Medicine Man

Medical Studies/Trials Young people are always encouraged to complete their education and postpone marriage and children to achieve more rewarding lifestyles.

However, a Penn State study found that for some young adults, getting married or living together and having children have provided positive benefits.

"In industrial countries, young people age 18 to 25 are expected to explore their identity, work and love by delaying marriage and parenthood," says lead author Alan Booth, distinguished professor of sociology, human development and demography. "It is believed that those individuals who fail to postpone these family transitions miss out on better career opportunities, make poor choices on partners, and may experience problems.

"However, our research has shown that early family choices may be a productive option for many young adults, especially those who are disadvantaged with respect to family income, parental education and structure, mother-child relationship, verbal ability, school attachment and delinquent behavior," he notes.

Booth, Elisa Rustenbach, graduate student in sociology, and Susan McHale, professor of human development and family studies, examined the family and personal characteristics of more than 8,000 young adults who participated in the National Longitudinal Study of Adolescent Health (Add Health). Half of the sample made an early family transition and half did not over a five-year period.

The researchers compared the depressive symptoms of those who made a transition with those who did not, and found very few differences in depressive symptoms between the two groups.

"The only exception was women who experienced a breakup of their live-in relationship. They were more likely to see an increase in depression compared to women who did not break up with the live-in partner or did not make a transition," Booth notes. Only 14 percent of those who made a transition were in this category.

The researchers selected depressive symptoms as a measure of wellbeing because they are associated with many types of adversity such as poor physical health, unemployment and harsh family relationships, and apply to males and females and people of all ages.

"The findings are even more remarkable when we take into account that young adults who transitioned into early families were more likely to come from low-income families, had parents with lower levels of education and likely lived in a household with one or no biological parents," Booth says.

In low-income families, teens may experience a divisive home environment and parents with poor parenting skills. Leaving to live together, marry or have children may provide an opportunity to escape from an unloving home and create a more positive family, according to the study.

The difference between men and women on early family transitions and protective family factors requires more study, however, he adds.

"Most research on emerging adulthood has been on college students," Booth notes. "Our study highlights the importance of study early family transitions in context, in light of the range of opportunities open to a person. Post-high school experiences of young adults are more diverse than popular belief, and early co-habitation or marriage and parenting may be productive for many young people, at least over the short haul."

http://live.psu.edu/

Medical Research News Many parents are convinced that the brains of their teenage offspring are different than those of children and adults.

New data confirms that this is the case. An article by Jay N. Giedd, MD, of the National Institute of Mental Health (NIMH), published in the April 2008 issue of the Journal of Adolescent Health describes how brain changes in the adolescent brain impact cognition, emotion and behavior.

Dr. Giedd reviews the results from the NIMH Longitudinal Brain Imaging Project. This study and others indicate that gray matter increases in volume until approximately the early teens and then decreases until old age. Pinning down these differences in a rigorous way had been elusive until MRI was developed, offering the capacity to provide extremely accurate quantifications of brain anatomy and physiology without the use of ionizing radiation.

Writing in the article, Dr. Giedd comments, "Adolescence is a time of substantial neurobiological and behavioral change, but the teen brain is not a broken or defective adult brain. The adaptive potential of the overproduction/selective elimination process, increased connectivity and integration of disparate brain functions, changing reward systems and frontal/limbic balance, and the accompanying behaviors of separation from family of origin, increased risk taking, and increased sensation seeking have been highly adaptive in our past and may be so in our future. These changes and the enormous plasticity of the teen brain make adolescence a time of great risk and great opportunity."

In an accompanying editorial, Elizabeth R. McAnarney MD, Department of Pediatrics, University of Rochester Medical Center, comments, "Finally neuroscientists are able to go under the '?leathery membrane, surrounded by a protective moat of fluid, and completely encased in bone?' to provide new insights into brain development. Changes in the brain during childhood and adolescent development that are being documented through exquisite imaging by Giedd and others hold the promise for the development of hypotheses about the potential origins of behaviors that we have observed clinically for years?."

"Novelty seeking/sensation seeking and risk taking," Dr. McAnarney continues, "is the basis for considerable growth during adolescence, as well as for the seemingly reckless behavior of some adolescents. Novelty seeking/sensation seeking and risk taking are topics of growing interest as adolescent brain development is defined better and as morbidity from adolescent risk taking mounts?.The implication of our growing knowledge of brain-behavior mechanisms of adolescent conditions should provide insights into the risk of particular adolescents for morbidity and mortality. Preliminary data are promising so that as we begin to understand the complexity of and specificity of each of these conditions, we shall be able to diagnose and treat conditions earlier."

The NIMH Longitudinal Brain Imaging Project began in 1989. Participants visit the NIMH at approximately two-year intervals for brain imaging, neuropsychological and behavioral assessment and collection of DNA. As of September 2007, approximately 5000 scans from 2000 subjects have been acquired. Of these, 387 subjects, aged 3 to 27 years, have remained free of any psychopathology and serve as the models for typical brain development.

Three themes have emerged from this and other studies in this new era of adolescent neuroscience. The first is functional and structural increases in connectivity and integrative processing as distributed brain modules become more and more integrated. Using a literary metaphor, maturation would not be the addition of new letters but rather of combining earlier formed letters into words, and then words into sentences and then sentences into paragraphs.

The second is a general pattern of childhood peaks of gray matter (frontal lobe, parietal lobe, temporal lobe and occipital lobe) followed by adolescent declines. As parts of the brain are overdeveloped and then discarded, the structure of the brain becomes more refined.

The third theme is a changing balance between limbic/subcortical and frontal lobe functions that extends well into young adulthood as different cognitive and emotional systems mature at different rates. The cognitive and behavioral changes taking place during adolescence may be understood from the perspective of increased "executive" functioning, a term encompassing a broad array of abilities, including attention, response inhibition, regulation of emotion, organization and long-range planning.

http://www.elsevierhealth.com/

Devices/Technology New evidence from a large randomized study is answering important questions about the best approach to percutaneous coronary intervention (PCI) in patients with a type of heart attack known as ST-segment-elevation myocardial infarction (STEMI).

In the study, drug-eluting stents outperformed bare-metal stents, and high-dose tirofiban, an anti-clotting medication, proved to be equally effective and have fewer side effects than the catheter lab standard, abciximab.

The study is being reported today in a Late-Breaking Clinical Trials session at the SCAI Annual Scientific Sessions in Partnership with ACC i2 Summit (SCAI-ACCi2) in Chicago. SCAI-ACCi2 is a scientific meeting for practicing cardiovascular interventionalists sponsored by the Society for Cardiovascular Angiography and Interventions (SCAI) in partnership with the American College of Cardiology (ACC). This study is also being simultaneously published online in JAMA: Journal of the American Medical Association.

"These findings may provide a robust scientific rationale for high-dose tirofiban as an alternative to abciximab in patients with STEMI," said Marco Valgimigli, MD, PhD, a cardiologist at the Cardiovascular Institute, Azienda Opedaliera Universitaria di Ferrara, Ferrara, Italy. "In addition, at mid-term follow-up our study did not confirm some of the safety concerns over the use of drug-eluting stents in patients with myocardial infarction. These findings are very reassuring, though we need long-term follow-up to rule out the possibility of late adverse events."

Drug-eluting stents -- which not only prop open the coronary arteries but slowly release medication that prevents re-narrowing of the arteries with scar tissue, or restenosis -- are widely used when PCI is performed for stable coronary artery disease. But many cardiologists use bare-metal stents when treating patients with heart attack because studies have reported conflicting results on the benefits of drug-eluting stents in this group of patients and have raised concerns over the risk of blood clotting inside the stent, or stent thrombosis. The new study has certain design advantages over previous studies, specifically its size and an enrollment and follow-up protocol that more closely reflects everyday clinical practice.

As for tirofiban and abciximab, both are in a class of medications known as glycoprotein 2b/3a inhibitors and prevent blood clotting by blocking hyperactivation of platelets. Tirofiban is an attractive alternative for several reasons: It is shorter-acting and is cleared from the body more readily than abciximab, it is less likely to cause a dangerous drop in the number of platelets in the blood, and it is far less expensive. However, previous studies have been too small or have used too low a dose of tirofiban to reach a definitive conclusion about which medication is better, Dr. Valgimigli said.

The new study, which involved 16 medical centers, enrolled 745 patients who were set to undergo PCI for STEMI. Patients were randomly assigned to an infusion of abciximab or high-dose tirofiban (25 microgram/kg) and, in a second round of randomization, to treatment with either uncoated or sirolimus-eluting stents.

To judge the effectiveness of tirofiban and abciximab, researchers examined electrocardiograms -- 722 of which were interpretable -- to determine the proportion of patients with at least a 50 percent return of the elevated "ST-segment" to its normal baseline. The results were equivalent in the two groups (83.6 percent in the abciximab group vs. 85.3 percent in the tirofiban group). In addition, there was no significant difference in the rate of major adverse cardiac events (MACE) -- a combination of death, repeat heart attack, and repeat procedure to open the treated coronary artery -- in the two groups: 4.8 percent vs. 4.5 percent, respectively, at 30 days and 12.3 percent vs. 9.9 percent, respectively, at eight months. The rates of minor and major bleeding did not differ in the two groups, but a marked drop in the blood platelet count -- a complication that could cause uncontrolled bleeding -- was more common among patients treated with abciximab (4.0 percent vs. 0.8 percent, p=0.004).

When comparing the two types of stents, investigators found an equivalent MACE rate at 30 days (3.9 percent vs. 5.9 percent, p=0.12) with sirolimus-eluting and bare-metal stents. However, at eight months, the MACE rate was significantly lower with drug-eluting stents (7.8 percent vs. 14.5 percent, p=0.0039). This difference was mainly driven by a 69 percent reduction in the need for a repeat procedure to reopen the treated coronary artery (3.2 percent with sirolimus-eluting stents vs. 10.2 percent with bare-metal stents, p=0.0004). The rates of death and repeat heart attack were similar, as was the incidence of stent thrombosis.

"Our study shows that tirofiban is 'noninferior' in its efficacy to abciximab in this high-risk patient population, and has a better safety profile," said Dr. Valgimigli. "We have also confirmed that, even in STEMI patients, drug-eluting stents are highly effective in reducing reintervention in the target vessel. More important, this came without an extra price to pay in terms of death, myocardial infarction or stent thrombosis."

Dr. Valgimigli will present the results of this study on Sunday, March 30 at 9:00 a.m. CDT in the Grand Ballroom, S100. This study will simultaneously publish in JAMA: Journal of the American Medical Association.

About SCAI

Headquartered in Washington, DC, the Society for Cardiovascular Angiography and Interventions is a 4,000-member professional organization representing invasive and interventional cardiologists in over 60 nations. SCAI's mission is to promote excellence in invasive and interventional cardiovascular medicine through physician education and representation, and advancement of quality standards to enhance patient care. SCAI's annual meeting has become the leading venue for education, discussion, and debate about the latest developments in this dynamic medical specialty.

About ACC

The American College of Cardiology is leading the way to optimal cardiovascular care and disease prevention. The College is a 34,000-member nonprofit medical society and bestows the credential Fellow of the American College of Cardiology upon physicians who meet its stringent qualifications. The College is a leader in the formulation of health policy, standards and guidelines, and is a staunch supporter of cardiovascular research. The ACC provides professional education and operates national registries for the measurement and improvement of quality care.

http://www.acc.org

Medical Science News While pondering the challenges of distinguishing one nanosize probe image from another in a mass of hundreds or thousands of nanoprobes, two investigators at Emory University and the Georgia Institute of Technology made an interesting observation. The tiny, clustered dots of light looked a lot like a starry sky on a clear night.

The biomedical researchers realized that astronomers had already made great strides in solving a problem very similar to their own-isolating and analyzing one dot (in this case, a star) in a crowded field of light. They hypothesized that a computer system designed for stellar photometry, a branch of astronomy focused on measuring the brightness of stars, could hold the solution to their problem.

Now, May Wang, Ph.D., at Georgia Tech, and Shuming Nie, Ph.D., and their collaborators have created a technology based on stellar photometry software that provides more precise images of single molecules tagged with nanoprobes, particles specially designed to bind with a certain type of cell or molecule and illuminate when the target is found. The clearer images allow researchers to collect more detailed information about a single molecule, such as how the molecule is binding in a gene sequence, taking scientists a few steps closer to truly personalized and predictive medicine as well as more complex biomolecular structural mapping. In addition to biomedical applications, the system could be used to clarify other types of nanoparticle probes, including tagged particles or molecules. Their research appears in the Proceedings of the National Academy of Sciences of the United States of America (PNAS).

"As more powerful imaging technologies are developed, scientists face a real challenge to quantitatively analyze and interpret these new mountains of data," said Wang. "This paper is only a start, but I expect that innovative computing and data processing will be increasingly used to reveal detailed and quantitative features not currently available to biomedical researchers."

"This work is pointing to a new era in light microscopy in which single-molecule detection is achieved at nanometer resolution," added Nie. "This is also an example of interdisciplinary research in which advanced computing meets nanotechnology. I envision major applications not only for single-molecule imaging but also for ultrasensitive medical diagnostics."

Because scientists frequently use several different colors of nanoprobes to color-code genes and proteins, a blended color dot is a common challenge when analyzing images. For every few green or red dots in an image, there could be a few yellow dots as well, indicating that at least two dots are clustering to create the appearance of a new color. Although less than precise nanoprobe images yield valuable information, the Georgia Tech and Emory research team knew that better technology was needed to pinpoint the exact distance in nanometers between probes to reveal important information about the size and binding geometry of targeted molecules.

"We had no way of knowing for sure if we were looking at one molecule or two or three molecules very near one another," said Wang. "The fuzzy dot images were not precise enough on the nanometer level to truly tell us how these markers reflect DNA, but this system allows us to collect quantitative data and prove-not hypothesize-how genes are behaving."

Instead of starting from scratch to create a system to isolate the clumped nanoprobe images, the Georgia Tech and Emory researchers pursued their stellar photometry idea by adapting DAOPHOT, a program written by Peter Stetson, Ph.D., at the Dominion Astrophysical Observatory, which was designed to handle crowded fields of stars. After adapting DAOPHOT, the research team used color-coded nanoparticles to beat the traditional diffraction limit by nearly two orders of magnitude, allowing routine superresolution imaging at 1-nanometer resolution. And by using DNA molecules, two color-coded nanoparticles are designed to recognize two binding sites on a single target. Then the particles are brought together within nanometer distances after target binding.

These distances are sorted out by highly efficient image processing technology, leading to the detection and identification of individual molecules based on the target's geometric size. Compared with other single-molecule imaging methods, the Georgia Tech and Emory system allows for higher speed detection involving much larger sample volumes (microliter to milliliters).

This work, which was supported in part by the NCI's Alliance for Nanotechnology in Cancer, is detailed in the paper "Nanometer-scale mapping and single-molecule detection with color-coded nanoparticle probes." An investigator from Georgia State University also participated in this study. This paper is available through open access at the journal's Web site.

View paper

http://nano.cancer.gov

Medical Science News Small pieces of nucleic acid, known as siRNAs (short interfering RNAs), can turn off the production of specific proteins, a property that makes them one of the more promising new classes of anticancer drugs in development. Indeed, at least two siRNA-based anticancer therapies, both delivered to tumors in nanoparticles, have begun human clinical trials. Now, three new reports highlight the progress that researchers are making in developing broadly applicable, nanoparticle-enabled siRNA anticancer therapeutics.

In the first report, Mark E. Davis, Ph.D., an investigator in the Nanosystems Biology Cancer Center at the California Institute of Technology, and former graduate student Derek Bartlett, Ph.D., now at the City of Hope, used mathematical modeling and results from dosing experiments in a mouse model of human cancer to explain therapeutic response with various dosing regimes for both targeted and untargeted siRNA-containing nanoparticles. The results of this work, published in the journal Biotechnology and Bioengineering, provide guidelines for optimizing the design of siRNA-based anticancer therapies.

In their experiments, the investigators used a cyclodextrin-based nanoparticle to deliver an siRNA agent designed to reduce production of ribonucleotide reductase subunit M2 (RRM2), which plays an important role in tumor growth. The investigators created two versions of their nanoparticle formulation, one targeted to transferrin, a protein overexpressed by many tumors, and the other untargeted. They also used two different dosing regimens, one consisting of three consecutive daily injections, the other consisting of three injections spaced 3 days apart.

Data from these experiments showed that targeted nanoparticles were far more effective than untargeted nanoparticles at reducing tumor growth. Dosing regimen, however, had no statistically significant impact on the outcome for either nanoparticle formulation. Closer examination of tumors removed from the animals following treatment showed that the targeted nanoparticles were able to deliver siRNA into the tumors, although the final distribution of siRNA throughout the tumors was not uniform. The investigators then modeled the observed responses; the results of these simulations led them to conclude that it is not necessary to persistently shut down protein production in order to achieve a therapeutic response using siRNA. Instead, they concluded, it is more important to maximize the number of cells reached with a sufficient dose of siRNA agent.

In a second report, Leaf Huang, Ph.D., and his colleagues at The University of North Carolina at Chapel Hill, describe their development of a self-assembling siRNA-liposomal formulation that they can then coat with poly(ethylene glycol) (PEG) linked to a targeting agent. This targeted liposome was fourfold more effective than an untargeted, but otherwise identical, liposome at delivering siRNA into tumors. Gene silencing activity was also higher for the targeted version, with the therapeutic effect lasting 4 days. The investigators also found that although the targeted nanoparticle effectively penetrated lung metastases, it did not enter liver cells. In addition, the targeted nanoparticle showed little immunotoxicity. These results appear in the Journal of Controlled Release.

Another paper published in the same journal, this one from Stefaan De Smedt, Ph.D., and his collaborators at Ghent University in Belgium, describes a method that could prove useful in both preclinical and clinical studies of nanoparticle-enabled siRNA therapeutics. Their new technique uses fluorescence fluctuation spectroscopy to measure the stability of these formulations, even at low concentrations, in human serum in less than 1 minute. Serum stability of siRNA-containing nanoparticles is essential to therapeutic efficacy, given that most studies have shown that naked siRNA has little effect on tumors. Using this method, the investigators were able to show that even PEGylated siRNA-containing liposomes were releasing the bulk of their cargo in serum.

The work from Drs. Davis and Bartlett, supported by the NCI's Alliance for Nanotechnology in Cancer, is detailed in the paper "Impact of tumor-specific targeting and dosing schedule on tumor growth inhibition after intravenous administration of siRNA-containing nanoparticles." An abstract of this paper is available through PubMed.

View abstract

The work from Dr. Huang's group is detailed in the paper "Efficient gene silencing in metastatic tumor by siRNA formulated in surface-modified nanoparticles." An investigator from Hokkaido Pharmaceutical University also participated in this study. An abstract of this paper is available through PubMed.

View abstract

The work from Dr. De Smedt and colleagues is detailed in the paper "A fast and sensitive method for measuring the integrity of siRNA-carrier complexes in full human serum." Investigators from the University of Leuven (Belgium) also participated in this study. An abstract of this paper is available through PubMed.

View abstract

http://nano.cancer.gov