Seminar Recap: Sex Dependent Neurotoxicity of Ambient Ultrafine Particulate Matter

Between its contributions to heart disease, stroke, lower respiratory infections in children, and chronic obstructive pulmonary disease, air pollution plays a big role in our health. In fact, the World Health Organization believes that air pollution contributes to over 7 million premature deaths annually.

Joshua Allen, Ph.D.

Joshua Allen, Ph.D.

“So they’re really making this firm statement now that air pollution is the largest single environmental health risk,” said Joshua Allen, Ph.D., research assistant professor of environmental medicine.

But the health risks don’t end there, as there are now close to a dozen studies linking autism and schizophrenia to early air pollution exposure. Hoping to expand on these findings, Allen is now studying how the ultrafine particles (UFPs) that accompany air pollution into the lungs can affect the growing brain.

His work has shown significant differences between how these UFPs affects neonatal male and female mice. He shared his results at the CTSI Seminar Series on Women’s Health on Oct. 28.

UFP study

To administer his study, Allen collected air using a device that draws in 5,000 liters of air per minute, and  concentrating it 10- to 20-fold. The resulting enriched air contained approximately 200,000 UFPs per cubic centimeter, or about the same amount present in the air around an active expressway.

He then exposed neonatal mice to the UFP-enriched air, and used a variety of tests to measure their neurological development.

In one learning test, the mice were rewarded with food after pressing a sequence of levers. Normally-developing mice would improve their test accuracy over time, but that didn’t happen for the male mice exposed to the UFP-enrich air. During the test, if they pressed an incorrect lever, a light would turn off, shutting the reward system down temporarily.

“What’s really interesting in males is that they don’t stop responding,” said Allen. “The whole box shuts down, and for a normal animal, you would expect the response to then stop, because they would never be reinforced when the lights areoff. But the males didn’t stop. They just kept whaling away on the levers.”

This effect adversely impacted their ability to learn, and also had implications for impulsivity. Allen said that it wasn’t his intention to study how the exposures affected males and females differently, but rather that the data pushed him in that direction.

Conclusions and future directions

Ultimately, both males and females did show some neurological damage after exposure, but males were significantly more sensitive to the UFP-enrich air.

“We think the protection in females is probably related to differences in microglia colonization, and it might be a testosterone-mediated mechanism,” said Allen.

Allen is now following up on several other studies that have shown certain types of air pollution, such as diesel exhaust particles, can affect males and females differently. He’s also looking at early-life air pollution exposure in humans and looking at whether home location correlates with the onset of the autism.

“This was all very surprising to us,” said Allen. “We didn’t start out as experts in this type of thing, and we’re learning as we go, but given the links between autism and air pollution, we want to know more about this topic.”

Preventive Medicine residency: Flexible and faith-restoring

As part of its Population Health pillar, the CTSI is supporting a resident in the University of Rochester General Preventive Medicine and Public Health Residency program. The Preventive Medicine Residency, which is within the Department of Public Health Sciences, places an emphasis on epidemiology andpopulation health skills, as well as the skills needed to improvedelivery of preventive healthcare to individuals.  The training program is at its core multi-disciplinary with residents itslearning by completing work central to the mission of numerousdepartments both inside and outside the Medical Center. These include the URMC Department of Patient Safety and Quality Improvement, the Center for Community Health, the National Center for Deaf Health, the Monroe County Department of Public Health and the American Cancer Society.

Elizabeth Helm, M.D., M.P.H

Elizabeth Helm, M.D., M.P.H

Elizabeth Helm, M.D., M.P.H., recently completed her Preventive Medicine residency, and spoke with CTSI Stories about her experiences.

Can you give a brief overview of the residency?

Part of the 2-year program is a Masters in Public Health, which definitely gave me a better appreciation of the health care system, epidemiology in general, and the changes from the Affordable Care Act.

Another core components of the residency are the practica rotations, including two required rotations. One is at the County Department of Health, which was a 3-4 month rotation, and that was incredibly useful. We learned about the resources available to the public in terms of immunization, tuberculosis, STD screening, treatment, and so on. It’s important as a physician to know what types of things are available to people, especially those without insurance, but I didn’t really know about all ofthose services from any previous curriculums.

The second required rotation is quality improvement, which lasted about 3 months. From that, I got a much better understanding of how quality improvement works within individual practices and a hospital system, as well as the governing bodies that require these quality improvements. We did this rotation on quality improvement with Dr. Panzer. It was eye opening to me because I didn’t realize that a lot of this stuff is mandated by CMS and Medicaid services. So if we want to remain accredited, these quality improvement projects aren’t optional. More importantly, quality improvement projects allow us to take better care of our patients and help others do so as well, potentially with less effort as system changes can make our jobs easier by providing automatic reminders or minimizing the likelihood that a human error gets through to a patient.

Aside from those two, the rest of the rotations are flexible?

Yes, and that ties into one of the most important things I want to share about this residency: The administration is incredibly supportive. Whatever you want to get out of this, they will help. For example, my co-resident really wanted to do occupational health and ended up focusing many of her elective rotation around this subject (which is a sister specialty to Preventive Medicine focusing on the different types of workers as individuals and populations) For me, that didn’t end up being as much of an interest, but I got to focus more on global health. In fact, I did my thesis on a global health issue, regarding the diet of pregnant women in Tibet, analyzing data collected by Tim Dye, Ann Dozier, Nancy Chin and others at the medical center and in Tibet.

So what other rotations did you end up selecting?

I did do one in occupational health, where we learned how people’s exposure at work can relate to their health, and how you can use the workplace as an opportunity to provide health care teaching and health screenings and things like that.

I did a rotation at Passport Health, a travel clinic run by the University of Rochester School of Nursing,which is where people go before they go abroad. When I came to URMC, I knew from the beginning that I wanted to live and work abroad,so that rotation helped me because it helped familiarize me with the health risks in various countries.

I also did a rotation at the American Cancer Society, which helped me understand nonprofits, how they function, and some of the extremely useful work that goes into it.

Another favorite rotation was at the Center for Community Health. I learned a lot about community engagement and enjoyed the opportunity to teach medical students about how to keep involved with community health improvement efforts throughout their careers.  I also spent time at the Healthy Living Center learning how to apply Self-Determination Theory to help people quit smoking, lose weight and follow healthly lifestyle habits under the direction of Geoff Williams, M.D., Ph.D and his staff.

Finally, I also enjoyed my mini-rotation at the National Center for Deaf Health.  I learned a ton about the barriers that the Deaf face in learning about healthy lifestyle habits let alone obtaining quality health care.

When you started, you already had a residency in family medicine. Why did you decide on a residency in preventive medicine as well?

When I finished my family medicine residency, I did kind of struggle with whether I should do this because I was already boarded in one thing. But, at that point, I was really burnt out clinically — I wasn’t loving the day-to-day work, because it seemed really constrained by the system. So I thought this would be a great opportunity for me to get more of a big-picture look, and that maybe a better understanding of the system would help me appreciate the day to day more. And I do think it really broadened my perspective on health care in general and what some of the problems were, and how we can work on solutions even in small units and in individual practices.

It really helped me renew my faith in the health care system, because I saw how big and complicated it is. Instead of being frustrated at how quickly I had to see patients, or how limited I was in addressing their issues, I saw that there’s a lot going on behind the scenes, and change is slow because the system is so big, so you can’t just get frustrated. You’ve got to work with what’s available instead of saying “The system doesn’t work.” Because it’s the system we live in, so we all have to make the best of it.

Who would you recommend this program to?

For medical students I would say that if you know you’re interested in a broad picture — in treating a population rather than an individual — this might be a good fit for you, especially if you’re finding the day-to-day clinical work frustrating. And for people who have done a clinical residency, like I did, then I’d recommend it for those who want to have a good understanding of clinical research and epidemiology and public health interventions, and how you can improve the health of a community, not just the health of your patients.

Seminar recap: Unwanted pregnancy — A high-risk perinatal condition?

Obesity, diabetes, high blood pressure, tobacco use — there are a variety of reasons that a pregnancy can be classified as “high risk.”

But one factor that isn’t currently considered by most healthcare providers is whether the pregnancy itself is wanted to begin with, and data collected by the Perinatal Data System suggests that it’s something that healthcare providers may want to start taking into account.

Tim Dye, Ph.D.

Tim Dye, Ph.D.

Tim Dye, Ph.D., Professor in the Department of Obstetrics and Gynecology, and director of biomedical informatics at the CTSI, shared data from an analysis of the Perinatal Data System, which includes several hundred thousand pregnant women from the 22-county region of the Finger Lakes and Central New York. The seminar, which took place on Tuesday, Oct. 14, was part of the CTSI Seminar Series on Women’s Health.


Dye began studying the topic in the 90’s, when New York State began funding the Perinatal Data System. As part of the completion of a birth certificate, women were asked a standardized question “Thinking back to just before you were pregnant, how did you feel about becoming pregnant?” Based on responses from the approximately 300,000 live births that Dye and his team have currently sorted in the upstate New York registry:

  • 65 percent of live births were intended at conception, meaning the woman wanted to become pregnant when she did, or even sooner.
  • 28 percent had mistimed pregnancies, meaning they’d wanted to become pregnant, but not until later in life.
  • 7 percent were unwanted pregnancies, meaning they did not want to become pregnant at the time of conception, or at any point in the future.

The 7 percent of unwanted pregnancies represented approximately 20,000 women, giving a large enough sample size for Dye’s team to make some associations. After parsing the data, Dye found that the strongest statistical relationships to unwanted pregnancies were women who live in poverty, women with lower educational levels, and women at both extremes of the age spectrum (under 17, or over 40).

Women with pre-existing medical conditions, such as hypertension, diabetes, or other chronic illnesses, were also more likely to have an unwanted pregnancy.

“So it’s probably the women who are least likely to be able to financially deal with having an unwanted pregnancy who are the most likely to have one,” said Dye.

Additionally, women with unwanted pregnancies are also more likely to have maternal infections. They were also more likely to have a pre-term birth.


Many people assume that those with unwanted pregnancies are less likely to have or seek prenatal care, said Dye. But this isn’t actually true, as Dye’s statistics showed that 98 percent of women with unwanted pregnancies do have some amount of prenatal care.

This means that most women are encountering healthcare professionals at some point before they give birth. But despite the suggestive data about the various risks, women with unwanted pregnancies were actually no more likely to be referred for high-risk care than were other women.

“We certainly see that pregnancies unwanted at conception that result in a live birth are different from other pregnancies,” said Dye. “So it could well be a marker for pregnancy that might lead to different kinds of complications, exposures, and risks.”

For many factors, we don’t fully understand why this is the case yet, said Dye. But since it’s not a variable that is even assessed at intake all the time, unwanted pregnancies aren’t often dealt with clinically at this point.

Said Dye: “That may be something that providers should start thinking about.”

CTSI Pilot Program: Exploring a new bladder cancer treatment

Approximately 75,000 people each year are diagnosed with bladder cancer, making it one of the most common cancers in the United States.

But for a variety of reasons, therapies have lagged behind.

Elizabeth Guancial, M.D.

Elizabeth Guancial, M.D.

“The outcomes have not improved in 30 years,” said Elizabeth Guancial, M.D., assistant professor of medicine, hematology/oncology. “For the most part, we use the same treatments that we did in the 70’s and 80’s.”

Guancial is hoping that she’s on the verge of a new potential treatment. Working alongside Shu-Yuan Yeh, Ph.D., she is testing therapies that involve targeting the estrogen receptor, which could potentially be administered as adjuvant treatment for those at risk for developing metastatic disease after their bladders have been removed.

Their research, which began over the summer, is supported by a CTSI Pilot Grant.

Guancial and Yeh’s research focuses on the patients who have a dangerous form of muscle-invasive bladder cancer, which can spread to other organs. These patients represent about 30 percent of those with the disease, and they are usually treated through surgical removal of the organ, which helps to keep the cancer from spreading.

Shu-Yuan Yeh, Ph.D.

Shu-Yuan Yeh, Ph.D.

Ideally, these patients would receive chemotherapy in the aftermath to prevent the cancer from returning. But many patients with bladder cancer are older and have other medical problems, said Guancial. If they are too sick for chemotherapy, then their outcomes are far worse — these patients see their cancer returning about 50 percent of the time.

Should Guancial and Yeh’s hypothesis prove correct, hormone therapy could be a potential treatment for these post-op patients.

“I don’t think that estrogen therapy could shrink down a tumor. I wouldn’t expect it to kill any cells,” said Guancial. “But it may be able to modulate the ability for bladder cancer to grow or metastasize to other sites.”

Bladder cancer can be tough to study in the mouse model since the organ is so tiny, making the implantation of cancer cells challenging. But Yeh has previously studied bladder cancer in mice, and has developed a method of study that does not include the risk of perforating the organ through surgery.

The CTSI Pilot Grant is allowing Guancial and Yeh to research the effects in mice in the hopes of generating data that would support an R01 application.

“There are important strengths in this Pilot Study,” said Richard Moxley, M.D., associate director for funding programs at the CTSI. “The investigative team is multidisciplinary and experienced in the methodology, the investigator has a strong mentor, and they are pursuing a very interesting hypothesis that suggests different roles for the estrogen receptor subtypes in the pathomechanism that underlies bladder cancer.

“If the mouse model and cell model data in these experiments prove promising, these findings are very likely to stimulate new therapeutic strategies in humans with bladder cancer.”

Guancial believes that human trials could proceed relatively quickly, if the treatment is proven effective in mice. The drugs that would target the estrogen receptor are already commonly used in patients with breast cancer, meaning they wouldn’t need to go through their own FDA approval.

“That kind of paves the way,” she said. “If this works within mice, we can think about moving on to people.”

Seminar recap: Reproductive Issues in People with Epilepsy

For those with epilepsy, the impact of the condition stretches far into other parts of their lives, affecting, among other things, their reproductive health.

Men with epilepsy have decreased sperm counts, and their sperm have abnormal morphology and impaired motility, making it harder for them to father children. Women, meanwhile, have higher rates of menstrual disorders due to their endocrine dysfunction, the type of epilepsy that they have, and they tend to have higher rates of polycystic ovary syndrome, due in part to the effect of epilepsy medications.

Lynn Liu, M.D.

Lynn Liu, M.D.

On Oct. 7, Lynn Liu, M.D., associate professor of neurology, pediatrics, and anesthesia at URMC, spoke at the CTSI Seminar Series on Women’s Health, sharing her experience treating patients with epilepsy who are attempting to have children, and offering directions for future studies.

Variety of issues

Before discussing hormonal issues, Liu mentioned the myriad obstacles that patients with epilepsy face.

Due to their condition, people with epilepsy are often barred from driving. This makes it tougher to get a job, putting many of them in lower economic brackets. Often, they live with family members, who are able to take care of them if and when they have a seizure.

“But if they’re not working, they feel overprotected by their family who feel obliged to take care of them, and they become more and more isolated,” said Liu.

These factors combine to raise the likelihood of mental health issues, which are borne out both in practice, and in the statistics — at least 30 percent of people with epilepsy have a mood disorder or some sort. They are also 10 times as likely to take their own lives.

They’re also less likely to marry, and more likely to divorce, said Liu, though she cautioned that this can depend on their age of epilepsy onset.

Physiological differences also exist, due to the release of hormones that occurs during seizure. Estrogen and progesterone levels are altered, which can affect fertility. Prolactin, a necessary hormone for sexual gratification, is also released during seizure, causing many patients with epilepsy to not have enough when they are intimate.

Treatment and other areas of need

Even if women are able to become pregnant, they must deal with the worry that they could have a seizure and fall, injuring the developing child. Seizure during delivery is also a concern; Liu recommends that her pregnant patients be reassured that a Caesarean section could be possible.

In the meantime, there are a variety of medications available to pregnant women with epilepsy. The challenge for both physicians and their patients is to find the right balance of medication that controls the seizures and doesn’t harm the fetus. Seizures themselves can cause birth defects, so they need to be controlled as much as possible, but medications can have side effects.

For example, said Liu. “All women of childbearing age should be on folic acid anyway, but “many of our seizure medicines have anti-folic properties,” so women with epilepsy especially should take folic acid.”

Various studies are currently being done on how much folic acid is appropriate, Liu said that data isn’t yet available on the ideal amount.

And while there are a few treatments available for men with epilepsy who are experiencing sexual dysfunction, there hasn’t been much research done on what can be done for women.

Said Liu: “It’s a lot harder of a question and an area worthy of a lot of exploration, because we don’t have a tremendous amount of options for women who have sexual dysfunction and decreased gratification.”

Director’s Update – October 2014

Every month, the CTSI Stories Blog will post excerpts from ongoing conversations with the institute’s co-directors.

Below, Harriet Kitzman discusses team science in the academic medical center, and how the Collaborations & Services pillar of the CTSI is supporting research collaboration.

Tell me a little bit more about team science in an academic medical center.HarrietKitzman2

There has been a transformation in the scientific community about the importance of teams in the development of solutions to our most complex problems. However, in many ways, the culture of academic medical (and health science) centers are yet to be aligned structurally with the ever increasing functions of teams.  We still are preparing through education and research training, for the self-sufficient independent scientist role. Similarly, academic reward systems have historically centered on the independent contributions of the scientist, many of which are difficult to identify in fully functioning collaborative science teams where novel ideas and approaches come not from individuals but from the synergy that emerges when dynamic ideas are integrated.

What is of interest is that teams in science are growing, often with little regard for the science of the process of doing team science. The science of team science (which is concerned with understanding and managing environmental conditions that support or hinders team science initiatives), is in many ways in its infancy. Although there is a long history of the study of small groups in the social sciences, and developing teams in business and health services, there is limited utilization of what has been learned in those fields to team science in academic health centers. More importantly, despite our understanding of the frequency with which fledgling teams fail, there are few projects that are focused on trying to understand why some fail and others are productive and sustained – the science of team science. The emerging complexity of teams will require us to focus on the functional aspects as well as the outcomes.  If we are to succeed, we will need to uncover the dynamic organizational patterns, socio-political climate, individual and groups functions that drive successful collaboration in team science. Our studies in the science of team science will need to be multi-level and utilize novel as well as accepted methods.

So understanding team science is the first step. What DO we know about it? 

Well, there was one study recently — Steve Dewhurst wrote about it in the Democrat & Chronicle — that talked about how the best team science combines novelty and conventionality. So a successful scientific team often is one that uses conventionally-accepted methods, but does so across disciplines to solve a new problem.

We already have a few programs in place that promote team science — the funding for the Incubator Program, for example, has always had a requirement for team science. Now, we’re studying some of the other things that go on here. For example, the SRB Data Blitz! — Tom Fogg has been the one developing that — we’re trying to measure outcomes of those events so we can do things systematically and determine what works.

How about the “Services” part of the “Collaborations & Services” pillar?

We are retaining services such as the Research Navigator and other programs that already exist within the CTSI under this pillar, and we’re working to enhance those services through other channels. Because regardless of how many navigators we have here, there needs to be something that directs researchers to the program, and the researchers themselves need to know that it can provide them with some assistance.

Going back to that study that Steve Dewhurst wrote about, an interaction with the CTSI is often a more formal or conventional type of relationship. It’s a contrast to the informal structures and interactions — the conversations that researchers have with others in different fields that they don’t always interact with — that really drives the novelty portion of team science. So while the Research Navigator Program gets the questions answered, it’s the more informal connections that actually create those new questions.

Previous director’s updates:

September 2014 – Karl Kieburtz talks about why the CTSI is beefing up its informatics team.
August 2014 – Nana Bennett discusses the new Population Health pillar.
July 2014 – Harriet Kitzman offers her takeaways from the Mini Summer Research Institute.
June 2014 – Karl Kieburtz gives an overview of the CTSI’s six pillars.

Seminar Recap: Studies in Uterine Fibroids

Most tumors, when discovered, are dealt with quickly — through removal, chemotherapy, or otherwise.

But uterine fibroids, benign in all but the rarest of circumstances, present an opportunity for researchers.

Donna Baird, Ph.D.

Donna Baird, Ph.D.

“Usually, when you find a tumor, you want to take it out,” said Donna Baird, Ph.D., principal investigator, epidemiology, for the National Institute of Environmental Health Sciences. “Fibroids are one of the rare times when you can look at tumor growth and describe it.”

Baird, a guest lecturer at the CTSI Seminar Series on Women’s Health on Sept. 30, shared her research on uterine fibroids, outlining her current work and offering new directions for future studies.

What we know

Uterine fibroids are smooth muscle tissue tumors which grow in the uterus of a majority of women in the middle to late reproductive years. They are extraordinarily common — in the United States, 70 percent of white women and 80 percent of African American women develop uterine fibroids at some point — and most of them are asymptomatic, with many women never realizing that they have them.

But some fibroids do grow to the point where treatment is necessary. Historically, uterine fibroids have been the leading cause of hysterectomies in the United States.

“So it’s a major health problem,” said Baird.

There are a handful of established risk factors — women in their middle-to-late reproductive years are most likely to develop fibroids, African Americans are at higher risk than white Americans, and early age of menarche and nulliparity also increase risk. But since uterine fibroid development is so common, simply measuring incidence may not provide much information about preventing development of disabling symptoms that are treated with major medical procedures, said Baird.

So, in a recent study, Baird’s group instead decided to focus on fibroid growth, enrolling 116 pre-menopausal women with clinically-relevant fibroids and measuring fibroid growth via MRIs over the course of a year.

While there was a wide variety of fibroid growth and shrinkage during the study period, the fibroids in the majority of women grew only a small amount — an average of 9 percent every six months.

Baird also found in a later study that about a third of fibroids seen at the beginning of pregnancy actually disappeared by 4 months after birth, consistent with their hypothesis that parity is protective because tumor tissue will be cleared during the process of postpartum uterine remodeling.

Current study

Since the publication of the growth study, Baird has begun a new study which involves a cohort of 1,696 African American women aged 23-34 in the Detroit area. Her group is following the women for five years and screening with ultrasound every 20 months to identify new fibroids and follow growth of already existing fibroids. They are testing whether Vitamin D could be a preventative in terms of fibroid development.

“If it were found to be effective, it would be wonderful — it’s cheap and it’s easy,” said Baird. “Of course, we have lots of other questions. For example, there’s an interesting hypothesis that heavy bleeding actually causes fibroids.”

They’re also hoping to identify other potential factors that put certain women at higher risk for growing fibroids. Through prevention, Baird and others are hoping to make a dent in the more than $6 billion spent on this understudied women’s health condition each year.

Said Baird: “I think down the road, this is what can happen, and there can be much less surgical treatment and many fewer hysterectomies.”