against HPV 16.
This study is not questioning the effectiveness of the newly marketed HPV vaccine, the Rochester scientists said. They pointed out that in many clinical trials involving thousands of women, the vaccine offered complete protection against the development of cervical cancer. And presumably some of these women were taking NSAIDs at the time.
“There’s no doubt the HPV vaccine showed 100 percent efficacy. Still, our data does suggest that it might be wise to limit the use of NSAIDs when you receive any vaccine,” said co-author Robert Rose, Ph.D., associate professor of Medicine and Microbiology and Immunology at the University of Rochester, and one of the virologists whose work led to the development of the new cancer vaccine.
Scientists do not completely understand the mechanism by which cox-2 influences the immune response in humans. They do believe the response may depend upon the dose and frequency of NSAID use.
The negative effects of blocking cox-2 could be more pronounced in people with compromised immune systems, such as AIDS or cancer patients, the study noted. Moreover, if a vaccine is in short supply and needs to be given in lower-than-optimal doses, taking an NSAID could hamper the immune response even more.
In addition to Phipps and Rose, graduate student Elizabeth Ryan was a co-author on the study, with assistance from students Matt Bernard and Christine Malboef.
Source: University of Rochester Medical Center
The research has widespread implications: study authors report that an estimated 50 to 70 percent of Americans use NSAIDs for relief from pain and inflammation, even though NSAIDs blunt the body’s natural response to infection and may prolong it.
“For years we have known that elderly people are poor responders to the influenza vaccine and vaccines in general,” said principal investigator Richard P. Phipps, Ph.D., a professor of Environmental Medicine, and of Microbiology and Immunology, Oncology and Pediatrics. “And we also know that elderly people tend to be heavy users of inhibitors of cyclooxygenase such as Advil, aspirin, or Celebrex. This study could help explain the immune response problem.”
The study is available online in the Dec. 1, 2006, Journal of Immunology, and was funded in part by the National Institutes of Health.
When a person is vaccinated, the goal is to produce as many antibodies as possible to effectively neutralize the infection. To do this, white blood cells called B-lymphocytes, or B cells, spring into action to produce those antibodies. B cells also serve as the immune system’s memory for future protection against the illness.
But Phipps and colleagues discovered that human B cells also highly express the cyclooxygenase-2 (cox-2) enzyme, which is not intrinsically bad unless it is overproduced, causing pain and fever. So, when a person takes a drug to block the cox-2 enzyme — and thereby reduce pain and fever — the drug also reduces the ability of B cells to make antibodies.
“The next step is to figure out the worst time to take drugs that inhibit cox-2 in the context of getting vaccinated. Is it the day before, the day of, or the day after” The timing is likely to be very important,” Phipps said. “But meanwhile, we believe that when you reach for the medicine cabinet to reduce pain at the injection site, that is probably the wrong thing to do.”
The findings are based on laboratory studies of blood samples from people who participated in early clinical trials for the HPV vaccine, and on studies of mice.
For the animal portion of the study, researchers vaccinated normal mice and mice engineered to be cox-2 deficient with a component form of the HPV vaccine. They analyzed the amount of antibodies the animals produced, focusing on the critical virus-neutralizing antibodies. The cox-2 deficient mice made 50 to 70 percent less of these key antibodies.
The same experiment was done on preserved blood samples from people who had been vaccinated against HPV-16, the strain linked to cervical cancer. Scientists reactivated the B cells in the blood samples and watched them churn out antibodies, as expected. But when researchers treated the B cells with a cox-2 inhibiting drug, the cells significantly diminished their production of antibodies — showing that cox-2 is essential for an optimal immune response against HPV 16.
This study is not questioning the effectiveness of the newly marketed HPV vaccine, the Rochester scientists said. They pointed out that in many clinical trials involving thousands of women, the vaccine offered complete protection against the development of cervical cancer. And presumably some of these women were taking NSAIDs at the time.
“There’s no doubt the HPV vaccine showed 100 percent efficacy. Still, our data does suggest that it might be wise to limit the use of NSAIDs when you receive any vaccine,” said co-author Robert Rose, Ph.D., associate professor of Medicine and Microbiology and Immunology at the University of Rochester, and one of the virologists whose work led to the development of the new cancer vaccine.
Scientists do not completely understand the mechanism by which cox-2 influences the immune response in humans. They do believe the response may depend upon the dose and frequency of NSAID use.
The negative effects of blocking cox-2 could be more pronounced in people with compromised immune systems, such as AIDS or cancer patients, the study noted. Moreover, if a vaccine is in short supply and needs to be given in lower-than-optimal doses, taking an NSAID could hamper the immune response even more.
In addition to Phipps and Rose, graduate student Elizabeth Ryan was a co-author on the study, with assistance from students Matt Bernard and Christine Malboef.
Source: University of Rochester Medical Center
New Protective Action For Powerful Anti-HIV Factor Identified
Scientists at the Gladstone Institute of Virology and Immunology (GIVI) have identified a previously unknown function of APOBEC3G (A3G), a protein that acts against HIV, a finding that may lead to new approaches for controlling HIV infection.
The work is published today, Oct. 2, 2006, in Proceedings of the National Academy of Sciences, USA.
The research, conducted by scientists in the laboratory of GIVI Director Warner C. Greene, MD, PhD, explains why CD4 T cells — the immune system cells targeted by HIV — are sometimes so susceptible to HIV infection and at other times are highly resistant.
Scientists have known that resistant CD4 T cells, called “resting cells,” are made up predominantly of CD4+ T cells that are in an inactive state, awaiting a stimulus to move into action. In these cells, A3G blocks HIV at an early step in its life cycle. However, when resting CD4 T cells are stimulated by a foreign protein or other signal, A3G is rapidly recruited into large RNA protein complexes within the cells. This change neutralizes the anti-HIV properties of A3G, opening the door to HIV infection.
In the current study, the researchers set out to decipher the protein and RNA components of the A3G RNA protein complexes. In so doing, Ya-Lin Chiu, PhD, a postdoctoral fellow in Greene’s laboratory, determined that the complexes help to prevent a threat within cells posed by a class of “jumping genes,” or retro-elements, which are sequences of DNA that change position within the genome, causing mutations, activating or inactivating other genes, or duplicating themselves, thereby increasing the quantity of DNA in each cell.
As with HIV, the replication and movement of these retro-elements to new chromosomal sites with potentially damaging effect involves copying DNA into RNA and then back into DNA again. The A3G RNA protein complex, Chiu determined, interrupts this retro-element replication cycle by binding the retro-element RNAs and sequestering them in the cytoplasm away from the nuclear machinery required for copying the RNA back into DNA and inserting the retro-element at a new chromosomal site.
Understanding A3G’s role in activated CD4 T cells could lead to a new strategy against HIV.
“If we can find a way to partially block A3G assembly into the large complexes during CD4 T cell activation, we could both preserve the potent anti-HIV effect of the small form of A3G and the protective function of the large A3G complex against select mobile genetic elements,” Greene said. Gladstone scientists are now exploring various ways to achieve this desired balance.
Other authors on the study were Gladstone postdoctoral fellows Mario Santiago PhD, and Vanessa B. Soros, PhD, and H. Ewa Witkowska and Steven C. Hall of the University of California, San Francisco, and Cécile Esnault and Thierry Heidmann from the Institut Gustave Roussy in Villejuif, France. Funding for the study came from the National Institutes of Health, San Francisco Women’s HIV Interdisciplinary Network, the American Foundation for AIDS Research, UCSF-GIVI Center for AIDS Research, Ligue Nationale Contre le Cancer, Sandler Family Foundation and the J. David Gladstone Institutes. The Gladstone Institute of Virology and Immunology is one of three research institutes of The J. David Gladstone Institutes, a private, nonprofit biomedical research institution. It is affiliated with UCSF, a leading university that consistently defines health care worldwide by conducting advanced biomedical research, educating graduate students in the health professions and life sciences, and providing complex patient care.
Source: University of California - San Francisco
The work is published today, Oct. 2, 2006, in Proceedings of the National Academy of Sciences, USA.
The research, conducted by scientists in the laboratory of GIVI Director Warner C. Greene, MD, PhD, explains why CD4 T cells — the immune system cells targeted by HIV — are sometimes so susceptible to HIV infection and at other times are highly resistant.
Scientists have known that resistant CD4 T cells, called “resting cells,” are made up predominantly of CD4+ T cells that are in an inactive state, awaiting a stimulus to move into action. In these cells, A3G blocks HIV at an early step in its life cycle. However, when resting CD4 T cells are stimulated by a foreign protein or other signal, A3G is rapidly recruited into large RNA protein complexes within the cells. This change neutralizes the anti-HIV properties of A3G, opening the door to HIV infection.
In the current study, the researchers set out to decipher the protein and RNA components of the A3G RNA protein complexes. In so doing, Ya-Lin Chiu, PhD, a postdoctoral fellow in Greene’s laboratory, determined that the complexes help to prevent a threat within cells posed by a class of “jumping genes,” or retro-elements, which are sequences of DNA that change position within the genome, causing mutations, activating or inactivating other genes, or duplicating themselves, thereby increasing the quantity of DNA in each cell.
As with HIV, the replication and movement of these retro-elements to new chromosomal sites with potentially damaging effect involves copying DNA into RNA and then back into DNA again. The A3G RNA protein complex, Chiu determined, interrupts this retro-element replication cycle by binding the retro-element RNAs and sequestering them in the cytoplasm away from the nuclear machinery required for copying the RNA back into DNA and inserting the retro-element at a new chromosomal site.
Understanding A3G’s role in activated CD4 T cells could lead to a new strategy against HIV.
“If we can find a way to partially block A3G assembly into the large complexes during CD4 T cell activation, we could both preserve the potent anti-HIV effect of the small form of A3G and the protective function of the large A3G complex against select mobile genetic elements,” Greene said. Gladstone scientists are now exploring various ways to achieve this desired balance.
Other authors on the study were Gladstone postdoctoral fellows Mario Santiago PhD, and Vanessa B. Soros, PhD, and H. Ewa Witkowska and Steven C. Hall of the University of California, San Francisco, and Cécile Esnault and Thierry Heidmann from the Institut Gustave Roussy in Villejuif, France. Funding for the study came from the National Institutes of Health, San Francisco Women’s HIV Interdisciplinary Network, the American Foundation for AIDS Research, UCSF-GIVI Center for AIDS Research, Ligue Nationale Contre le Cancer, Sandler Family Foundation and the J. David Gladstone Institutes. The Gladstone Institute of Virology and Immunology is one of three research institutes of The J. David Gladstone Institutes, a private, nonprofit biomedical research institution. It is affiliated with UCSF, a leading university that consistently defines health care worldwide by conducting advanced biomedical research, educating graduate students in the health professions and life sciences, and providing complex patient care.
Source: University of California - San Francisco
Causes Of Global Death And Disease In The Next 25 Years
In 1993, the World Bank sponsored the 1990 Global Burden of Disease study carried out by researchers at Harvard University and the World Health Organization (WHO). This study provided the first comprehensive global estimates of death and illness by age, sex, and region. It also provided projections of the global burden of disease and mortality up to 2020. The study and its projections have been crucial in national and international health policy planning. Colin Mathers and Dejan Locar (from the World Health Organization, Geneva) have now updated the projections based on 2002 data on mortality and burden of disease and published their results in the international open-access journal PLoS Medicine.
As for the earlier report, the researchers used projections of socio-economic development to model future patterns of mortality and illness for three different scenarios: a baseline scenario, a pessimistic scenario that assumes a slower rate of socio-economic development, and an optimistic scenario that assumes a faster rate of growth.
They predict that between 2002 and 2030 under all three scenarios life expectancy will increase around the world, fewer children under the age of 5 years will die, and the proportion of people dying from non-communicable diseases such as heart disease and cancer will increase. Although deaths from infectious diseases will decrease overall, HIV/AIDS deaths will continue to increase. Despite this increase, 50% more people are predicted to die of tobacco-related disease than of HIV/AIDS in 2015. By 2030, the three leading causes of illness will be HIV/AIDS, depression, and ischemic heart disease in the baseline and pessimistic scenarios. In the optimistic scenario, road-traffic accidents (which increase with socioeconomic development) will replace heart disease as the number 3 killer.
In an accompanying editorial, the PLoS Medicine editors ask whether they are publishing “the right stuff”, i.e. research and commentary whose goal it is to reduce mortality and suffering from the most relevant conditions–and whether research funding and health expenditure are consistent with these results.
Citation: Mathers CD, Loncar D (2006) Projections of global mortality and burden of disease from 2002 to 2030. PLoS Med 3(11): e442. (http://dx.doi.org/10.1371/journal.pmed.0030442)
Source: Public Library of Science
As for the earlier report, the researchers used projections of socio-economic development to model future patterns of mortality and illness for three different scenarios: a baseline scenario, a pessimistic scenario that assumes a slower rate of socio-economic development, and an optimistic scenario that assumes a faster rate of growth.
They predict that between 2002 and 2030 under all three scenarios life expectancy will increase around the world, fewer children under the age of 5 years will die, and the proportion of people dying from non-communicable diseases such as heart disease and cancer will increase. Although deaths from infectious diseases will decrease overall, HIV/AIDS deaths will continue to increase. Despite this increase, 50% more people are predicted to die of tobacco-related disease than of HIV/AIDS in 2015. By 2030, the three leading causes of illness will be HIV/AIDS, depression, and ischemic heart disease in the baseline and pessimistic scenarios. In the optimistic scenario, road-traffic accidents (which increase with socioeconomic development) will replace heart disease as the number 3 killer.
In an accompanying editorial, the PLoS Medicine editors ask whether they are publishing “the right stuff”, i.e. research and commentary whose goal it is to reduce mortality and suffering from the most relevant conditions–and whether research funding and health expenditure are consistent with these results.
Citation: Mathers CD, Loncar D (2006) Projections of global mortality and burden of disease from 2002 to 2030. PLoS Med 3(11): e442. (http://dx.doi.org/10.1371/journal.pmed.0030442)
Source: Public Library of Science
Effective HIV Control May Depend On Viral Protein Targeted By Immune Cells
| An effective response of the immune system's 'killer' T cells against infection with HIV may depend on exactly which viral protein is targeted, according to an international group of researchers. A new study finds that HIV-infected individuals in whom virus-specific CD8 T cells are targeted against the Gag protein have lower viral levels than do those with CD8 responses directed against other viral proteins. The report from the Partners AIDS Research Center at Massachusetts General Hospital (PARC-MGH), the University of Oxford and University of KwaZulu-Natal in South Africa is receiving early online release in Nature Medicine.
Understanding which immune responses are effective in control of HIV is of critical importance in vaccine development," says Philip Goulder, MD, PhD, of PARC-MGH and Oxford, the senior author of the study. "Previous approaches have focused on a 'more is better' approach, seeking to generate responses against a broad range of viral proteins, but these results challenge that dogma." While many strategies for developing a vaccine to control HIV focus on the activity of the CD8 T lymphocytes that recognize and destroy virus-infected CD4 T cells, the fact that even patients in the last stages of AIDS can have measurable CD8 responses indicates that those responses are not always effective. To investigate how variations in CD8 response alter the ability to control HIV, the research team enrolled almost 600 South African patients who had not yet been treated for their HIV infections. The researchers comprehensively mapped the CD8 responses against all viral proteins and also investigated whether the versions of HLA Class I molecules involved in the immune system's recognition of HIV protein fragments made a difference. When new viruses are produced within an infected cell, Class I molecules grab viral fragments and display them at the cell surface, thereby alerting CD8 cells that the cell has been infected and should be destroyed. Earlier studies, including a 2004 Nature report from the same group, showed that the genetically determined version of an individual's HLA Class I molecules could strongly influence immune control of HIV. The current study found that only CD8 responses against the Gag protein were associated with significantly reduced viral levels and that individuals with responses against several different Gag fragments had even lower viral loads. In contrast, those with stronger responses against other HIV proteins -- including Env, a protein that is the focus of several vaccine studies -- had higher viral levels indicating poorer control of HIV. In people receiving no antiretroviral treatment, the improved HIV control associated with Gag-specific CD8 response would probably translate into asymptomatic infection for more than a decade, compared with progression to AIDS within two to three years of infection in those with no Gag responses. The reason why patients' particular HLA Class I molecules are linked to different HIV disease outcomes now appears to be related to the number of Gag fragments displayed by different versions of the Class I molecule. Mechanisms underlying the different effects of the protein-specific immune responses are unknown and require further investigation. The researchers suggest that responses against proteins like Env might be inherently less effective or might only be generated in response to elevated viral loads. Therefore, the findings of this study, which reflect chronic HIV infection, might not apply in situations in which vaccination generates an immune response before infection occurs. "The possibility that there may be fundamental differences between the impact of Gag and non-Gag CD8 responses on the ability to control HIV has clear relevance to vaccine development," says Goulder, who is an associate professor of Medicine at Harvard Medical School. Co-authors of the Nature Medicine report from Doris Duke Medical Research Institute at the University of KwaZulu-Natal are first author Photini Kiepiela, Kholiswa Ngumbela, Christina Thobakgale, Dhanwanthie Ramduth, Eshia Moodley, Shabashini Reddy, Chantal de Pierres, Zenele Mncube, Nompumelelo Mkhwanazi, Karen Bishop, Mary van der Stok, Kriebashnie Nair, Nasreen Kahn, and Hoosen Coovadia. Other co-authors are Isobella Honeyborne, Hayley Crawford, Rebecca Payne, Alasdair Leslie, Julia Prado, Andrew Prendergast, John Frater, and Noel McCarthy, University of Oxford; Christian Brander and Bruce Walker, Partners AIDS Research Center at Massachusetts General Hospital; Gerald Learn, David Nickle, Christian Rousseau and James Mullins, University of Washington School of Medicine; and David Heckerman, Microsoft Research. The study was supported by grants from the U.S. National Institutes of Health, the Wellcome Trust, and the Mark and Lisa Schwartz Foundation. Walker is a Howard Hughes Medical Institute investigator and a Doris Duke Distinguished Clinical Science Professor, and Goulder is an Elizabeth Glaser Pediatric AIDS Foundation Scientist.
| Massachusetts General Hospital |
Stem Cell Activity Deciphered In The Aging Brain
Neurobiologists have discovered why the aging brain produces progressively fewer new nerve cells in its learning and memory center. The scientists said the finding, made in rodents, refutes current ideas on how long crucial "progenitor" stem cells persist in the aging brain.
The finding also suggests the possibility of treating various neurodegenerative disorders, including Alzheimer's disease, dementia and depression, by stimulating the brain's ability to produce new nerve cells, said senior study investigator Ashok K. Shetty, Ph.D., professor of neurosurgery at Duke University Medical Center and medical research scientist at Durham VA Medical Center.
Results of the study appear online in the journal Neurobiology of Aging. The research was funded by the National Institutes of Health and the U.S. Department of Veterans Affairs.
Previous studies by Shetty and others had demonstrated that as the brain ages, fewer new nerve cells, or neurons, are born in the hippocampus, the brain's learning and memory center. In one study, Shetty and colleagues showed that the production of new neurons in rats slows down dramatically by middle age -- the equivalent of 50 years in humans.
But scientists did not know what causes this decline.
The common assumption had been that the brain drain was due to a decreasing supply of neural stem cells in the aging hippocampus, said lead study investigator Bharathi Hattiangady, Ph.D., research associate in neurosurgery. Neural stem cells are immature cells that have the ability to give rise to all types of nerve cells in the brain.
In the current study, however, the researchers found that the stem cells in aging brains are not reduced in number, but instead they divide less frequently, resulting in dramatic reductions in the addition of new neurons in the hippocampus.
To conduct their census, the researchers attached easy-to-spot fluorescent tags to the neuronal stem cells in the hippocampus in young, middle-aged and old rats.
They found that in young rats, the hippocampus contained 50,000 stem cells -- and, significantly, this number did not diminish with aging. This finding, the researchers said, suggested that the decreased production of new neurons in the aged brain was not due to a lack of starting material.
The researchers then used another fluorescent molecule to tag all stem cells that were undergoing division in the process of staying "fresh" in case they were recruited to become mature nerve cells.
They found that in young rats, approximately 25 percent of the neural stem cells were actively dividing, but only 8 percent of the cells in middle-aged rats and 4 percent in old rats were dividing. This decreased division of stem cells is what causes the decreased neurogenesis, or birth of nerve cells, seen with aging, the scientists said.
"This discovery provides a new avenue to pursue in trying to combat the cognitive decline associated with conditions such as Alzheimer's disease and with aging in general," Hattiangady said.
The team now is searching for ways to stimulate the brain to replace its own cells in order to improve learning and memory function in the elderly.
One approach being explored is to treat older rats with drugs designed to mimic the action of compounds called neurogenic factors, which encourage stem cells in the brain to divide, Shetty said. The researchers also are grafting neural stem cells grown in culture dishes into the hippocampus, to stimulate those already present. Additional approaches include using behavioral modification techniques, such as physical exercise and exposure to an enriching environment, that are known to stimulate proliferation of stem cells.
|
Eat To Live: Saving food traditions
By JULIA WATSON for UPI
As environmentalists rush to save the earth fearful for the future of large swathes of it, foodies rush to save national cuisines whose traditions they think have already disappeared.
Italian Carlo Petrini founded Slow Food in 1986 to protect our food heritage. He was galvanized to do so by the affront of a McDonald's restaurant opening in Rome's historic Piazza di Spagna. He realized traditional dishes, produce, livestock were all vanishing, under the assault of fast food convenience, the power of supermarkets and the might of the industrial agribusiness.
Another Italian, Egeria di Nallo, head of political science at the University of Bologna, has made her own quiet and influential contribution to the preservation of food customs. She has created a network of women throughout Italy, proud home cooks every one, who will conjure up a meal of traditional dishes in their own kitchens for eight or so international members of Home Food, as the organization is called.
Once a month, these self-styled 'Cesarine' -- loosely 'empresses' of the kitchen, passionate about good cooking -- produce a meal for 8 or so paying guests who have registered in response to the monthly newsletter. They have been vetted for their cooking skills and divided, without apparently raising any hackles, into four social categories -- popular, middle class and two levels of the aristocracy. Whichever social spectrum the guests choose to dine in, each enables people to experience real Italian cooking in the homes of the cooks themselves.
Professor di Nallo, despondent at the lack of authentic Italian food in restaurants, launched the growing group two years ago. Now she has more than 50 Cesarine ready at their chopping boards. On different menus across Italy this coming January are regional specialties from the goose meat salami of Lombardy, to presnitz -- pasta filled with walnuts, almonds, sultanas and pine nuts -- from the Italy-Austria border, and Rome's aniseed dougnuts, all made with devotion and expertise by these proud amateurs.
It's not only in Europe that the call is out to protect food heritages. But it isn't working so effectively elsewhere. Last year, Mexico applied to UNESCO, the cultural arm of the U.N. for formal recognition of its food traditions. It wanted them acknowledged as part of their country's cultural heritage. But they were turned down.
Now the French are knocking at UNESCO's door with the same intent. L'Institut Européen d'Histoire et des Cultures de l'Alimentation, an institute of food history and culture has joined with Tours University to gather up food professionals, writers, even the ex-minister of culture, to get behind a push to have France's gastronomic heritage recognized by UNESCO.
Perhaps they believe in a French kind of way that their classic cuisine stands a better chance to get the juices of those whose decision it will be flowing more readily than they did when Mexico's gastronomy was up for review.
At any rate, it is interesting that the movement to protect food as a cultural heritage is growing. And it's coming to a high end restaurant menu near you.
Increasingly, chefs are writing the provenance of their prime ingredients next to their dishes. At the Blue Duck Tavern in Washington D.C., there is even a separate column, with the name of each producer in capital letters. Nora Pouillon, at Restaurant Nora in the nation's capital, uses her menu "as a message board. If there is a campaign around a certain topic, such s fish that is nearly extinct, I note it on the menu so that the customers can learn."
It's almost impossible to order a plain ol' pork chop in an up-market eatery these days. The cut will be touted as coming from an acorn-fed Berkshire pig, a traditional breed with a better pedigree than you or me. And demand for a proper heritage turkey has been so great this year, it's far too late to think of ordering one now (though you could try at http://www.localharvest.org). Smaller than the supermarket balloon, it will have scampered around the thistly fields for between 24 and 30 weeks, instead of the 18 weeks it takes a flavorless White Breasted Tom to reach its requisite 32 pounds sale-weight.
These aspirations to save our food heritage shouldn't be sneered at as the stuff of the privileged classes. Our food is far too cheap. It prices hard-working small farmers around the globe out of the market. The pleasure in eating food that has been thoughtfully raised is immediate in the mouth. It's all about taste. And the well-being of the animal and the earth that raises the produce. Since we don't need to eat a lump of protein every day, it shouldn't necessarily make our weekly shopping a more expensive venture. We are paying a high price for convenience shopping and convenience eating.
Instead of satisfying that meat urge with a quick-to-throw-on-the-plate steak or chicken breast, take a little more time to put together this slow-braise casserole adapted from Nigel Slater. It will give you more than one meal with far cheaper meat.
--Italian-style slow-cooked aromatic lamb
--Serves 4 with left-overs
--1 pound dried cannellini or navy beans
--8 lamb shoulder or neck chops
--2 medium red onions, peeled and cut into eighths
--4 carrots, cut into thick chunks on the diagonal
--4 stalks of celery, cut on the diagonal into thick slices
--6 cloves garlic, peeled and bashed with the side of a knife
--2 small dried red chilies
--1 bottle quaffable red wine
--1 ½ pints chicken stock
--2 oranges
--4 large portobello mushrooms
--2 tablespoons balsamic vinegar
--4 bay leaves and a small tied bunch of fresh thyme
--olive oil
--salt to taste
--Soak the beans overnight.
--Also overnight, marinade the lamb in a glass or china bowl with the next seven ingredients plus several long curls of scrubbed orange peel taken off with a potato peeler and then the oranges sliced into eighths.
--Next day, bring the beans to a boil covered with fresh water and boil for 10 minutes, then cover and turn off heat.
--Coat the bottom of a heavy bottomed pan with oil, dry off the chops and brown them both sides in batches and set aside in a heavy bottom lidded casserole.
--Drain off the marinade and fry everything left, together with the mushrooms, for around 10 minutes till softened. Add to the casserole.
--Pour enough of the marinade into the sauté pan to scrape up any frying residue and pour over the meat.
--Bring the rest of the marinade to a boil in the pan, then add to the casserole with all remaining ingredients including the drained beans, cover with greaseproof parchment paper and the lid and leave to simmer gently for about 1 ½ hours.
--If you allow 2 days for this, you can refrigerate it and spring off the fat. And the dish will develop more flavor.
Copyright 2006 by United Press International. All Rights Reserved.
CT scans used to analyze wood
US government scientists say they are developing ways to use computerized tomography imaging to analyze various types of wood.
The U.S. Department of Energy researchers at the Oak Ridge National Laboratory say their findings might lead to important applications in the pulp, paper and nascent bioenergy industries.
Oak Ridge National Laboratory researcher Justin Baba is working to develop analytical tools to determine parameters such as fiber length and arrangement, cell wall thickness and density from CT scans. Those scans could replace more destructive, chemical-dependant, methods of analyzing wood samples that currently compromise the information collection process.
For bioenergy, after some basic measurement standards are established, Baba says the scans will be able to show the cellulosic content of wood to help create a cellulose-based biofuel supply.
Copyright 2006 by United Press International. All Rights Reserved.
Stem Cell Activity Deciphered In The Aging Brain
| Source: | Duke University Medical Center |
The finding also suggests the possibility of treating various neurodegenerative disorders, including Alzheimer's disease, dementia and depression, by stimulating the brain's ability to produce new nerve cells, said senior study investigator Ashok K. Shetty, Ph.D., professor of neurosurgery at Duke University Medical Center and medical research scientist at Durham VA Medical Center.
Results of the study appear online in the journal Neurobiology of Aging. The research was funded by the National Institutes of Health and the U.S. Department of Veterans Affairs.
Previous studies by Shetty and others had demonstrated that as the brain ages, fewer new nerve cells, or neurons, are born in the hippocampus, the brain's learning and memory center. In one study, Shetty and colleagues showed that the production of new neurons in rats slows down dramatically by middle age -- the equivalent of 50 years in humans.
But scientists did not know what causes this decline.
The common assumption had been that the brain drain was due to a decreasing supply of neural stem cells in the aging hippocampus, said lead study investigator Bharathi Hattiangady, Ph.D., research associate in neurosurgery. Neural stem cells are immature cells that have the ability to give rise to all types of nerve cells in the brain.
In the current study, however, the researchers found that the stem cells in aging brains are not reduced in number, but instead they divide less frequently, resulting in dramatic reductions in the addition of new neurons in the hippocampus.
To conduct their census, the researchers attached easy-to-spot fluorescent tags to the neuronal stem cells in the hippocampus in young, middle-aged and old rats.
They found that in young rats, the hippocampus contained 50,000 stem cells -- and, significantly, this number did not diminish with aging. This finding, the researchers said, suggested that the decreased production of new neurons in the aged brain was not due to a lack of starting material.
The researchers then used another fluorescent molecule to tag all stem cells that were undergoing division in the process of staying "fresh" in case they were recruited to become mature nerve cells.
They found that in young rats, approximately 25 percent of the neural stem cells were actively dividing, but only 8 percent of the cells in middle-aged rats and 4 percent in old rats were dividing. This decreased division of stem cells is what causes the decreased neurogenesis, or birth of nerve cells, seen with aging, the scientists said.
"This discovery provides a new avenue to pursue in trying to combat the cognitive decline associated with conditions such as Alzheimer's disease and with aging in general," Hattiangady said.
The team now is searching for ways to stimulate the brain to replace its own cells in order to improve learning and memory function in the elderly.
One approach being explored is to treat older rats with drugs designed to mimic the action of compounds called neurogenic factors, which encourage stem cells in the brain to divide, Shetty said. The researchers also are grafting neural stem cells grown in culture dishes into the hippocampus, to stimulate those already present. Additional approaches include using behavioral modification techniques, such as physical exercise and exposure to an enriching environment, that are known to stimulate proliferation of stem cells.
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