|T H E N I H C A T A L Y S T||J U L Y A U G U S T 2006|
A Poster Day Sampler of 9 from among 200+
POSTBACS EXPLORE PATHWAYS TO DISEASE, APPROACHES TO TREATMENT.
All in the Family
Aixa Alemán-Díaz, University of Michigan, Ann Arbor
The Role of Family and Culture in Health Decision Making: A Conceptual Model
During the past year, Alemán-Díaz and Koehly have developed a protocol to study how family interactions affect the sharing of accurate health information and health-promoting behaviors.
The study will focus on multigenerational Latino families living in the United States. Several members of each familytypically the parents and grandparents of young childrenwill be asked about their family social structure and their perceptions of common health problems such as diabetes and heart disease. The same family members will then complete a Family Health History (FHH) tool, such as the CDC's Family Healthware!", which will assess risk for various diseases based on genetic, environmental, and behavioral factors.
Upon completing the FHH, participants will be told of their disease risk based on family health history and given tips for disease prevention based on behavioral assessments.
The researchers are interested in what happens next, when the participants go back to their families armed with this new information. They will do two follow-ups, at several weeks and six months after the administration of the FHH, to look for changes in perceptions of what causes common diseases and their own risks of disease, as well as changes in health-related attitudes and behaviors.
Importantly, says Alemán-Díaz, they want to focus not just on individual family members but on how the information affects the entire family system.
For example: Has the family changed the way it shares information about health issues or makes health-care decisions? Have family members developed a more accurate picture of their risk of disease based on what the study participants learned about their risk? Have family members made lifestyle changes to reduce their disease risk?
This study is part of a larger effort to understand how family relationships influence health perceptions and decision making. Studies on other demographic groups are in the works, says Alemán-Díaz, who graduated from the University of Michigan in Ann Arbor in 2005 and plans to study cultural anthropology and public health in graduate school.
She will stay at NHGRI through this fall and help put her protocol into action working with families in the Houston, Texas, area in partnership with the University of Texas M.D. Anderson Cancer Center.
Shaan Alli, Baruch College, City University of New York
Circadian Rhythm of Pro-inflammatory Cytokines in Rheumatoid Arthritis
Patients with rheumatoid arthritis (RA), an autoimmune disease that causes pain, swelling, and stiffness in the joints, often observe that their symptoms are worst in the early morning.
Work by Alli and Goldbach-Mansky in collaboration with Marc Blackman's group at NCCAM suggests that this phenomenon may be associated with natural daily variations in cortisol, a steroid hormone produced by the adrenal gland that can suppress the immune system.
Secreted at high levels in stressful situations, cortisol increases blood pressure and blood sugar and suppresses the production of some inflammatory agents of the immune system. Aside from stress-related spikes, cortisol levels exhibit a circadian rhythmpredictably low in the middle of the night and peaking in the morning.
Alli and his colleagues hypothesized that the secretion of hormones might be influenced by the hyperactive immune system of RA patients and contribute to the development of their signs and symptoms. So they collected blood from RA patients and healthy control subjects at 20-minute intervals for 24 hours and measured the levels of several hormones and inflammatory molecules that might contribute to RA symptoms: TNF-a, GM-CSF, IL-8, and IL-6.
In both patients and control subjects, all four molecules showed a circadian variation, with the highest levels occurring in the early morning near the end of the low-cortisol period.
Although analysis of their data is ongoing, one interesting finding, says Alli, is that RA patients had significantly higher levels of IL-6 levels in the early morning than did control subjects, suggesting that cortisol might be important to keep IL-6 levels in check in RA patients. In general, RA patients had higher levels of immune mediators than control subjects at all times of day, but the differences were often not statistically significant.
The correlation between daily fluctuations in cortisol and RA symptoms fits in nicely with clinical data showing that steroid hormones similar to cortisol are often an effective treatment for RA, says Alli. Future studies on the behavior of the immune system in RA patients, he adds, might do well to take into account the time of day that samples are collected.
Kamun Chan, Bard College, Annandale-on-Hudson, N.Y.
Effects of Prolactin Over-expression on the Progression of Breast Cancer
Chan has been studying breast tumor development in Vonderhaar's lab since August 2005. Her research concerns the complex and poorly understood relationship between the hormone prolactin and the development of breast cancer. Prolactin promotes breast milk production and is secreted in large amounts by the pituitary gland in pregnant and breastfeeding women. Prolactin is also made locally by breast tissue and breast cancer cells.
In addition, the Nurses' Health Study at Harvard University, Boston, showed that pre-and postmenopausal women with the highest serum prolactin levels have an increased risk of developing breast cancer.
To explore this dynamic on a cellular level, Chan designed a system to overexpress prolactin in four cell lines that represent different stages of breast cancer development normal breast tissue, preneoplastic (some oncogenes have been activated but the tissue has not yet succumbed to the uncontrolled proliferation of full-blown cancer), invasive breast cancer, and metastatic breast cancer. Chan can control whether or not prolactin is overexpressed in her cells by adding the antibiotic doxycycline to the culture medium.
Chan plans to stay in the lab for another year to continue her project. Now that her system is ready to go, she will test how prolactin affects cell proliferation and cell motility, which is necessary for cancers to metastasize. Then she will inject her prolactin-overexpressing cells into mice and look at the aggressiveness of any resulting tumors. She hopes eventually to tease out the cellular signaling pathways that prolactin uses to influence tumor growth.
Chan is also a fellow in the NIH Academy, a program that aims to educate young researchers about health disparities in the United States. In addition to conducting her research, she has been participating in workshops and seminars on how and why disease and health care differ among population subgroups in this country.
Immunity to Hepatitis C
Brittany Holmes, University of ColoradoBoulder
Immunological Memory in Hepatitis C: A Comparison of Treatment-induced Recovery and Spontaneous Recovery
Hepatitis C, a liver disease caused by an RNA virus (HCV), spreads from person to person through contact with infected blood or blood products. Occasionally, people who contract hepatitis C recover spontaneously, especially if they are "young, lucky, and female," says Holmes, who has been studying the disease in Rehermann's lab since last October.
In most cases, however, HCV causes chronic hepatitis, and treatment with interferon and the antiviral drug ribavirin is necessary to stamp out the infection. If left untreated, HCV infection can cause liver failure or liver cancer.
Interestingly, people who fend off HCV on their own develop an immunological memory of the virus, so that if they encounter HCV again, T cells optimized to kill the virus are rapidly activated. People who require treatment to be cured appear not to develop this population of protective memory T cells. Holmes aimed to understand why.
She mixed immune cells from patients who had recovered spontaneously from hepatitis C with HCV proteins and saw a vigorous immune response. T cells proliferated and began to secrete interferon-g, an important weapon in the immune system arsenal.
When she did the same experiment with immune cells from HCV patients who recovered after treatment, she got a much weaker response. There was no difference between patients who were treated within the first six months of contracting the virus and those who were treated later, she says.
She found that T cells from both untreated and treated patients were able to respond to many different pieces of HCV, but in each case the response in the untreated cohort was more intense. The immune response of the treated patients fell shorter in "strength, not breadth," she observes.
Before she heads to Nashville, Tenn., to Vanderbilt Medical School in the fall, Holmes will continue her research from a couple of new angles.
She will explore whether genetic differences in HLAs, immune system molecules that help recognize foreign invaders, affect the ability to recover from HCV without treatment, as well as whether the frequency of spontaneous recovery varies with different HCV strains.
Sickle Cell Strategies
Vicki R. McGowan II, University of Maryland, Baltimore County
Clinical Evaluations in Sickle Cell Disease: A Story in Three Acts
Sickle cell disease is a genetic disorder that causes red blood cells, normally doughnut-shaped, to become rigid and misshapen. These abnormal cells obstruct blood vessels and are prone to rupture, causing an array of health complications, including anemia, chronic renal failure, stroke, and pulmonary hypertension. There is no cure for the disorder. Effective management of sickle cell complications relies on addressing symptoms early.
Pulmonary hypertension (increased blood pressure in the artery leading from the heart to the lungs) is a major complication of sickle cell disease. The most accurate test currently for measuring pulmonary hypertensionright heart catheterizationis invasive and therefore less than ideal for use in frequent monitoring. McGowan is exploring the value of two less-invasive alternatives for routine monitoring of pulmonary hypertension.
McGowan's team measured serum lactate dehydrogenase (LDH) levels taken from 213 sickle cell patients and ranked them into three groups: low, medium, and high. LDH is usually present in serum only when cells rupture, a characteristic of sickle cell disease. Seventy percent of patients with high levels of LDH also had pulmonary hypertension, suggesting that "LDH shows promise as a marker for hemolysis in sickle cell patients and may suggest a risk of pulmonary hypertension," says McGowan.
The team also demonstrated the value of echocardiography in assessing pulmonary hypertension. Tricuspid valve regurgitant jet velocity (the speed at which blood flows back into the atrium through the tricuspid valve), as measured by echocardiogram, correlated well with pulmonary pressures measured directly by right heart catheterization and with patients' performance of a timed six-minute walk used to assess cardiopulmonary function. These results bolster previous findings that echocardiography is a reliable means of measuring pulmonary hypertension.
A third area of her work involves the design of a clinical trial to further study benefits of treating sickle cell disease with a combination of hydroxyrurea and erythropoietin two drugs that typically are administered independently but were reported by NIDDK's Griff Rodgers in a 1993 article in the New England Journal of Medicine to have a synergistic effect.
The "essential goal is to extend [Rodgers'] findings," says McGowan, who begins medical school this fall at the Virginia College of Osteopathic Medicine in Blacksburg.
Binging and Weight Gain
Margaret Mirch, Cornell University
Effects of Binge Eating on the Energy Intake, Satiation, and Satiety of Overweight Children during Buffet Meals
The percentage of overweight children in the United States has tripled since 1980. Overweight children who binge-eat gain more weight and fat mass than overweight children who do not exhibit this tendency. It is speculated that external stimuli, such as the sight and smell of food, motivate binge-eaters to consume food beyond satiation. Mirch's research explores the role binge-eating plays in the developmental progression of obesity.
Mirch's lab conducted an experiment to assess energy intake and satiety duration of overweight children and to examine the contribution binge-eating behavior plays in food consumption. Study participants were overweight children, ages 6 to 12. Each participant completed two surveys: One addressed eating and weight patterns; the other was a 57-item food-preference questionnaire.
After an overnight fast, the children were presented with a 27-item food array and told, "Let yourself go and eat as much as you like. You may eat as much of anything that you would like to, but you do not have to eat anything you do not like." The duration of the meal and the calories consumed were recorded. To establish the duration of satiety, participants were asked to refrain from eating or drinking until they reported the onset of hunger.
On the second day, after an overnight fast, participants consumed a standardized breakfast consisting of a 500-cc shake containing 787 kcal. Again, the satiety duration was recorded. After reporting hunger onset, the children were presented with a second buffet identical to the one of the previous day. Again, calories consumed were recorded. Immediately before and after food was presented, participants were asked to rate on a visual analog scale their hunger, their desire to eat, and their fullness.
Overweight children who exhibited binge-eating behavior had a significantly greater desire to eat and, when given access to large quantities of palatable food, consumed more calories than children who did not binge. The study also showed that binge-eating children feel hungry sooner than their non-bingeing counterparts.
"Training children to attend to physical hunger signals" rather than sensory cues, Mirch says, might be a way to slow weight gain in children with binge-eating tendencies.
More studies are needed to elucidate the "behavioral, genetic, and neurohumoral mechanisms" that may account for deficits in appetite regulation among binge-eating children, she adds.
Mirch plans to continue her work in nutrition science this fall when she enters Boston University's graduate program in nutrition.
Shrikant Tele, University of Maryland, College Park
The Development of Multifunctional Liposomes with Targeting, Imaging, and Triggered Release Properties
Most anticancer drugs are good at killing cancer cells, but they can also wreak havoc on healthy tissues. Encasing drugs inside a protective lipid particle and targeting the particle directly to the tumor would go a long way toward increasing the efficacy and decreasing the toxicity of chemotherapy, says Tele, who has been developing this technology with Blumenthal and Puri.
Tele is working on two aspects of drug delivery using lipid particleshow to target the particle to the tumor, and how to get the particle to release its contents once it gets there. The route of delivery of the lipid particle is determined by the targeting ligand(s) and the biophysical properties of the liposomes.
To get the particles to congregate at the site of the tumor, Tele plans to decorate the outside of the particles with specific antibodies that bind to molecules found only on the surface of tumor cells. Each type of tumor will probably require a different antibody, he says.
At first he will use the anti-HER2-neu antibody, which recognizes a growth factor receptor expressed by about one-third of breast cancers. He will also experiment with anti-HER2-neu Affibodies (TM)", commercially available molecules that function like antibodies but are smaller and easier to handle.
Liposomes "dump their payload" upon temperature regulation, says Tele. The particles they use hold together very well at body temperature (37 degrees C) but disintegrate at slightly higher temperatures (4142 degrees C). He plans to use a focused ultrasound device for local heating of breast cancer tissue.
To help during the development and testing stages, Tele has incorporated dyes into the particles so they can be tracked inside the body with imaging equipment. After several attempts, he found a dye that doesn't adversely affect the structure of the particles or their temperature-dependent breakdown. He plans to continue his stay and this research for another year, after which he hopes to go to graduate school.
April Timberlake, Harvard University
The Relationship between Temperament, Autistic Traits, and Cognitive Functioning in a Sample of Typically Developing Children and Adolescents
People with autism spectrum disorders (ASD) have difficulty communicating, interacting socially with others, and adapting to change. ASD now affect about 0.30.6 percent of the population and are becoming more common, says Timberlake, a 2005 Harvard graduate who came to NIH last October to study social cognition with Giedd.
ASD cover a wide rangefrom the relatively mild behavioral and pragmatic speech abnormalities of people with Asperger's syndrome to the odd, repetitive behaviors and very limited speech and social interaction observed in people with severe classical autism.
Studies have shown that people with ASD have problems with specific skills, such as strategizing, planning, and shifting attention back and forth among tasks that are collectively called executive functioning. The brains of people with autism also look a little unusual in MRI studiesfor example, they have less gray matter than normal in the temporal lobes.
Because ASD comprise a spectrum of conditions, conceptually this continuum could be extended down to the general population. Timberlake wanted to know whether autistic traits in typically developing people are associated with ASD-like findings in executive functioning and brain structure. Also, because ASD disproportionately affect males, she asked whether males were generally more likely than females to have many autistic traits.
Timberlake worked with a group of 88 typically developing children, half male and half female, from ages 8 through 18. Their parents filled out the Social Responsiveness Scale (SRS), a 65-item questionnaire that assesses social and communication skills and flexibility; the children underwent tests for executive functioning and an MRI to look at brain structure.
Timberlake emphasizes that the study "needs more power"the number of subjects was too small and the analysis of brain structure too rough to glean very many statistically significant results. She is working to overcome these limitations.
But, she notes, there were a few significant findings and many interesting trends. Children with poorer communication skills on the SRS tended to do less well on the executive functioning tests. Children with high SRS scores (many autistic traits) had reduced gray matter in the right temporal lobe. Finally, boys on average had higher SRS scores than girls.
Such findings suggest that autistic traits in typically developing children are associated with executive dysfunction and some group-level brain differences, as observed in ASD, says Timberlake, who begins medical school in the fall.
Bone Density Blues
Caitlin Toomey, Cornell University
Is Major Depression Associated with Decreased Bone Mineral Density? A Comprehensive Meta-Analysis of All Published Studies
More than 1.5 million osteoporotic fractures occur annually in the United States, many requiring hospitalization. Low bone mineral density (BMD), usually determined by dual-energy X-ray absorptiometry, is viewed as a major risk factor for osteoporosisand several studies have suggested a link between major depression and low BMD.
To assess the evidence in support of a link between low BMD and depression, Toomey conducted a meta-analysis of data from 16 studies that compared BMD in depressed individuals and nonde-pressed controls. Some of these studies used DSM (Diagnostic and Statistical Manual of Mental Disorders) criteria to define depression; others relied on less stringent methods, such as the Geriatric Depression Scale, which Toomey says are not as reliable.
BMD values from the antero-posterior spine (AP spine), the total femur, and the femoral neck were analyzed. Overall analysis showed that in all three anatomic areas, BMD was significantly lower in depressed subjects.
When the data were limited to studies that used DSM criteria, BMD values of the total femur and AP spine of depressed patients were even lower than those in the broader analysis described above. There was no similar reduction in the femoral neck BMD in subjects whose depression was diagnosed by DSM criteria. Toomey notes, however, that because this data subset included far fewer subjects, the findings should be interpreted with caution.
In addition, Toomey analyzed a subset of data derived from studies that examined BMD in men and found that only total femur BMD was lower in depressed subjects than in their nondepressed counterparts. No difference was detected in the AP spine or femoral neck BMDs in depressed men versus men without depression. Again, because the numbers were relatively small, Toomey urges caution in interpretation. "We think there probably is some effect in men, but not as large" as that in women, she says.
The results of this meta-analysis do support a correlation between major depression and low BMD, Toomey says, but further studies are required to elucidate the exact nature of the relationship. Toomey's group speculates that people with major depression fail to reach optimal peak bone density, which is usually established by age 30.
Meanwhile, she adds, patients with low BMD might well be screened for depression, and patients diagnosed with depression might well have their BMD evaluated. Toomey starts medical school this fall at the Vanderbilt University School of Medicine in Nashville.
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