In a new analysis presented today VYTORIN(R) (ezetimibe/simvastatin) significantly reduced LDL “bad” cholesterol by an average of 52.5 percent and C-reactive protein (CRP) by an average of 31.0 percent, compared to averages of 38.0 percent and 14.3 percent, respectively, achieved with Zocor(R) (simvastatin) (p

VYTORIN is also indicated for the reduction of elevated total cholesterol and LDL cholesterol in patients with homozygous familial hypercholesterolemia, as an adjunct to other lipid-lowering treatments (e.g. LDL apheresis) or if such treatments are unavailable.

VYTORIN is a prescription medicine and should not be taken by people who are hypersensitive to any of its components. VYTORIN should not be taken by anyone with active liver disease or unexplained persistent elevations of serum transaminases. Women who are of childbearing age (unless highly unlikely to conceive), are nursing or who are pregnant should not take VYTORIN.

Selected cautionary information for VYTORIN

Muscle pain, tenderness or weakness in people taking VYTORIN should be reported to a doctor promptly because these could be signs of a serious side effect. VYTORIN should be discontinued if myopathy is diagnosed or suspected. To help avoid serious side effects, patients should talk to their doctor about medicine or food they should avoid while taking VYTORIN. In three placebo-controlled, 12-week trials, the incidence of consecutive elevations (>3 X ULN) in serum transaminases were 1.7 percent overall for patients treated with VYTORIN and 2.6 percent for patients treated with VYTORIN 10/80 mg. In controlled long-term (48-week) extensions, which included both newly-treated and previously-treated patients, the incidence of consecutive elevations ( >3 X ULN) in serum transaminases was 1.8 percent overall and 3.6 percent for patients treated with VYTORIN 10/80 mg. These elevations in transaminases were generally asymptomatic, not associated with cholestasis and returned to baseline after discontinuation of therapy or with continued treatment. Doctors should perform blood tests before, and periodically during treatment with VYTORIN when clinically indicated to check for liver problems. People taking VYTORIN 10/80 mg should receive an additional liver function test prior to and three months after titration and periodically during the first year.

Due to the unknown effects of increased exposure to ezetimibe (an ingredient in VYTORIN) in patients with moderate or severe hepatic insufficiency, VYTORIN is not recommended in these patients. The safety and effectiveness of VYTORIN with fibrates have not been established; therefore, co-administration with fibrates is not recommended. Caution should be exercised when initiating VYTORIN in patients treated with cyclosporine and in patients with severe renal insufficiency.

VYTORIN has been evaluated for safety in more than 3,800 patients in clinical trials and was generally well tolerated at all doses (10/10 mg, 10/20 mg, 10/40 mg, 10/80 mg). In clinical trials, the most commonly reported side effects, regardless of cause, included headache (6.8 percent), upper respiratory tract infection (3.9 percent), myalgia (3.5 percent), influenza (2.6 percent) and extremity pain (2.3 percent).

About Merck/Schering-Plough Pharmaceuticals

Merck/Schering-Plough Pharmaceuticals is a joint venture between Merck & Co., Inc. and Schering-Plough Corporation formed to develop and market in the United States new prescription medicines in cholesterol management. The collaboration includes worldwide markets (excluding Japan).

Merck Forward-Looking Statement

This press release contains “forward-looking statements” as that term is defined in the Private Securities Litigation Reform Act of 1995. These statements are based on management’s current expectations and involve risks and uncertainties, which may cause results to differ materially from those set forth in the statements. The forward-looking statements may include statements regarding product development, product potential or financial performance. No forward-looking statement can be guaranteed, and actual results may differ materially from those projected. Merck undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events, or otherwise. Forward-looking statements in this press release should be evaluated together with the many uncertainties that affect Merck’s business, particularly those mentioned in the cautionary statements in Item 1 of Merck’s Form 10-K for the year ended Dec. 31, 2004, and in its periodic reports on Form 10-Q and Form 8-K, which the Company incorporates by reference.

Schering-Plough Disclosure Notice

The information in this press release includes certain “forward-looking statements” within the meaning of the Securities Litigation Reform Act of 1995, including statements relating to VYTORIN. Forward-looking statements relate to expectations or forecasts of future events. Schering-Plough does not assume the obligation to update any forward-looking statement. Many factors could cause actual results to differ materially from Schering-Plough’s forward-looking statements, including market forces, economic factors, product availability, patent and other intellectual property protection, current and future branded, generic or over-the-counter competition, the regulatory process, and any developments following regulatory approval, among other uncertainties. For further details about these and other factors that may impact the forward-looking statements, see Schering-Plough’s Securities and Exchange Commission filings, including Item 1A. Risk Factors in the Company’s 2005 10-K.

VYTORIN(R) is a trademark of MSP Marketing Services (C) LLC. All other brands are trademarks of their respective owners and are not trademarks of MSP Marketing Services (C) LLC.

i Apo B is the protein component of lipoproteins that carry cholesterol in the blood, including LDL, IDL and VLDL.

1 – Pearson TA, Mensah G, Alexander RW, et al. AHA/CDC Scientific Statement: Markers of Inflammation and Cardiovascular Disease, Application to Clinical and Public Health Practice. Circulation. (2003;107:499-511)

2 – American Heart Association. “Inflammation, Heart Disease and Stroke: The Role of C-Reactive Protein.” Available at americanheart/presenter.jhtml?identifier=4648. Accessed on 2/06/06

merck

View drug information on Zocor.

A new research study being published in the October 15th issue of Biological Psychiatry suggests that maternal smoking may increase the level of distress of newborns.

Studies have consistently found that prenatal cigarette smoke exposure is associated with increased rates of behavior problems, irritability, attention-deficit/hyperactivity disorder, the risk of violent offenses, conduct disorder, adolescent onset of drug dependence, and the risk for criminal arrest in offspring. This study adds another potential negative outcome to the list of reasons for mothers to stop smoking while pregnant.

Most of the effects of tobacco either during pregnancy or on postnatal outcomes are attributed to nicotine. However, smoking is associated with reduced monoamine oxidase A (MAO-A) activity, enzymes that degrade brain neurotransmitters in smokers. Prenatal smoke exposure-induced low MAO-A activity in fetal life may dysregulate brain neurotransmission, creating a potential vulnerability to develop behavioral disorders later in life. This dysregulation can occur with or without interaction with nicotine’s effect on the developing brain.

French scientists compared blood biomarkers of MAO-A activity in smoking and non-smoking pregnant women and in the cord blood of their newborns. They also assessed the newborns’ comfort level during their first 48 hours of life. They found that MAO-A activity is reduced both in pregnant smokers and in their newborns. The newborns of smoking mothers also showed significantly more discomfort than those of non-smoking mothers, potentially related to MAO-A inhibition.

Corresponding author Dr. Ivan Berlin explained that this paper’s findings “may have implications for future research because it proposes a biological explanation for the previously demonstrated relationship between smoking during pregnancy and behavioral disorders in the offspring.”

“We know that maternal smoking can negatively affect a newborn in many ways, such as contributing to low birth weight. Berlin and colleagues provide new evidence that the newborns of mothers who smoke experience more behavioral discomfort, and they suggest a mechanism that helps to explain the cause of this discomfort,” commented Dr. John Krystal, Editor of Biological Psychiatry. Although additional studies are needed, this work highlights the importance of targeting pregnant women for help to stop smoking.

Source: Elsevier

Commenting on the latest survey by Nottingham University into smoking outside NHS hospitals, Karen Jennings, UNISON Head of Health, said:

“UNISON supports a smoke-free workplace and campaigned long and hard to bring in the current legislation. At the same time, employers must be supportive to workers who are smokers, and help those who want to give up.

“The NHS employs more than 1m people who represent a broad cross section of the public , including smokers. Employers should develop smoking policies and have outside areas that conform to the legislation and ensure that employees, public and patients use the designated outside areas.

“What we would not want is for smokers to be driven underground and cause a fire risk by smoking in cupboards or on stairwells.”

unison

UroToday – A two to four week course of antibiotic therapy is often used in patients with an elevated PSA to exclude inflammation as an etiology of the elevated level. This talk reviews the data regarding variations in PSA, etiology and the practice of antibiotic use.

Fluctuations in PSA are anticipated as the concentration of PSA in prostatic fluid is approximately a million fold higher than in serum. To begin with, there are both lot-to-lot differences in PSA assays – as well as method-to-method differences between the methodologies used. As such, it’s prudent to have a patient get their PSA measurements at the same laboratory on a consistent basis to avoid this variation. If one looks at the variation of the PSA test over a two week period there is a 15% coefficient of variation in the total PSA, a 17% variation in the pre PSA and a 14% free PSA variation. The median PSA, as reported by Catalona, for men in their forties is 0.7ng/ml, for men in their fifties 0.9ng/ml, for men in their sixties 1.3ng/ml, and for men in their seventies 1.7ng/ml. Eastham reported on year to year fluctuations in PSA. He found that 26 to 37% of men with increased PSA had a level return to normal on the next annual evaluation. Forty-five to 55% of men with increased PSA had the level return to normal within four years. In 65 to 83% of those men, it remained normal for years afterwards. For those who had a prostate biopsy recommended for abnormal PSA levels 40 to 53% would have had their PSA parameters fall below the biopsy criteria during the four years of follow-up. The suggestion is that more than one PSA should be used to confirm an abnormal PSA level prior to a biopsy.

There are also seasonal variations in the PSA. The French arm of the European randomized study screening for prostate cancer showed there were significantly higher PSA concentrations in summer than in other seasons. This resulted in a 23% increase in the likely hood of being referred for prostate biopsy during the summer season. Finasteride can also affect the PSA level. Finasteride will decrease both the total and free PSA by approximately 50%. As such, the free to total PSA ratio remains unchanged. This suggests that an abnormal decrease in the free to total ratio could potentially be due to cancer rather than Finasteride therapy. Furthermore, the use of one milligram per day of Finasteride for alopecia results in a 40% PSA decrease in men ages 40 to 49 and a 50% decrease in men ages 50 to 59. The herbal remedy saw palmetto has not been shown to alter PSA levels in a large double blind randomized multicenter trial.

Antibiotic therapy for an elevated PSA has the theoretical advantage of treating infection, providing cost effective therapy by avoiding prostate biopsies and decreasing patient inconvenience and morbidity from the biopsy. The disadvantages include unnecessary antibiotic expense, potential side effects and adverse reactions and an increase in multidrug resistant organisms. In chronic prostatitis, it has been shown that the total PSA, free PSA and pro-PSA are all significantly higher in patients with infection. A 28 day course of fluoroquinolone therapy in patients with chronic bacterial prostatitis resulted in a median PSA decrease from 8.3 to 5.3ng/ml as reported by Dr. Schaeffer. In 42% of patients with a PSA greater than 4ng/ml the PSA decreased to less than 4ng/ml after antibiotics. Dr. Catalona is evaluating the role for PSA velocity in men with an elevated PSA with regard to inflammation as an etiology. He points out that the traditional PSA velocity cut off for prostate biopsy is 0.75ng/ml/year in men with a PSA above 4 and for men with a PSA less than 4ng/ml a cut off of 0.3 to 0.5ng/ml/year should be used. If you look at the cancer detection rate by PSA velocity in patients treated with antibiotics 36% of his preliminary cohort had a negative PSA velocity of whom about one-third of those undergoing biopsy were found to have cancer. In those who had an unchanged or positive PSA velocity following an antibiotic treatment all had a biopsy and the majority were found to have cancer. This was a small preliminary cohort which is undergoing further evaluation. He points out that a decrease in PSA does not rule out prostate cancer and a lack of decrease of PSA does rule in cancer. The point being, that repeated PSA measurements provide more valid information for patient management and he does believe that an empirical course of antibiotics is a reasonable measure performing prostate biopsy.

It is very important to appreciate that there is increasing drug resistance as reported by Dr. Richard Macchia at the AUA New York Section meeting in 2007. They found that the incidence of fluoroquinolone resistance in 2.6% of patients in the year 2006 compared to 0.8% in 2005 and 0.6% in 2004. Ecoli, the most common organism responsible for bacteria prostatitis in men undergoing prostate biopsy was found in 91% of patients who had a positive urine culture or infective complications following prostate biopsy and 86% of these were resistant to fluoroquinolones

The rationale and evidence-based recommendations for management of an elevated PSA would include repeat confirmation of a newly elevated PSA without the use of antibiotics as an initial test. Patients should be counseled not to ejaculate for forty-eight hours prior to the repeat PSA test. The test should be standardized in the same laboratory, and a urinalysis, and if indicated urine culture performed. An expressed prostatic secretion with >20 WBC/HPF should be considered prostatitis and sent for culture and potentially treated with antibiotics. Significant fluctuations in PSA should raise the suspicion of inflammation or infection as an etiology and in these patients it remains controversial; however, this would be the population of patients to consider a short course of two weeks of antibiotics. This remains a nonevidence based practice, which needs to be individualized to the patient. Using PSA velocity in a short and longer-term fashion may be a way to stratify patients for the need for prostate biopsy. Those who undergo a course of fluoroquinolone antibiotics should not have a prostate biopsy within one month of completing the antibiotics to allow the colonic flora to reestablish itself to a normal state.

References:

Eastham JA et al JAMA 289 2695-2700, 2003
Ornstern DK et al J. Urol 157 219-228, 1997
Schaeffer AJ et al J. Urol 174 161-164, 2005

Presented by: Michelle Ramirez, DO, and Christopher P. Evans, MD, at the Masters in Urology Meeting – July 31, 2008 – August 2, 2008, Elbow Beach Resort, Bermuda

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Novartis Pharma AG announced that Visudyne(reg) (verteporfin), currently the only treatment for some forms of “wet” Age-Related Macular Degeneration (AMD), was launched today in Japan. AMD is the leading cause of blindness in people over age 50. Visudyne was approved by the Japanese Ministry of Health, Labour and Welfare (MHLW) in October 2003 for the “wet” form of age-related macular degeneration with all types of subfoveal choroidal neovascularization (CNV).

“We are very pleased that we are able to bring this drug to the Japanese marketplace,” said Flemming Ornskov, MD, President and Chief Executive Officer of Novartis Ophthalmics, the eye health unit of Novartis Pharma AG. “The progressive loss of central vision associated with AMD can have a devastating impact on a patient’s quality of life. Without this treatment a person on average may be legally blind after just two years from diagnosis”.

In Japan, the loss of vision is defined legally as the case when the corrected vision of both eyes are under 0.1 or when the corrected vision of first an eye is under 0.02 and with the vision of the second another eye being under 0.6.

Approval was based on the results of a well-designed 12-month clinical study conducted in Japan, which confirmed the efficacy and safety profile of Visudyne. In fact approximately 3 patients out of 4 participating in this study either maintained or improved their vision as a result of Visudyne therapy. Visudyne was evaluated in Japan as a therapeutic drug for the wet form of AMD following its designation as an orphan drug in June 1997.

AMD is the leading cause of legal blindness in people over the age of 50. Its associated vision loss has been shown to significantly decrease quality of life. Everyday tasks such as driving and walking can be severely affected. Awareness of the condition and treatment in the initial stages of the disease are essential for patients to take the necessary steps that lead to diagnosis and early treatment to halt progression of AMD.

Vision loss from AMD occurs in two forms: dry and wet. The dry form is associated with atrophic cell death of the central retina. The wet form is caused by growth of abnormal blood vessels (CNV) under the central part of the retina or macula. These vessels leak fluid and blood and cause scar tissue that destroys the central retina. This results in a deterioration of sight over a period of months to years.

Visudyne therapy is a two-step procedure. Following intravenous administration, Visudyne is activated by a non-thermal laser light. The process is known as photodynamic therapy. Visudyne selectively targets abnormal blood vessels under the retina, resulting in a reduction in their growth, without affecting normal/healthy retina tissue. This, in turn, stops the leakage associated with wet AMD. However, it is important for patients to be diagnosed and treated early if they are to gain maximal benefit from treatment with Visudyne.

Visudyne is the only drug approved for the treatment of some forms of wet AMD, the leading cause of blindness in people over the age of 50, and has been used in more than 250,000 patients worldwide. Visudyne is commercially available in more than 70 countries mainly for the treatment of predominantly classic subfoveal CNV and in over 40 countries for occult subfoveal CNV caused by AMD. It is also approved in more than 55 countries, including the EU, U.S. and Canada, for the treatment of subfoveal CNV due to pathologic myopia (severe near-sightedness). In some countries Visudyne is also approved for presumed ocular histoplasmosis or other macular diseases.

The foregoing press release contains forward-looking statements that can be identified by terminology such as “able to bring”, “may be “, or similar expressions, or by express or implied discussions regarding potential future sales of Visudyne.

Such forward-looking statements involve known and unknown risks, uncertainties and other factors, which may cause the actual results and assumptions to be materially different from any future results, performance or achievements expressed or implied by such statements. There can be no guarantee regarding potential future sales of Visudyne.

In particular, management’s expectations regarding commercialization of Visudyne could be affected by, among other things, additional analysis of Visudyne clinical data; new clinical data; unexpected clinical trial results; unexpected regulatory actions or delays or government regulation generally; the company’s ability to obtain or maintain patent or other proprietary intellectual property protection; competition in general; increased government pricing pressures; and other risks and factors referred to in the Company’s current Form 20-F on file with the US Securities and Exchange Commission.

Should one or more of these risks or uncertainties materialize, or should underlying assumptions prove incorrect, actual results may vary materially from those anticipated, believed, estimated or expected. Novartis is providing the information in this press release as of this date and does not undertake any obligation to update any forward-looking statements contained in this press release as a result of new information, future events or otherwise.

With worldwide headquarters in Basel, Switzerland, the Novartis Ophthalmics Business Unit is a global leader in research, development and manufacturing of leading ophthalmic pharmaceuticals that assist in the treatment of age-related macular degeneration, eye inflammation, glaucoma, ocular allergies and other diseases and disorders of the eye. Novartis Ophthalmics products are available in more than 110 different countries. . Novartis Ophthalmics products are made in Switzerland, France, the United States and Canada. For more information, visit www.novartisophthalmics or www.novartisophthalmics/us.

Novartis AG (NYSE: NVS) is a world leader in pharmaceuticals and consumer health. In 2003, the Group’s businesses achieved sales of USD 24.9 billion and a net income of USD 5.0 billion . The Group invested approximately USD 3.8 billion, in R&D. Headquartered in Basel, Switzerland, Novartis Group companies employ about 78 500 people and operate in over 140 countries around the world. For further information please consult novartis.

View drug information on Photodynamic Therapy; Visudyne.

The lesson learned in eradicating dandelions from your yard could apply in treating breast cancer as well, said researchers from Baylor College of Medicine in Houston in a report that appears online in the Journal of the National Cancer Institute.

“It’s not enough to kill the dandelion blossom and stalk that appear above ground,” said Dr. Michael Lewis, assistant professor of molecular and cellular biology and a faculty member in the Lester and Sue Smith Breast Cancer Center at BCM. “You have to kill the root beneath the soil as well.”

In a study involving women with breast cancer, he and colleagues at BCM showed that while conventional anti-cancer drugs can kill the bulk of breast cancer tumors, they leave behind many of the breast cancer stem cells from which tumor cells arise, setting the stage for the tumor to come back.

“What we found is that one reason chemotherapy frequently does not work is that you kill the bulk of the tumor but leave many of the stem cells behind,” said Lewis. “It appears that these cells, by their nature, are resistant to the effects of anti-cancer drugs.”

However, treatment with the drug lapatinib and anti-cancer drugs appears to kill both the tumor and the stem cells, reducing the threat of relapse in patients whose tumors carry a protein marker called HER2, Lewis said.

In their study, he and colleagues took biopsies from the tumors of patients before and after treatment.

The study had two parts. In the first, 31 patients whose tumors did not have the HER2 marker received conventional chemotherapy. In the second part of the study, 21 patients whose tumors carried the HER2 marker, received treatment with lapatinib and two other common breast cancer drugs. (The HER2 marker meant that the tumors would be susceptible to lapatinib.)

The researchers stained the samples to highlight the subset of tumor cells that contained the stem cells, which can be identified by the presence of certain markers on the cell surface. This enabled them to estimate the percentage of stem cells in the biopsy. In addition, stem cells in the laboratory can grow into colonies of cells that scientists call mammospheres. Because of this, they could also measure those to estimate what proportions of stem cells are present in a sample.

In the group that received conventional chemotherapy, the number of tumor cells decreased markedly. However, after the treatment, the proportion of cancer stem cells (identified by special markers and mammosphere formation) to differentiated tumor cells was greater than before treatment. In other words, there was a higher percentage of stem cells because the chemotherapy killed the regular tumor cells but left stem cells behind.

In the group that received lapatinib, the number of tumor cells again decreased dramatically. However, the percentage of breast cancer stem cells did not change or even went down slightly (although the change did not reach statistical significance). Consistent with this, the percentage of patients who received lapatinib had significant tumor shrinkage at greater rates than that seen in patients who received conventional therapy.

“The tumor shrank dramatically,” said Dr. Jenny Chang, associate professor of medicine at BCM and medical director of the BCM Breast Care Cancer Center. “But in contrast to treatment with conventional chemotherapy, the relative proportion of stem cells did not go up. This means the stem cells were killed off with the same frequency as the bulk of the tumor. This is the first time this has been demonstrated.”

Finding drugs that work specifically against stem cells is a course for the future, said Lewis. He plans to start by characterizing the markers specific to breast cancer stems cells, and inhibiting them one-by-one.

###

Others who took part in this work include: Xiaoxian Li, Jian Huang, Carolina Gutierrez, C. Kent Osborne, Meng-Fen Wu, Susan G. Hilsenbeck, Anne Pavlick, Xiaomei Zhang, Gary C. Chamness, Helen Wong and Jeffrey Rosen, all of BCM.

Funding for this work came from the Breast Cancer Research Foundation, the Emma Jacobs Clinical Breast Cancer Fund, the Helis Foundation, the NCI Breast Cancer Special Program of Research Excellence, the National Cancer Institute, Glaxo Smith Kline and the U.S. Army Medical Research and Materiel Command.

Click here to access the article online.

Source: Kimberlee Norton

Baylor College of Medicine

Researchers at the Garvan Institute of Medical Research are developing a tool-kit to educate doctors on osteoporosis and provide them with a focussed set of effective, easy-to-use risk factor tests that will lead directly to preventive programs designed to reduce the risk and impact of the condition.

Garvan’s Professor John Eisman said the two-year project is the latest extension of the world renowned Dubbo Osteoporosis Study which, since its inception 18 years ago, has provided landmark advances in global understanding of osteoporosis.

“We have shown that a tendency to fall over, weak muscles and low bone density all contribute to the risk of osteoporotic fractures and that bone and weight loss are predictors of poor health outcomes,” said Professor Eisman.

“We have also debunked the myth that osteoporosis is an elderly women’s disease. Both men and women lose bone as they get older and 25-30 per cent of men will have an osteoporotic fracture in their life-time,” he said.

Osteoporosis is a condition in which bones become fragile and brittle, leading to a higher risk of breaks or cracks. It happens when bones lose minerals such as calcium faster than the body can replace them resulting in thinner, less dense bones.

Dr Christine Bennett, chair of the MBF Foundation Steering Committee and Chief Medical Officer at MBF, said that currently older people are more likely to have osteoporosis than high cholesterol so preventing this cruel disease is vital for healthy ageing.

“The Dubbo Study has shown there are markedly greater health care costs than previously considered for osteoporosis,” Dr Bennett said. “This exciting new initiative has the potential to reduce these costs and improve our quality of life as we get older.”

###

The MBF Foundation is a charitable institution set up by MBF to support and manage important health initiatives for the community using a portion of MBF Group’s investment income each year. Projects undertaken encompass three key areas – wellness and obesity, supporting healthy ageing and keeping healthcare affordable.

Contact: Jackie Crossman
Research Australia

A team from MIT and the Centers for Disease Control and Prevention has found a genetic explanation for why the new H1N1 “swine flu” virus has spread from person to person less effectively than other flu viruses.

The H1N1 strain, which circled the globe this spring, has a form of surface protein that binds inefficiently to receptors found in the human respiratory tract, the team reports in the July 2 online edition of Science.

“While the virus is able to bind human receptors, it clearly appears to be restricted,” says Ram Sasisekharan, the Edward Hood Taplin Professor and director of the Harvard-MIT Division of Health Sciences and Technology (HST) and the lead MIT author of the paper. Sasisekharan and his laboratory co-workers have been actively investigating influenza viruses.

That restricted, or weak, binding, along with a genetic variation in an H1N1 polymerase enzyme, which MIT researchers first reported three weeks ago in Nature Biotechnology, explains why the virus has not spread as efficiently as seasonal flu, says Sasisekharan. However, flu viruses are known to mutate rapidly, so there is cause for concern if H1N1 undergoes mutations that improve its binding affinity.

“We need to pay careful attention to the evolution of this virus,” says Sasisekharan.

On June 11, the World Health Organization declared a level 6 pandemic alert for H1N1. More than 300 people have died and more than 70,000 people have been infected, according to the WHO.

Genetic variation

Sasisekharan and CDC senior microbiologist Terrence Tumpey have previously shown that a flu virus’s ability to infect humans depends on whether its hemagglutinin protein can bind to a specific type of receptor on the surface of human respiratory cells.

In the new Science paper, Sasisekharan, Tumpey and colleagues compared the new H1N1 strain to several seasonal flu strains, including some milder H1N1 strains, and to the virus that caused the 1918 flu pandemic. They found that the new strain, as expected, is able to bind to the predominant receptors in the human respiratory tract, known as umbrella-shaped alpha 2-6 glycan receptors.

However, binding efficiency varies between flu strains, and that variation is partly determined by the receptor-binding site (RBS) within the hemagglutinin protein. The team found that the new H1N1 strain’s RBS binds human receptors much less effectively than other flu viruses that infect humans.

The researchers also found that the new H1N1 strain spreads inefficiently in ferrets, which accurately mimics human influenza disease including how it spreads or transmits in humans. When the ferrets were in close contact with each other, they were exposed to enough virus particles that infection spread easily. However, when ferrets were kept separate and the virus could spread only through airborne respiratory droplets, the illness spread much less effectively.

This is consistent with the transmission of this virus seen in humans so far, says Sasisekharan. Most outbreaks have occurred in limited clusters, sometimes within a family or a school but not spread much further.

“One of the big payoffs of long-term investments in carbohydrate biology and chemistry research is an understanding of the relationships between cell surface carbohydrate structure and viral infectivity,” said Jeremy M. Berg, director of the National Institute of General Medical Sciences of the National Institutes of Health, which partly funded the research. “Tools developed in building such understanding help in the response to events like the recent H1N1 outbreak.”

Second mutation

The researchers also pinpointed a second mutation that impairs H1N1′s ability to spread rapidly.

Recent studies have shown that a viral RNA polymerase known as PB2 is critical for efficient influenza transmissibility. (RNA polymerase controls the viruses’ replication once they infect a host.) The new H1N1 strain does not have the version of the PB2 gene necessary for efficient transmission.

MIT researchers led by Sasisekharan first reported the PB2 work in the June 9 online issue of Nature Biotechnology. That study also found that the new H1N1 strain has substantial genetic variability in the proteins targeted by current vaccines, making it likely that existing seasonal vaccines will be ineffective against the new strain.

Moreover, the researchers discovered that the new strain might just need a single change or mutation that could lead to inefficient interaction with the influenza drug oseltamivir, commonly known as Tamiflu, raising the possibility that strains resistant to Tamiflu could emerge easily.

The research done at MIT was funded by the Singapore-MIT Alliance for Research and Technology and the National Institutes of General Medical Sciences.

Source:
Patti Richards

Massachusetts Institute of Technology

View drug information on Tamiflu capsule.

Contrary to an earlier report, smoking appears to have no effect on the progression of multiple sclerosis (MS), according to a study published in the October 9, 2007, issue of Neurology®, the medical journal of the American Academy of Neurology.

Researchers in the Netherlands surveyed 364 people at both the initial and secondary stages of MS, 263 of whom were smokers.

The study showed there is no association between cigarette smoking and the progression of MS. Due to the high number of smokers with MS, it had previously been suggested there was a correlation between the progression of the disease related to smoking.

“Because the cause of MS as well as reasons for progression is generally unknown, there have been many genetic and environmental factors tested,” said study author Marcus W. Koch, MD, with the University of Groningen in the Netherlands. “Cigarette smoking is one more factor we can rule out.”

Koch says the finding is in conflict with a previous study that suggested cigarette smoking increased the rate of MS progress. “Differences in that study’s size and methodology may account for this discrepancy. Since our study involved more people, and participants were personally interviewed, we feel it makes our results more accurate.”

This study was supported by MS Anders in the Netherlands

The American Academy of Neurology, an association of more than 20,000 neurologists and neuroscience professionals, is dedicated to improving patient care through education and research. A neurologist is a doctor with specialized training in diagnosing, treating and managing disorders of the brain and nervous system such as stroke, Alzheimer’s disease, epilepsy, Parkinson’s disease, and multiple sclerosis.

For more information about the American Academy of Neurology, visit aan.

American Academy of Neurology (AAN)
1080 Montreal Ave.
St. Paul, MN 55116
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neurology

ONCOLOGY: Loss of the breast cancer gene BRCA1 in the absence of genetic mutations is controlled by the protein HOXA9

Women with BRCA1 genetic mutations that prevent their BRCA1 protein from being expressed or functioning properly are predisposed to develop breast and ovarian cancers. BRCA1 expression is also often reduced in breast tumors from women who do not have predisposing genetic mutations and the reason for this is not known. However, Valerie Weaver and colleagues, at the University of California, San Francisco, have now generated data that provide an explanation for the loss of BRCA1 expression in sporadic human breast tumors in the absence of BRCA1 genetic modifications by analyzing human breast cancer tissue and cell lines. Specifically, they generate several lines of evidence to indicate that the protein HOXA9 restricts breast tumor aggression by inducing BRCA1 expression and infer that the frequently observed downregulation of the HOXA9 gene in sporadic human breast cancers leads to loss of BRCA1 expression in the absence of BRCA1 genetic modifications.

TITLE: HOXA9 regulates BRCA1 expression to modulate human breast tumor phenotype

IMMUNOLOGY: A NOD(1) to antibacterial host defense via type I IFNs

Type I IFNs are immune molecules that have a central role in antiviral host defense. New research, performed by a team of researchers at the National Institutes of Health, Bethesda, and Kyoto University Graduate School of Medicine, Japan, has now shown that their production can be triggered by stimulation of the protein NOD1 and that this contributes to protection against the bacterium Helicobacter pylori in mice.

The protein NOD1 is found inside the epithelial cells that line the various body cavities, including the intestines and stomach. It functions to sense specific microbial components, responding by triggering an inflammatory immune response. In this study, which was led by Warren Strober and Tomohiro Watanabe, stimulating NOD1 in human epithelial cells was unexpectedly found to activate a signaling pathway that leads to the production of type I IFNs. While detailed analysis uncovered the molecules in the pathway, the physiologic significance of this pathway was revealed by the observation that mice lacking the receptor for type I IFNs and mice in which the signaling pathway was inhibited showed increased susceptibility to H. pylori infection. These data expand our knowledge of the role of both NOD1 and type I IFNs in host defense.

TITLE: NOD1 contributes to mouse host defense against Helicobacter pylori via induction of type I IFN and activation of the ISGF3 signaling pathway

HEMATOLOGY: Setting the story straight: HDL does not regulate blood clotting

HDL cholesterol is considered good cholesterol and its levels in the blood correlate inversely with hardening of the arteries, a condition that is a major cause of heart attack and stroke. Previous studies have indicated a role for HDL as a regulator of blood clotting (blood coagulation). Specifically, it was found that HDL helped the anticoagulant protein APC degrade the blood clotting protein FVa. However, a team of researchers, led by Björn Dahlbäck, at Lund University, Sweden, has now isolated HDL from human plasma using a different purification technique and found that HDL does not have the ability to perform this function, rather this property of HDL is instead caused by contaminating negatively charged phospholipid membranes.

TITLE: Reevaluation of the role of HDL in the anticoagulant activated protein C system in humans

HEMATOLOGY: Linking Treg immune cells to graft-versus-host-disease

Treatment for a number of leukemias, lymphomas, and other medical conditions is transplantation with bone marrow cells that can generate all blood cells from a genetically nonidentical individual (a process known as allogeneic hematopoietic stem cell transplantation [HSCT]). Despite treatment with immunosuppressive drugs, some patients go on to develop graft-versus-host-disease (GVHD), a condition in which immune cells derived from the transplanted cells attack and destroy the recipient’s body. This is one of the most common and clinically important problems affecting long-term HSCT survivors and it is associated with a relative deficiency in immune cells known as Tregs in the blood. Jerome Ritz and colleagues, at the Dana-Farber Cancer Institute, Boston, have now determined that Treg deficiency occurs in patients in which the number of immune cells known as CD4+ T cells takes a long time to rebound following HSCT.

TITLE: Altered regulatory T cell homeostasis in patients with CD4+ lymphopenia following allogeneic hematopoietic stem cell transplantation

NEPHROLOGY: New player in salt retention by the kidney

It is important that the amount of salt we consume is matched by the amount released by our kidneys into the urine. This is because the amount of salt in our body determines how much fluid is retained, and too much salt in our body means excess fluid is retained and blood pressure rises. One cause of high blood pressure is abnormal retention of sodium, the component of salt responsible for regulating fluid levels, by the kidney. Drugs that block sodium transport systems in the kidney are used to treat disease states such as high blood pressure caused by abnormal renal sodium retention. Although drugs known as thiazides have been used to treat high blood pressure for many years, data indicate that not all the sodium transport mechanisms in the kidney targeted by thiazides have been identified. However, Dominique Eladari and colleagues, at INSERM U872, France, have now determined in mice that thiazides target the protein SLC4A8 and that this is an ion exchanger that mediates thiazide-sensitive sodium retention in a region of the kidney known as the cortical collecting ducts.

TITLE: The Na+-dependent chloride-bicarbonate exchanger SLC4A8 mediates an electroneutral Na+ reabsorption process in the renal cortical collecting ducts of mice

Source:
Karen Honey
Journal of Clinical Investigation