A study revealing new information about how viral proteins move between cells and alert the immune system suggests that a double-punch approach to vaccine design would make them more effective.

"Our findings suggest a potentially important design principle for vaccines and challenge the prevailing theory used for vaccine design," said Christopher C. Norbury, Ph.D., assistant professor of microbiology and immunology, Penn State College of Medicine, Penn State Milton S. Hershey Medical Center. "Ultimately, our information suggests that vaccines should target both pathways that generate T cells, which are our killer cells, to allow the most efficient protection against viruses."

The study, conducted by Penn State College of Medicine and National Institutes of Health investigators and titled, "CD8+ T Cell Cross-Priming via Transfer of Proteasome Substrates," was published May 28, 2004, in the journal Science.

Some viruses, like chickenpox, travel outside of cells in the body's bloodstream. When introduced to the body, these viruses trigger antibodies that destroy the virus. For example, the chickenpox vaccine contains dead virus that, when administered, trains the body to recognize and create antibodies to kill the virus. The body is then prepared to react if exposed to live virus.

However, some viruses, like human immunodeficiency virus (HIV) and smallpox, travel inside cells where antibodies cannot penetrate. These viruses are transferred from cell to cell and only specialized white blood cells called T cells, which can penetrate cell walls, can kill them.

"There's a great deal of research going into the design of vaccines to target these types of difficult-to-destroy viruses," Norbury said. "Most focus on how to boost or improve the body's own T cell response to the virus."

CD8+ T cells play an important role in the elimination of tumor cells and disease-causing agents such as viruses. For the T cells to respond to a viral infection, "professional" antigen-presenting cells (pAPCs) must present small pieces of viral proteins, called peptides, on their surfaces. This triggers a seek-and-destroy response in T cells.

There are two pathways through which to activate the T cells. In one pathway, called direct priming, the small pieces of viral protein presented on the pAPCs surfaces can be generated when the infected protein is made by pAPC. Alternately, the other pathway, known as cross-priming, involves transfer of some form of protein, previously thought to be peptides, to the pAPC where it can be presented to T cells.

"Although direct priming is relatively well-understood, less is known about cross-priming," Norbury said. "The prevailing hypothesis for cross-priming suggests that peptides are transported by carrier proteins from virus infected cells to pAPC."

Norbury and colleagues used vaccinia virus - the virus in the smallpox vaccine - and influenza A virus, in a mouse model to further investigate how the cross-priming pathway works. The team found that it is not peptides that are shared with recipient cells, but rather full-length, intact proteins. And, whereas, the previous theory suggested that proteasomes in the donor cell cut up the proteins into peptides prior to transfer to the recipient cell, Norbury's team found that the proteins are taken up by pAPCs and cut up after they are transferred to the recipient cells.

In a previous study, the team found that the protein pieces presented via direct priming are usually very short-lived but produce peptides very efficiently. However in cross-priming, because transfer to another cell takes time, rapidly degraded proteins are inefficient at generating peptides.

"Some viruses can only be seen via cross-presentation. Thus, it's important to make vaccines targeting both pathways," Norbury said. "If the proteins used in the vaccine are rapidly degrading, they will only target one pathway. Therefore vaccines should include both types of proteins."

In addition to Norbury, study investigators were: Jonathan W. Yewdell, Sameh Basta, David C. Tscharke, Michael F. Princiotta, Peter Berglund, James Gibbs, and Jack R. Bennink, Laboratory of Viral Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, and Keri B. Donohue, graduate student, Department of Microbiology and Immunology, Penn State College of Medicine, and Integrative Biosciences Graduate Program, Penn State University Huck Institute for Life Sciences.

Contact: Valerie Gliem
vgliem@psu.edu
814-865-9481
Penn State
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Tyler Dunlap, a 27-year-old newlywed in San Francisco, is just one of the many American men eagerly awaiting the results of a large clinical trial in India.

The trial is studying a new male contraceptive, RISUG (Reversible Inhibition of Sperm Under Guidance): a reversible, nonhormonal contraceptive that provides 10 or more years of protection after a 10-15 minute procedure. Researchers received approval this week to begin enrolling additional study volunteers, after a delay of nearly four years.

"RISUG would be exciting because it would mean that, finally, I could take control of my own future, instead of leaving it to someone else," says Tyler Dunlap, a 27-year-old San Francisco newlywed. "Being in a committed long-term relationship means that I don't want to rely on condoms for birth control. I'm not ready for a vasectomy, though. This new procedure could be the answer that gives men the decisive control we lack with current contraceptives."

In the RISUG study, doctors inject a gel into the tube that sperm travel through after they are produced (known as the vas deferens). The gel then disables the sperm as they swim by. In study animals, male fertility returns if the RISUG is flushed out with another injection that dissolves the gel.

Elaine Lissner, director of the nonprofit Male Contraception Information Project in San Francisco, says she is not surprised that American men are watching the RISUG trial with keen interest. She emphasizes that the method has the potential to be the first truly affordable, reversible, long-term male contraceptive.

In 2002, when enrollment in the Indian study was halted, more than 140 men were already using RISUG. Concern about side effects and insufficiency of safety data caused a temporary suspension of the project. However, expert panels subsequently concluded that the major side effect -- several weeks of non-painful scrotal swelling in about a third of the subjects --was not enough to stop the study.

Additional Safety Tests

Since 2002, researchers have conducted several additional laboratory safety tests on RISUG.

"When we first began using RISUG in volunteers more than 15 years ago, we didn't have access to the more sophisticated toxicity tests available today," says Dr. H. C. Das, one of the lead investigators. "Last year we sent RISUG to an FDA-registered laboratory in the United States for more tests, and the results came back clean. We've also done more studies at the Industrial Toxicology Research Centre in Lucknow, India with the latest equipment. We're glad to be able to provide men this additional reassurance."

Dr. R. S. Sharma, deputy director general of the Indian Council of Medical Research (ICMR), concurs that the safety results were "very satisfactory." The ICMR is working to arrange study sites throughout India, beginning with Jaipur, Ludhiana, Udhampur, and India's capital New Delhi. Three data monitoring committees will watch for any safety concerns.

Next Steps

But Lissner cautions that progress will be slow without sufficient political will. "A reversibility study in men is key," she stresses. "And we're hoping that the Indian government is committed enough to this research to get the next batch of RISUG made to the FDA's latest Good Manufacturing Practice standards. If it is, the results will carry more weight internationally. Then men in other countries -- such as the US -- can hope for faster government approval."

Currently, RISUG's developers are arranging a collaboration with US researchers. Lissner says that to gain FDA approval, US researchers will have to begin with animal tests, so studies in North American men would not start for several years. Still, she notes that "We shouldn't be discouraged. We already know that RISUG works, which is half the battle in drug development. Men in studies in India have been using it for more than a decade. Now we just have to finish our homework."

RISUG's chief developer, Prof. Sujoy Guha of the Indian Institute of Technology, says myths about men not being interested in contraception are just that: myths. "I get letters from men all over the world who beg to come to India and participate in this study at their own expense."

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Article adapted by Medical News Today from original press release.
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Notes:
Statements are readily available from many other American men awaiting the results of the RISUG trial.

For more information on the study, visit http://www.newmalecontraception.org/.
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For the first time, patients suffering from chronic obstructive pulmonary disease (COPD), were studied during a commercial flight lasting almost six hours. Their blood oxygen content underwent a considerable reduction, more marked than could have been predicted using the currently accepted guidelines. However, the oxygen reduction was generally well tolerated by those subjects who, prior to departure, had a blood oxygen content equal to or greater than the recommended pre-flight value.

A German team, whose study also appears in April's ERJ, conducted similar experiments on patients with cystic fibrosis. They conclude that these patients can also travel on flights of several hours' duration without excessive risk.

What, in today's world, could be more commonplace than a plane trip lasting a few hours, whether for business or pleasure? Yet, while such flights are unproblematic for most of us, they can be dangerous for people with certain conditions. This is particularly true of lung disease sufferers, especially those with either chronic bronchitis (known to doctors as chronic obstructive pulmonary disease or COPD) or cystic fibrosis. Under scrutiny, therefore, is the air pressure on board commercial aircraft, whose passengers are subjected to a virtual altitude of 1,500 to 2,500 metres depending on the length of flight. At such altitudes, the air contains some 30% less oxygen, a matter not to be taken lightly for patients whose blood oxygen level is already precarious because of their respiratory condition.

For several years, doctors have been working on this issue and trying to develop recommendations, both on the minimum oxygen level needed inside planes and on methods for identifying, in advance, patients who could encounter problems while flying. These methods include respiratory capacity measurement and assessment of whether the subject can walk fifty metres without getting excessively breathless. Measurement of arterial oxygen tension (PaO2) was also recommended: above a certain value, it was deemed to indicate that the level would remain acceptable during the flight.

Real flight conditions

In fact, these various recommendations have created quite a lot of debate, especially since they partially contradict one another.

So four Norwegian doctors decided to undertake a study in the conditions of a real flight. Their results can be seen in April's issue of the ERJ, the scientific publication of the European Respiratory Society (ERS).

While most of the existing data came from experimental studies based either on inhalation of air with artificially reduced oxygen levels or on time spent in a depressurised caisson, the Oslo team took an innovative approach and conducted a study on board a real commercial flight.

The researchers decided to assess the effects of oxygen-reduced air on 18 COPD patients during a flight from Oslo to Las Palmas (five hours and forty minutes in duration) with the cabin pressure equivalent at cruising height to an average altitude of 1,829 metres (6,000 feet).

"The experimental nature of the earlier studies made it impossible to incorporate the various stresses that travellers encounter during their journey: the need to carry luggage, the often lengthy trek to the departure gate, the cramped conditions in the plane, the dryness of the cabin air, turbulence and other factors", explains Aina Aker, the article's main author.

"But our work has been able to include all of these elements, and we have also studied the influence of hypoxia duration by taking measurements twice during the flight", adds Ole Henning Skjnsberg, Aker's colleague at the Department of Pulmonary Medicine of Ullevl University Hospital, Oslo.

Rigorous selection of subjects

The Norwegian researchers set themselves two goals: to measure various parameters during the flight and to compare the values measured on the ground before the journey with those obtained in the air.

First, they measured the various dissolved gases and the oxygen saturation in the subjects' arterial blood, noting possible clinical manifestations, such as when the subjects moved around the aircraft cabin.

These measurements were taken twice during the flight: approximately one hour after the plane reached cruising height, and three hours later, following a light meal without alcohol.

Aker and her colleagues also looked at whether certain parameters connected with the respiratory volumes and blood gases measured prior to departure could be correlated with the data registered in-flight, and, if so, whether they allowed prediction of what would happen during the journey.

The 18 patients (five women and 13 men, aged 49 to 73) were recruited through a lung rehabilitation centre that organises rehabilitation programmes in warmer climates specially designed for people with chronic bronchitis or emphysema.

An important detail: the subjects selected had not suffered an exacerbation for at least two months, and all but one used bronchodilators. Additionally, to avoid any risk of misinterpretation, they had to be clear of any symptoms that could suggest cardiac or neurological compromise, any lung disease other than their COPD and anaemia.

Risk of fatigue after five hours

"We had, of course, made sure that the rehabilitation centre had pronounced all of our subjects fit to fly without additional oxygen", the authors explain, "and that they could all walk at least fifty metres without excessive breathlessness, which we verified with a treadmill test."

After an hour at cruising height, the investigators found a considerable drop in blood oxygen pressure (averaging 20%), while, quite logically, arterial oxygen saturation had decreased from 96,1% before departure to 90,4% in-flight. This held true while subjects remained seated; moving around the cabin caused arterial oxygen saturation to fall even more, to 87,4%.

The Norwegian team also measured arterial carbon dioxide pressure and found it to fall slightly after the first hour of flying, in parallel with a marked rise in heart rate.

"The reduction observed after four hours of flying constitutes in our view evidence of a compensatory hyperventilation developed by subjects to maintain their arterial oxygen saturation", Skjnsberg comments. "This could indicate that such patients may be at risk of respiratory fatigue during longer flights."

Comparison of pre- and in-flight data revealed a number of correlations and confirmed that arterial oxygen pressure on the ground can allow prediction of in-flight values. However, the Norwegian team's measurements show that the current guidelines are inappropriate.

For example, the guidelines assume that arterial oxygen pressure will be adequate if, before departure, it exceeds a certain level (9.3 kiloPascals), yet four patients meeting that criterion had an in-flight oxygen saturation of below 84%. Five others who met the criterion complained of mild breathing difficulties during the flight - even though they remained seated - and eight more experienced symptoms when moving around the cabin.

The Oslo researchers emphasise, though, that the rarefaction was well tolerated by most of the patients, and only one presented severe breathlessness at rest, which was further exacerbated during movement around the cabin.

What about cystic fibrosis patients?

The same questions apply to patients with another very disabling lung disease, cystic fibrosis, who need or wish to travel by air. The news is good for those patients too, according to another study also published in April's ERJ.

A team from Munich University, led by Rainald Fischer, examined lung function, arterial blood gases and respiratory symptoms in 36 cystic fibrosis sufferers under simulated air travel conditions.

Following tests in Munich (approximately 500 metres above sea level), the patients were reviewed a fortnight later after spending seven hours in a laboratory in the Bavarian Alps, at an altitude of 2,650 metres.

As with the COPD patients, arterial oxygen pressure fell significantly at the higher altitude. A third of the subjects were found to have values below 6.6 kPa, which is the minimum value recommended by US and British guidelines for obstructive pulmonary disease sufferers using commercial flights.

Likewise, the German team also found that the fall was greater during physical exertion (on an exercise bicycle), but only one patient complained of feeling unwell during such exertion. So the German team can conclude that cystic fibrosis patients with a ground PaO2 of more than 8 kPa are perfectly capable of tolerating, for several hours, an altitude equivalent to that found in the cabin of a commercial aircraft. Nevertheless, Fischer and colleagues suggest to include results of spirometry (e.g. FEV1) in future guidelines, in order to emphasise the role of bronchial obstruction in a hypoxic environment.

Which means there is no automatic reason to forbid such patients the joys of far-flung adventures.

EUROPEAN RESPIRATORY JOURNAL (ERJ), Vol. 25, No 4
http://erj.ersjournals.com
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In the last seven years, Mercy Jaiswal has been physically assaulted three times. She was beaten with pots filled with hot coffee. She was kicked so powerfully that her leg was covered with a massive bruise that would linger for months. Most recently, she was thrown "like a rag doll," sustaining a fractured arm that required surgery and six months of recovery time. Mercy Jaiswal is a registered travel nurse. All of her injuries occurred when she was at work in a Long Island healthcare facility, delivering professional nursing care to the patients that she "loves so dearly."

To help deter these shocking attacks, the Nurses Association is promoting a bill (A6186/S3441) aimed at violence against nurses. The proposed bill would make it a Class C felony to assault and cause physical injury to a registered nurse or licensed practical nurse while on duty. This provision already exists for assaults on police officers, peace officers, firefighters, and emergency medical technicians. The bill was passed by the State Senate on Wednesday, April 2; it now awaits a decision by the Assembly.

Each year, 430,000 nurses become victims of violent crimes in their workplaces, according to the U.S. Department of Justice. These numbers may be low, as there is a severe underreporting of violence against nurses because of the attitude that it is just 'part of the job.' Legislation can change this dangerous misperception.

"Nurses need to know that violence against them will be fully prosecuted," said Tina Gerardi, RN, chief executive officer for the Nurses Association. "And their potential attackers need to know the same thing."

"Each year thousands of nurses are attacked in the workplace," said Assemblyman David Koon (D-Perinton), sponsor of the bill. "Violence should not be 'just part of the job' for nurses. It is important for the state to establish that violent or abusive acts against nurses will have severe consequences, as they do for attacks on police, firefighters, and emergency service personnel."

Protecting nurses from attack will also positively impact patients and the nursing shortage. "Violence against nurses affects patients and the quality of patient care," said Senator Marty Golden (R-Brooklyn), who sponsored the bill in the Senate. "At a time when there is a serious nurse shortage in our state, violence removes nurses from the workforce and discourages others from choosing nursing as a profession."

NYSNA's other legislative priorities this year include safe nurse staffing ratios (A6119/S1551), prohibiting mandatory overtime (A1898-B/S6342), and promoting advanced education for RNs (A2480/S294).

With more than 36,000 members, the New York State Nurses Association is the state's largest professional association and union for Registered Nurses.

It fosters high standards of nursing education, research, and practice; engages in legislative activity; and represents RNs for collective bargaining. Its mission is to advance the profession of nursing and protect the public's health.

New York State Nurses Association
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