HIV/AIDS has “taken a strong hold” on local populations of many small Caribbean islands, and HIV/AIDS experts say the epidemic is at a “tipping point” in the region, Loretta McLaughlin, a senior fellow at the… Harvard AIDS Institute, writes in a Boston Globe opinion piece. According to data collected by the Caribbean Epidemiology Centre, HIV prevalence for 17 countries in the region, excluding Haiti and Guyana, is between 1% and 2.5%, but the rates are moving “relentlessly and seemingly inexorably upward,” McLaughlin, a former Globe editorial page editor, says. Although the Clinton Foundation and the Global Fund To Fight AIDS, Tuberculosis and Malaria have provided medical expertise and millions of dollars for HIV/AIDS programs in the region, those working to fight the disease know that understanding local customs and practices is key to fighting the epidemic, she writes. Sexual activity among young people, a low marriage rate, a high teenage birth rate, and cultural and religious taboos remain challenges to HIV prevention, McLaughlin says. Although the number of HIV-positive people seems “sparse because the general populations are so small, the ramifications pose just as severe economic and human consequences as anywhere else,” McLaughlin writes (McLaughlin, Boston Globe, 7/2).

“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. Continue reading →

When HIV-positive mothers breastfeed exclusively, their babies have only a low risk of postnatal infection with HIV*. But early introduction of animal milks and solid foods increases HIV transmission risks. This evidence demands a revision of the present UNICEF, WHO, and UNAIDS infant-feeding guidelines, according to an Article published in this week’s issue of The Lancet.

The promotion of breastfeeding has been ranked as the most cost-effective intervention for child survival, and could prevent 13-15% of child deaths in low-income countries. However, in some circumstances, breastfeeding can transmit HIV. Previous estimates that the risk of postnatal transmission is between 10% and 20%, do not distinguish between exclusive and mixed breastfeeding.

Hoosen Coovadia, Nigel Rollins (University of KwaZulu-Natal, South Africa), and colleagues did a non-randomised intervention cohort study to assess the HIV-1 transmission risks and survival associated with exclusive breastfeeding and other types of infant feeding. They found that exclusive breastfeeding** carried significantly lower risk of HIV transmission than all types of mixed breastfeeding. Infants who received formula milk in addition to breastmilk, before or after 14 weeks, were nearly twice as likely to acquire HIV infection as infants who received breastmilk only, and the addition of solids increased the risk 11-fold. Furthermore, mortality by 3 months of age for replacement fed babies was more than double that of those who were exclusively breastfed.

The authors conclude: “The key policy finding of our study is the definite demonstration that early introduction of solid foods and animal milks increases HIV transmission risks compared with exclusive breastfeeding from birth. These data, together with evidence that exclusive breastfeeding can be supported in HIV-infected women [and uninfected women], warrant revision of the present UNICEF, WHO, and UNICEF infant feeding-guidelines that were revised in 2000″.

In an accompanying Comment, Wendy Holmes (Macfarlane Burnet Institute for Medical Research and Public Health, Melbourne, Australia) and Felicity Savage (Centre for International Health and Development, London, UK) state: “The increased resources now available to prevent HIV infection in children should be invested in ways that also improve maternal and child health in general. But very little is earmarked for promotion of breastfeeding. Investment in promoting, protecting, and supporting exclusive breastfeeding to 6 months has the greatest potential to improve HIV-free child survival in settings with both high and low HIV prevelance”.

###

Notes:

*Exclusive breastfeeding ordinarily protects the integrity of the intestinal mucosa, which thereby presents a more effective barrier to HIV. Exclusive breastfeeding is also associated with fewer breast health problems than is mixed feeding, such as subclinical mastitis and breast abscesses, which in turn are associated with increased breastmilk viral load.

** High rates of cumulative exclusive breastfeeding, using the most rigorous definitions, were achieved with home-based support provided by locally-recruited and trained counsellors.

Contact: Nigel Rollins
Lancet Continue reading →

Suspected cases of measles in Bucks County have triggered an investigation by the Pennsylvania Department of Health – authorities say Lancaster County may also be linked. Health authorities in Pennsylvania say there is a chance some people may have been exposed to the virus it various locations.

The following locations and times have been listed by the Pennsylvania Department of Health:

April 19. Tanger Outlet Center, Lancaster County, 11am-midday
April 19. Bird in Hand Bake Shop, Lancaster County, 11:30am-5:30pm
April 19. Riehl’s Quilts and Crafts, Lancaster County, 11:30am-5:30pm
April 19. Lapp’s Wooden Toys, Lancaster County, 11:30am-5:30pm

The majority of Americans have immunity against measles, either because they were infected before vaccines existed or received the MMR (Measles Mumps Rubella) vaccine when they were children.

There are some people, though, who can become infected, and they include:

Infants less than 12 months old (they have not been vaccinated yet)
In 1963-1967 some people received an inactivated vaccine. People who received these and were never revaccinated
Individuals who have only had one MMR vaccine dose and were born after 1957
People coming in from areas around the world were vaccination rates are low, or measles is common

If any member of your household is at risk of measles and develops measles-like symptoms up to two weeks after exposure to the virus, contact your doctor and follow their advice.

In a communiqu?©, the Pennsylvania Department of Health wrote:

“Any health care provider who suspects measles should immediately call their local health department or the Pennsylvania Department of Health at 1-877-PA-HEALTH for consultation and to arrange testing.

Measles signs and symptoms may include a high fever, watery eyes, a runny nose, and a few days later a red rash that typically starts on the face and spreads downwards. The rash is usually gone within four to seven days.

An infected person can pass the measles on to other people four days before the rash appears and four days after it begins. The disease can spread via coughing, sneezing, direct contact with nasal and throat secretions, and even talking directly in front of an infected person. Contaminated surfaces can be infectious for up to two hours.

Some people are at risk of measles complications, which may include pneumonia, ear infection, inflammation of the brain (encephalitis), diarrhea, and even death. Infected pregnant mothers are at a higher risk of premature delivery and miscarriage.

Source: Pennsylvania Department of Health

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Why does an apple a day keep the doctor away? New research published in the open access journal BMC Microbiology contributes to our understanding of why eating apples is good for you.

Microbiologists from the National Food Institute at the University of Denmark fed rats on a diet that was rich in whole apples, apple juice, pur?©e or pomace, or put them on a control diet. They then analysed the microbial content of the rats’ digestive systems to see if eating apples had any impact on the numbers of presumed ‘friendly’ bacteria in the gut. “Certain bacteria are believed to be beneficial for digestive health and may influence the risk for cancer. We faced a well-known problem though – many types of bacteria cannot be easily cultured in the lab”, said research leader Professor Tine Rask Licht. The team therefore used genetics instead of culture techniques to examine the microbiology of the intestines. 16S rRNA is a molecule that is only found in bacteria and its make up is unique to each species or strain. “By working out the sequences of 16S rRNA molecules in the rats’ intestines and matching these to known bacterial profiles of 16S rRNA, we could determine which microorganisms were abundant in each group of rats”, explained Licht.

So what was the verdict? “In our study we found that rats eating a diet high in pectin, a component of dietary fiber in apples, had increased amounts of certain bacteria that may improve intestinal health”, said co-researcher Andrea Wilcks. “It seems that when apples are eaten regularly and over a prolonged period of time, these bacteria help produce short-chain fatty acids that provide ideal pH conditions for ensuring a beneficial balance of microorganisms. They also produce a chemical called butyrate, which is an important fuel for the cells of the intestinal wall”.

Of course, further research is needed to determine whether the digestive system of humans responds to apples in the same way as rats, but these findings certainly suggest that Europe’s favourite fruit has a well-deserved place in our 5-a-day.

Notes:

Effects of apples and specific apple components on the cecal environment of conventional rats: role of apple pectin
Tine R Licht, Max Hansen, Anders Bergstrom, Morten Poulsen, Britta N Krath, Jaroslaw Markowski, Lars O Dragsted and Andrea Wilcks
BMC Microbiology (in press)

Article available at journal website: biomedcentral/bmcmicrobiol/

Source: Graeme Baldwin

BioMed Central Continue reading →

Understanding the structure of proteins involved in inhibiting HIV-1 infection could help in the battle against AIDS, and University of Minnesota researchers have taken a crucial step in that direction.

Hiroshi Matsuo, Ph.D., and Reuben Harris, Ph.D., co-investigators of the research and assistant professors in the Department of Biochemistry, Molecular Biology and Biophysics at the University of Minnesota have determined the structure of APOBEC3G – a protein that inhibits the AIDS virus, HIV. This discovery is the first to shed light on the atomic structure of the protein.

The research was released online Feb. 20, 2008 on the Nature Web site and it will be featured in an upcoming print publication of the journal.

Proteins could be compared to miniature machines, each of which carries out a specific function. The APOBEC3G “machine” is capable of modifying HIV DNA so that the virus is no longer infectious.

HIV-1, however, has unfortunately developed a way to evade this potent cellular protein with its own protein called Vif, which literally triggers the destruction of APOBEC3G.

The discovery will help researchers manipulate APOBEC3G to make it effective in combating HIV. Current studies also will help develop methods to neutralize Vif before it has a chance to destroy the protein.

“This new information is a crucial step toward understanding how APOBEC3G and Vif talk to each other,” Harris said. “Furthermore this new information will undoubtedly help researchers identify candidate drugs for future novel HIV-1/AIDS therapies.”

###

This research was funded by grants from the National Institutes of Health and from the Minnesota Partnership for Biotechnology and Medical Genomics and the Medica Foundation.

Source: Nick Hanson

University of Minnesota Continue reading →

The Joint United Nations Programme on HIV/AIDS (UNAIDS) welcomes a new United Nations (UN) Security Council resolution on HIV which has been adopted at the UN Security Council in New York. The resolution calls for increased efforts by UN Member States to address HIV in peacekeeping missions. It also calls for HIV prevention efforts among uniformed services to be aligned with efforts to end sexual violence in conflict and post-conflict settings.

“The Security Council has made major strides in addressing sexual violence in conflict. But rape is still a weapon of choice. This is an atrocious human rights violation and a public health threat,” said United Nations Secretary General Ban Ki-moon. “I urge all Member States to link efforts to combat HIV with our campaigns against sexual violence and for the rights of women.”

The resolution builds on the previous UN Security Council resolution 1308, which was adopted in 2000. The new resolution calls on the United Nations and UN Member States to bolster global and regional partnerships and integrate comprehensive HIV programmes into efforts to prevent conflict, ensure security and build peace.

“Global, national and personal insecurity undermine efforts to prevent new HIV infections and increase access to HIV services for both peacekeepers and civilians,” said the President of Gabon, Ali Bongo Ondimba. “This resolution will help to mitigate the impact of HIV among uniformed services and civilian populations affected by conflict and increase access to HIV services.”

The resolution, which was tabled by Gabon, President of the Security Council for June 2011, recognises that HIV can have a uniquely devastating impact on all sectors and levels of society and that in conflict and post-conflict situations these impacts may be felt more profoundly. It also recognizes that conditions of violence and instability in conflict and post-conflict situations can exacerbate the spread of HIV because of displacement, conflict-related sexual violence and reduced access to HIV services.

Since the adoption of resolution 1308 in 2000, progress has been made in addressing HIV and security. About 60% of UN Member States have integrated HIV programmes for military, police and other uniformed personnel. However the quality of programmes is variable and resources to fund the programmes are often insufficient.

“Peacekeepers can play a leading role in HIV prevention as they secure peace around the world,” said Michel Sidib?©, Executive Director of UNAIDS. “Uniformed personnel can act as agents of positive change, particularly in relation to preventing sexual violence in conflict and post-conflict situations.”

Evidence shows that the threat AIDS poses to peace and security is far more nuanced than initially thought. Both the characteristics of conflict and the epidemic itself have evolved significantly over the past 10 years with sexual violence being increasingly used as a tactic of war. Addressing this requires a broadening and strengthening of HIV programmes for peacekeepers to ensure an effective response to HIV and sexual violence in conflict and post-conflict settings.

“Renewed commitment around the new agenda is needed to ensure that the AIDS response effectively contributes to all UN peacekeeping efforts to ensure security and promote and build peace,” said Alain Le Roy, Under-Secretary General for United Nations Peacekeeping Operations.

During the UN Security Council session, both the United Nations Secretary-General Ban Ki-moon and the Executive Director of UNAIDS paid tribute to the late US Ambassador to the United Nations, Richard Holbrooke, for championing resolution 1308. In 2000, Ambassador Holbrooke said, “Resolution 1308 should be well known and it should be fully implemented. It should not be the end of the process, but only a cornerstone for the future.”

Reinvigorated efforts around a new HIV security agenda will be instrumental in addressing the impact of AIDS on peace and security. UNAIDS will work with member states to scale-up access to HIV prevention, treatment, care and support for all uniformed services, including police, immigration, prison and the navy, to prevent HIV and end violence against women and girls.

Source:

UNAIDS Continue reading →

Monogram
Biosciences, Inc. (Nasdaq: MGRM) announced today that its collaborator
Pfizer Inc (NYSE: PFE) has reported results of a phase III study of its
investigational HIV medication, maraviroc, for treatment-naive adult
patients infected with CCR5-tropic HIV-1.

The data was reported by Pfizer at the International Aids Society
conference in Sydney, Australia. “Pfizer’s results indicate reduction in
viral load and increased CD4 counts,” said Christos Petropoulos, Monogram
Chief Scientific Officer. “In addition, the trial showed a safety profile
that was better than in the control arm. This further supports the safety
of maraviroc as a new treatment option for treatment-experienced patients.”

Monogram’s Trofile(TM) Assay has been used to select patients for all
of the drug’s clinical trials.

Pfizer has previously reported 24 week data from its phase III trials
of maraviroc in treatment-experienced patients and has recently announced
that the 48 week analysis has confirmed these 24 week findings. An NDA is
pending with the U.S. Food and Drug Administration and an approvable letter
has been received from the F.D.A. in respect of the use of maraviroc in
treatment- experienced patients. The data reported today by Pfizer is in
respect of a potential new indication in treatment-naive patients that
would be subject to a separate FDA submission.

About Monogram Biosciences, Inc.

Monogram is advancing individualized medicine by discovering,
developing and marketing innovative products to guide and improve treatment
of serious infectious diseases and cancer. The Company’s products are
designed to help doctors optimize treatment regimens for their patients
that lead to better outcomes and reduced costs. The Company’s technology is
also being used by numerous biopharmaceutical companies to develop new and
improved antiviral therapeutics and vaccines as well as targeted cancer
therapeutics. More information about the Company and its technology can be
found on its web site at monogrambio.

Forward-Looking Statements

Certain statements in this press release are forward-looking. These
forward-looking statements include references to the potential use of our
Trofile Assay as a molecular diagnostic for patient selection for Pfizer’s
CCR5 antagonist maraviroc, if approved by the FDA and European authorities,
and the potential approval of maraviroc for use in treatment-na??ve
patients. These forward-looking statements are subject to risks and
uncertainties and other factors, which may cause actual results to differ
materially from the anticipated results or other expectations expressed in
such forward-looking statements. These risks and uncertainties include, but
are not limited to: the risk that regulatory authorities may not require a
molecular diagnostic for patient selection for maraviroc; the risk that
maraviroc will not be approved by the FDA or European authorities for use
in treatment-experienced patients; the risk that Pfizer will not submit
marketing applications for use of maraviroc in treatment-na??ve patients and
that the FDA will not approve such marketing applications; risks related to
the implementation of the collaboration with Pfizer; risks associated with
establishing and maintaining logistics arrangements in European and other
non-U.S. markets for Trofile; risks and uncertainties relating to the
performance of our products; the growth in revenues and actual market
acceptance of our products; the impact of competition; whether payors will
authorize reimbursement for our Trofile; whether the FDA or any other
agency will decide to further regulate Trofile and our other products; the
ultimate validity and enforceability of our patent applications and
patents; the possible infringement of the intellectual property of others;
whether licenses to third party technology will be available; and whether
we will be able to raise sufficient capital in the future, if required. For
a discussion of other factors that may cause our actual events to differ
from those projected, please refer to our most recent annual report on Form
10-K and quarterly reports on Form 10-Q, as well as other subsequent
filings with the Securities and Exchange Commission. We do not undertake,
and specifically disclaim any obligation, to revise any forward-looking
statements to reflect the occurrence of anticipated or unanticipated events
or circumstances after the date of such statements.

Trofile is a trademark of Monogram Biosciences, Inc.

Monogram Biosciences, Inc.
monogrambio Continue reading →

A review of measures taken to address a 2004 outbreak of the highly infectious Norwalk virus at The Johns Hopkins Hospital has provided the first solid documentation of expenses and efforts in the United States to stop the infection from spreading among patients, staff and visitors. Total hospital costs for the three-month outbreak – including extra cleaning supplies, staff sick leave, diagnostic tests, replacement staff, and salaries and lost revenue from closed beds – were estimated at more than $650,000.

The outbreak at The Johns Hopkins Hospital (JHH) was one of at least 24 at Maryland hospitals during the first half of 2004. Norwalk virus is highly contagious because only small amounts, as few as 10 to 100 viral particles, can lead to infection. It is spread or passed from person to person through fecal matter when people fail to wash their hands properly after using the bathroom and when people touch or share handling of the same objects, such as doorknobs.

“We hope our approach will help other hospitals prepare for or manage an outbreak,” says Cecilia Johnston, M.D., an instructor at Hopkins in infectious diseases who led the investigation.

“Outbreaks need to be identified quickly and dealt with immediately, and relying on standard infection control procedures is not adequate,” she adds. “It may be necessary to close the infected units, isolate the infection source, get strict on hand hygiene, conduct a thorough washing down of units, and keep repeating these steps until the outbreak is stopped. Health care workers especially need to be vigilant about these steps because they are the group primarily affected by outbreaks.”

Reporting in the Sept. 1 edition of the journal Clinical Infectious Disease, Johnston and her team of Hopkins patient safety experts describe how an outbreak spread among 265 health care workers and 90 patients between February and May 2004.

No one at Hopkins died from their infection, but 13 afflicted hospital staff either visited the emergency room for treatment or required hospitalization after becoming severely dehydrated. Norwalk-like viruses, formally known as noroviruses, cause serious gastrointestinal illness for which no treatment currently exists except for keeping the patient well hydrated. Symptoms include nausea, vomiting, diarrhea and severe stomach cramps. Those infected generally recover on their own within two to three days after symptoms appear.

“Health care workers really do need to be on the lookout for norovirus infections, and if there is an outbreak, hospitals need to address it very aggressively,” says senior hospital epidemiologist Trish Perl, M.D., a professor of medicine and pathology at The Johns Hopkins University School of Medicine. “Our experience shows that people can get very sick and that it costs a lot to fix the problem and address disruptions to staffing.”

First reported in the hospital’s coronary care unit, or CCU, the JHH outbreak quickly spread over a two-week period but remained clustered in the CCU, a nearby echocardiography laboratory and a floor housing psychiatric services where patients and staff frequently interact, especially during group therapy sessions.

The outbreak was detected soon after it began when two staff members who worked closely together became ill with diarrhea. Their illnesses were immediately reported to Hopkins’ infection control team, which monitors hospital operations daily for potential hazards to patient safety.

A norovirus outbreak was immediately suspected because there had been numerous reports of illness throughout the Baltimore region.

As part of their investigation, nurse managers began screening all staff and patients for any signs of gastrointestinal illness. Patient stool samples confirmed that the culprit was a norovirus, and genetic testing later verified that it was the same viral strain, genogroup II.4, that caused a series of widely publicized outbreaks in nursing homes and on cruise ships traveling from Europe and the United States in 2002.

As the investigation proceeded, staff implemented strict precautions to control the outbreak and prevent it from spreading. Patients with symptoms were placed in isolation, by being moved to either private rooms or into the same room with other sick patients. Group therapy sessions in psychiatry were temporarily halted, and no new patients were admitted to the units primarily affected. Sick staff were sent home for as long as they had symptoms plus an additional 72 hours, sufficient time for the illness to pass and no longer be contagious.

The investigation showed that many of the initial health care workers in the CCU who became ill had attended a social event outside of the hospital, where one of the non-staff guests was already experiencing symptoms. Others likely became ill after touching a patient chart that had been handled by another ill colleague.

Standard precautions to guard against infection were also followed, including a mandatory, hospital-wide staff review of basic infection control procedures with an emphasis on more frequent hand washing, accompanied by a thorough washing down of all affected hospital facilities. Even the CCU was closed for 24 hours to allow for a thorough cleaning, with all exposed surfaces getting washed down with bleach solution.

The easiest known way to kill noroviruses is through repeat washing of surfaces using bleach solutions containing at least 10 percent sodium hypochlorite. However, researchers say that even after intense cleaning efforts, norovirus particles have been found to cling to carpet surfaces, elevator buttons, bed rails and dining room tabletops.

To address any virus remaining, all disposable supplies in infected areas were thrown out and replaced with fresh ones, an effort that cost more than $53,000.

Because the norovirus outbreak was citywide, staff from outside of JHH were not allowed to work on site, while Hopkins staff, in turn, were banned from working at other facilities. Even visitors to the Hospital were asked screening questions to identify stomach problems and, if present, were told not to see patients for 72 hours. Staff working on units hit by the outbreak wore gowns and gloves to guard against unwittingly picking up or spreading the disease. All group meals or shared-food events were banned inside the Hospital.

After three months of intense efforts to prevent the spread of infection, new infections stopped by early May 2004. The outbreak was deemed to be over, and affected units returned to normal activity.

The researchers’ review showed that the number of patients infected, or so-called attack rate of the virus, in the CCU was low, at 5 percent (seven patients out of 133), but was notably higher for health care workers, at 30 percent (29 out of 97). The attack rate numbers were higher for psychiatry services, at 17 percent for patients (39 out of 233) and 38 percent for staff (76 out of 200).

Everyone infected experienced diarrhea or vomiting, while some others experienced such symptoms as chills and muscle aches.

Calculations of costs associated with the cleanup included expenses for cleaning supplies ($96,000), staff sick leave and overtime ($89,000), plus lost revenue from closing the units and echocardiogram laboratory to new patients ($418,000). Indeed, nearly 460 hours of sick leave were used by staff on the CCU, 138 hours in the echocardiogram lab, and more than 2,000 hours in psychiatry services.

Expenses not taken into account were those associated with other areas of the hospital where few cases were reported and no restrictions were placed on the unit. Costs incurred outside of main units were not included in this estimate because researchers were not certain that the infection had indeed resulted from contact within the hospital and not from exposure in the community. In addition, costs associated with lengthier stays in the hospital and more intensive patient care were also not factored into the estimates because researchers would have had to guess at what the patients’ length of stay would have been in the absence of a norovirus outbreak.

Researchers say their next step is to evaluate which specific infection control strategies and procedures are most effective at preventing noroviruses from spreading.

The U.S. Centers for Disease Control and Prevention estimate that each year more than 23 million people become infected with Norwalk or Norwalk-like viruses, and the disease is considered a leading cause of foodborne illness, after people have contaminated food with dirty hands.

Funding for the study was provided by The Johns Hopkins Hospital. Testing services were provided by the state of Maryland’s Department of Health and Mental Hygiene, with additional confirmations provided by the National Institutes of Health.

Besides Perl and Johnston, other members of the Hopkins team involved in this investigation and study were Haoming Qiu; John Ticehurst, M.D.; Conan Dickson, Ph.D.; Patricia Rosenbaum; Patricia Lawson; Amy Stokes; Charles Lowenstein, M.D.; Michael Kaminsky, M.D.; Sara Cosgrove, M.D., M.S.; and Kim Green, Ph.D.

Johns Hopkins Medical Institutions
901 S. Bond St., Ste 550
Baltimore, MD 21231
United States
hopkinsmedicine Continue reading →

Scientists have discovered a new way to attack dangerous pathogens, marking a hopeful next step in the ever-escalating battle between man and microbe.

In a paper published online Feb. 10 in the journal PLoS Pathogens, scientists demonstrate that by stopping bacteria’s ability to degrade RNA – a “housekeeping” process crucial to their ability to thrive – scientists were able to stop methicillin-resistant Staphylococcus aureus or MRSA both in the laboratory and in infected mice.

The team, headed by a microbiologist at the University of Rochester Medical Center, is now developing closely related compounds designed to be much more potent than the one discussed in the paper.

The new approach shows promise against the most severe strains of MRSA as well as the toughest type of MRSA infection for antibiotics to infiltrate – bacteria enmeshed in biofilms.

“This offers a whole new way to go on the offensive against some of the world’s most dangerous bugs,” said the leader of the group, Paul Dunman, Ph.D., associate professor of Microbiology and Immunology at the University of Rochester Medical Center and formerly of the University of Nebraska. “We’re hoping our research opens the door to an entirely new class of antibiotics.”

The team also includes scientists from the University of Nebraska, the University of Arkansas, Vanderbilt University, and the University of North Texas Health Science Center.

MRSA infections are among the most virulent infections known. The superbug causes nearly 500,000 hospitalizations and 19,000 deaths in the United States each year – more deaths than caused by AIDS. The bug can be acquired in the community or in hospitals.

MRSA and other dangerous microbes are so deadly largely because of their ability to adapt quickly to changing conditions. Bacteria’s knack for adaptation hinges on their ability to constantly churn out new molecules of RNA, which carry crucial messages that tell a cell what proteins to make and in what quantities.

The new research focuses on a critical cellular step that is part of the process, known as RNA degradation. Once an RNA molecule is no longer needed, the molecule is sliced and diced up, and its components are returned to the pool of available raw material that the cell taps again and again to construct other RNA molecules as needed.

“In bacteria, RNA degradation is crucial. The cells are replicating very quickly and responding to environmental changes very rapidly. In less than three minutes, a new RNA transcript is made, the protein is made, and then the RNA is degraded, and that material is made available to make other RNA molecules,” Dunman said.

Dunman’s team discovered that a molecule known as RnpA is central to the degradation process. After nailing down the activity of RnpA, the team tested more than 29,000 compounds in its search for one that inhibits its activity. The team found one, a small molecule called RNPA1000, that brings MRSA nearly to a standstill.

Throwing a monkey wrench into bacteria’s RNA recycling system might harm MRSA in a number of ways. One possibility is that since messenger RNA molecules are not destroyed like they should be, the bacteria are overcome by an array of confusing instructions that should have been turned off. Another possibility is that bacteria are unable to make essential new RNA molecules, since the supply of raw material is not available.

“We believe this basically makes the bacterial cell go haywire. The cell is producing proteins it no longer needs, and it can’t produce proteins that it does need,” said Dunman.

The team found that RNPA1000 is active against the predominant MRSA types circulating in the United States, vancomycin intermediate susceptible S. aureus (VISA) and vancomycin-resistant S. aureus (VRSA). The compound also showed significant antimicrobial activity against a host of other bugs tested, including Staphylococcus epidermidis, antibiotic-resistant Streptococcus pneumoniae, Streptococcus pyogenes, and vancomycin-resistant Enterococcus faecium.

Especially promising was its activity against MRSA biofilms, whose formation is central to the bacterium’s virulence in medical settings. Today’s antibiotics have a tough time breaking through MRSA biofilms on equipment like catheters, but RNPA1000 brought the bacteria to a halt even when they were ensconced within biofilms.

The agent does not affect other drugs used to treat MRSA infections, including vancomycin, daptomycin, or rifampicin; it does affect oxacillin, making it more potent. That find might make it possible to eventually combine an agent like RNPA1000 with other drugs that also target the infection.

The compound was also moderately effective in mice. In an experiment with infected mice, all of the untreated mice died from their infection, but half the mice survived when treated with a large dose of RNPA1000. The compound is also somewhat toxic to human cells at the largest doses. Those findings make it unlikely that RNPA1000 itself will end up as an antibiotic and spurred Dunman and colleagues to design safer, more potent alternatives.

“This is a great starting point,” said Dunman. “We’ve identified a compound that is very active against RnpA, and now we can use chemistry to try to increase its potency by hundreds of times, as well as make it less toxic to human cells. We’ve gotten a lead from the drug screen, and now we’re building a better molecule.”

Dunman is a leader in the development and use of array technology to study microbes and explore fresh approaches to the development of antibiotics. While microarrays are widely used by scientists to take what amounts to a snapshot of the activity of thousands of genes in a cell, Dunman adds a twist. His team employs the technology constantly to watch what happens to RNA molecules after they’ve been made, typically taking dozens of snapshots in the span of hours to get an ongoing, intimate look at RNA degradation.

The paper caps a six-year effort that began when the first author, Patrick Olson, was a high school student working as an intern in Dunman’s laboratory in Nebraska. Olson is now in graduate school at Washington University in St. Louis, working toward both his medical and doctoral degrees.

Notes:

In addition to Dunman and Olson, other authors of the paper include post-doctoral associate Christelle Roux of the University of Rochester; Lisa Kuechenmeister, Kelsi Anderson, Tami Lewis, Oluwatoyin Asojo, and Khalid Sayood of the University of Nebraska; graduate student John Morrison of the University of Nebraska Medical Center, currently a visiting scientist in Dunman’s Rochester laboratory; Sonja Daily, Karen Beenken, and Mark Smeltzer of the University of Arkansas; Michelle Reniere and Eric Skaar of Vanderbilt University; and William Weiss, Mark Pulse, Phung Nguyen, and Jerry Simecka of the University of North Texas Health Science Center.

These researchers are among scientists at two dozen laboratories around the world with which Dunman works. He is also a founder and owner of Caddis Research LLC, which is developing antimicrobial agents that target bacteria that pose a threat to public health, and he is a consultant for Pfizer Research.

The project was funded by the National Institute of Allergy and Infectious Diseases, the American Heart Assn., and the Nebraska Research Initiative.

Source:
Tom Rickey
University of Rochester Medical Center Continue reading →

Scientists at Johnson & Johnson Pharmaceutical Research and Development (J&JPRD) have identified a novel
anti-tuberculosis (TB) compound that works better and faster than the current standard of care in mouse models of TB
infection. Also, preliminary studies in healthy human volunteers show that the drug is safe. The findings are published in
the December 9 issue of Science Express, the online version of the journal Science, and will be published in the January 14
print edition. The studies are reported by scientists at J&JPRD and colleagues at the Swedish Institute for Infectious
Disease Control in Solna, Sweden, and Piti?-Salp?tri?re School of Medicine in Paris, France.

The compound, called R207910, belongs to a new family of anti-TB agents called diarylquinolines (DARQ) and appears to have
better, and more differentiated antibiotic properties than currently used drugs for TB, individually and in combination.
R207910 was better at clearing infection from the lungs of mice than the triple cocktail regimen currently recommended by the
World Health Organization (WHO). Also, cocktail regimens containing R207910 cleared infection in mice in half the time than
the currently used regimen.

“The drug acts through a novel mechanism of action, and is therefore active against all multi-drug resistant (MDR) strains of
TB tested so far,” says Dr. Koen Andries, D.V.M., Ph.D., Distinguished Research Fellow, Antimicrobial Research at J&JPRD. “A
combination including R207910 but excluding rifampin, one of the current TB drugs, looks especially promising. A combination
excluding rifampin would be compatible with anti-HIV drugs, making it suitable for treating patients co-infected with HIV and
TB.”

The World Health Organization (WHO) has declared TB a global health crisis. TB now infects one-third of the world’s
population and causes close to nine million new cases of active TB and 2 million deaths each year. Unfortunately, many TB
strains have become resistant to several antibiotics used today to treat the disease. More than 300,000 new cases of
multi-drug-resistant TB per year are detected, mainly in Eastern Europe and Central Asia.

“For a long time, there has been a move to find a drug that is safe and effective and completely cures the patient in a
shorter time,” Andries says. “A new drug that could shorten or simplify effective treatment of TB would dramatically improve
TB control programs.”

No new anti-TB drugs have been brought into the clinic in the past 40 years, and although doctors have effective first-line
TB drugs that work, there have been difficulties getting these medicines to the patients who need them as well as effectively
treating patients with drug resistant disease.

One out of three people in the world are infected with latent TB. Even in the developed world, one out of twenty carry the TB
bacillus. In some developing countries, one in two people are infected. A carrier of latent TB has a 10 percent life-long
risk to develop TB. However, in HIV patients, that risk is 10 percent per year.

“That is the main reason why there is now such a resurgence of tuberculosis in countries that were previously hit by HIV,”
Andries says. “The HIV epidemic has worsened the TB epidemic substantially.”

TB is currently treated with a cocktail of antibiotics, including rifampin, isoniazid, and pyrazinamide, which must be taken
for six to nine months. The TB symptoms disappear after several weeks, and patients begin to feel healthy. However, to
completely clear the infection, they must continue therapy at least four more months. This is often difficult, especially for
people living in remote areas in developing countries, and discontinuing treatment prematurely increases the risk of
developing resistant bacteria.

To ensure compliance, TB patients are monitored under the DOT (Directly Observed Treatment) program, with patients taking
their cocktail of medicines each day under the supervision of a healthcare worker.

R207910 Study Findings

“Our findings suggest that at least in mice, R207910 seems to have the desired properties of simplifying and shortening the
treatment duration, and perhaps, more,” says Andries. In bacterial cell cultures, R207910 was effective against many
different strains of mycobacteria, including strains that are resistant to other drugs. The drug is bactericidal, meaning
that it kills the TB bacilli.

In mouse models, the studies showed that a cocktail regimen containing this compound reduced bacterial load after one month
to the same level as the currently used regimen after two months of treatment, shortening normal treatment time by 50
percent. After two months treatment with the R207910 containing cocktail, no TB bacilli could be isolated from the lungs
anymore, a finding that the French group that did those studies called “unprecedented”.

The mouse studies also show that this new compound quickly enters the bloodstream and is actually concentrated in lung
cells-which harbour the TB bacilli-killing the bacilli soon after they enter the body. Also, R207910 lingers in the body for
days continuing to kill bacilli even when administered only once a week in mice.

R207910 is unique in the way it works. The compound attacks an enzyme called ATP synthase, the energy source for the
bacterium. Given its new mechanism of action and apparent impact on drug resistant strains of TB, according to Andries,
R207910 could lead to a shift in the current treatment paradigm for tuberculosis. “Preliminary data show R207910 has the
desired properties we need and holds a great deal of promise,” he said.

However, Koen added, considerable work needs to be done to fully determine this compound’s clinical potential. Since the
compound seems to be safe and well tolerated in Phase I studies with healthy human volunteers, R207910 will now be tested in
humans with active pulmonary TB.

Dr. Andries’ coauthors are Peter Verhasselt, Hinrich G?hlmann, Jean-Marc Neefs, Hans Winkler, Jef Van Gestel, Philip
Timmerman, and Didier de Chaffoy at Johnson & Johnson Pharmaceutical Research and Development, LLC in Beerse, Belgium; Jerome
Guillemont at Johnson & Johnson Pharmaceutical Research and Development in Val de Reuil, France; Min Zhu at Johnson & Johnson
Pharmaceutical Research and Development, LLC in Raritan, NJ; Ennis Lee, and Peter Williams at Johnson & Johnson
Pharmaceutical Research and Development, LLC in High Wycome, UK; Emma Huitric and Sven Hoffner at Swedish Institute for
Infectious Disease Control in Solna, Sweden; Emmanuelle Cambau, Chantal Truffot-Pernot, Nacer Lounis, and Vincent Jarlier at
Piti?-Salp?tri?re School of Medicine in Paris, France. Nacer Lounis is currently at Johns Hopkins University School of
Medicine in Baltimore, MD.

The study was supported by Johnson & Johnson Pharmaceutical Research and Development, and animal work in Paris was also
supported by annual grants from Association Fran?aise Raoul Follereau, INSERM and, Minist?re de l’Education Nationale et de
la Recherche.

About R207910

A French chemist from the Johnson & Johnson pharmaceutical group synthesised the substance; and the team in Beerse, Belgium
discovered its anti-TB action. The compound has been transferred to its sister company, Tibotec, whose lead compounds are for
HIV/AIDS, for clinical development.

About Johnson & Johnson Pharmaceutical Research & Development

Johnson & Johnson Pharmaceutical Research & Development, (J&JPRD) is part of Johnson & Johnson, the world’s most broad-based
producer of healthcare products. J&JPRD, with its headquarters in Raritan, New Jersey (USA), has sites throughout Europe and
the United States. J&JPRD leverages drug discovery, drug evaluation, and drug development in a variety of therapeutic areas
to address unmet medical needs worldwide. The company’s major therapeutic areas of focus include hematology, oncology,
infectious disease, obesity and metabolic disorders, neurology and psychiatry, pain and women’s health.

About Tibotec

Tibotec is a pharmaceutical research and development company with headquarters in Belgium and operating subsidiaries in the
United States and Ireland. The company, like J&JPRD, is a subsidiary of Johnson & Johnson. Tibotec’s lead development
compounds are for the treatment of HIV/AIDS and the pandemics of TB and HIV/AIDS are closely intertwined. Drug interactions
between HIV/AIDS drugs and TB drugs are particularly problematic.

(This press release contains “forward-looking statements” as defined in the Private Securities Litigation Reform Act of 1995.
These statements are based on current expectations of future events. If underlying assumptions prove inaccurate or unknown
risks or uncertainties materialize, actual results could vary materially from the Company’s expectations and projections.
Risks and uncertainties include general industry conditions and competition; economic conditions, such as interest rate and
currency exchange rate fluctuations; technological advances and patents attained by competitors; challenges inherent in new
product development, including obtaining regulatory approvals; domestic and foreign health care reforms and governmental laws
and regulations; and trends toward health care cost containment. A further list and description of these risks, uncertainties
and other factors can be found in Exhibit 99(b) of the Company’s Annual Report on Form 10-K for the fiscal year ended
December 28, 2003. Copies of this Form 10-K are available online at sec or on request from the Company. The Company assumes no obligation to update any
forward-looking statements as a result of new information or future events or developments.)

For more information on Johnson & Johnson, please visit the Company’s website at
jnj.

Contact: Seema Kumar (U.S.)
seemaprdus.jnj
908-218-6460 / Cell: 908-392-4718

Frederik Wittock (Belgium)
fwittockprdbe.jnj
+32 14 60 57 24 / Cell: +32 476 92 50 77

Mark Krajnak (U.S.)
mkrajnakprdus.jnj
908-704-5906 / Cell: 609-571-2228

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