Clinical Briefs

New Video Shows Communication Between Brain Cells

An NIH researcher has captured video images of a previously unknown form of communication between brain cells that might hold clues to the way learning shapes the brain. The videos, offered as a resource for educators teaching high school, undergraduate, and graduate students, are available on the Web.

These newly recorded signals are emitted along the length of nerve fibers. Earlier research has documented the transmission of signals across the synapse. The new videos show that when neurons communicate, electrical signals emitted along the length of neurons stimulates nearby brain cells known as glia, or glial cells. As a result, the glial cells begin making a substance called myelin, which coats the nerve fibers and allows electrical charges to travel with greater speed through the brain’s networks.

Other studies have shown that the process of myelination underlies learning and is crucial for the development of new skills. Additional research might help clarify how signaling between neurons and glial cells triggers myelination and influences skill development, according to R Douglas Fields, PhD, of the National Institute of Child Health and Human Development’s (NICHD ) Nervous Systems Development and Plasticity Section.

The teaching resource on the website features short video clips that document these previously unknown non-synaptic signals.

“For the last 100 years researchers have studied how information traverses the brain, crossing synapses and traveling from one nerve cell to the next,” said Fields. “We can now see another type of communication, in which cells along a neuron’s length can sense the chemical signals the neuron releases.”

To detect these signals, Fields observed neurons under a microscope. Nerve fibers, or axons, are long projections that stretch between neurons. The longest human axon stretches from the base of the spine to the big toe. Working with the corresponding neuron of mice, Fields stimulated the neuron with electrical charges and recorded his findings in three videos now available on the Web. The videos can be viewed here.

Level of Tumor Protein Indicates Cancer’s Chance of Spreading

Researchers at NIH and the University of Hong Kong have discovered that high levels of a particular protein in cancer cells are a reliable indicator that a cancer will spread. By measuring the protein’s genetic material in tumors that had been surgically removed from patients, along with measuring the genetic material from surrounding tissue, the researchers could predict at least 90% of the time whether a cancer would spread within two years. The findings raise the long-term possibilities of new tests to gauge the likelihood that a cancer will spread and, ultimately, of a treatment that could prevent cancer from spreading.

The protein, known as CPE-delta N, is a form of carboxypeptidase E (CPE). Ordinarily, CPE is involved in processing insulin and other hormones. CPE-delta N, a variant of CPE, was present in high amounts in tumors that had spread and, to a much lesser degree, in surrounding tissues.

“Testing for CPE-delta N, if combined with existing diagnostic methods, offers the possibility of more accurately estimating the chances that a cancer will spread,” said Alan E Guttmacher, MD, director of the NICHD, which supported the study. “Conceivably, a patient’s CPE-delta N levels could be a key guide in individualizing their cancer care to improve outcome.”

The researchers estimated the likelihood of metastasis in tumor samples and tissues from patients with liver cancer and two rare tumors, pheochromocytoma and paraganglioma. They found that tumor samples from patients whose cancers had later metastasized had elevated levels of CPE-delta N.

Tests indicating high levels of the protein predicted the spread of a cancerous tumor even when conventional staging—diagnostic techniques to gauge the extent and seriousness of a cancer—indicated that spread was unlikely. The finding raises the possibility that testing for CPE-delta N might be used in combination with conventional staging to further refine treatment. For example, if conventional staging indicated that a cancer was unlikely to spread, but a patient’s tumor had high CPE-delta N levels, that patient might be referred for more intensive therapies normally reserved for higher stage cancers.

The researchers tested for CPE-delta N indirectly, by measuring levels of a molecule that assists in manufacturing the protein. RNA works with the information in a gene to make a particular protein — in this case, CPE-delta N.

In an analysis of tissue from 99 patients with liver cancer, the researchers compared the amount of CPE-delta N RNA from the patients’ tumors with the RNA levels in surrounding tissue. The researchers found that when the level of CPE delta-N RNA in tumors was more than twice that in the surrounding tissue, the cancer was highly likely to return or to metastasize within two years. At or below this threshold level, the cancer was much less likely to recur. Using this threshold measure, the researchers accurately predicted metastasis or recurrence in more than 90% of cases. Conversely, their predictions that tumors would not return in the two-year period were accurate 76% of the time.

Surveillance Ordered for TMJ Implants

FDA ordered three manufacturers of temporomandibular joint (TMJ) implants to conduct postmarket surveillance studies to determine the length of time before the implants are removed or replaced due to pain or other reasons. The TMJ connects the lower jaw (mandible) to the temporal bone in the skull. A person may have an implant to replace the socket in the temporal bone or the rounded edge of the lower jaw that glides in the temporal bone socket because of an injury, arthritis, physical abnormality, or lost mobility.

The three manufacturers, TMJ Solutions, TMJ Medical, and Biomet Microfixation, make all of the currently approved TMJ devices marketed in the United States. The companies will have 30 days to submit a study plan, which will need to be approved by the agency before any postmarket studies can begin.

TMJ implants can also be used to treat temporomandibular disorder (TMD) that has not responded to more conservative treatments such as limiting jaw movement, soft diet, jaw splint or adjustments, medicine to reduce pain, or physical therapy.

The FDA analyzed TMJ implant-related adverse event reports submitted over the last six years. The analysis described a substantial number of patients who had implants replaced within three years or less after implantation because of extreme pain. This is considerably shorter than the expected minimum five-year life span of the device, based on premarket mechanical testing.

TMJ implant manufacturers were required to collect postmarket data on their implants as part of the approval process. However, the data collected did not adequately address the timing or reasons for replacement, and the studies lost contact over the years with many of the enrolled patients.

The TMJ implant postmarket surveillance studies must address: time between initial implant and removal; association between patient diagnosis and the timeframe between implant and removal; for replacement implants, the time between implant and subsequent removal or replacement; reasons for removal or replacement; associations between patient demographic and clinical data and the need for removal/replacement; and assessment of devices that have been removed from patients. As part of its review, the FDA will consider whether labeling changes, additional preclinical and clinical testing requirements, or other regulatory actions are necessary.

New App Allows Doctors to View Medical Images on iPhone® and iPad®

A new mobile radiology application that will allow physicians to view medical images on the iPhone and iPad manufactured by Apple Inc has been cleared by FDA for use.

The application is the first approved by FDA for viewing images and making medical diagnoses based on CT, MRI, and nuclear medicine technology, such as positron emission tomography. It is not intended to replace full workstations and is indicated for use only when there is no access to a workstation.

Radiology images taken in the hospital or physician’s office are compressed for secure network transfer then sent to the appropriate portable wireless device via software called Mobile MIM. Mobile MIM, manufactured by Cleveland-based MIM Software Inc, allows the physician to measure distance on the image and image intensity values, and to display measurement lines, annotations, and regions of interest.

In its evaluation, the FDA reviewed performance test results on various portable devices. These tests measured luminance, image quality, and noise in accordance with international standards and guidelines. The FDA also reviewed results from demonstration studies with qualified radiologists under different lighting conditions. All participants agreed that the device was sufficient for diagnostic image interpretation under the recommended lighting conditions.

The display performance of mobile devices can experience significant variations in luminance levels even between mobile devices of the same model. The Mobile MIM application includes sufficient labeling and safety features to mitigate the risk of poor image display due to improper screen luminance or lighting conditions. The device includes an interactive contrast test in which a small part of the screen is a slightly different shade than the rest of the screen. If the physician can identify and tap this portion of the screen, then the lighting conditions are not interfering with the physician’s ability to discern subtle differences in contrast. In addition, a safety guide is included within the application.

New Mental Health Campaign Targets People Affected by Oil Spill

SAMHSA, in collaboration with the Ad Council, has expanded its efforts to provide information, support, and resources to individuals and families affected by the Deepwater Horizon oil spill.

“While the immediate crisis is over, many Gulf Coast residents continue to need support as they work to rebuild their lives after the Deepwater Horizon oil spill. It is natural for some people to need help over time in dealing with the emotional trauma and distress experienced from such an event and associated losses,” said SAMHSA Administrator Pamela S Hyde, JD.

The campaign is designed to raise awareness of the early warning signs of serious emotional distress, and to provide access to free resources to those affected in the Gulf state region. The television PSA, featuring Surgeon General Regina Benjamin, and other PSAs aim to help those living in the Gulf states get the assistance they may need to treat and alleviate long term psychological distress.

“For many who live on the Gulf Coast, this disaster has affected us very deeply,” said Benjamin. “We want anyone who is feeling distressed to know that getting help can be as simple as making a phone call or sending a text message.”

The new television, English and Spanish radio ads, and outdoor PSA’s were created by Grey New York, Clear Channel Creative Services Group, and Lamar Advertising through the Ad Council. The PSAs direct audiences to call a toll-free number (1-800-985-5990), or text TALKWITHUS to 66746 for a safe, confidential way to receive free counseling, information, and support from trained professionals (Standard text messaging and data rates apply). The toll-free Oil Spill Distress Helpline, funded by SAMHSA, links callers to local crisis centers, where local and trained professionals answer the calls and provide confidential assistance. Haitian Creole and Spanish-language operators are also available.

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Most Hospitals and Doctors Plan to Adopt Electronic Records

Four-fifths of the nation’s hospitals, and 41% of office-based physicians, currently intend to take advantage of federal incentive payments for adoption and meaningful use of certified electronic health records (EHR) technology, according to survey data released last month by the Office of the National Coordinator (ONC) for Health Information Technology. The survey information was released as the registration period opened for the Medicare and Medicaid EHR Incentive Programs. The data comes from surveys commissioned by ONC and carried out in the course of regular annual surveillance by the American Hospital Association and the CDC’s National Center for Health Statistics (NCHS).

The AHA survey found that 81% of hospitals plan to achieve meaningful use of EHRs and take advantage of incentive payments. About two-thirds of hospitals (65%) responded that they will enroll during Stage 1 of the Incentive Programs, in 2011-2012.

The NCHS survey found that 41% of office-based physicians are currently planning to achieve meaningful use of certified EHR technology and take advantage of the incentive payments.  Four-fifths of these, or about a third of all office-based physicians (32.4%), responded that they will enroll during Stage 1 of the programs.  Only 14% of respondents said they were not planning to apply for meaningful use incentives.

Additional survey data from NCHS show that significantly increasing numbers of primary care physicians have already adopted a basic EHR, rising by 50% from 19.8% of primary care physicians in 2008 to 29.6% in 2010. Basic EHRs provide a beginning point for use of electronic health records in physician offices, but most physicians would need to further upgrade their EHR systems or their use of the systems in order to qualify for meaningful use incentive payments.

Incentive payments for the adoption and meaningful use of certified EHR technology were authorized in the Health Information Technology Economic and Clinical Health Act (HITECH) in 2009. Incentive payments will be made through the Medicare and Medicaid programs. High rates of adoption and meaningful use could result in as much as $27 billion in incentive payments over 10 years.

Non-hospital-based physicians and other eligible professionals can obtain incentive payments of as much as $44,000 under Medicare or $63,750 under Medicaid. Under both Medicare and Medicaid, eligible hospitals may receive millions of dollars for implementing and meaningfully using certified EHR technology.

Provider registration for the Medicare EHR Incentive Program and some Medicaid EHR Incentive Programs opened January 3, 2011. Most states will allow provider registration to begin for their Medicaid EHR Incentive Programs during the spring and summer of 2011.

FDA Asking for Limits on Acetaminophen

The FDA is asking manufacturers of prescription combination products that contain acetaminophen to limit the amount of acetaminophen to no more than 325 mg in each tablet or capsule. The agency also is requiring manufacturers to update labels of all prescription combination acetaminophen products to warn of the potential risk for severe liver injury.

Acetaminophen, also called APAP, is a drug that relieves pain and fever and can be found in both prescription and OTC products. It is combined in many prescription products with other ingredients, usually opioids such as codeine (Tylenol with Codeine®), oxycodone (Percocet®), and hydrocodone (Vicodin®). OTC acetaminophen products are not affected by the action.

The elimination of higher-dose prescription combination acetaminophen products will be phased in over three years and FDA does not expect it to create a shortage of pain medication. Patients and healthcare professionals are being notified of the new limitation on acetaminophen content, and of the labeling change, in a drug safety communication issued by CDER. The FDA believes that prescription combination products containing no more than 325 mg of acetaminophen per tablet are effective for treating pain.

FDA officials noted that there is no immediate danger to patients who take these combination pain medications and they should continue to take them as directed by their healthcare provider. The risk of liver injury primarily occurs when patients take multiple products containing acetaminophen at one time and exceed the current maximum dose of 4,000 milligrams within a 24-hour period.

Acetaminophen is also widely used as an OTC and fever medication, and is combined with other OTC ingredients, such as cough and cold ingredients. The actions FDA is taking for prescription acetaminophen products do not affect OTC acetaminophen products.

Because of continued reports of liver injury, FDA is proposing that boxed warnings, the agency’s strongest warning for prescription drugs, be added to all acetaminophen prescription products. Most of the cases of severe liver injury occurred in patients who took more than the prescribed dose of an acetaminophen-containing product in a 24-hour period, took more than one acetaminophen-containing product at the same time, or drank alcohol while taking acetaminophen products.

An FDA advisory committee discussed the issue at a meeting in June 2009, and recommended strengthening the warning about severe liver injury on the drug labels of prescription products containing acetaminophen.

Opioid Analgesic Approved with Strict Controls

FDA has approved Abstral® (fentanyl) transmucosal tablets to manage breakthrough pain for adults with cancer. Fentanyl immediate-release transmucosal medications are administered on the soft surfaces of the mouth (inside of the cheek, gums, tongue), or the nasal passages or throat where they dissolve and are absorbed. Abstral is indicated for the management of breakthrough pain in patients with cancer, ages 18 years and older, who already use opioid pain medication around the clock and who need and are able to safely use high doses of an additional opioid medicine. Breakthrough pain is pain that comes on suddenly for short periods of time and is not alleviated by a patient’s normal pain management plan. These patients are considered opioid tolerant because of their current opioid medication use.

Abstral is available only through a Risk Evaluation and Mitigation Strategy (REMS) program, which is intended to minimize the risk of misuse, abuse, addiction, and overdose. Under this program, pharmacies, distributors, and healthcare professionals who prescribe to outpatients are required to enroll in the program to prescribe, dispense, and distribute this product. FDA has standardized key components of the REMS program to facilitate the adoption of a single shared system. These components include the REMS document, the Patient-Prescriber Agreement, and the enrollment form. FDA has also directed the sponsors of this class of products to work together on a single shared system to implement the REMS.

“This approval is also a significant step toward reducing the burden on the healthcare system of implementing REMS programs,” said John Jenkins, MD, director of FDA’s Office of New Drugs. “When fully implemented, FDA expects that prescribers, pharmacies, and distributors of all immediate release transmucosal fentanyl products will be able to use standardized materials and a single shared system to implement the REMS.”

The safety of Abstral was evaluated in 311 opioid-tolerant cancer patients with breakthrough pain. Two hundred and seventy of these patients were treated in multiple-dose studies. The duration of therapy for patients in multiple-dose studies ranged from one to 405 days with an average duration of 131 days and with 44 patients treated for at least 12 months.

Common adverse reactions include nausea, constipation, drowsiness, and headache. Serious adverse events, including deaths, have been reported in patients with other immediate-release transmucosal fentanyl products. The deaths occurred as a result of improper patient selection and/or improper dosing.

Possible Gene Target Found for Treating Lymphoma

Researchers have identified a mutation in a gene that could lead to targeted therapies for certain lymphoma patients whose cure rates are currently poor. Mutation of the MYD88 gene was found to be one of the most frequent genetic abnormalities in a form of cancer known as diffuse large B cell lymphoma. MYD88 encodes a protein that is crucial for the normal immune response to invading microorganisms. New experiments show a mutation in the MYD88 protein sequence can cause uncontrolled cellular signaling, leading to survival of malignant cells. The study, led by researchers from NCI, appeared online in Nature, December 22, 2010.

Louis M Staudt, MD, PhD, and colleagues at the Metabolism Branch of the Center for Cancer Research at NCI have worked to identify proteins that play a role in the development of the ABC subtype because these proteins may provide targets to improve the treatment of patients with this form of lymphoma. To identify these critical proteins, the researchers performed a genetic screen in which thousands of genes were inactivated. They found that ABC lymphoma cells were killed when they inactivated the genes encoding MYD88 and IRAK1, another cell signaling protein that works with MYD88.

The scientists then looked for genetic mutations that might explain why the ABC lymphoma cells were so dependent upon MYD88. Sequencing of the MYD88 gene in 382 lymphoma biopsy samples revealed that 29% of ABC lymphoma samples had the same mutation, which altered a single amino acid in the MYD88 protein, but this mutation was rare or absent in other lymphoma subtypes. The mutant form of MYD88 sustained the survival of the ABC lymphoma cells but the non-mutated version did not, suggesting that mutations in the MYD88 gene could play an important role in the development of ABC diffuse large B cell lymphomas.

To understand how MYD88 might promote ABC lymphoma cell survival, the researchers examined proteins that interact with MYD88 in the lymphoma cells. The mutant form of MYD88 spontaneously assembled a protein complex that included IRAK1, identified in the genetic screen, and a related protein, IRAK4. In this protein complex, IRAK4 functioned as an enzyme to modify IRAK1, which was required for the mutant MYD88 protein to promote lymphoma cell survival. This particular finding may have direct therapeutic implications since pharmaceutical companies are developing IRAK4 inhibitors for use in inflammatory and autoimmune diseases, according to the scientists.

Three High-Risk Populations Targeted for Suicide Prevention Efforts

The National Action Alliance for Suicide Prevention has added three new task forces to address suicide prevention efforts within high-risk populations: American Indians/Alaska Natives; youth who identify as lesbian, gay, bisexual, or transgender; and military service members and veterans. This brings to six the number of task forces formed by the Action Alliance, the public-private partnership forged in September this year to advance the National Strategy for Suicide Prevention.

In the US, suicide claims over 34,000 lives annually—the equivalent of 94 suicides per day, or one suicide every 15 minutes. State and local prevention efforts are having a positive impact as rates of suicide have been falling among teenaged and elder males, two of the hardest hit groups. Suicides are increasing among other groups, however, such as AI/AN youth and military members.

Studies from organizations such as the Suicide Prevention Resource Center report that lesbian, gay, and bisexual youth are from 1.5 to seven times more likely to report having attempted suicide than their non-LGBT peers, transgender youth are believed to have higher rates of suicidal behavior as well. Co-leading the LGBT Youth Task Force are Kevin Jennings, assistant deputy secretary of the Office of Safe and Drug-Free Schools, US Department of Education, and Charles Robbins, executive director of The Trevor Project, a leading national organization focused on crisis and suicide prevention efforts among LGBT youth.

“This task force will bring together the best minds in the country to combat suicide and make sure that every LGBT youth has the opportunity to grow up in a supportive, accepting community and to enter adulthood safely,” Robbins said.

Cancer Costs Projected to Reach $158 Billion in 2020

Based on growth and aging of the US population, medical expenditures for cancer in the year 2020 are projected to reach at least $158 billion (in 2010 dollars) — an increase of 27% over 2010, according to an NCI analysis. If newly developed tools for cancer diagnosis, treatment, and follow-up continue to be more expensive, medical expenditures for cancer could reach as high as $207 billion, said the researchers. The analysis appeared online, January 12, 2011, in the Journal of the National Cancer Institute.

The projections were based on the most recent data available on cancer incidence, survival, and costs of care. In 2010, medical costs associated with cancer were projected to reach $124.6 billion, with the highest costs associated with breast cancer ($16.5 billion), followed by colorectal cancer ($14 billion), lymphoma ($12 billion), lung cancer ($12 billion), and prostate cancer ($12 billion).

If cancer incidence, survival rates, and costs remain stable and the US population ages at the rate predicted by the US Census Bureau, direct cancer care expenditures would reach $158 billion in 2020, the report said.

However, the researchers also did additional analyses to account for changes in cancer incidence and survival rates and for the likelihood that cancer care costs will increase as new technologies and treatments are developed. Assuming a 2% annual increase in medical costs in the initial and final phases of care—which would mirror recent trends—the projected 2020 costs increased to $173 billion. Estimating a 5% annual increase in these costs raised the projection to $207 billion. These figures do not include other types of costs, such as lost productivity, which add to the overall financial burden of cancer.

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Darvon and Darvocet Removed from US Market

Xanodyne Pharmaceuticals Inc, which makes Darvon® and Darvocet®, the brand version of the prescription pain medication propoxyphene, has agreed to withdraw the medication from the US market at FDA’s request. FDA has also informed the generic manufacturers of propoxyphene-containing products of Xanodyne’s decision and requested that they voluntarily remove their products as well.

FDA sought market withdrawal of propoxyphene after receiving new clinical data showing that the drug puts patients at risk of potentially serious or even fatal heart rhythm abnormalities. As a result of these data, combined with other information, including new epidemiological data, the agency concluded that the risks of the medication outweigh the benefits.

FDA is advising healthcare professionals to stop prescribing propoxyphene to their patients, and patients who are currently taking the drug should contact their healthcare professional as soon as possible to discuss switching to another pain management therapy.

Propoxyphene is an opioid used to treat mild to moderate pain. First approved by FDA in 1957, propoxyphene is sold by prescription under various names both alone (eg, Darvon) or in combination with acetaminophen (eg, Darvocet).

Since 1978, FDA has received two requests to remove propoxyphene from the market. Until now, the FDA had concluded that the benefits of propoxyphene for pain relief at recommended doses outweighed the safety risks of the drug.

In January 2009, the FDA held an advisory committee meeting to address the efficacy and safety of propoxyphene. After considering the data submitted with the original drug applications for propoxyphene, as well as subsequent medical literature and postmarketing safety databases, the committee voted 14 to 12 against the continued marketing of propoxyphene products. In making this recommendation, the committee noted that additional information about the drug’s cardiac effects would be relevant in weighing its risks and benefits.

In June 2009, the European Medicines Agency (EMEA) recommended that the marketing authorizations for propoxyphene be withdrawn across the European Union. A phased withdrawal of propoxyphene is underway. In July 2009, FDA decided to permit continued marketing, but required that a new boxed warning be added to the drug label alerting patients and healthcare professionals to the risk of a fatal overdose. In addition, the agency required Xanodyne to conduct a new safety study assessing unanswered questions about the effects of propoxyphene on the heart.

An FDA review of data from that study showed that, even when taken at recommended doses, propoxyphene causes significant changes to the electrical activity of the heart. These changes, which can be seen on an electrocardiogram (ECG), can increase the risk for serious abnormal heart rhythms that have been linked to serious adverse effects, including sudden death. The available data also indicate that the risk of adverse events for any particular patient, even patients who have taken the drug for many years, is subject to change based on small changes in the health status of the patient, such as dehydration, a change in medications, or decreased kidney function.

“With the new study results, for the first time we now have data showing that the standard therapeutic dose of propoxyphene can be harmful to the heart,” said Gerald Dal Pan, MD, director of the Office of Surveillance and Epidemiology, CDER. “However, long-time users of the drug need to know that these changes to the heart’s electrical activity are not cumulative. Once patients stop taking propoxyphene, the risk will go away.”

VA Using Private Contractor to Retrieve Patient Files Quicker

VA is working on several innovations designed to significantly reduce the average time needed to obtain healthcare records from private physicians, including hiring a private contractor to retrieve patient files. When private medical records support a veteran’s application for benefits, a contractor will quickly retrieve the records from the healthcare provider, scan them into a digital format and send the material to VA through a secure transmission.

This pilot project hopes to validate initial estimates that a specialized contract can yield records required to process veterans’ disability compensation claims in seven to 10 days instead of VA’s average 40 days. In addition, the contract frees VA staff to focus on core duties to process claims more quickly.

Exploring economical contract support for time savings is one of more than three dozen initiatives supporting VA’s claims transformation plan, which aims to ensure that by 2015, veterans’ claims are decided within 125 days.

VA officials emphasize that in all cases veterans must sign documents approving the release of their medical records to the department from private healthcare providers.

The test is expected to involve about 60,000 records requests among regional benefits offices in Phoenix, New York City, St Louis, Portland,OR, Chicago, Indianapolis, and Jackson, MS. At the conclusion of the test, VA officials will decide whether to cancel, modify, or expand any changes in procedures nationwide.

Survey Puts Drunk Driving Rates Above 20% in Some States

A new survey by SAMHSA indicates that on average 13.2% of all persons 16 or older drove under the influence of alcohol and 4.3% of this age group drove under the influence of illicit drugs in the past year.

The survey’s state-by-state breakdown of drunk and drugged driving levels shows significant differences among the states. Some of the states with the highest levels of past year drunk driving were Wisconsin (23.7%) and North Dakota (22.4%). The highest rates of past year drugged driving were found in Rhode Island (7.8%) and Vermont (6.6%).

States with the lowest rates of
past year drunk driving included Utah (7.4%) and Mississippi (8.7%). Iowa and New Jersey had the lowest levels of past year drugged driving (2.9% and 3.2% respectively).

Levels of self-reported drunk and drugged driving differed dramatically among age groups. Younger drivers aged 16 to 25 had a much higher rate of drunk driving than those aged 26 or older (19.5% versus 11.8%). Similarly, people aged 16 to 25 had a much higher rate of driving under the influence of illicit drugs than those ages 26 or older (11.4% versus 2.8%).

The one bright spot in the survey is that there has been a reduction in the rate of drunk and drugged driving in the past few years. Survey data from 2002 through 2005 combined when compared to data gathered from 2006 to 2009 combined indicate that the average yearly rate of drunk driving has declined from 14.6% to 13.2%, while the average yearly rate of drugged driving has decreased from 4.8% to 4.3%. Twelve states have seen reductions in the levels of drunk driving and seven states have experienced lower levels of drugged driving. However, according to the National Highway Traffic Safety Administration’s Fatal Accident Reporting System census, one in three motor vehicle fatalities (33%) with known drug test results tested positive for drugs in 2009.

State Estimates of Drunk and Drugged Driving is based on the combined data from the 2002 to 2005 and 2006 to 2009 National Surveys on Drug Use and Health (NSDUH) and involves responses from more than 423,000 respondents aged 16 or over. NSDUH is a primary source of information on national and state-level use of tobacco, alcohol, illicit drugs (including non-medical use of prescription drugs), and mental health in the United States.

Teen Marijuana Use On Rise

Fueled by increases in marijuana use, the rate of eighth graders saying they have used an illicit drug in the past year jumped to 16%, up from last year’s 14%, with daily marijuana use up in all grades surveyed, according to the 2010 Monitoring the Future Survey (MTF).

For twelfth graders, declines in cigarette use accompanied by recent increases in marijuana use have put marijuana ahead of cigarette smoking by some measures. In 2010, 21.4% of high school seniors used marijuana in the past 30 days, while 19.2% smoked cigarettes.

The survey also shows significant increases in use of Ecstasy. In addition, nonmedical use of prescription drugs remains high. MTF is an annual series of classroom surveys of eighth, tenth, and twelfth graders conducted by researchers at the University of Michigan, Ann Arbor.

Most measures of marijuana use
increased among eighth graders, and daily marijuana use increased significantly among all three grades. The 2010 use rates were 6.1% of high school seniors, 3.3% of tenth graders, and 1.2% of eighth graders compared to 2009 rates of 5.2%, 2.8%, and 1.0%, respectively.

The MTF survey also showed a significant increase in the reported use of MDMA, or Ecstasy, with 2.4% of eighth graders citing past-year use, compared to 1.3% in 2009. Similarly, past-year MDMA use among tenth graders increased from 3.7% to 4.7% in 2010.

Also of concern is that the downward trend in cigarette smoking has stalled in all three grades after several years of marked improvement on most measures. Greater marketing of other forms of tobacco prompted the 2010 survey to add measures for 12th graders’ use of small cigars (23.1%) and of tobacco with a smoking pipe known as a hookah (17.1%).

Prescription drug abuse remains a serious concern. Although Vicodin® abuse decreased in 12th graders this year to 8%, down from around 9.7% the past four years, other indicators confirm that nonmedical use of prescription drugs remains high. For example, the use of OxyContin®, another prescription opiate, stayed about the same for 12th graders at 5.1% in 2010. Six of the top 10 illicit drugs abused by 12th graders in the year prior to the survey were prescribed or purchased over the counter. The survey again found that teens generally get these prescription drugs from friends and family, whether given, bought, or stolen.

However, the survey says binge drinking continued its downward trend. Among high school seniors, 23.2% report having five or more drinks in a row during the past two weeks, down from 25.2% in 2009 and from the peak of 31.5% in 1998. In addition, 2010 findings showed a drop in high school seniors’ past-year consumption of flavored alcoholic beverages, to 47.9% in 2010 from 53.4% in 2009. Past-year use of flavored alcohol by eighth graders was at 21.9 percent, down from 27.9% in 2005.

The MTF survey also measures teen attitudes about drugs, including perceived harmfulness, perceived availability, and disapproval, all of which can predict future abuse. Related to its increased use, the perception that regular marijuana smoking is harmful decreased for 10th and 12th graders. Disapproval of smoking marijuana decreased significantly among eighth graders.

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United States, Latin America Partner on Cancer Research

The National Cancer Institute formalized bilateral partnerships last month with the governments of Argentina, Brazil, Mexico, and Uruguay, to accelerate progress against cancer in Hispanic populations in the United States and Latin America, and improve cancer research. Dr John Niederhuber, NCI director, representing the U.S. Department of Health and Human Services, signed formal letters of intent to collaborate in cancer research efforts. These countries, along with Chile, which signed a letter of intent in June, and the United States, comprise the United States-Latin America Cancer Research Network. The Network is committed to developing a comprehensive understanding of the cancer burden among Hispanic populations in Latin America and the United States, and to enhance the cancer research and care infrastructures in both regions of the hemisphere.

Spearheaded by NCI’s Office of Latin American Cancer Program Development, this partnership will support the co-development of programs in three broad scientific areas: cancer research and clinical trials; multinational and multidisciplinary training programs; and technology and capacity building. The Latin American countries and the United States will link their research efforts through the cancer Biomedical Informatics Grid, an information network enabling the US-LACRN members to share data and knowledge. The network participants will also initiate pilot projects to expand research efforts and improve the delivery of cutting-edge cancer treatments to patients in the United States and Latin America.

In Latin America, cancer is among the top three deadliest diseases, and its incidence in these countries continues to rise. Cancer also takes a large toll on Hispanic/ Latino populations in the United States. It is estimated that the U.S. Hispanic population will climb to nearly 60 million, and represent approximately 19% of the U.S. population by 2020. Reducing the burden of cancer in the United States and abroad will depend heavily on understanding and controlling cancer in this population.

For the first pilot project of this collaboration, the countries identified research concepts that are intended to improve breast cancer management in Latin America. At the same time, they will provide an opportunity to enhance research training, capacity building, and establishment of a sustainable clinical research infrastructure for future projects. The effort builds on collaborative resources among the countries as well as cosponsorships of workshops and conferences with domestic and international foundations and organizations to support cancer research in Latin America.

Second Copy of Gene Explains Rare Bone Cancer

Scientists have discovered that a familial form of a rare bone cancer called chordoma is explained not by typical types of changes or mutations in the sequence of DNA in a gene, but rather by the presence of a second copy of an entire gene. Inherited large structural changes, known as copy number variations, have been implicated in some hereditary diseases, but have seldom been reported as the underlying basis for a familial cancer. This finding appeared online Oct 4, 2009, in Nature Genetics, and was done by researchers at the National Cancer Institute and their colleagues.

Usual types of gene mutations and gene duplications are permanent changes to the DNA that a person inherits from parents. These changes often alter the expression of the affected gene in ways that lead to cancer and other diseases. The new finding highlights the importance of CNVs, as well as typical specific genetic mutations, in the genetic development of cancer.

Chordoma affects about 1 in every 1 million people in the United States, with about 300 new cases diagnosed each year. Those affected with the disease usually develop a tumor at the base of the skull, or at any point along the spinal column, including the tailbone. The growths are thought to arise from remnants of the notochord, an embryonic precursor to the spinal column. There are few effective treatments and no cure for chordoma; many people with the non-familial form of chordoma die within 10 years of diagnosis.

The researchers based their initial finding on a study of a large family with a history of chordoma that spanned several generations. Because of the familial nature of this cancer, the researchers searched for a genetic alteration that could help explain the increased risk to family members. Initially they considered possible defects on chromosome 7, but no mutation was found that was shared by all affected relatives. The researchers then conducted further linkage studies, which look for patterns that appear in every affected member of a family, and found six new areas in the genome that warranted further study. The area that looked to be the most promising was on chromosome 6, in a region that contained a gene related to notochord development that is called the T gene or brachyury.

The scientists then looked for CNVs in the region on chromosome 6 that included the T gene in DNA from seven families (65 people, including 21 chordoma patients) in which at least two blood relatives had the disease. The scientists found that in four of the families, all of those with the disease had a second copy of the T gene. The duplications were not found in the chordoma patients from the other three families or in 100 healthy normal controls.

Based on their finding that duplications of the T gene cause an increased risk for chordoma in some families, the scientists suggest that future efforts to identify novel genes for familial cancers may benefit from screening for complex genomic rearrangements in addition to using traditional gene-mapping approaches.

Prostate Tumors Can Change Immune Cell Function in Mice

Researchers have discovered that prostate tumors in mice can cause immune cells known as CD8+ T cells to change their function from cells that have antitumor activity to cells that suppress immune responses. This finding by researchers at the National Cancer Institute, has important implications for the design of immune-based therapies for cancer. The new study, available online, appeared in the Oct. 15, 2009, issue of the Journal of Immunology. According to the research team, studying this process in mice may help explain why some cancer patients have an initial response from immune-based therapy but which fails over time.

In mice and humans, when the immune system encounters a pathogen or other foreign invader, it responds by mounting an immune response. Part of this response involves the recruitment and activation of CD8+ T cells, which are also called cytotoxic T cells or killer T cells, to help destroy the invader. CD8+ T cells also play a role in immune responses against tumor cells. Other T cells, known as CD4+ T regulatory cells, work to suppress CD8+ T cell activity. Immune suppression by these regulatory T cells helps prevent the body from attacking its own cells. A high level of CD4+ T regulatory cells is also associated with poor prognosis of some cancers. Moreover, research in mice has shown that blocking the immune suppressive activity of these regulatory T cells enhances the body’s immunity against tumors, causing tumor growth to slow and improving the antitumor immune responses elicited by cancer vaccines.

Recent evidence in mice has suggested that CD8+ T cells can develop suppressive activities similar to those of CD4+ T regulatory cells. In addition, CD8+ suppressor cells have been found in cancer patients. The presence of these suppressor cells could explain earlier findings by Hurwitz’s team that prostate tumor-specific CD8+ T cells injected into prostate tumor-bearing mice migrate to the tumors but then become unresponsive, or tolerized, to the tumor cells. It remained unclear, however, whether the suppressive CD8+ T cells have suppressor activity before they reach the tumor or whether they are converted into suppressor cells by the tumor.

Researchers found that CD8+ T cells acquire immune suppressive functions after they enter the mouse tumor microenvironment, which encompasses nearby noncancerous cells and immune cells in addition to tumor cells. The researchers found that tumor-specific CD8+ T cells isolated from the tumors were able to suppress the proliferative capacity of nonspecific T cells, whereas tumor-specific CD8+ T cells isolated from lymph nodes of the mice were unable to do so.

This anti-proliferative activity appeared to be caused, in part, by substances secreted by the CD8+ T cells after they had been converted to suppressor cells. One of these substances, TGF-beta, is a protein that controls cell proliferation and differentiation and plays a role in cancer and other diseases. TGF-beta is thought to be involved in the immune-suppressive activity of CD4+ T-regulatory cells.

Next, the team investigated whether the conversion of tumor-specific CD8+ T cells to suppressor cells could be prevented. To do this, they administered tumor-specific CD4+ and CD8+ T cells to prostate tumor-bearing mice. Some CD4+ T cells act as helper cells and enhance the activity of other immune cells, including CD8+ T cells. The researchers found that, under these conditions, CD8+ T cells isolated from the prostate tumors no longer suppressed the proliferation of other T cells. Moreover, these cells produced less TGF-beta than cells that were not exposed to CD4+ T cells.

The researchers propose that activated CD4+ T cells that enter tumors may secrete factors that support the CD8+ T cell antitumor functions, or may help other immune cells located in the tumor block the processes by which CD8+ T cells acquire their suppressive activity. In the future, the researchers plan to focus on defining the mechanisms by which tumor-specific CD8+ T cells gain their suppressive functions upon entering the mouse tumor microenvironment.

Kidney Disease Data Available Sooner Than Expected

Incidence and prevalence data for end-stage kidney disease in the United States will be available online from the U.S. Renal Data System a year earlier than usual, the National Institute of Diabetes and Digestive and Kidney Diseases announced last month. In addition, the data will be updated online every 3 months and will show quarterly counts of patients at

The first of the new tables shows incidence and prevalence counts through December 2008. As the tables are updated quarterly, an additional 3 months of counts will be added. The next update in December 2009 will include patient counts through March 2009. Previously, incidence and prevalence data had been made available only through yearly updates of the USRDS Annual Data Report ( Because the report includes detailed data from multiple sources, reporting lagged by about 18 months while data were merged and verified. For example, the 2009 report, which became available this month, has complete data only through 2007.

Data from the USRDS is used by researchers, government officials, health program planners, and others to develop research goals, assess public health needs, set program priorities, and inform policymakers and the public.

More than half a million people in the United States have end-stage kidney disease, requiring frequent dialysis treatments or a kidney transplant. People with the disease account for just 1.2% of the Medicare population, but accounted for 7.3% of Medicare costs in 2007. The total cost for the disease was $35.32 billion, including coverage by Medicare and other payers, such as employer group health plans.

Drug Targets Large Brain Tumors in Mice

The drug vorinostat is able to cross the blood-brain barrier and reduce the development of large metastatic tumors in mice brains by 62% when compared to mice that did not receive the drug, according to a new study. In humans, the drug has been approved by the Food and Drug Administration for the treatment of a cancer called cutaneous T-cell lymphoma, but can be used experimentally to study its effectiveness against other cancers. This research, by investigators at the National Cancer Institute and their collaborators, appeared online Sept. 29, 2009, in Clinical Cancer Research.

For people, while various therapies are improving the survival of breast cancer patients, the incidence of breast cancer spreading to the brain is increasing. Brain metastases of breast cancer have proven to be largely untreatable because the blood-brain barrier, which arises from the specialized structure of blood capillaries in the brain, severely limits drug access, and many drugs are actively transported out of brain at this barrier. Consequently, the one-year survival estimate for breast cancer patients after a diagnosis of brain metastasis is only about 20%.

Vorinostat has been found to slow the growth of primary tumors of several different types of cancer in mice. Previous studies have suggested that the drug can be taken up by the brain, although little was known about its effects on metastatic tumors. Therefore, to study the effect of vorinostat on the formation of brain metastases, scientists used a mouse model of human breast cancer. Human breast cells were cultured in the laboratory, and were injected into mice with compromised immune systems. The breast cancer cells then migrated to the brain, forming metastases.

The researchers found that vorinostat was absorbed readily into normal mouse brains, and accumulation of the drug was up to three-fold higher in some metastases treated with this drug when compared to surrounding brain tissue. Vorinostat also reduced the development of tiny tumors (micrometastases) in mice by 28% when compared with mice that did not receive this therapy.

The ability of vorinostat to reduce metastatic lesions in the brain was linked to a novel double-barreled mechanism — the drug can cause breaks in both strands of a DNA helix and can also lower the activity of a DNA repair gene called Rad52. The researchers hypothesize that the inability of the cancer cells to repair DNA damage would then slow the rate of tumor cell metastasis.

In June of this year, several researchers affiliated with this study published a paper in Molecular Cancer Therapeutics showing that vorinostat could enhance the effect of radiation therapy in mice with brain cancer metastasis. Mice that received implants of human breast tumors in their brains lived the longest after treatment with both vorinostat and radiation, demonstrating that the drug enhances the sensitivity of cancer cells to radiation therapy. The researchers believe that this finding combined with the new study establish a preclinical basis for testing the drug in clinical trials in humans.

NIDCR Launches On Targeting Facial Defects Research

Although about half of all birth defects involve the face and skull, scientists remain unclear about why most occur. In an attempt to integrate available clinical information on facial birth defects, the National Institute of Dental and Craniofacial Research (NIDCR) issued the first 11 research and technology grants of its new FaceBase Consortium last month. The five-year initiative will systematically compile the biological instructions to construct the middle region of the human face and precisely define the genetics underlying its common developmental disorders, such as cleft lip and palate. The mid-face includes the nose, upper lip, and the palate, or roof of the mouth.

As a key part of the initiative, a one-stop, encyclopedic database of head and skull, or craniofacial, development will be created and maintained to allow scientists to mine the riches of the information enabling them to more rapidly and effectively generate hypotheses and accelerate the pace of their research. The database, called FaceBase, will be free and publicly accessible to the scientific community. Its organizers anticipate that FaceBase will have a prototype ready within the next year and a fully functioning database soon after.

The NIDCR began organizing FaceBase 2 years ago. The initiative builds on two broad organizing principles. The first is to encourage the formation of multidisciplinary research teams and then a higher level of integration into a consortium with the idea being that not every research problem will be or even can be solved with a single approach. Most will require a range of tools and expertise, allowing a more powerful research synergy to peel away the many layers of biological complexity and reach the essence of the question. The 11 grants announced today will support the FaceBase Consortium, a collection of collaborative research teams at various sites around the country.

The second is for each team to target its efforts at one specific aspect, or theme, of craniofacial development. This will allow the initiative to cast a more comprehensive research net that avoids duplication of effort. The research teams will coordinate their efforts through a designated FaceBase hub that manages data integration, data sharing and organizational needs.

Another essential aspect of the initiative is the FaceBase database, which will build on the lessons learned of other biology-focused databases but mold its content to the specific interests and needs of craniofacial researchers. That includes learning how best to house data on biochemical, molecular, genetic and imaging studies. It also includes learning how best to display thousands of visual images of tissue morphology, or shape, after a specific gene has been disrupted in zebrafish, mice, and other organisms, a standard approach to determine a gene’s function. These images then will be linked to molecular data from other studies and these datasets will be made available to the scientific community.

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FDA Issues Warnings to Makers of Topical Ibuprofen Products

The Food and Drug Administration issued warning letters to eight companies marketing unlawful over-the-counter topical drug products containing the pain reliever ibuprofen. The products, which contain ibuprofen in combination with a variety of other active ingredients and are marketed for pain relief, are unapproved new drugs that require an approved new drug application in order to be legally marketed.

Orally administered ibuprofen has been approved as a safe and effective treatment for pain and inflammation. There are no approved applications for topical ibuprofen products. Although the FDA has proposed to add orally administered ibuprofen to the applicable OTC monograph, it has never proposed that topical ibuprofen be added to any OTC monograph. Topical ibuprofen is often promoted as a “safer” alternative that can be used in place of oral ibuprofen because of certain side effects such as stomach ulcers and cardiovascular effects that are associated with prolonged use of oral ibuprofen. However, these safety claims for topical ibuprofen have not been reviewed by the FDA, nor has the agency evaluated what side effects might be associated with such products.

The names of the products and manufacturers that received warning letters are: Emuprofen, BioEntopic 15% Ibuprofen Crème, Ibunex Topical Ibuprofen, LoPain AF 15% Ibuprofen Crème, IB-RELIEF, Profen HP, IbuPRO-10 Plus, IBU-RELIEF 12. The FDA warning letters advise the companies that they may not continue to market their products without FDA approval. The FDA is requesting a written response from the companies within 15 business days of receipt of the warning letters stating how they will correct these violations and prevent similar violations in the future.

Accelerated Approval Given to Hib Booster

Last month, the Food and Drug Administration approved Hiberix, a Haemophilus influenzae Type b (Hib) vaccine, as a booster dose for children 15 months through 4 years old. Hiberix is manufactured by GlaxoSmithKline, with US headquarters in Research Triangle Park, NC, and Philadelphia.

A nationwide shortage of Hib vaccine began in December 2007 due to a voluntary recall by the manufacturer and subsequent production suspension of PedvaxHIB and COMVAX, two of four vaccines licensed in the United States for primary and booster immunization against invasive disease due to Hib. Both PedvaxHIB and COMVAX vaccines are manufactured by Merck & Co. Inc. (Whitehouse Station, NJ).

This shortage resulted in a recommendation by the Centers for Disease Control and Prevention to temporarily defer the Hib vaccine booster dose for children who were not at high risk for infection, until the vaccine supply could be restored. This deferral was in effect from December 18, 2007, through June 25, 2009.

According to FDA, the current vaccine supply is sufficient to reinstate the booster dose and begin catch-up vaccination, but is not yet ample enough to support mass vaccination of all children whose boosters were deferred. Before the availability of Hib vaccines, Hib disease was the leading cause of bacterial meningitis among children under 5 years old in the United States. Hib disease can also cause pneumonia, severe swelling in the throat, infections of the blood, joints, bones, and tissue covering of the heart, as well as death. Hib disease is spread through the air by coughing and sneezing.

Hiberix is used in nearly 100 countries. The FDA based its conclusion that Hiberix is safe and effective for use as a booster dose in certain children in the United States on data from seven clinical studies conducted in Europe, Latin America, and Canada that involved more than 1,000 children. As part of the approval, the manufacturer, GlaxoSmithKline, will conduct a post-market study in the United States to evaluate the safety and immunogenicity of primary and booster vaccination with Hiberix compared to a Hib vaccine already licensed in the United States. The study is intended to confirm the clinical benefit of booster immunization with Hiberix in accordance with the accelerated approval regulations, and to provide additional data on Hiberix for young infants.

Baby Boomers Continuing Drug Use Into Later Years

Many baby boomers (Americans born between 1946 and 1964) are continuing to use illicit drugs as they grow older, causing the rate of illicit drug use to go up within the 50-to 59-year-old age segment of the population. According to a new analytical publication produced by the Substance Abuse and Mental Health Services Administration, those aged 50 to 59 reporting use of illicit drugs within the past year has nearly doubled from 5.1% in 2002 to 9.4% in 2007, while rates among all other age groups are statistically staying the same or decreasing.

An Examination of Trends in Illicit Drug Use among Adults Aged 50 to 59 in the United States is the first in a series of new scientific reports being published periodically by SAMHSA’s Office of Applied Studies that will provided detailed analyses on important substance abuse and mental health issues challenging the nation.

The report analyzes many aspects of this phenomenon, including the types of illicit substances involved, different demographic and behavioral factors associated with higher rates of use, and other issues. The data used in the analysis comes from a wide range of sources including 16,656 respondents aged 50 to 59 participating in the 2002 through 2007 National Surveys on Drug Use and Health—the nation’s premier national public health survey of its kind. The full report is available on the web at

Researchers Sequence Exomes of Twelve People

In a pioneering effort that generated massive amounts of DNA sequence data from 12 people, a team supported by the National Institutes of Health has demonstrated the feasibility and value of a new strategy for identifying relatively rare genetic variants that may cause or contribute to disease. The proof-of-concept findings were published online last month in the journal Nature.

The new strategy involves isolating and sequencing all exons which are the parts of the human genome that contain the information needed to produce proteins, the building blocks of the body. The complete set of exons—referred to as the “exome” —makes up only 1% of the human genome. By selecting only the exome to sequence, the important information about an individual can be obtained at a much lower cost than sequencing a person’s entire genome. Assessment of the results of exome sequencing is based on knowledge of the genetic code and allows for a more informative interpretation of genetic variants. Using the exome strategy, like other methods of direct DNA sequencing, investigators also can detect rare variants that typically provide a stronger indication of disease susceptibility.

The research, conducted by scientists from the University of Washington in Seattle and Agilent Technologies in Santa Clara, CA, was funded by the National Heart, Lung, and Blood Institute, the National Human Genome Research Institute, and the Eunice Kennedy Shriver National Institute of Child Health and Human Development. It was carried out as part of The Exome Project, a program jointly managed by the NHLBI and the NHGRI that was established to develop, validate, and begin to apply a cost-effective, high-throughput approach for exome sequencing that can be deployed in large, well-phenotyped human populations.

To demonstrate the utility of their approach, researchers focused on the exomes of eight people (four Yoruba, two East Asians, two European-Americans), whose DNA had previously been characterized by the International HapMap Project. The HapMap Project was an effort that produced a comprehensive catalog of common human genetic variation across the human genome. In addition, the study included four unrelated people with Freeman-Sheldon syndrome, a rare inherited disorder caused by mutations in the MYH3 gene, to see if exome sequencing had the power to detect the MYH3 mutations known to exist in their DNA. The researchers began by shearing the 12 samples of genomic DNA into fragments and then using special probes to capture only those fragments that contained exons. The resulting 12 collections of exomes were then sequenced and analyzed. Altogether, the project determined 300 million bases of DNA sequence—the largest data set reported so far of human coding sequence produced by more advanced second-generation sequencing technologies.

Comparison of the exome sequences to the publicly available human genome sequence highlighted the sensitivity of this technique for detecting genetic variations, both common and rare. The investigators were able to identify a range of these DNA misspellings such as rare and common single letter variations known as single nucleotide polymorphisms, or SNPs, and insertions and deletions of sequences within genes.

From the DNA of the four people with Freeman-Sheldon syndrome, the researchers were able to pinpoint the causal genetic variant by applying a multi-step systematic strategy to filter out common variants and variants that were specific to each individual. The findings demonstrate that sequencing the exomes of a small number of unrelated individuals with a disorder that is due to a single gene can serve as a genome-wide scan for the causative gene. Within large population studies, the researchers suggest that exome sequencing could be used to uncover genes that contribute to the risk for more common, multigenic diseases such as diabetes or cancer.

Gene Therapy Patients Maintain Visual Improvement One Year Later

Three young adults who received gene therapy for a blinding eye condition remained healthy and maintained previous visual gains 1 year later, according to an August online report in Human Gene Therapy. One patient also noticed a visual improvement that helped her perform daily tasks, which scientists describe in an Aug 13 letter to the editor in the New England Journal of Medicine.

These findings emerged from a phase I clinical trial supported by the National Eye Institute and conducted by researchers at the University of Pennsylvania, Philadelphia, and the University of Florida, Gainesville. This is the first study that reports the 1-year safety and effectiveness of successful gene therapy for a form of Leber congenital amaurosis (LCA), a currently untreatable hereditary condition that causes severe vision loss and blindness in infants and children.

The three patients in the study—aged 22, 24, and 25—have been legally blind since birth due to a specific form of LCA caused by mutations in the RPE65 gene. The protein made by this gene is a crucial component of the visual cycle. The RPE65 protein is necessary for the production of a retina-specific form of vitamin A that is required for the light-sensitive photoreceptor cells to function. Mutations in the RPE65 gene prevent this production, which halts the visual cycle and blocks vision. The RPE65 disease offers an opportunity for treatment in that it leaves some photoreceptors intact. In this study, researchers pinpointed an area of intact photoreceptors in the retina of each patient. They injected healthy copies of the RPE65 gene under the retina in this area in an attempt to repair the visual cycle.

One year after the procedure, the therapy had not provoked an immune response in the eye or in the body. Though the patients’ visual acu

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NIH Takes Aim At Fragile X Syndrome

The National Institutes of Health has developed a research plan to advance the understanding of fragile X syndrome and its associated conditions, fragile X-associated tremor/ataxia syndrome and fragile X-associated primary ovarian insufficiency. Fragile X syndrome causes intellectual and developmental disabilities and results from a mutation in a gene on the X chromosome.

The plan puts forward goals to guide future research, setting research priorities for each of the conditions. One major priority of the plan is to investigate the biological processes underlying all three disorders, and how to better diagnose and treat them. Other priorities include studying how widespread the gene variations are in the population and investigating how the three conditions affect families.

Although the three disorders have very different symptoms, all result from variations in the same gene, known as the Fragile X Mental Retardation 1 (FMR1) gene. Full mutation of the gene means that cells do not produce a protein involved with communications between neurons in the central nervous system. The resulting disorder, Fragile X syndrome (FXS), occurs in approximately one in 2,500 births. People with FXS often have intellectual disabilities that range from mild to severe. They may also have emotional and behavioral problems, including attention problems, hyperactivity, anxiety, aggression, and autism or autism spectrum disorder.

People with a less dramatic change in the gene have what is called a pre-mutation, which increases their chance of having a child with FXS. These people may not have any apparent health problems or may have symptoms of Fragile X-associated tremor/ataxia syndrome or Fragile X-Associated Primary Ovarian Insufficiency.

To develop the plan, the NIH convened three working groups of experts, one for each of the conditions. Members of each group included experts from the scientific community, members of advocacy groups for individuals and their families affected by the disorders, and other federal agencies. The research plan identifies research goals for each of the three conditions, and outlines strategies for better diagnosis, treatment, and prevention of the three disorders.

The report also highlights ongoing research, including collaborative efforts from several NIH institutes: the NICHD, the National Institute of Neurological Disorders and Stroke, the National Institute of General Medical Sciences, the National Institute of Mental Health, and the National Institute on Aging. The NIH funds a network of centers devoted to Fragile X syndrome and its associated conditions, as well as studies by independent scientists. The release is available at

Genetic Variant Linked to High BP in African-Americans

A team led by researchers from the National Institutes of Health reported the discovery last month of five genetic variants related to blood pressure in African-Americans…findings that may provide new clues to treating and preventing hypertension. The effort marks the first time that a relatively new research approach, called a genome-wide association study, has focused on blood pressure and hypertension in an African-American population. About one-third of US adults suffer from hypertension. The condition is considerably greater in the African-American community, in which the condition affects 39% of men and 43% of women.

To produce their findings, researchers analyzed DNA samples from 1,017 participants in the Howard University Family Study, a multigenerational study of families from the Washington, DC metropolitan area who identified themselves as African-American. Half of the volunteers had hypertension and half did not. To see if there were any genetic differences between the two groups, researchers scanned the volunteers’ DNA, or genomes, analyzing more than 800,000 genetic markers called single-nucleotide polymorphisms.

The researchers found five genetic variants significantly more often in people with hypertension than in those without the condition. The variants were associated with high systolic blood pressure, but not with diastolic blood pressure or combined systolic/diastolic blood pressure.

In May, two major international studies used the genome-wide association approach to identify 13 genetic variants associated with blood pressure and hypertension in people with primarily European and South Asian ancestry. While each variant was associated with only a slight increase in blood pressure, that work found that the more variants an individual had, the greater his or her risk of hypertension. Two genes identified by one of those studies were also associated with blood pressure in the new study.

The researchers found that all of the five genetic variants associated with blood pressure were located in or near genes that code for proteins thought to be biologically important in hypertension and blood pressure. Previous research had implicated two of those genes in blood pressure regulation, and additional analyses revealed that all of the variants are likely involved in biological pathways and networks related to blood pressure and hypertension.

An existing class of anti-hypertension drugs, called calcium channel blockers, already targets one of the genes, CACNA1H. However, the additional genes may point to new avenues for treatment and prevention.

To follow up and expand upon their findings in African-Americans, the researchers scanned DNA from 980 West Africans with and without hypertension. The work confirmed that some of the genetic variants detected in African-Americans were also associated with blood pressure in West Africans.

Transmission Pattern Discovery May Help Prevent Rotavirus Epidemics

New vaccines have the potential to prevent or temper epidemics of the childhood diarrhea-causing disease rotavirus, protect the unvaccinated, and raise the age at which the infection first appears in children, according to federal researchers in a study last month. The findings were based on changing patterns of rotavirus transmission in the United States, where the disease is rarely fatal, and they have implications for combating epidemics in other countries where the death toll is much higher.

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Stem-Like Immune Cells Destroy Tumors in Mice

A new approach to stimulating immune cells enhances their anticancer activity, resulting in a powerful anti-tumor response in mice, according to a study by researchers at the National Cancer Institute. The work appeared online June 14, 2009, in Nature Medicine.

Researchers found that a subset of immune cells, T lymphocytes called CD8+ memory stem cells, were capable of mediating strong anti-tumor immune response. These potent cells were generated in the laboratory by stimulating anti-tumor T cells in the presence of drugs designed to mimic an important signaling pathway called Wnt, which describes a complex network of proteins whose interactions are essential during development and stem cell maintenance. Under the influence of Wnt, T lymphocytes acquired stem cell-like properties of multipotency and self-renewal; that is, they generated differentiating daughter cells while regenerating themselves when transferred back to mice from the lab. These stem cell-like qualities enabled tiny numbers of T cells (about 40,000 cells) to trigger the destruction of large melanoma tumors (containing about one billion malignant cells).

This therapy, in which mice received CD8+ T memory stem cells together with a tumor vaccine and an immune system stimulant known as interleukin 2, improved the survival of treated mice compared with similar treatments using other types of memory T cells.

Current clinical immunotherapies based on the transfer of tumor-specific T cells generated and expanded in the laboratory rely on the use of large numbers of tumor-specific T cells and have had beneficial but sometimes limited success. If confirmed in humans, the use of tumor-reactive CD8+ memory stem cells could reduce the numbers of tumor-specific T cells needed for successful immunotherapy, thus making this type of therapy easier to develop, so that more patients could benefit.

These findings mark the latest advance in the field of cancer immunotherapy using tumor-specific T cells, which researchers believe is moving from proof-of-concept to a promising treatment for patients with metastatic cancer.

Gene Variant Linked to Chemotherapy Resistance in Breast Cancer Patients

Researchers have found links between an individual’s genetics and their response to treatment with chemotherapy. The findings, by researchers at the National Cancer Institute and their colleagues, show how a genetic variant located in the SOD2 gene may affect how a person responds to the chemotherapy drug cyclophosphamide. Cyclophosphamide is used in the treatment of breast and other cancers.

The SOD2 gene produces a key protein that protects cells from damage by molecules known as reactive oxygen species, or free radicals. Reactive oxygen species are produced by normal cellular processes and the action of some chemotherapy drugs. The findings represent the first preliminary evidence pointing toward a mechanism and a potential biomarker for cyclophosphamide resistance in breast cancer patients. The study appeared online June 9, 2009, in Clinical Cancer Research.

Most genes in human cells are present in two copies—one inherited from the mother and the other from the father. These gene copies can vary from one another. Some variations in genes play an important role in how a gene is expressed or how its protein product functions.

The variant identified by the researchers in the SOD2 gene affects both the structure and the function of the encoded protein, an enzyme known as manganese superoxide dismutase (MnSOD), and it affects the ability of MnSOD to reach its proper location in the cell and its activity level. MnSOD normally functions inside cellular compartments known as mitochondria, and helps protect cells from damage caused by reactive oxygen species formed during cellular metabolism. Excessive levels of reactive oxygen species can be toxic to cells. Indeed, some anticancer drugs depend on increased production of reactive oxygen species to kill cancer cells. Furthermore, some studies have indicated that because MnSOD neutralizes reactive oxygen species, it can modify the effects of chemotherapy drugs. For example, in laboratory and animal models, increased activity of MnSOD protects cells against the toxic effects of doxorubicin, which is a widely used anticancer drug.

In the new study, the research team investigated whether the variation affected survival in two separate groups of women with breast cancer: 248 women in the United States and 340 women in Norway. Some of the women received chemotherapy, and some did not receive chemotherapy. The team first analyzed DNA from the women to determine which types of the SOD2 gene they had. The researchers found that, among patients who received chemotherapy, those who had one form had decreased survival, and those with another form had the poorest survival. In contrast, the genotype of SOD2 did not affect survival among those who did not receive chemotherapy.

Next, the team looked at the relationship between SOD2 genotype and the type of chemotherapy the women received. The data were analyzed according to which of three types of commonly used chemotherapy drugs were administered: doxorubicin, 5-fluorouracil, or cyclophosphamide. Both doxorubicin and cyclophosphamide generate reactive oxygen species in cancer cells during treatment. The researchers determined that the presence of a particular variant was associated with decreased survival of patients treated with chemotherapy regimens that contained any of the three drugs. However, the most significant effects were found with the drug cyclophosphamide. Women with a distinct variant form of SOD2 and who received cyclophosphamide-containing chemotherapy had the poorest survival.

The research team says more work is necessary to confirm these findings and to examine the precise mechanism by which a genotype influences the response of cancer cells to cyclophosphamide. The team plans to examine the influence of several variations on the resistance to other chemotherapies.

Common Autism Drug No Better Than Placebo, Study Shows

Citalopram, a medication commonly prescribed to children with autism spectrum disorders, was no more effective than a placebo at reducing repetitive behaviors, according to researchers funded by the National Institute of Mental Health. The study was published in the June 2009 issue of Archives of General Psychiatry.

The researchers say their findings do not support using citalopram to treat repetitive behaviors in children with ASD. Also, the greater frequency of side effects from this particular medication compared to placebo illustrates the importance of placebo-controlled trials in evaluating medications currently prescribed to this population.

Researchers in the Studies to Advance Autism Research and Treatment (STAART) network, funded by five NIH institutes, conducted a six-site, randomized controlled trial comparing the effectiveness and safety of using citalopram (Celexa) versus placebo to treat repetitive behaviors in children with ASD. The study included 149 participants, ages 5–17, who had autism, Asperger disorder, or pervasive developmental disorder-not otherwise specified (PDD-NOS).

After12weeksoftreatment,roughlyoneoutofthreechildreninbothgroups—32.9%ofthosetreatedwithcitalopramand34.2%thosetreated with placebo—showed fewer or less severe repetitive symptoms. “Adverse symptoms were common in both groups, probably reflecting common childhood ailments as well as the changing nature of symptoms associated with ASD,” noted Bryan King, MD, director of child and adolescent psychiatry at Seattle Children’s Hospital and lead author on the study, in a statement. However, reports of increased energy, impulsiveness, decreased concentration, hyperactivity, diarrhea, insomnia, and dry skin were more common in the citalopram group.

According to the researchers, the study results may challenge the underlying premise that repetitive behaviors in children with ASD are similar to repetitive and inflexible behaviors in OCD.

Aspirin and Anti-Clotting Drug Reduce Risk of Dialysis Access Failure

For the first time, a combination of aspirin and the anti-platelet drug dipyridamole, has been shown to significantly reduce blockages and extend the useful life of new artery-vein access grafts used for hemodialysis, according to a study by the Dialysis Access Consortium. The study, supported by the National Institute of Diabetes and Digestive and Kidney Diseases, was published in the May 21, 2009, New England Journal of Medicine.

Artery-vein access grafts, called arteriovenous grafts, fail most often due to narrowing of blood vessels at the graft site and subsequent clotting, which block the flow of blood. A blocked graft cannot be used for dialysis, and is a major cause of worsening health in dialysis patients. The DAC trial found that the combination treatment decreased the rate of loss of primary unassisted graft patency — the useful life of a graft before it becomes blocked the first time — by 18%, and the rate of developing significant stenosis by 28%, compared to placebo. Previous smaller clinical trials of anti-clotting therapies failed to show that these drugs improve AV graft patency, or that they could be used safely in dialysis patients.

A total of 649 participants with new AV grafts were recruited for the trial at 13 clinical sites in the United States, and were randomly assigned to treatment with dipyridamole plus aspirin or a placebo. The trial took place over a period of 5 years. NIDDK established the multicenter Dialysis Access Consortium in September 2000 to design and implement a series of randomized, controlled, clinical trials over a 5-year period to identify effective therapies to reduce the rate of graft and fistula failure in dialysis patients.

Injectable Form of Ibuprofen Approved for Use in Hospitals

The Food and Drug Administration last month approved Caldolor, the first injectable dosage form of the common pain medication ibuprofen, to treat pain and fever for patients unable to take oral medications.

Caldolor, manufactured by Cumberland Pharmaceuticals, Inc., Nashville, Tenn., will be available for hospital use only. It is approved to be administered in 400 mg to 800 mg doses, over 30 minutes, every 6 hours for acute pain. To treat fever, the drug is approved in a 400 mg dose administered over 30 minutes, followed by 400 mg every 4 to 6 hours, or 100-200 mg every 4 hours, as necessary.

In a clinical trial of 319 women who had undergone an elective abdominal hysterectomy, patients were less likely to request morphine for pain on an as-needed basis when administered Caldolor.

According to the product’s labeling, Caldolor should be used with caution in patients with congestive heart failure, kidney impairment, at-risk for blood clots, and those with a prior history of ulcers or gastrointestinal bleeding. When used in such patients, attention to using the lowest effective dose for the shortest time period is important to reduce the risk of serious adverse events. The drug has also been associated with high blood pressure, serious skin reactions, and serious allergic reactions.

The most common adverse reactions reported in the controlled clinical trials were nausea, flatulence, vomiting, and headache.

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Clinical Briefs

DNA Test for Two Types of HPV Approved

The first DNA test that identifies the two types of human papillomavirus that cause the majority of cervical cancers among women in the United States was approved last month by the Food and Drug Administration. The test, called Cervista HPV 16/18, detects the DNA sequences for HPV type 16 and HPV type 18 in cervical cells. Differentiating these HPV types gives healthcare professionals more information on a patient’s risk of subsequently developing cervical cancer. A positive Cervista 16/18 test result indicates whether HPV type 16, 18 or both types are present in the cervical sample.

The FDA also approved the Cervista HPV HR test, which is the second DNA test that detects essentially all of the high-risk HPV types in cervical cell samples. The Cervista HPV HR test uses a method similar to the Cervista HPV 16/18 test to detect the DNA sequences of these HPV types. In women age 30 and older or women with borderline cytology, the Cervista HPV 16/18 test can be used together with cytology and the Cervista HPV HR test to assess risk of cervical disease.

HPV is the most common sexually transmitted infection in the United States. The U.S. Centers for Disease Control and Prevention estimates that more than 6 million Americans become infected with genital HPV each year and that more than half of all sexually active women and men become infected at some time in their lives.

For most women, the body’s own defense system clears the virus and infected women do not develop related health problems. However, some HPV types can cause cell abnormalities on the lining of the cervix that later can become malignant. While there are many different types of HPV, types 16 and 18 cause about 70 percent of all cervical cancers.

Cervista HPV 16/18 and Cervista HPV HR are manufactured by Madison, Wis.-based Third Wave Technologies.

FDA Assesses Anthrax-Detecting Nanotech

The Food and Drug Administration has completed a “proof-of-concept” study of a test that quickly and accurately detects the presence of even the smallest amount of the deadly anthrax toxin. The proof-of-concept study developed by FDA researchers relies on a nanotechnology-based test platform built from tiny molecular-sized particles. This assay, the europium nanoparticle-based immunoassay (ENIA), was able to detect the presence of a protein made by the anthrax bacteria known as protective antigen (PA). PA combines with another protein called lethal factor to form anthrax lethal factor toxin, the protein that enters cells and causes toxic effects.

The researchers showed that ENIA is capable of detecting PA in quantities that are 100 times lower than current tests, such as the enzyme-linked immunosorbent assay (ELISA). Both the ELISA and ENIA rely on antibodies that have an affinity for the anthrax protein of interest.

The FDA test is a modifi ed version of ELISA, which is already commonly used to detect anthrax and other infections. The researchers call their new test “europium nanoparticle-based immunoassay,” because atoms of europium are key to the assay’s sensitivity.

The ENIA uses molecular spheres (called nanospheres) covered with thousands of light-emitting atoms of europium, which acts as a signal that PA is present. The CBER team further enhanced the signal by modifying the nanospheres so they held additional atoms of europium, making the test more sensitive.

The ENIA detected PA in 100% of samples of mouse plasma compared to 36.4% through ELISA.

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