Survival Matching Should Be Used To Allocate Kidneys To Transplant Recipients

Providing kidney transplants to patients with the best probability of longer survival would reduce repeat transplant operations and improve life span after kidney transplant, says a U-M researcher in a commentary published in the New England Journal of Medicine March 16.

Alan B. Leichtman, M.D., professor of Internal Medicine at U-M and his co-authors endorsed new concepts designed to improve kidney allocation. These concepts were circulated in February by the Organ Procurement and Transplantation Network (OPTN). The OPTN is the federal contract that oversees solid organ recovery and allocation in the United States.

“We strongly support the concept of rank ordering donated kidneys based upon their potential post-transplant survival, and matching that survival to that of waitlisted kidney transplant candidates,” says Leichtman, the commentary’s lead author.

“The current deceased donor kidney allocation system allows distribution of kidneys with very short potential survival to candidates with long expected survival. Candidates with long potential lifetimes that received kidneys with short expected survival have twice the repeated transplantation rate than similar recipients who received organs with a longer expected survival rate.”

The current U.S. deceased donor kidney allocation system relies primarily upon how long a candidate has been waiting for an organ. However, systems for liver and heart transplantation allocation are based upon candidate medical urgency. The lung allocation system allocates organs based upon a mixture of medical urgency and expected one-year post-transplant survival.

The Organ Procurement and Transplantation Network has released for public comment three proposed concepts for deceased donor kidney allocation.

1) Using a Kidney Donor Profile Index to rank deceased donor kidneys according to the length of time that the kidney would be expected to function in an average kidney transplant recipient.

2) Allocating the 20% highest quality kidneys to the 20% of candidates with the longest expected post-transplant survival.

3) Allocating the remaining 80% of kidneys such that candidates who are within 15 years (older or younger) of the donor’s age have highest priority.

Because of the current system and the aging of the candidate pool, post-transplant life span following kidney transplantation in the United States has declined on average by 18 months since 1995, Leichtman says.

The authors say that computer simulations based on the current donor pool suggest that more than 35,000 years of post-transplant survival are lost each year under the current system. Additionally, more than 10,000 years of incremental post-transplant survival — extra years of life that would not have been achieved without the benefit of transplant — also are lost each year.

“We are wasting hundreds of thousands of potential years of life,” Leichtman says. “The proposal for survival matching as described in the concept document has the potential to reclaim many of these lost years of life, and therefore warrants serious consideration.”

The authors also support using the proposed Kidney Donor Profile Index. The new index provides a more granular and accurate survival estimate for organs.

“We suspect that utilization rates of shorter-lived kidneys will increase with accurate information about their survival potential and reduced opportunity for potentially short-lived candidates to be allocated kidneys with long estimated post-transplant survival,” the authors wrote.

About 80,000 people are listed nationwide for a kidney transplant. Demand continues to increase, some of it driven by an unnecessarily high rate of repeat transplantations because kidneys and recipients weren’t well matched, says Leichtman.

Kidney transplants are the most common transplants done at the University of Michigan Transplant Center and nationwide. But more than half of those who get wait-listed for a kidney transplant in the U.S. never receive a transplant.

“The lost potential life years, and the increase in the waiting list resulting from an unnecessarily high rate of repeat transplantation are intolerable consequences of the current kidney transplant allocation system,” Leichtman says. “There likely are further opportunities for improvements to the proposed system, but the core proposals presented in the concept document, adoption of the KDPI and survival matching, warrant the strongest endorsement and the earliest possible implementation by the kidney transplant community.”

Public comment is open until April 1 on the proposed concepts. Comments can be e-mailed to kidneypolicyunos.

Journal citation: 10.1056/NEJMp1102728

Additional authors: Robert A. Wolfe, Ph.D., professor emeritus in the University of Michigan School of Public Health and Keith P. McCullough. M.S. Both Dr. Wolfe and Mr. McCullough are investigators at the Arbor Research Collaborative for Health in Ann Arbor, Mich.

Source:
University of Michigan Health System

U.S. Should Impose Higher Taxes, Stricter Regulations On Tobacco Products As Part Of Cancer Prevention Efforts, Advisory Panel Recommends

The President’s Cancer Panel on Thursday recommended that the federal government place strict regulations on tobacco marketing and sales and increase taxes on tobacco products to help reduce cancer in the U.S., the AP/San Francisco Chronicle reports. The panel said that 2007 has had the steepest decline in cancer deaths but that still more than 500,000 U.S. residents will die from cancer this year. Nearly two-thirds of those deaths could be avoided with lifestyle changes, the panel said.

The panel recommended that lawmakers refuse campaign funds from the tobacco industry and that states work to reduce smoking by making public schools and universities smoke-free and offering smoking cessation programs at correctional facilities and through state-funded programs, including Medicaid.

In a report to President Bush, panel members wrote, “The panel recommends foremost that the influence of the tobacco industry — particularly on America’s children — be weakened through strict federal regulation of tobacco products and marketing.” The Bush administration is opposed to raising taxes to fund spending increases.

Additional Recommendations
The panel said government policies often compromise cancer-fighting efforts because they hinder the availability of healthy food and physical education (Freking, AP/San Francisco Chronicle, 8/16). “Ineffective policies, in conjunction with limited regulation of sales and marketing in the food and beverage industry, have spawned a culture that struggles to make healthy choices — a culture in dire need of change,” the panel wrote (Reuters/New York Post, 8/17). Schools should replace junk food with healthy food in vending machines and make physical education mandatory from kindergarten through 12th grade, the panel recommended (AP/San Francisco Chronicle, 8/16).

According to the panel, the “issues discussed in this report have suffered to varying degrees from politicization that continues to derail or limit progress toward a healthier population that is less burdened by cancer. We cannot continue to fund tobacco- and obesity-related research, thinking it will solve the problems caused by cancer risk-promoting behaviors and products, and also acquiesce to the demands of the industries that encourage those behaviors and produce those products” (Wayne, CQ Today, 8/16).

The panel, established in 1971, is made up of three members and meets four times a year to monitor the nation’s campaigns to fight and eliminate cancer. The current panel members are LaSalle Leffall, a renowned surgeon and chair of the panel; pro bicyclist and cancer survivor Lance Armstrong; and Margaret Kripke, chief academic officer of the M.D. Anderson Cancer Center at the University of Texas (AP/San Francisco Chronicle, 8/16).

Lawmakers’ Efforts
Senate Health, Education, Labor and Pensions Committee Chair Edward Kennedy (D-Mass.) said, “The recommendations eloquently reaffirm what is widely recognized throughout the public health community: that giving the [FDA] the power to regulate tobacco products is the most important step Congress can take to reduce smoking and the immense toll of illness and death it causes,” adding, “It is absolutely essential to reduce smoking, especially among the nation’s youth.”

The HELP Committee this month approved legislation (S 625) that would give FDA authority to regulate tobacco products and advertising. In addition, the House and Senate each have passed bills (HR 3162, S 1893) that would increase cigarette taxes to fund the reauthorization and expansion of SCHIP. Bush has threatened to veto both measures. Bush has not threatened to veto the tobacco regulation measure, but the administration has said it has concerns about the bill, CQ Today reports (CQ Today, 8/16).


The report is available online. (.pdf)

“Reprinted with permission from kaisernetwork. You can view the entire Kaiser Daily Health Policy Report, search the archives, or sign up for email delivery at kaisernetwork/dailyreports/healthpolicy. The Kaiser Daily Health Policy Report is published for kaisernetwork, a free service of The Henry J. Kaiser Family Foundation . © 2005 Advisory Board Company and Kaiser Family Foundation. All rights reserved.

Military Approves H1N1 Testing With Idaho Technology JBAIDS

Idaho Technology’s Joint Biological Agent Identification and Diagnostic System (JBAIDS) has been approved by the military to run tests for the H1N1 virus. Deployed across the globe, including in Iraq and Afghanistan, by all four branches of the military, the JBAIDS instrument will be used to test military personnel and their families for Influenza A, swine flu A and H1 swine flu in less than an hour. More traditional means of testing can take days to deliver results. Given the proximity in which soldiers live and work, the speed to result will enable a swift response and quarantine of the infected, minimizing the spread of the virus.

In response to the recent outbreaks of the H1N1 virus, the Chemical Biological Medical Systems – Joint Project Management Office (CBMS-JPMO) requested JBAIDS be evaluated for Emergency Use Authorization by the Food and Drug Administration to identify the H1N1 virus. The use of the JBAIDS allows the armed services the ability to identify, isolate and control the spread of the H1N1 virus with a system that is already deployed in the field.

Testing was conducted at the United States Army Medical Research Institute for Infectious Diseases (USAMRIID), Fort Detrick, Maryland, using test kits manufactured by the Centers for Disease Control (CDC). Results revealed accurate identification of the H1N1 virus on the JBAIDS instrument. Idaho Technology provided a team of scientists that hastened the development so the delivery of the tests could begin this month.

“Protecting our military forces has been Idaho Technology’s core mission with the JBAIDS. We stand ready to assist the military in any way we can and to be a resource in the fight to stop the spread of the H1N1 virus through fast and reliable detection,” said Kirk Ririe, chief executive officer of Idaho Technology.

Source
Idaho Technology

New Method To Grow Arteries Could Lead To ‘Biological Bypass’ For Heart Disease

A new method of growing arteries could lead to a “biological bypass” – or a non-invasive way to treat coronary artery disease, Yale School of Medicine researchers report with their colleagues in the April issue of Journal of Clinical Investigation.

Coronary arteries can become blocked with plaque, leading to a decrease in the supply of blood and oxygen to the heart. Over time this blockage can lead to debilitating chest pain or heart attack. Severe blockages in multiple major vessels may require coronary artery bypass graft surgery, a major invasive surgery.

“Successfully growing new arteries could provide a biological option for patients facing bypass surgery,” said lead author of the study Michael Simons, M.D., chief of the Section of Cardiology at Yale School of Medicine.

In the past, researchers used growth factors – proteins that stimulate the growth of cells – to grow new arteries, but this method was unsuccessful. Simons and his team studied mice and zebrafish to see if they could simulate arterial formation by switching on and off two signaling pathways – ERK1/2 and P13K.

“We found that there is a cross-talk between the two signaling pathways. One half of the signaling pathway inhibits the other. When we inhibit this mechanism, we are able to grow arteries,” said Simons. “Instead of using growth factors, we stopped the inhibitor mechanism by using a drug that targets a particular enzyme called P13-kinase inhibitor.”

“Because we’ve located this inhibitory pathway, it opens the possibility of developing a new class of medication to grow new arteries,” Simons added. “The next step is to test this finding in a human clinical trial.”

Other authors on the study included Bin Ren, Yong Den, Arpita Mukhopadhyay, Anthony A. Lanahan, Zhen W. Zhuang, Karen L. Moodie, Mary Jo Mulligan-Kehoe, Tatiana V. Byzova, and Randall T. Peterson

The Journal of Clinical Investigation Vol. 120, No. 4 (April 2010)

Source:
Karen N. Peart
Yale University

Lower IQ In Children Linked To Pre-Birth Air Pollution Exposure, Study

Research conducted in New York City found that children exposed to urban air pollution before birth were more likely to have a lower IQ than
less exposed children. The researchers said the levels of IQ reductions they found would be enough to affect children’s academic
performance.

The study was the work of Dr Frederica P Perera of the Mailman School of Public Health at Columbia University, New York, New York, and
colleagues, and was published online on 20 July in the journal Pediatrics.

Helped by funds from the National Institute of Environmental Health Sciences (NIEHS), a component of the National Institutes of Health, the US
Environmental Protection Agency and some private foundations, Perera and colleagues measured New York City children’s prenatal exposure to
polycyclic aromatic hydrocarbons (PAHs) and then linked it to IQ scores measured when they reached 5 years of age.

PAHs are chemicals that get into the air as a result of burning coal, diesel, oil and gas, plus other organic substances such as tobacco. Motor vehicles
are thought to be the main contributor in urban areas.

The researchers found that children with above the median level of exposure to PAH had overall and verbal IQ scores that were 4.31 and 4.67 points lower
respectively than those children whose exposure was below the median (median PAH exposure was defined to be 2.26 nanograms per cubic meter, or ng/m3).

Perera and colleagues concluded that:

“These results provide evidence that environmental PAHs at levels encountered in New York City air can affect children’s IQ adversely.”

Perera, who is professor of Environmental Health Sciences and director of the Columbia Center for Children’s Environmental Health at Columbia
University Mailman School of Public Health, said we should be concerned about these findings because such reductions in IQ score are enough to
make a difference to children’s performance at school.

“The decrease in full-scale IQ score among the more exposed children is similar to that seen with low-level lead exposure,” she added.

“Fortunately, airborne PAH concentrations can be reduced through currently available controls, alternative energy sources and policy interventions,”
said Perera, adding that:

“The good news is that we have seen a decline in air pollution exposure in our cohort since 1998, testifying to the importance of policies to reduce
traffic congestion and other sources of fossil fuel combustion byproducts.”

The children in the study, who were followed from before birth up to 5 years of age, were born to nonsmoking black or Dominican-American women
aged between 18 to 35 living in Washington Heights, Harlem or the South Bronx in New York.

The researchers asked the expectant mothers to wear personal air monitors to measure PAH exposure during pregnancy, during which time they also
filled in questionnaires.

When the children reached 5 years of age, 249 of them took an IQ test known as the Wechsler Preschool and Primary Scale of Intelligence-Revised.
This test gives verbal, performance and full-scale IQ scores.

Using statistical tools called multivariate linear regression models, the researchers then looked for links between the children’s IQ scores at age 5 and
their pre-birth exposure to PAH pollutants.

These models allow them to take out the effect of factors that might interfere with the results (potential confounders), such as second-hand smoke
exposure, lead exposure, mother’s education and the quality of the home caretaking environment (this data came from the mothers’ questionnaire
responses).

“Prenatal Airborne Polycyclic Aromatic Hydrocarbon Exposure and Child IQ at Age 5 Years.”
Frederica P. Perera, Zhigang Li, Robin Whyatt, Lori Hoepner, Shuang Wang, David Camann, and Virginia Rauh.
Pediatrics,
published online July 20, 2009.
doi: 10.1542/peds.2008-3506

Source: CCCEH.

: Catharine Paddock, PhD

Gene Mutation Alone Causes Transmissible Prion Disease

For the first time, Whitehead Institute researchers have shown definitively that mutations associated with prion diseases are sufficient to cause a transmissible neurodegenerative disease.

The discovery is reported in the August 27 edition of the journal Neuron.

Until now, two theories about the role mutations play in prion diseases have been at odds. According to one theory, mutations make carriers more susceptible to prions in the environment. Alternatively, mutations themselves might cause the disease and the spontaneous generation of transmissible prions.

Prions cause several diseases, including Creutzfeldt-Jakob disease (CJD) in humans, bovine spongiform encephalitis (BSE, or “mad cow disease”) in cows, and scrapie in sheep. Some prion diseases, like BSE, can be transmitted from feed animals to humans. Deciphering the origins of prion diseases could help farmers and policy-makers determine how best to control a prion disease outbreak in livestock and to prevent prion transmission to humans.

Prions are misfolded versions of a protein called PrP. In its normal form, PrP is expressed in the brain and other neural tissues. But specific events, such as exposure to prions from the environment, can cause PrP to change from its normal shape to that of a prion. Once in the prion shape, the protein can convert other normal PrP proteins to the abnormal shape. As PrP proteins convert to prions, they form long chains that damage brain and nerve cells, causing the neurodegenerative and behavioral symptoms characteristic of prion diseases.

To determine if a mutation in the PrP gene can cause a transmissible prion disease, Walker Jackson, first author of the Neuron article and a postdoctoral researcher in the lab of Whitehead Member Susan Lindquist, engineered a knock-in mouse expressing a PrP gene carrying the mutation associated with the human prion disease fatal familial insomnia (FFI).

In knock-in experiments, the researcher removes a gene of interest, makes specific changes to it in a test tube, and then places it back in its original place in the genome. In this case, Jackson replaced the mouse PrP gene with an altered version carrying the FFI mutation. This version also carried a sequence from human PrP that prevented the mice from acquiring normal mouse prions that could potentially be in the environment.

“It’s more difficult to create a knock-in mouse, instead of randomly integrating the mutated gene into the mouse’s genome,” says Jackson. “But creating a knock-in like this makes sure the gene is expressed when and where it normally would be. That’s the number one reason we think this disease model worked so well, compared to others’ experiments.”

As adults, the mice exhibited many of the same traits as human FFI patients: reduced activity levels and sleep abnormalities. When Jackson examined the mice’s brains, they resembled those of human FFI patients, with prominent damage to the thalamic region of the brain.

After establishing that the mice have the behavioral and pathological characteristics of FFI, Jackson injected diseased brain tissue from the FFI mice into healthy mice. The healthy mice also carried the same human derived barrier as the FFI mice, preventing their infection by normal mouse prions and ensuring that the only prion they could acquire was the one engineered by Jackson. After injection with the affected tissue, the healthy mice exhibited similar symptoms and neuropathology as the mice with the FFI mutation.

The mutated gene engineered by Jackson had created a transmissible prion disease that could not be attributed to any prions in the environment.

“One of the major tenets of the prion hypothesis is that a single amino acid change in PrP, associated with human disease, is sufficient to cause the spontaneous production of infectious material,” says Lindquist, who is also a professor of biology at MIT and a Howard Hughes Medical Institute investigator. “Many people have tried and come close. But this is the first time it has been nailed.”

This study was supported by the Department of Defense (DoD) and the National Institutes of Health (NIH).

Nicole Giese

Susan Lindquist’s primary affiliation is with Whitehead Institute for Biomedical Research, where her laboratory is located and all her research is conducted. She is also a Howard Hughes Medical Institute investigator and a professor of biology at Massachusetts Institute of Technology.

Full Citation:

“Spontaneous generation of prion infectivity in fatal familial insomnia knock-in mice”


Neuron, August 27, 2009

Walker S. Jackson (1), Andrew Borkowski (1,2), Henryk Faas (3), Andrew Steele (1), Oliver King (1), Nicki Watson (1), Alan Jasanoff (3,4), and Susan Lindquist (1,2).

1. Whitehead Institute for Biomedical Research, Nine Cambridge Center, Cambridge, MA 02142
2. Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, MA 02142
3. Frances Bitter Magnet Laboratory, Massachusetts Institute of Technology, 166 Albany St., NW14, Cambridge, MA 02139
4. Departments of Biological Engineering, Brain & Cognitive Sciences, and Nuclear Science & Engineering, Massachusetts Institute of Technology, 150 Albany St., NW14, Cambridge, MA 02139

Source:
Nicole Giese

Whitehead Institute for Biomedical Research

Payer Status Often Determines Nursing Home Hospitalizations

The decision by nursing homes whether or not to treat an ill resident on-site or send them to a hospital are often linked to that person’s insurance status. A new study out this month shows that on average individuals enrolled in Medicaid are 27 percent more likely to be sent to the hospital than individuals with private insurance – decisions that often result in higher costs of care and poor health outcomes.

“Nursing homes have an incentive to hospitalize some residents more often than others,” said Helena Temkin-Greener, Ph.D., M.P.H., senior author of the study and associate professor of Community and Preventive Medicine at the University of Rochester Medical Center. “This study provides strong evidence that these financial incentives may motivate consideration of payer source in the decision whether or not to hospitalize an individual.”

While it has long been observed that Medicaid nursing home residents have higher hospitalization rates, it had been assumed this is because these residents are more likely to congregate in facilities with fewer resources to provide onsite care. A new study published in the journal Medical Care Research and Review for the first time looks at hospitalization rates within individual nursing homes to see if patients with Medicaid are treated differently from those with private insurance.

“Nursing homes, in many instances, have discretion in whether to keep a patient in the facility and expend additional care resources, or transfer the resident to the hospital,” said Shubing Cai, Ph.D., lead author of the study and investigator at Brown University. “While we know that nursing homes tend to provide similar quality of care to all residents, hospitalization decisions are often different from the decisions involved in the provision of daily care and have a significant impact on the long-term health of residents.”

Medicaid – the joint federal and state health insurance program – pays for nursing home care for elderly individuals who meet the program’s assets and income requirements. Eligibility varies from state to state but generally requires that the value of a person’s income and assets be below a percentage of the federal poverty guidelines. While Medicaid and private insurance pay for nursing home-related care, costs associated with hospitalization are covered by Medicare – the federal health insurance program for the elderly.

Because Medicaid often reimburses nursing homes at a rate lower than private pay insurance – and often below the cost necessary to provide the onsite intensive care – nursing homes have a strong financial incentive to send sick Medicaid patients to the hospital where the cost will be absorbed by Medicare and the hospital. This decision is further complicated in states with “bed-hold” policies which continue to pay the nursing home for Medicaid residents while they are hospitalized. In New York State to qualify for these payments nursing homes need to meet an occupancy threshold. Nursing homes are not eligible to receive bed-hold payment for patients with private insurance or those paying out-of-pocket.

Bed-hold policies were created to help preserve continuity of care for patients by ensuring that there would be a bed in the same nursing home waiting for them when they returned from the hospital. While well-meaning, these policies have created further incentive to send residents to the hospital for care and, because these costs are born by Medicare and not Medicaid, states have little financial incentive to change these policies. States with bed-hold policies include, among others California, Ohio, and, until very recently, New York.

As it is often more expensive to care for an individual in a hospital setting, these decisions ultimately drive higher federal health care spending. These expenditures can be even more pronounced when the patient could have been adequately cared for in the nursing home in the first place. It has been estimated that approximately half of all hospitalizations of nursing home residents are unnecessary or avoidable. In 2004, Medicare paid $188 million for potentially avoidable hospitalizations among long-stay nursing home residents in New York State alone.

Hospitalization of elderly patients is also associated with poor outcomes leading to further physical and psychological decline. Patients are exposed and more vulnerable to infections in a hospital setting, experience a disruption in care, and have been shown to decline in functional status and become confused.

The study followed 67,256 nursing home residents in 545 for-profit and not-for-profit facilities in New York State – representing 83 percent of the state’s entire nursing home population. Hospitalization rates were highest in for-profit nursing home where Medicaid residents where 34 percent more likely to be hospitalized than private-pay residents within the same home if it qualified for bed-hold payment. Medicaid residents were 17 percent more likely to be hospitalized than private-pay residents in a not-for-profit home if the home qualified for bed-hold payment and 25 percent more likely to be hospitalized if the home did not qualify.

The authors point to efforts to provide nursing home residents more access to the care they need while staying in their residence. Private companies, such as Evercare, that provide outside, on-demand care directly to nursing homes have been associated with fewer hospitalizations. Additionally, a pay-for-performance project has been launched by the Centers for Medicare and Medicaid Services which provides payments to nursing homes based on quality measures, including hospitalization rates. Ultimately, the authors contend that the two federal programs need to devise a coordinated response.

“To reduce hospitalizations of Medicaid residents and improve both quality of care and costs, policy-makers will need to align Medicaid and Medicare’s incentives,” said Cai.

Cells Derived From Different Stem Cells: Same Or Different?

Stem cells are considered by many to be promising candidate sources of cells for therapies to regenerate and repair diseased tissues. There are two types of stem cell considered in this context: embryonic stem (ES) cells, which are derived from early embryos; and induced pluripotent stem (iPS) cells, which are derived by reprogramming cells of the body such that they have the ability to generate any cell type. Recent data indicate that ES and iPS cells are molecularly different, raising the possibility that cells derived from these two sources could be distinct.

A team of researchers, led by Darrell Kotton and Gustavo Mostoslavsky, at Boston University School of Medicine, Boston, has now, however, determined that mouse iPS and parental ES cells show highly similar capacity to be differentiated in vitro into definitive endoderm progenitors – the cells from which thyroid, lung, liver, and pancreas are derived. Importantly, there was considerable overlap between the genetic programs of definitive endoderm derived from ES and iPS cells in vitro and definitive endoderm isolated from mouse embryos. The authors therefore conclude that their data support the notion that iPS cells could be used for the development of cell-based therapies for diseased endoderm-derived tissues.

TITLE: Mouse ES and iPS cells can form definitive endoderm despite differences in imprinted genes.

Source:
Karen Honey

Journal of Clinical Investigation

Identification Of New Antibiotic Target And New Antibiotic Mechanism May Lead To New Broad-Spectrum Antibacterial Agents, Tuberculosis Treatments

A team of Rutgers University scientists led by Richard H. Ebright and Eddy Arnold has identified a new antibiotic target and a new antibiotic mechanism that may enable the development of broad-spectrum antibacterial agents effective against bacterial pathogens resistant to current antibiotics. In particular, the results could lead the way to new treatments for tuberculosis (TB) that involve shorter courses of therapy and are effective against drug-resistant TB.

The researchers showed how three antibiotics – myxopyronin, corallopyronin and ripostatin – block the action of bacterial RNA polymerase (RNAP). RNAP is the enzyme that transcribes genetic information from DNA into RNA, which, in turn, directs the assembly of proteins, the building blocks of all biological systems. Blocking bacterial RNAP kills bacterial cells.

The research findings are reported in the journal Cell, published online Oct. 16 and in the Oct. 17 print issue of the journal.

The shape of the RNAP molecule is key to the action of the three antibiotics, Ebright explained. “RNAP has a shape reminiscent of a crab claw, with two prominent pincer-like projections,” he said. “Just as with a real crab claw, one pincer stays fixed and one pincer moves – opening to allow DNA into the enzyme and closing to keep DNA in the enzyme. The pincer that moves does so by rotating about a hinge, termed the ‘switch region,’ located at its base.”

The studies showed that the three antibiotics bind to this hinge and, further, that by jamming the hinge, they prevent the pincer from opening to let DNA into the enzyme, Ebright said.

Once the target and mechanism of the three antibiotics were elucidated, the researchers proceeded to determine the structure of RNAP bound to one of the three antibiotics. “This has allowed us to define how the enzyme and the antibiotic interact and to characterize how the enzyme changes shape in response to the antibiotic,” Arnold said. “Perhaps more important, this has allowed us to explore ways to change the chemical structure of the antibiotic to make tighter interactions with the enzyme for higher potency.”

The three antibiotics exhibit potent activity against a broad spectrum of bacterial species, including the bacterium that causes TB, and exhibit no cross resistance with current antibacterial agents.

“The three antibiotics are attractive candidates for development as broad spectrum antibacterial agents,” Ebright said, “and their target within RNAP – the hinge or ‘switch region’ – is an attractive target for identification of new broad-spectrum antibacterial therapeutic agents.”

Arnold points out that the binding site for the three antibiotics has attractive features for design of new agents. “The target site is a pocket that accommodates a variety of chemical types. The nature of the binding site and mechanism of inhibition are analogous to those of the HIV-1 reverse transcriptase non-nucleoside inhibitors, which include four FDA-approved drugs for treating HIV-1 infections. The parallels are encouraging and suggest that multiple classes of agents can be developed to target the new site.”

Ebright, a Howard Hughes Medical Institute investigator, is a professor in the Department of Chemistry and Chemical Biology and a member of the Waksman Institute of Microbiology at Rutgers, The State University of New Jersey. Arnold, also a professor of chemistry and chemical biology, is a member of the Center for Advanced Biotechnology and Medicine (CABM), jointly operated by Rutgers and the University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School.

Jayanta Mukhopadhyay from Ebright’s laboratory and Kalyan Das from Arnold’s laboratory carried out much of the work.

The research team also included Rolf Jansen and Herbert Irschik of the Helmholtz Center for Infection Research in Braunschweig, Germany.

Most antibacterial compounds are able to kill actively growing TB bacteria but are unable to kill resting, dormant TB bacteria. As a result, most antibacterial compounds can rapidly reduce populations of TB bacteria in infected patients to low numbers but cannot rapidly reduce these numbers to zero. Antibacterial compounds that target RNAP, however, are able to kill both active and dormant TB bacteria since RNAP plays essential roles in, and is required for survival of, both active and dormant TB bacteria.

A class of antibacterial compounds known as rifamycins, which target RNAP, are current first-line treatment of TB and are the sole current treatments that can relatively rapidly reduce populations of TB bacteria to zero. Unfortunately, rifamycins are too toxic to administer at doses that most rapidly clear infection. Also, resistance to rifamycins occurs frequently, due to mutations that alter their binding site on RNAP.

The three antibiotics studied by Ebright and co-workers also target RNAP; however, they target a new site on RNAP, different from the site on RNAP targeted by rifamycins. “A key point about these antibiotics is that their binding site on RNAP is different from, and does not overlap with, the binding site for rifamycins,” Ebright said. “As a result, these antibiotics can function simultaneously with rifamycins and can be co-administered with rifamycins for more rapid clearance of infection. As a further result, these antibiotics do not exhibit cross-resistance with rifamycins. Mutations that alter the binding site for rifamycins on RNAP and confer resistance to rifamycins do not confer resistance to these antibiotics.

The standard course of therapy for most bacterial infections is about two weeks, but TB is different. The shortest course of therapy for TB is six to nine months. “That is, if you can use rifamycins,” Ebright notes. “If you have a patient who cannot tolerate rifamycins, or if you have a patient whose infection is resistant to rifamycins, that patient is looking at 18 to 24 months of therapy.”

“The Holy Grail in TB therapy is to reduce the course of therapy from six months to two weeks – to make treatment of TB like treatment of other bacterial infections,” Ebright said. “If you could develop a two-week therapy for TB, you could eradicate TB. With a six-month course of therapy for a disease that is largely centered in the third world, the logistical problems of administering therapy over space and time make eradication a nonstarter. But if there were a two-week course of therapy, the logistics would be manageable, and the disease would be eradicated.”

The hope is that the new findings will bring that goal closer.

###

Source: Joseph Blumberg

Rutgers University

Obtaining Biogas From Food Industry Waste

The AZTI-Tecnalia technological centre, experts in food research, have put a biogas plant into operation in order to investigate novel systems of sustainable energy production based on the use of waste and sub-products from the food industry. This new plant exploits the enormous potential of obtaining biogas from the organic matter contained in agricultural food waste, and will help the food industry to reduce the environmental impact caused by organic waste.

The plant, located at the AZTI-Tecnalia premises in Derio, aims to obtain biogas rich in methane by the process of anaerobic digestion* of the organic material contained in the sub-products from food, in order to transform it into electrical and heat energy. In the same way, for 2010, the technological centre foresees adapting the plant and making a commitment to that renewable source of energy which has seen the greatest surge in recent years: hydrogen. So, the aim is to be able to obtain hydrogen and methane from the same combined fermentation process.

AZTI-Tecnalia specialists are thus researching the viability of obtaining benefit from a number of agricultural food sub-products, alone or in combination (co-digestion) with other elements from various sources, such as sludge from purifying plants or food waste from mass consumption. Amongst others are mixtures from animal husbandry silage (purines), together with waste from agricultural food industries (leftovers from fruit and vegetable markets, milk whey, fish ends, aquaculture waste, etc.

With the biogas plant it is possible to reduce the environmental impact caused by organic waste. The emissions of greenhouse effect gases into the atmosphere are reduced, smells are considerably reduced and the final value of the waste is enhanced, As a consequence, the industry can adapt itself to environmental and social requisites, at the same time as its processes are more efficient through making better use of available resources.

The plant is available to government bodies and to food enterprises and environmental services who are interested in developing R+D projects applied to the energy valuation of food sub-products, with the aim of obtaining information for decision-making in the installation of this kind of plant at an industrial scale.

AZTI-Tecnalia is supporting the food industry in sustainable development, implementing measures to enhance its environmental performance. The biogas plant complements the activities undertaken by the centre at its food processing pilot plant, in which valuation trials of sub-products as new sources of raw materials for transformed foodstuffs are also carried out. Likewise, more profitable and innovative options are being sought in order to manage subproducts and waste generated by the food industry and studies of the Life Cycle Analysis (LCA) of the products are undertaken, analysing where the main costs and environmental impacts lie, and proposing, in consequence, situations for the enhancement and optimisation of the process.

Notes:

* Anaerobic digestion is a biological process which transforms organic material into biogas and into a digested sludge, which can be used as organic enhancement in agricultural applications. Biogas mainly consists of carbon dioxide and methane, the latter with a high calorific value and which, thereby, can be used as a renewable source of electrical and/or thermal energy, or as a fuel for vehicles.

Source:
Oihane Lakar
Elhuyar Fundazioa