Science Weekly: Superheroes – a warning

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The downside of superheroes; decision-making in ant colonies; a scan for autism; plus, has P=NP been solved?

New York Times Front Page News – 14 August 2010

Target Health wants to congratulate Dr. Erin Gainer, CEO of HRA Pharma, Paris, on the approval of ella™ (ulipristal acetate) tablets for emergency contraception (See FDA below) and for reaching the front page of the New York Times this past Saturday. The product has been available in Europe under the brand name ellaOne.

Target Health is pleased to be a partner of this project since 2006. Target Health was the US FDA Agent for this program and performed the statistical analysis for both pivotal trials as well as the integrated summary of safety (ISS) and efficacy ISE). In addition, we performed monitoring for one of the pivotal trials and wrote both of the clinical study reports.  Target e*CRF® was used for the pivotal trials performed in the US and Europe. This is the 19th product approved that used Target e*CRF for pivotal trials.

For more information about Target Health contact Warren Pearlson (212-681-2100 ext 104). For additional information about software tools for paperless clinical trials, please also feel free to contact Dr. Jules T. Mitchel or Ms. Joyce Hays. Target Health’s software tools are designed to partner with both CROs and Sponsors. Please visit the Target Health Website, and if you like the weekly newsletter, ON TARGET, you’ll love the Blog.

Growing Organs and Helping Wounds Heal

Protein pattern: This computer rendering shows ripples on fabric made from protein. Such fabrics could be used as scaffolds for growing organs. Credit: ACS/ Nano Letters

 

A stretchy new fabric made by linking together the proteins found in muscle tissue could provide a scaffold for growing new 1) ___organs. It could also be used as a coating for bandages to help wounds heal quickly and with less scarring. The fabric was made in the laboratory of Kevin Kit Parker, a professor at Harvard’s School of Engineering and Applied Science.

When the body grows new tissue, cells secrete fibronectin – a strong, stretchy type of protein that acts as a supportive scaffold. The shape and structure that fibronectin adopts directs the subsequent growth of new 2) ___cells, giving the resulting tissue the correct form.

Parker’s team creates the fabric by depositing fibronectin molecules on top of a water-repelling polymer surface. This causes the proteins, which are normally bundled up, to unravel. Next, the protein layer is stamped onto a dissolvable, water-attracting polymer sheet on top of a piece of glass. Adding water and warming the mixture to room temperature makes the 3) ___proteins link together to form the fabric. It also dissolves the polymer so that the fabric can be peeled away and collected.

The team made swatches of material 10 nanometers thick and about 2.5 centimeters wide. The researchers can control the architecture and mechanical characteristics of the fabric by using different proteins, or changing the way they are aligned.

Different research groups are developing ways to grow replacement tissue in the lab, but a big challenge is providing the right direction for the growth of new cells. Researchers have previously made cellular 4) ___scaffolds by flushing the living cells from harvested livers and hearts, and by creating cellular skeletons made from polymers.

By building the new scaffold from the protein up, Parker’s team can program direction cues into the architecture of the scaffold, and thus direct the growth of cells in the desired direction. Using natural proteins rather than synthetic polymers or decellularized organs reduces the likelihood that the new tissue will be rejected once it’s implanted. In one experiment, the research team grew heart muscle cells on top of a piece of finished fabric. The fabric caused the muscle cells to link together to form a tissue that “beat,” when stimulated 5) ___electrically, for one week.

Other than building three-dimensional scaffolds for organ reconstruction, the new fabric could be embedded in bandages, accelerating 6) ___wound healing and minimizing scar formation. The material could also find other novel uses. An appealing feature is its unusual elasticity. The fibronectin protein, which forms the base thread of the fabric, is part of the molecular machinery that allows muscles to contract and 7) ___relax.

“Fibronectin is compressed like a spring when you’re contracting your 8) ___muscle, and when you relax, it pushes it back,” says Parker. This structure gives the fabric its elasticity, and allows it to be stretched up to 18 times its original length. “When you pull on the fabric, you unfold the proteins,” providing additional strength, says Parker.

Parker’s team is exploring the mechanical properties of the new fabric, examining its strength and stretchiness. The new stamping method could let them make larger, more complex fabrics. “The base technology is down,” says Parker. “Now we need to facilitate the spinout applications.”

ANSWERS

 

1) organs; 2) cells; 3) proteins; 4) scaffolds; 5) electrically

Mass Food Poisoning

Salmonella

Food poisoning has been recognized as a disease of man since as early as Hippocrates. In the fifth century BC, the great plague of Athens, probably caused by contaminated cereals, led to the defeat of the Athenians in the Peloponnesian War. In the pre-scientific Middle Ages, illnesses resulting from contaminated food were often attributed to the wrath of God or malevolent spirits. Heavily infectious ergot, a poisonous mold that produces the potent toxin ergotamine, induced a spasmodic muscle condition, which the Church named “St. Anthony’s Fire” and interpreted as retribution by God on heretics.

The historical record of mass food poisoning in Europe offers a cautionary tale. From the ninth to the 19th centuries, Europe suffered a succession of epidemics caused by contamination of rye with ergot consumption of which induces hallucinations, bizarre behavior and violent muscle twitching.

These symptoms gave rise at various times to the belief that victims were possessed by evil spirits. Witch-hunting and persecution were commonplace–and the New World was not immune. One leading explanation for the notorious 1691-1692 Salem witch trials in the US relates to ergot contamination. Three young girls suffered violent convulsions, incomprehensible speech, trance-like states, odd skin sensations and delirious visions in which supposedly they saw the mark of the devil on certain women in the village. The girls lived in a swampy meadow area around Salem where rye was a major staple of their diet. Records indicate that the rye harvest was complicated by rainy and humid conditions, exactly the situation in which ergot would thrive.

Worried villagers feared the girls were under a spell cast by demons, and the girls eventually named three women as witches. The subsequent panic led to the execution of as many as 20 innocent people. The girls’ symptoms are typical of ergot poisoning, and when the supply of infected grain ran out, the delusions and persecution likewise disappeared. Even the madness of King George III, which played a role in the American Revolution, may have been induced by accidental arsenic poisoning.

The sale of rancid, contaminated or adulterated food was commonplace until introduction of hygiene, refrigeration, and vermin controls in the 19th century. Discovery of techniques for killing bacteria using heat and other microbiological studies by scientists such as Louis Pasteur contributed to the modern sanitation standards that are ubiquitous in developed nations today. This was further underpinned by the work of Justus von Liebig, which led to the development of modern food storage and food preservation methods. In more recent years, a greater understanding of the causes of food-borne illnesses has led to the development of more systematic approaches such as the Hazard Analysis and Critical Control Points (HACCP), which can identify and eliminate many risks.

In the twentieth century, there were heroic efforts of modern industrial societies to make food safer. In the early days of the FDA a “Poison Squad” was formed, consisting of young scientists who willingly acted as guinea pigs to test the toxic effects of chemical additives. Today, the government has focused on the hazards of food bioterrorism. Source: Henry I. Miller, a physician and fellow at the Hoover Institution, was the founding director of the FDA’s Office of Biotechnology. He is the co-author of The Frankenfood Myth.

Women’s Cholesterol Levels Vary With Phase Of Menstrual Cycle

In a typical menstrual cycle, estrogen levels steadily increase as the egg cell matures, peaking just before ovulation. Previous studies have shown that taking formulations which contain estrogen such as oral contraceptives or menopausal hormone therapy, can affect cholesterol levels. However, the results of studies examining the effects of naturally occurring hormone levels on cholesterol have not been conclusive.

According to an article published online in The Journal of Clinical Endocrinology and Metabolism (August 2010), it was shown that women’s cholesterol levels correspond with monthly changes in estrogen levels and that this natural variation might indicate a need to take into account the phases of a woman’s monthly cycle before evaluating cholesterol levels. On average, the total cholesterol level of the women in the study varied 19% over the course of the menstrual cycle.

The study compared estrogen with cholesterol and triglyceride levels among 259 healthy women between 18 and 44 years old. For 94% of the volunteers, 14 or more measurements were taken over two menstrual cycles. Women charted the phases of their cycles with at-home fertility monitors, which detect hormone levels that indicate ovulation. Most of the women were physically active and did not smoke. Only 5% consistently had total cholesterol levels greater than 200 mg/dL, considered borderline high-risk for heart disease. However, cholesterol levels among 19.7% of the women reached 200 mg/dL at least once.

Results showed that as the level of estrogen rises, high-density lipoprotein (HDL) cholesterol also rises, peaking at the time of ovulation. HDL cholesterol is believed to be protective against heart disease. In contrast, total cholesterol and low-density lipoprotein (LDL) cholesterol levels-as well as another form of blood fat known as triglycerides-declined as estrogen levels rose. The decline was not immediate, beginning a couple of days after the estrogen peak at ovulation. Total cholesterol, LDL cholesterol and triglyceride levels reached their lowest just before menstruation began.

According to the authors, further research may help clarify the optimal point in the cycle for doctors to measure women’s cholesterol levels and help clinicians develop standardized procedures for measuring cholesterol in premenopausal women and determining their heart disease risk.

Human Clinical Trial Of Dengue Vaccine Begins

About 2.5 billion people in more than 100 countries worldwide live in areas where they are at risk of dengue infection. Dengue fever is caused by any of four related viruses – DENV-1, DENV-2, DENV-3 and DENV-4 – which are transmitted to humans by Aedes mosquitoes. Dengue virus is prevalent in the tropical and subtropical regions of the world and each year infects about 50 million to 100 million people. Dengue fever accounts for 25,000 deaths annually; most of them in children.

Most people infected with dengue virus experience no symptoms at all or only a mild fever. Others develop flu-like symptoms, headache, and joint and muscle pain. A smaller portion of those infected experience the more severe dengue hemorrhagic fever/shock syndrome (DHF/DSS), which can cause high fever, pain, bleeding, a drop in blood pressure, and, in some cases, coma or death.

There is no vaccine to prevent dengue infection or drug treatment for those who become infected. Current treatment recommendations include bed rest, drinking fluids, and taking medicine to reduce fever. The only way to prevent infection is to avoid being bitten by Aedes mosquitoes. These mosquitoes are most active during the day and thrive in urban environments, two factors that make them difficult to avoid.

After more than a decade of development at the NIH, a vaccine to prevent infection by the mosquito-borne dengue virus has begun human clinical testing. The vaccine was developed by scientists at the National Institute of Allergy and Infectious Diseases (NIAID) and is undergoing clinical study at the Johns Hopkins Bloomberg School of Public Health in Baltimore.

The new vaccine is tetravalent, meaning that it is designed to protect against all four dengue viruses, also called serotypes. This is especially important because of the way the immune system responds. A person who develops antibodies against one serotype of dengue virus is protected against only that specific serotype. To be fully protected against the four forms of dengue, a person must have antibodies against all four serotypes of the virus. However, having some antibodies to dengue may be worse than having none. According to the authors, someone who has antibodies against only one or a few of the virus serotypes is actually at higher risk of developing the severe form of the disease upon infection by another serotype. But a person who is immune to all four serotypes cannot be reinfected, and, therefore, is less likely to develop DHF/DSS.

Development of the vaccine was led by Stephen S. Whitehead, Ph.D., and Brian Murphy, M.D., of NIAID’s Laboratory of Infectious Diseases. The researchers started by testing seven monovalent vaccines, each of which is designed to protect against a single dengue serotype. The overall strategy was to identify the best individual candidate for each serotype, based on safety and ability to induce an immune response, and to then combine those into a tetravalent vaccine. To optimize the immune response to each dengue serotype, the researchers are testing three different candidate combinations of the four monovalent vaccines. The candidate vaccines are live-attenuated, or created by making the live virus harmless or less virulent.

Evaluation of a second candidate combination vaccine has been initiated at the University of Vermont in Burlington, and trials of the third candidate will begin shortly thereafter at Johns Hopkins. These early clinical trials are designed to test the vaccine’s safety and ability to stimulate immune responses in healthy adults ages 18 to 50. After a baseline assessment, participants will receive one dose of the assigned vaccine or placebo. At follow-up study visits over the next six months, the researchers will assess their health and dengue symptoms and collect blood and urine samples for analysis. After determining which tetravalent vaccine is most promising, that candidate will be tested in a trial in a new group of volunteers in Brazil, where dengue has become highly prevalent.

The next stage of testing, a Phase II trial, will involve more participants and will test for differences in preliminary signs of effectiveness between people who have been exposed to dengue and those who have not, as well as the need for a booster shot within a few months of the initial vaccination.

Stress May Delay Women Getting Pregnant

A study published online in Fertility and Sterility (August 2010), supports the widespread belief that stress may reduce a woman’s chance of becoming pregnant. The study is the first of its kind to document, among women without a history of fertility problems, an association between high levels of a substance indicative of stress and a reduced chance of becoming pregnant.

The study showed that women who had higher levels of a substance called alpha-amylase were less likely to get pregnant than were women with lower levels of the substance. Alpha-amylase is secreted into saliva by the parotid gland, the largest of the salivary glands. Although alpha-amylase digests starch, in recent years many studies have used it as a barometer of the body’s response to physical or psychological stress. The substance is secreted when the nervous system produces catecholamines, compounds that initiate a type of stress response.

To conduct the study, the authors charted the ovulation cycles of 274 English women aged 18-40 years who were trying to conceive, and who participated in the Oxford Conception Study. The clinical trial sought to determine whether daily information from a fertility-monitoring device would increase the conception rate in women wishing to achieve pregnancy. The women were given at- home fertility test kits to track the phases of their monthly cycles.

On the sixth day of each cycle, a saliva sample was collected which was subsequently tested for alpha-amylase. The women’s saliva samples were also analyzed for cortisol, another hormone produced by the adrenal glands in response to stress. Each woman took part in the study until she became pregnant, or at the end of six menstrual cycles.

Results showed that during the fertile window — the six days when conception is most likely to occur — women with high alpha-amylase levels were less likely to conceive than were women with low levels. The study did not find a correlation between cortisol levels and the chances of conception. Overall, the 25% of women in the study who had the highest alpha-amylase levels had roughly an estimated 12% reduction in getting pregnant each cycle in comparison to women with the lowest concentrations.

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FDA Approves EllaTM Tablets for Prescription Emergency Contraception

The FDA has approved ellaTM (ulipristal acetate) tablets for emergency contraception. The prescription-only product prevents pregnancy when taken orally within 120 hours (five days) after a contraceptive failure or unprotected intercourse. It is not intended for routine use as a contraceptive. ellaTM is a progesterone agonist/antagonist whose likely main effect is to inhibit or delay ovulation. Since May 2009, the prescription product has been available in Europe under the brand name ellaOne.

An FDA Advisory Committee for Reproductive Health Drugs discussed ellaTM in June, 2010. The committee unanimously voted that the application for ellaTM provided compelling data on efficacy and sufficient information on safety for the proposed indication of emergency contraception.

The safety and efficacy of ellaTM were demonstrated in two Phase III clinical trials. One study was a prospective, multi-center, open-label, single-arm trial conducted in the United States; the other was a randomized, multi-center, single-blind comparator-controlled trial conducted in the United States, United Kingdom and Ireland.  

Side effects most frequently observed with ellaTM in the clinical trials include: headache, nausea, abdominal pain, pain/discomfort during menstruation (dysmenorrhea), fatigue, and dizziness. The profile of side effects for ellaTM is similar to that of FDA-approved levonorgestrel emergency contraceptives. According to the product’s labeling, women with known or suspected pregnancy and women who are breastfeeding should not use ellaTM. A patient package insert also will be provided to ensure that women are fully informed of the benefits and risks involved in the use of ellaTM.

ellaTM is manufactured by Paris-based Laboratoire HRA Pharma. ellaTM will be distributed by Watson Pharma Inc., of Morristown, N.J.

For more information about our expertise in Medical Affairs, contact Dr. Mark Horn. For Regulatory Affairs, please contact Dr. Jules T. Mitchel or Dr. Glen Park.