Science Weekly: Rebuilding HMS Beagle, and Hubble’s 20th birthday

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Recreating Charles Darwin’s ship; how to dial the space station; Hubble turns 20; Arabic science; and Stephen Hawking at the Albert Hall

Annual Meeting – Society For Clinical Data Management

This year the annual meeting of the Society for Clinical Data Management will be held in Minneapolis this week. Let us know if you are attending. A publication entitled “How Electronic Data Capture (EDC) Can Be Integrated Into The Comprehensive Data Monitoring Plan (cDMP).” The goal of this paper is to demonstrate how three powerful EDC tools can be used to monitor data and how both the CRAs and data managers can become a very powerful team in the area of clinical data management. The three very powerful tools that should be available to all EDC systems include: 1) online edit and logic checks that fire at the time of data entry or in batch mode; 2) queries that are generated by the monitors; and 3) report of changes and reasons for changes to the database.

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.

Brain Freeze

A Brain Freeze, also known as Ice-cream 1) ___, cold-stimulus headache, or its given scientific name sphenopalatine ganglioneuralgia (meaning “nerve pain of the sphenopalatine ganglion”), is a form of brief cranial pain or headache commonly associated with consumption (particularly quick consumption) of cold beverages or foods such as ice cream and popsicles. It is caused by having something cold touch the roof of the mouth (palate), and is believed to result from a nerve response causing rapid constriction and swelling of blood 2) ___ or a “referring” of pain from the roof of the mouth to the head. The rate of intake for cold foods has been studied as a contributing factor.

Brain Freezes is commonly experienced when applying ice-cream (or similar) to the 3) ___ of the mouth or when swallowing it. Typically the headache appears in about 10 seconds and lasts about 20 seconds although some people experience much longer lapses of pain, with the pain seeming to relate to the same side of the head as the cold substance was applied to the palate, or to both sides of the head in the case of 4) ___. The most effective way to prevent it is to consume the cold food or liquid at a slower rate. Keeping it in one’s mouth long enough for the palate to become used to the 5) ___ is also an effective preventative.

Brain Freeze is the direct result of the rapid cooling and rewarming of the capillaries in the 6) ___. A similar but painless blood vessel response causes the face to appear “flushed” after being outside on a cold day. In both instances, the cold temperature causes the capillaries in the sinuses to 7) ___ and then experience extreme rebound dilation as they warm up again.

In the palate, this dilation is sensed by nearby pain 8) ___, which then send signals back to the brain via the trigeminal nerve, one of the major nerves of the facial area. This nerve also senses facial pain, so as the nerve signals are conducted, the brain interprets the pain as coming from the 9) ___- the same “referred pain” phenomenon seen in heart attacks. Research suggests that the same vascular mechanism and nerve implicated in “brain freeze” cause the aura (sensory disturbance) and pulsatile (throbbing pain) phases of 10) ___.It is possible to suffer from a brain freeze in both hot and cold climate conditions. To relieve pain, some doctors suggest pressing the 11) ___ against the roof of the mouth to warm the area.

ANSWERS: 1) headache; 2) vessels; 3) palate; 4) swallowing; 5) temperature; 6) sinuses; 7) constrict; 8) receptors; 9) forehead; 10) migraines; 11) tongue

Julius Wagner-Jauregg (1857-1940)

Wagner-Jauregg was born Julius Wagner on March 7, 1857, in the village of Wels, Austria. While attending medical school at the University of Vienna, Wagner-Jauregg received thorough training in experimental biology and met the father of psychoanalysis, Sigmund Freud, who was studying at the Institute of General and Experimental Pathology. The two remained lifelong friends.

In 1880 Wagner-Jauregg was awarded a medical degree for his thesis on the heart under conditions of acceleration. Originally, Wagner-Jauregg hoped to practice general medicine, but when Vienna’s two teaching hospitals turned him down, he reluctantly accepted a position as an assistant in the university’s psychiatric clinic. Although he had little training in mental illness, he quickly became a qualified instructor in psychiatry and neurology. Wagner-Jauregg was a clinician, skilled in detailed observation and careful case analysis. Using the latest techniques of animal experimentation, he spent his life working to advance the biological understanding of mental illness. His first research entailed the investigation of how certain chemicals stimulate breathing after strangulation.

In 1889 Wagner-Jauregg was appointed professor of psychiatry at the University of Graz and for the next four years studied the effect of the thyroid gland on behavior. An ardent vivisectionist, he discovered that when the thyroid was removed from a cat, the animal’s behavior became convulsive and violent. Cretinism in humans, Wagner-Jauregg put forth in an early paper, was due to a malfunction of the thyroid. During his years in Graz, he travelled frequently in central and southeastern Austria studying peasants with goiter and found that small amounts of iodine reduced their hugely swollen necks. He urged the sale of iodized salt in alpine regions, a measure the Austrian government undertook belatedly in 1923.

In 1893 Wagner-Jauregg was made a full professor at the University of Vienna and appointed director of the Hospital for Nervous and Mental Diseases and the State Mental Asylum. As a member of the Austrian Board of Health, he helped draft important legislation protecting the rights of the mentally ill and regulating the certification of the insane. At his urging, psychiatry became a compulsory subject in the undergraduate curriculum.

While still only a medical assistant, Wagner-Jauregg studied the beneficial effect of high fever on psychotic patients. For a monograph that he published in 1888, he surveyed instances where epidemics of typhoid, malaria, smallpox, and scarlet fever had swept through mental asylums. In 30 cases reaching back to antiquity, he described how bouts of high fever had brought dramatic relief in cases of melancholy, mania, and paresis. At the end of his monograph, Wagner-Jauregg suggested that malaria might be used experimentally to induce a “fever cure” in psychotic patients, although at the time he lacked the authority to undertake so radical a treatment.

The monograph received little notice when it was published. In it, Wagner-Jauregg had formulated two bold hypotheses: first, that some psychoses were organic in nature, and second, that one disease might be employed to eradicate another disease. In Graz, he had produced fever with injections of tuberculin, a protein used to treat tuberculosis, until it was learned that tuberculin was unsafe. In Vienna, he injected paralytic patents with typhus vaccine and staphylococci but was disappointed by the results. Most of the cures proved tube temporary, and patients soon relapsed.

It was not until World War I that conditions were ripe for a radical trial. By then a series of important discoveries had confirmed the link between paresis and syphilis. In 1905 researchers had identified the syphilis bacillus, Spirochaete pallida. A year later, the Wasserman test for syphilis revealed that paresis was a progressive disease of the brain caused by untreated syphilis. In Wagner-Jauregg’s time, paresis accounted for 15% of the patients confined to mental hospitals. The disease was thought to be incurable and invariably ended in insanity, paralysis, and death within three to four years.

In the final years of World War I, Wagner-Jauregg was treating victims of shell shock when he encountered a soldier suffering from malaria. On June 14, 1917, Wagner-Jauregg used blood drawn from the malarial soldier to infect nine patients suffering from paresis. Quinine, the medicine used to treat malaria, was withheld until each patient had endured seven to eleven attacks of fever. The results were astonishing. Six patients experienced a dramatic remission of symptoms, and three were able to return to normal life. In 1919 Wagner-Jauregg began full-scale clinical trials.

At first, Wagner-Jauregg’s reports were greeted with considerable skepticism by the medical community. Some physicians considered it unethical to deliberately induce a disease as serious as malaria. Others feared the outbreak of malaria epidemics in major metropolitan centers. But trials elsewhere produced similar results. Employing only a mild strain of malaria easily cured by quinine, mortality remained low while complete recovery was experienced by thirty to forty percent of all patients. Patients who had only recently contracted syphilis could be cured completely when the “malaria cure” was used in conjunction with injections of Salvarsan and Neosalvarsan, two drugs used to treat early syphilis. In 1927 Wagner-Jauregg became the first psychiatrist to be awarded the Nobel Prize in physiology or medicine.

Safer methods of inducing fever were tried–preparations of colloidal sulfur, hot-water baths, and “fever cabinets”–but none had the high rates of success typical of malaria. Until the discovery of penicillin during World War II, malaria remained the preferred treatment for advanced syphilis. Medical opinion differed on just how the fever cure worked since it seemed unlikely that the fever killed all of the spirochete bacteria, which cause syphilis. Instead, it was believed that the stress produced by the malaria attack in some way strengthened the body’s defenses against the syphilitic infection. Stress treatments such as electroshock continue to play a role in the treatment of psychiatric disorders.

In 1928, one year after receiving the Nobel Prize, Wagner-Jauregg retired at the age of seventy-one. He died on September 27, 1940, in Vienna at age eighty-four, shortly before the discovery of penicillin made his fever cure obsolete. Wagner-Jauregg was honored philatelically by Austria in 1957, the 100th year of his birth (Stanley Gibbons 1289, Scott 615).

Lifestyle Intervention Improves Risk Factors In Type 2 Diabetes

Overweight and obesity affect more than 60% of adult Americans – a rate that has been increasing rapidly. Obesity is associated with a number of significant conditions including diabetes and cardiovascular disease. About 24 million people in the United States have diabetes, diagnosed or undiagnosed. It is the main cause of kidney failure, limb amputations, new onset blindness in adults and a major cause of heart disease and stroke. The longer a person has diabetes, the greater the chances of developing serious damage to the eyes, nerves, heart, kidneys, and blood vessels.

Type 2 diabetes, which accounts for up to 95% of all diabetes cases, becomes more common with increasing age. The disease is strongly associated with overweight and obesity, inactivity, family history of diabetes, history of gestational diabetes, impaired glucose metabolism, and racial or ethnic background. The prevalence of diagnosed diabetes has more than doubled in the last 30 years, due in large part to the upsurge in obesity.

An intensive lifestyle intervention program designed to achieve and maintain weight loss has been shown to improve diabetes control and cardiovascular disease risk factors in overweight and obese individuals with type 2 diabetes. The results are published in the Sept. 27, 2010, issue of the Archives of Internal Medicine. The Look AHEAD (Action for Health in Diabetes) is a multi-center, randomized clinical trial investigating the effects of an intensive lifestyle intervention program. It will also evaluate the effect of reduced caloric intake and increased physical activity on the incidence of major cardiovascular events such as heart attack, stroke, and cardiovascular-related death.

At study entry, 5,145 participants at 16 centers across the United States were randomly assigned to one of two interventions. Those in a so-called “intensive lifestyle intervention group” met regularly with a lifestyle counselor in a combination of group and individual sessions. They were given specific caloric consumption and exercise goals, were encouraged to maintain a diet and exercise diary, and were taught behavioral skills such as problem solving and goal setting. After the first year, participants were seen individually at least once monthly, had at least one additional phone or email contact each month, and were invited to attend additional group classes. Those in the “diabetes support and education group” were invited to group sessions each year focused on diet, physical activity, or social support. They were not weighed at these sessions or counseled on behavioral strategies.

At the time of enrollment, participants were between 45 and 76 years of age. Most were obese with a mean body mass index (BMI) of 36. BMI is a measure of weight in relation to height. A BMI of 18.5 to 24.9 is considered healthy, a BMI of 25 to 29.9 is overweight, and 30 or more is obese. Thirty-seven percent of participants were from racial and ethnic minority groups, and approximately 60% were women. Over 94% of participants remain involved after four years and will continue to be followed for up to 13.5 years.

Over the first four years of Look AHEAD, participants in both groups showed positive changes in their health. On average, across all four years, participants in the intensive lifestyle group lost significantly more weight than participants in the support and education group. On average, members of the lifestyle group lost 6.2% of their initial body weight, and members of the support and education group lost 0.9% of their initial body weight. The intensive intervention group also experienced greater improvements in fitness, diabetes control, blood pressure, HDL (good) cholesterol, and triglycerides. The diabetes support group showed larger reductions in LDL (bad) cholesterol, a change associated with the increased use of cholesterol-lowering medications. The study results do not break down results by demographic groups such as gender, age, race or ethnicity.

Longer-term follow-up of Look AHEAD participants will determine whether improvements in risk factors including blood pressure, lipids and glucose control can be sustained – independently and as a consequence of continued weight loss – and whether the intensive lifestyle intervention is effective in reducing the incidence of illness and death due to cardiovascular disease. These results will not be available for several years. Other important study objectives include understanding the impact of weight loss and improved fitness on diabetes complications, general health, quality of life, and psychological outcomes. Researchers also will evaluate the cost and cost-effectiveness of the intensive lifestyle intervention compared to diabetes support and education.

VIROLOGY

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NIH Scientists Discover How Dengue Virus Infects Cells

Dengue (http://www.cdc.gov/dengue/), which is transmitted by mosquitoes, infects up to 100 million people each year. People bitten by an infected mosquito first develop a fever, followed by other symptoms such as joint pain, rash and nausea. Without treatment, symptoms may become more severe. Patients with the severe form of the disease, dengue hemorrhagic fever, may develop difficulty breathing, bruising, bleeding from the nose or gums, and breakdown of the circulatory system. According to the WHO, ach year, 22,000 people – most of them children – die from dengue.

According to an article published online in PLoS Pathogens, a key step has been discovered in how the dengue virus infects a cell. The study showed how the dengue virus releases itself from the protective membrane that shields it as it penetrates deep inside the cell. The discovery allows the study of the invasion process in the laboratory and provides a means to test potential treatments for the virus.

To infect a cell, the virus binds to the cell membrane. The cell membrane engulfs the virus, enveloping it in a pouch-like structure known as an endosome. To begin the infection process, the virus delivers its hereditary material into the cytosol, the fluid interior of the cell, where it begins reproducing itself. To do so, however, it must first release itself from the endosome. The virus does this by fusing its membrane with the endosomal membrane. When the two membranes come together, they form a pore through which the virus’ genetic material is released.

Scientists have used their understanding of HIV to develop drugs that block the fusion process and infection. To study the fusion stage of viral entry, viral fusion has typically been observed at the cell surface or fusion of a virus with an artificial membrane. However, those working with denguehave been unable to get the virus to fuse under either of these conditions.

In the present study, dengue virus and cell membranes were taggedwith molecules that would glow when the virus and membranes fused. They also exposed samples of the virus to an artificial membrane under various conditions, to identify factors that would allow fusion to take place. The study first confirmed that a protein controlling fusion is active only under acidic conditions. However, conditions in the endosome are always acidic, and this alone was not enough to guarantee fusion, they found. In additional experiments using artificial and cell membranes along with fluorescent markers, it was discovered that fusion occurred only when the membranes were negatively charged. When the endosome begins its journey, the endosomal membrane has a neutral charge. The negative charge is present only after the endosome has been taken deep within the cell.

Gene Variations That Alter Key Enzyme Linked To Prostate Cancer

In 2010, it is estimated that there will be 217,730 new cases of prostate cancer, and 32,050 deaths.

Phosphodiesterase enzymes, of which there are nearly a dozen, regulate cellular activity in hormone producing organs such as the testes, prostate gland, adrenal gland and ovaries. PDE11A regulates cyclic adenosine monophosphate, a compound involved in supplying cells with energy.

According to an article published online in the Journal of Clinical Endocrinology and Metabolism (1 October 2010), gene variations that alter PDE11A in prostate cancer have also been linked to genes found previously for susceptibility to testicular cancer and adrenal gland tumors. The genetic variations all impair the enzyme phosphodiesterase 11A (PDE11A), which helps regulate a cell’s responses to hormones and other signals. Previous studies have linked genetic variations that inactivate PDE11A with increased susceptibility to testicular cancer and adrenal tumors.

The study examined DNA of tissue from 50 men with prostate cancer and 287 men who did not have prostate cancer. Results showed 8 variations in the PDE11A gene that decreased the production or activity of PDE11A. Of the men with prostate cancer, 30% had one or more of these variations, compared with 10% of the men who did not have prostate cancer. Of the detected variations, 5 had been detected in previous studies and 3 were previously unknown.

Tadalafil, a drug used to treat erectile dysfunction, also inhibits PDE11A. The authors called for future studies to determine if tadalafil or other drugs that inhibit PDE11A might affect the prostate in men who have a variant gene for PDE11A.

There is no current clinical evidence to date linking tadalafil to prostate cancer or to other cancers.

TARGET HEALTH excels in Regulatory Affairs and Public Policy issues. Each week we highlight new information in these challenging areas.

FDA Issues Draft Guidance On When an IND Is Required

Target Health commends FDA for this and 2 other draft guidances (Safety Reporting and FAQ’s – Statement of Investigators – Form 1572) for clarifying areas for which there has been much confusion and thus unnecessary additional work in getting safe and effective drugs to the market.

The FDA has issued a draft guidance on determining when a research study can be conducted without an IND. This guidance is intended to assist clinical investigators, sponsors, and sponsor-investigators determining whether human research studies must be conducted under an investigational new drug application (IND), as described in Title 21 of the Code of Federal Regulations, part 312 (2126 CFR part 312) (the IND regulations). This guidance describes when an IND is required, specific situations in which an IND is not required, and a range of issues that, in FDA’s experience, have been the source of confusion or misperceptions about the application of the IND regulations.

Currently, an IND is not required as long as :

1. The drug product is lawfully marketed in the United States.

2. There is no intent to report the investigation to FDA as a well-controlled study in support of a new indication and no intent to use it to support any other significant change in the labeling of the drug.

3. In the case of a prescription drug, the investigation is not intended to support a significant change in the advertising for the drug.

4. The investigation does not involve a route of administration, dose, patient population, or other factor that significantly increases the risk (or decreases the acceptability of the risk) associated with the use of the drug product (21 CFR 312.2(b)(1)(iii))

5. The investigation is conducted in compliance with the requirements for review by an IRB (21 CFR part 56) and with the requirements for informed consent (21 CFR part 50).

6. The investigation is conducted in compliance with the requirements of § 312.7 (i.e., the investigation is not intended to promote or commercialize the drug product).

The current draft guidance attempts to clarify the following:

1. What is the definition of a drug product that is lawfully marketed in the United States

2. When is the risk associated with the product significantly increased (or the acceptability of the risk significantly decreased)?

3. What does it mean when the sponsor intends to:

  • a. report the investigation to FDA as a well-controlled study in support of a new indication
  • b. use it to support any other significant change in the labeling of the drug
  • c. use it to support a significant change in the advertising (for prescription drugs only) for the drug?

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.