So much has changed for the better in the quarter century since infectious disease specialist and Professor of Medicine Christopher Grace, M.D., and his colleagues founded the network of Comprehensive Care Clinics (CCC) that serve people with Human Immunodeficiency Virus throughout Vermont.

Twenty-five years ago, patients with HIV/AIDS contracted disfiguring and deadly infections and cancers, suffered terribly, and were doomed to die. The human toll on the patients, most of whom were still young, and on their loved ones was catastrophic. Mostly they needed hospice care, or a plan that included it eventually. Today they need job training and routine cholesterol checks. Their future has been altered in that most of them now have a future.

“I never used to ask when they’d gotten their last tetanus shot,” says Deborah Kutzko, A.P.R.N., of her HIV-positive patients at Fletcher Allen’s Comprehensive Care Clinic, for whom tetanus was low on the list of concerns. “Now we’re doing tetanus shots and mammograms and colonoscopies because we fully expect them to live a normal lifetime.”

“That’s been the biggest change in HIV practice,” says Kemper Alston, M.D., professor of medicine and director of infection prevention at Fletcher Allen, “the shift from a traditional hospital-based, hospice-based illness model to more of a social one.” Behind that change is the significant advancement in medications that control the level of the Human Immunodeficiency Virus. While in the early years of the epidemic patients had to take fistfuls of pills several times a day —
sometimes 30 to 40 daily pills laden with highly toxic medications — the advent of protease inhibitors in 1996 led to the development of highly active antiretroviral treatment (HAART).

“That was a game changer,” says Grace, who in addition to directing the CCC is director of the Infectious Disease Division at the College of Medicine and Fletcher Allen. “It’s almost like a switch was turned, and outcomes changed.” As a rule, today’s patient only needs to take one pill, once a day. The drawback is that the medications cost in the range of $22,000 to $28,000 per year. Most insurances cover some or all of that, but for patients faced with a 50 percent copay or those without insurance, the Ryan White Care Act fills the gap.

“There is virtually nobody in our clinic who should be on drugs who isn’t because they can’t afford it, which is truly wonderful,” says Kutzko.

The goal of the program in 1987 was to develop a model of care for those with a complex, deadly, and socially-stigmatizing disease that could be delivered in a rural state such as Vermont, where the level of medical expertise was limited. The team felt that the direct personal relationship between the patient and the care team was key, so the model used a specialty
outreach design that focused on bringing the expertise to the patient in their own community. The clinic program is actually four clinics, specifically placed in each of Vermont’s geographical quadrants. The initial clinic was established in 1987, about five years after the first reported case of the disease in Vermont, and is located in the Fletcher Allen Infectious Disease division in Burlington; it’s still the largest of the four. The three satellites are in Rutland (founded in 1994), Brattleboro (1995), and St. Johnsbury (1996).

The idea behind the clinics was to bring medical care to the patients, so that, for example, a Bennington patient who called in with uncontrollable diarrhea wouldn’t have to make the nightmarish drive all the way to Burlington or Albany or Boston to be seen by medical personnel.

“We created a ‘medical home’ before the term was invented,” says Grace, surrounding the patient with all points of care that he or she might need, including doctors, nurses, social workers, psychiatrists, and dieticians. The word cocoon comes up frequently in conversations about the clinics. The clinic nurse is on site at each of the satellite clinics. The clinic physicians, psychiatrist, and dietician drive to the satellite clinics monthly, while working with the clinic nurse by phone between visits. These clinic days can be long ones, with round trips of 200 to 300 miles in addition to the hours spent providing care to a full day’s schedule of patients. Vermont winters add to the challenge of making this model of care work.

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Funding for the expanded clinics came from a 1994 Special Projects of National Significance (SPNS) grant under the Ryan White HIV/AIDS Program through the U.S. Health Resources and Services Administration. Grace and Kutzko spent two years planning the clinic program, which entailed patient and hospital surveys, data collection, grant writing, innumerable meetings with AIDS service organizations, local hospitals, administrators, patients, and patient advocacy groups. The hospitals were very supportive, and more than willing to provide space for the clinics, generally located within other departments, partly for purposes of confidentiality. They named them the Comprehensive Care Clinics because they knew patients might shy away from an “HIV Clinic.” Grace and his colleagues have published their results, which show that the model provided the same expert care to rural Vermonters with HIV as they would have received in any urban university program.

“We certainly had HIV/AIDS patients here in the community,” says Tom Huebner, Rutland Regional Medical Center CEO, “and we had internists and family practitioners dealing with it, but they didn’t have the level of expertise that was needed, so we said yes almost immediately.”

Northeastern Vermont Regional Hospital’s CEO Paul Bengtson echoes that sentiment. “Without a lot of fanfare, it was set
up and running pretty quickly,” he says, noting that the only real concern expressed was by patients, who were worried about confidentiality. at has not proved to be an issue.

In Burlington, the clinic was initially housed in the oncology department at University Health Center.

“We were at the very end of a hall, which was perfect,” says Kutzko, since the majority of patients hadn’t even told their families and friends of their HIV-positive status. “We had our own little waiting room, and people would just hang out. We tried hard to make it a safe place.” Many of those patients were wasting, covered with Kaposi’s sarcomas, but they were treated warmly by the staff, who joked with them and were welcoming.

“That’s what you have to do when you’re treating a bad disease with toxic medicine,” says Grace. “You have to create that welcoming atmosphere.”

In addition to a clinician and a nurse practitioner, each clinic is staffed with a social worker. New patients routinely meet with the nurse practitioner and social worker before seeing a physician, which was a fairly unique approach to care. Both Kutzko and the team social workers have sat in primary care physicians’ waiting rooms so they could be on hand when patients were given HIV diagnoses.

“A lot of ground work is done before a new patient comes in to see the doc,” says Grace. “We wait until some of the social and psychiatric issues are stabilized before we even see them, because if they’re not stabilized then they’re not going to take their meds.”

Once the proper medications have been successfully established, ideally patients only need to be seen every four to six months. There are those who visit more often, particularly for help with psychosocial issues.

“I always looked at my job as handling barriers to care: what do we need to do to make sure that person comes back for the next appointment?” says Ellen Postlewaite, M.Ed., the Burlington clinic’s social worker from its inception until her retirement earlier this year. Some of the more common barriers included issues around money, insurance, transportation, and the anticipated stigma, as well as a sense of resignation in the early days of “What can they do for me since I’m going to die anyway?” she says. In addition, many patients had pre-existing psychiatric issues, while others suffered reactive depression in response to their diagnosis.

A psychiatric nurse practitioner and a dietician were brought on board to round out the team — the two now travel to each of the satellite locations monthly. Postlewaite also routinely helped patients get community support from various AIDS service
organizations, con rmed that they were set with insurance or some form of coverage, and that they had needed social support.

“In the beginning, I tell people that if you choose to talk to someone, make it someone who has the ability to support you,” says Postlewaite, adding that there are still plenty of patients who don’t feel comfortable talking about HIV and AIDS outside the clinic walls. Kris (not his real name) is one such individual. After testing positive in 2000 he waited three
years before telling his family. They all live locally, and he didn’t want the news to adversely affect the family’s reputation.

“There’s a lot more education now about how HIV does not equal AIDS does not equal death,” says Kris, 39, but at the same time he feels there’s still plenty of ignorance on the part of the general public. He thinks many at-risk Vermonters aren’t getting tested because they don’t understand that HIV is still something to be concerned about. “‘Oh, HIV. Isn’t that taken care of? Don’t we have that cured yet?’ Those are words people have said to me,” says Kris, explaining that, while he wants to educate people, “as soon as I step out and say something, then I’m the poster child. I want to believe that the stigma is over, but once I take that step, it’s all over. I don’t want HIV to be why people are looking at me.”

Gary Barto is another CCC patient; he’s been seeing Dr. Grace since 1992, and he and his wife, Susan, helped with hospital administration training services when the Rutland clinic was getting going. Gary Bartos helped deliver a primer on HIV patient care to doctors and nurses on staff there. “They were going to be the hand holders,” says Gary, “and they needed to know that it was safe to hold hands.”

The couple speak candidly about Gary’s infection (“I can be open about it in certain circles,” he says, “but it’s not something I run around broadcasting”), in part because he didn’t fit the patient stereotype. He says he doesn’t know how he contracted the virus — he’s not “the one people think of” — and was shocked when he tested positive 11 days before the couple’s wedding. Susan has accompanied Gary to every appointment at the clinic, which Kutzko says is common. “We have a lot of partners and even parents who come to visits,” she said, “and we try to make family members feel comfortable coming to clinic if the patient wants them there.”

The question of an HIV-positive patient “profile” is part of the reason new cases go undetected, often for years. So one of the goals of the clinics’ medical teams is to encourage primary care doctors to routinely test for HIV, rather than waiting until all other possible avenues have been considered. Kutzko describes a new patient who exhibited classic HIV symptoms, including swollen lymph nodes and significant weight loss, but who nevertheless wasn’t diagnosed by his doctors for five years.

“It’s not something they think about,” she says. “There’s this myth that we don’t have HIV here in Vermont, or it’s just too embarrassing to ask the question.” Others might be concerned that their patients will feel judged, or that assumptions are being made about their lifestyle choices. Grace maintains that in areas where HIV is not prevalent, it is just not on physicians’ radar. He and his colleagues want to change that. The Centers for Disease Control standards recommending routine testing for everyone between the ages of 16 and 64, as a matter of standard medical care, will help.

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Deborah Kutzko has been the driving force behind a protocol that encourages local obstetricians to routinely test pregnant
women; Fletcher Allen now has a policy that every woman who comes to the hospital to deliver must be tested.

According to Kutzko, roughly 17 percent of the CCC’s patients are women, and to date, no pregnant woman in their care has given birth to an HIV-positive infant. That’s because after the first trimester, every HIV-positive mother-to-be is given enough medication to get her viral load down to an undetectable level. Newborns are continued on medications, administered at six-hour intervals for one month, and then tested intermittently until 18 months.

Tanya (not her real name), 42, an alcoholic, was pregnant with twins when she learned she was HIV positive. Like Gary Barto, she didn’t fit the profile, so even though she’d been sick before her pregnancy and undergone extensive blood tests and the removal and biopsy of a lymph node, it wasn’t until the time of glucose testing, around 24 weeks, that she was also tested for HIV. ough she was careful to avoid alcohol and to properly take her medications during the remainder of her
pregnancy, when her twins were six months old, she was overcome with despair and reversed that approach. She stopped visiting the CCC and her husband, Michael, had to force her to take her pills. Eventually, she went back, but with trepidation, concerned that she would not be welcomed.

“The reason I’m here today is because they never judged me,” Tanya says, explaining that the entire staff was “pro-Tanya” — even providing Christmas presents for her children, unsolicited.

“It’s like a big family,” Michael says. One that gently encouraged Tanya to take her medications, while helping her feel empowered to do so.

“All I could think when I saw them was, I have HIV,” she says of her pills. That’s a common sentiment, one that adherence nurse Casey Lapointe, R.N., encounters routinely. One patient who was diagnosed years ago had stopped taking his medicine around the year 2000, and only recently decided to come back to the clinic for care. He told Lapointe, “When I take those pills, I’m reminded of HIV every day, and I don’t want that.” She suggested he think of them differently, as being what’s keeping him alive, for himself, and his partner, and even his job. Two months later he returned, telling her that he had a new outlook toward the medication.

The role of adherence nurse evolved as the hospice nurse’s job was phased out. It’s not a common part of most medical teams because the decision to take medications as prescribed is individual. In the case of HIV, however, it’s a public health issue.

Lapointe, whose patients affectionately call her the “pill police,” sees some patients every week, lling their pill boxes and ensuring that they understand the importance of taking their medications routinely. Others use alarm watches or figure out the best place to keep the pill bottle so they don’t miss a dose — that often means the bedside table, which isn’t an option for the many CCC patients who are homeless.

“We ask what life looks like for them,” says Lapointe, recalling one patient who kept his medication in his socks until, he says, someone stole them. “It’s understanding what their day to day looks like,” but also recognizing that not everyone has a routine. For patients who start the day with a cigarette, Lapointe suggests keeping pills next to the cigarette box.

“It’s a huge lifestyle change to say, ‘Now you have to take pills every day of your life for the rest of your life, and by the way, you can’t miss more than  five percent of your meds,’” says Lapointe. She hopes her job may one day be rendered moot, as advances in care continue.

“It’s a wily virus,” says Postlewaite, “and it mutates around the medications.” Because they’re strong drugs, there are also concerns about long-term side effects, including bone demineralization and renal function.

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It’s the keeping track of medications that at least one patient cites as a significant benefit of the CCC. Michael, 49, has been a patient in the St. Johnsbury clinic for close to 15 years. He was diagnosed in 1984, while living in Burlington, by a physician who told him he had less than five years to live, the longest life expectancy at the time. He was told to find a specialist, but that would have meant traveling to New York or San Francisco, so instead he did nothing for a decade (“I think I got through the first ten years by pickling myself,” he says, laughing). When he did get around to seeking treatment, Associate Professor of Medicine Mary Ramundo, M.D., the St. Johnsbury clinic’s physician, tried various combinations of medications before finding the one that was effective. Michael says that having the clinic religiously monitoring him meant they were more quickly able to find the combination of medicines that would work to control the virus, in a way that a general practitioner could not.

The St. Johnsbury clinic is the smallest of the four; Ramundo says she averages between 12 and 15 patients, many of whom are brought over from the nearby Northeast Correctional Complex. Because of the clinic’s relatively small size, there is no on-staff social worker. Instead, it has an extremely close working relationship with the Vermont Committee for AIDS Resources, Education and Service (CARES), so every time the clinic’s location has changed, the St. Johnsbury Vermont CARES office has moved alongside it. For someone like Michael, who lives just a few miles away, having the clinic nearby has literally meant the difference between life and death. Echoing the comments of many CCC patients, he appreciates Ramundo’s expertise and the fact that she knows him as an individual.

“We have a one-on-one relationship, and I’m talking to somebody who’s knowledgeable,” he says. In Brattleboro, Alston hears the same thing. His patients know he drives 150 miles each way to see them, and they are grateful. “They know that with less than perfect weather conditions, it’s sometimes a big deal to get there,” Alston says, “so the attendance is really good and they’re appreciative, and at some level they realize they’re getting specialty care in their little clinic.”

In Brattleboro, uniquely among the clinics, Alston shares duties with a physician from Dartmouth-Hitchcock Medical Center, Jeffrey Parsonnet, M.D., in an arrangement that was established at the outset. That means a doctor is on site every two weeks, rather than every four, as in St. Johnsbury and Rutland (where Grace is the physician on staff).

All sites have enjoyed minimal personnel turnover, and that continuity has not gone unnoticed. Grace attributes that longevity to “the dedication of the staff, being part of an important mission for Vermont, and, I like to think, a well-run program.”

“For patients, when things are chaotic, having the same caregivers is reassuring,” says Alston. “ at’s been a huge attribute of this clinic.” The ratio of providers to patients at all four locations mean individualized care not found in other HIV clinics, particularly those in larger cities, where physicians can have thousands of patients, some of whom might eventually fall through the cracks, Alston says. He has patients who have moved to Florida and then come back, once they’d spent time sitting in waiting rooms and realizing “what a good thing they had here.”

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In Vermont, roughly 30 to 50 new patients come to the clinics each year for treatment. According to Erin LaRose, grant manager at the Vermont Department of Health (VDH), the Green Mountain State “owns” 420 HIV cases and serves 588 people with HIV who are owned elsewhere. The CCC clinics see roughly 450 of those patients. VDH surveillance information suggests there are another 100 or so individuals who are HIV positive but don’t know it.

As always, one key to limiting new infections is reaching those who are most at risk. The CCC, speared on by Postlewaite and the VDH, have worked together to establish gettestedvermont.com, which they’re using to spread the word about all aspects of HIV, from infection to testing and treatment. Clinic staff are also contacting service providers working with vulnerable and notoriously diffcult to reach populations — those dealing with poverty, domestic violence, and drug treatment — to let them know that no client will be refused testing and treatment. Those are the people whose numbers are rising.

“We’re seeing more people whose native intelligence is hovering around the mentally disabled level,” says Kutzko. “Or it’s people who are having sex for a place to live, or folks who are destitute or regular drug users. It’s a hard place to get people tested.”

But it’s testing that could play a major role in minimizing the spread of the virus, since data have shown that some 21 percent of U.S. residents who are infected with HIV are not aware of it. Until there is a cure, the route to cutting down on new cases depends on suppressing viral loads, thereby minimizing the risk of transmission. That’s a different approach than early responses, which focused more on behavioral change, including safe-sex practices — “which quite frankly never really worked,” says Grace — and had little effect on checking the nearly 50,000 new cases per year that consistently appear in
the U.S.

“A lot of the younger folks grew up in an era where there was always HIV around them,” says Kutzko, “and they’re
more blasé about it” because they don’t see people dying from it. Indeed, the rates of sexually transmitted diseases — including chlamydia and gonorrhea — in all populations are soaring, both nationwide and locally. Even syphilis, once thought to be under control, is on the rise, particularly among men who have sex with men, and potentially contributing to new incidences of HIV.

Daniel Daltry, MSW, who is VDH Program Chief for HIV, STDs, and Hepatitis, says the Comprehensive Care
Clinics are a resource for all infectious disease — particularly HIV, of course, but also for STDs.

“I feel like I have a golden resource in my pocket,” says Daltry, “knowing that Comprehensive Care is there for anyone who tests positive, or for someone who might have a complicated infectious disease.”

For patients, acceptance is perhaps one of the most important pieces, second only to regular and proper use of medications. “It’s always on my mind, it’s always something I think about, but now it’s become a background, a sub-line to my life,” says Kris. “For the first five years or so, you’re always thinking about it — when life is going to end — and you’re constantly thinking about your mortality. The last five years or so, it’s just become a background thing to me. I don’t think about it every day. I don’t think about my mortality. I just take my meds and think about it every three months when I get my checkup, and make sure my health stays in check.”

The years medical students spend at UVM remain treasured memories long afterward, which is reflected in their record support for their alma mater — the College of Medicine consistently ranks in the top three medical schools in the nation for percentage of alumni giving. Another facet in that reflection is the tradition that Grady, Ritter, and Schwartz as co-editors first inaugurated back in the early days of the 1960s: the Pulse, the student organized and staffed annual that celebrates its 50^th anniversary this year.

Nationally, the yearbook is an institution in decline; the number of annuals produced in the U.S. is only about 40 percent of what it was 15 years ago. But despite the rise of the Internet, and the pervasiveness of Facebook, there is still something to be said for a memory book that won’t disappear with a crashed hard drive, or be inaccessible when CDs join 8-track tapes in the land of outmoded storage media.

In 1961, there was no Facebook (nor even, yet, a Mark Zuckerberg), nor was there yet computer-aided design and typesetting to speed the production of a publication. Making a yearbook meant doing everything by hand — from taking and developing photographs, to banging out copy in triplicate forms on a typewriter, to setting up the layout boards and mailing the whole lot off to a faraway printer. Michael Grady knew all too well what a time-consuming process it could be: four years earlier, he’d gone through the whole effort as the editor of his Boston College yearbook, the Sub Turri. Now, in addition to finishing their clinical studies and interviewing for internships and residencies, the three students would immerse themselves part-time in the graphic arts.

First, though, recalls retired orthopedic surgeon Sherwin Ritter, M.D.’62, there was the little matter of paying for it all. “It doesn’t seem like much now, but each copy cost fifteen dollars then, and we weren’t really sure how we were going to get it,” says Ritter. But Dean Robert Slater, M.D., was supportive, and the trio found a strong champion in A. Bradley Soule, M.D.’28, who was then chairman of the Department of Radiology and an influential voice within both the administration and the alumni community. Slater and Soule arranged for a special fee to be added to the tuition bill. “I can still hear a few people screaming bloody murder about it,” remembers Ritter. “But we got the money we needed, and most students supported it.” They also had a secret weapon in their fellow senior student, Joseph Guardino. “Joe had been in business before he came to med school,” says Grady, recalling his late friend and classmate. “He was a great salesman. Once Joe got in the room with you, he wasn’t going to leave before you’d agreed to buy an ad,” says Grady. And buy them they did; flipping through the back pages of that first Pulse today, one is greeted by a host of gone-butnot- forgotten retail landmarks of the Burlington area, from Magram’s department store to Valade’s Terminal Restaurant and Cafeteria, and Winooski’s Forest Hills Factory Outlet. One other member of the class of ’62, Daniel Palant, rounded out the crew as faculty section editor.

After securing funding, what followed were several months of finding a book producer (they ultimately went with a printer from Texas), organizing and writing the book’s text, and taking candid photos, group shots, and individual studio portraits of all four classes of medical students. The “studio” was the kitchen of Ritter’s apartment on Loomis Street. “I hung up a sheet and got an old folding camera with a leather bellows. I took every portrait and, indeed, almost every other shot in the book with that old thing.” Some of those shots were straightforward depictions of the life on campus at the old College of Medicine building at the corner of Pearl and Prospect Streets and at the new Medical Alumni Building situated next to where the Given Building would soon rise. More photos were taken where medical students were then clinically educated — the Mary Fletcher and Bishop DeGoesbriand hospitals. Some shots were more complicated, including a photo of the façade of Mary Fletcher Hospital with lit windows in the shape of the numerals 1–9–6–2. Today, a designer could use PhotoShop to achieve that effect in five minutes. Fifty years ago, it was mostly accomplished by a crew of switch-flicking students running through the hospital corridors a few minutes after dusk and explaining to many patients that they would be sitting in the twilight for a few minutes.

The three co-editors dedicated the first yearbook to the people of Vermont, and they secured a dedicatory letter from then Governor F. Ray Keyser, Jr. “Things were a lot simpler back then,” says Grady. “We called up the governor’s office, asked if we could come see him, and they told us, sure, come on down.”

After all their hard work, Grady, Ritter, and Schwartz’s excitement was high in late spring of ’62 when cartons filled with the new publications arrived at the College. But, to their collective horror, a printing error had saturated every photo with ink. “Everything was just a murky blob,” recalls Ritter. Luckily, the printer agreed to make good, and a new, corrected print run arrived in time for distribution before graduation, which in those days occurred in mid-June.

In the five decades since, in changing graphic styles as the years have unrolled, the Pulse has recorded the yearly changes of the heart of the College: its students. And it is that bonding of students and alma mater that Sherwin Ritter recalls most strongly today: “They were four years of memorable experiences and associations with classmates and medical school faculty,” he says. “Memories and values that have been with me for all my years in post-graduate training and throughout my years of practice.”

Web Extra:  View a flipbook of the 1962 yearbook.

The NIH itself identified a new initiative called the “Challenge Grants in Health and Science Research,” through which approximately 200 grants were allocated for innovative projects that “focus on specific knowledge gaps… that would benefit from an influx of funds to quickly advance the area in significant ways.”

Patience, and a high tolerance for repetition, is mandatory in the world of biomedical investigation, where proving a hypothesis can easily consume a decade, and years pass in the blink of an eye. Three $500,000 NIH Challenge Grants were secured by investigators at the College of Medicine. These researchers only had two years to obtain results, but they rose to the challenge to deliver solid and sometimes surprising findings.

Starting from Scratch

A large multidisciplinary study with both animal research and human study arms, the Challenge Grant led by Rae
Nishi, Ph.D., professor of anatomy and neurobiology, faced the steepest hurdle. She’d gathered experts from the university to help examine the effects of nicotine and prototoxin genes on adolescent behavior, and in particular, whether teens who smoke experience any long-term changes in their brains. With the Challenge Grant in hand, Nishi and her colleagues, at a remarkably amped-up pace, ticked through their long to-do list. For the animal arm of the study, they bred bioengineered mice — breeding colonies without the prototoxin gene and cross-breeding them with mice whose neurons carried a fluorescent protein, so that the structure of the neurons could be studied in “wild type” or non-bioengineered mice versus the genetically manipulated “knockout” mice. In another arm of the study, they recruited 200 human participants, conducted behavioral testing, and collected and genotyped hundreds of DNA samples to determine the genetic makeup of the subjects who were tested.

“We proposed something no one had ever thought about before — we really ‘dreamt big,’” says Nishi. Nicotine mimics a normal brain chemical, acetylcholine, a neurotransmitter in the brain. This activates the brain’s reward center through receptors called nicotinic acetylcholine receptors. Nishi and her team wondered if a teen’s smoking addiction could be tied to a difference in the sensitivity of the nicotinic receptors to acetylcholine. Specifically, the group examined the novel LY6-neurotoxin-like gene — or LYNX1 — suspected to be the likeliest gene to be involved in this process. Prototoxins — molecules that associate with nicotinic receptors in the brain — act like little brakes in the reception process. These molecules can prevent the nicotinic receptor from fully opening, thus slowing down its function. Nishi and her colleagues wondered if addiction to smoking was tied to an inefficient LYNX1 gene.

The study’s subjects — adolescent mice and adolescent humans — underwent behavioral testing with and without the influence of nicotine. The team compared mice without the gene to normal mice, administered nicotine at the dose required to achieve the most pleasing response and observed how it influenced behavior. They then compared the genotyping data to determine any correlations to the mouse’s susceptibility to nicotine. In the human subjects, Alexandra Potter, Ph.D., assistant professor of psychiatry, and colleagues employed a computer test, “Go/No Go,” that measures stop signal reaction time, along with surveys and a variety of psychiatric behavior measures. While the human behavior failed to exactly match the animal behavior results, both arms clearly illustrated how nicotine benefitted subjects.

Nishi and her team continue to work on a no-cost extension of the grant, and are in the process of analyzing the data. They have identified some very interesting trends from both arms of the study that follow a different path than the original hypothesis — a genetic link to anxiety versus susceptibility to addiction. “We found that it’s a more complicated issue than just the activities of the reward center,” says Nishi. “It looks like these prototoxin molecules are more tied to anxiety and depression, which are both big factors in the need for a cigarette. The hypothesis is more complicated than we originally thought: people get hooked because the initial hit activates the reward center. But then, when you stop, you feel more anxious and depressed and that drives you to smoke again. Our work showed what genetically may tie to that response.” Members of the research team presented an abstract on their preliminary findings at the 2011 Society for Neuroscience meeting and will be submitting several papers and applying for grants once the analyses are complete.

This intense study notably generated results, but also concrete economic gains. “We hired three full-time research assistants, paid partial salaries for four investigators, purchased major equipment from two local Vermont vendors, MBF Bioscience and Med Associates. We also paid two consultants to assist in analyzing the human genetic data and several part-time staffers to collect data and run the human studies,” says Nishi, as she details the sort of expenditures that these kinds of intense research studies generate. “It was a hugely ambitious project to pursue in two years, but we got quite a bit out of it.”

A Combustion Conundrum

Recognizing a significant correlation between air pollution and the development of disease, Professor of Medicine Naomi Fukagawa, M.D., Ph.D., and colleagues used Challenge Grant funding to analyze the biological effects of emission particles — both petrodiesel and biodiesel — from a food systems perspective.

“Very little is known about whether biodiesel is better, worse or the same for the environment and for people,” says Fukagawa, who adds that the world’s push to break free from fossil fuel dependence has spurred on research in this realm.

She points out that biodiesel, often produced from food sources, can have a significant impact on food availability and pricing — raising corn prices, and shifting soybean use into biodiesel production. With about 925 million people categorized as hungry in the world, this creates a conflict: Are agricultural crops for humans, animals, or fuel?

Over 25 years of basic and applied research have led to the acceptance that petrodiesel fuel emissions have an impact on such health conditions as asthma, chronic bronchitis, chronic obstructive airway disease, cardiopulmonary diseases, and cancer. But, the mechanisms for the effects of the airborne particulate matter produced by these emissions remain unknown. “Combustion of biodiesel fuels is associated with lower emission of particulate matter,” explains Fukagawa. “However, the health consequences of exposure to exhaust from combustion of pure soy biodiesel or a 20 percent soy biodiesel blend are unclear.”

As a first step, Fukagawa and her team previously published data on the mechanisms and outcomes associated with asbestos exposure, extending this to studies of diesel versus biodiesel emissions and fine particulate matter concentrations. In one experiment, biodiesel exhaust particles appeared to induce more lung inflammation and oxidative stress than petrodiesel particles after three days. The researchers also examined the impact of these particles in mice without the gene for apolipoprotein E (ApoE), a major component of very lowdensity lipoproteins, which is involved in the uptake and distribution of blood lipids. Mice deficient in ApoE are characterized by the development of atherosclerosis. After six weeks of inhalation of pure soy biodiesel, the ApoE-deficient mice appeared to have more atherosclerotic lesions than those exposed to filtered air.

With several journal manuscripts in progress, the group is already anticipating its next challenge, to determine the relative contribution of pure soy biodiesel versus the presence of petrodiesel in a 20 percent soy biodiesel blend and pure petrodiesel in producing the differential responses, which would affect exhaust particle size and composition.

Investigating the Clot Mystery

Assistant Professor of Medicine and hematologist Neil Zakai, M.D., harnessed the ongoing NIH-supported REGARDS (Reasons for Geographic and Racial Differences in Stroke) study to investigate potential causes of a higher incidence in African-Americans of venous thromboembolism (VTE). VTE consists of deep vein thrombosis (DVT) — a blood clot that develops in the deep veins of the leg — and pulmonary embolism (PE), which occurs when a piece of the clot breaks off and travels to the lung.

The U.S. Centers for Disease Control estimates that 300,000 to 600,000 Americans suffer VTE each year and between 60,000 to 100,000 people die each year, as a result. However, the reasons underlying the 30 to 60 percent higher incidence in African-Americans of VTE were unknown.

For five years, REGARDS has been regularly surveying the health of more than 30,000 people, about half of whom are African-American, throughout the country. Between 2003 and 2007, the project focused on the collection of baseline information on medical conditions and blood samples from these volunteers, which are currently stored at UVM’s Colchester Research Facility.

First up for Zakai and colleagues was a review of the data on hospitalizations for the African-American participants, who were then administered a phone questionnaire to determine whether or not they had suffered a VTE. If the answer was “yes,” the team retrieved their hospital records regarding the event. In total, the group identified more than 1,000 potential events to review. Zakai and colleagues Mary Cushman, M.D., professor of medicine and a REGARDS co-investigator, and Aaron Folsom, M.D., from the University of Minnesota, reviewed the clinical characteristics surrounding 470 potential events following a protocol that required two reviewers per event and a discussion among the three clinicians to resolve any disagreements.

“We want to understand if and why African-Americans have higher rates of VTE events than whites,” says Zakai, whose recent article in the Journal of Thrombosis and Haemostasis on this topic provided a review of VTE trends in diverse racial groups, as well as a review of genetic and environmental risk factors for VTE and information about how these factors add to differences in VTE according to race.

“By understanding why there are differences and who is at most risk for VTE, we can begin to develop better and more targeted preventive measures to help reduce VTE in everyone,” say Zakai and his co-author Leslie McClure, Ph.D., of the University of Alabama at Birmingham.

Zakai, who with his colleagues is currently constructing the database to house all of the collected information that will allow an analysis of the clinical characteristics of the VTE events, is hopeful about the results yielded from the project.

The team’s next goal is to combine the new data with information gleaned from the national Longitudinal Investigation of Thromboembolism Etiology (LITE) study, which has followed 20,000 people, mostly white, for roughly 18 years.

“While differences in VTE by race due to genetic predisposition will probably always be present,” say Zakai and McClure in the Journal of Thrombosis and Haemostasis article, “understanding the reasons for racial differences in VTE will help providers develop strategies to minimize VTE in all populations.”

Few mosquitoes meet their end this way: gilded, mounted on a pedestal, and entombed in a vacuum chamber. Michelle von Turkovich, a research technician in the Department of Pathology, has prepared and dried this mosquito, then placed it in a sputter coat machine, which covers every crevice of the creature with a thin layer of gold and silvery-white palladium. After sputter coating, the mosquito looks something like Han Solo in carbonite. She slides fly and pedestal into the cylindrical body of the scanning electron microscope, switches on the vacuum, and takes hold of a dial. That’s when things get wondrous.

“I think of it like landing on the surface of Mars,” she says, twirling the dial. We focus down on the creature, then zoom in closer. Legs, hairs, a compound eye, all in opaque and ghostly gray. Closer. A carpet of fine hairs pops into view on what had looked like a smooth body. Closer, up to one hair, which reveals a subtle ribbed texture.

The scanning electron microscope (SEM) that von Turkovich pilots is one of ten advanced microscopy systems available to researchers at the UVM Microscopy Imaging Center (MIC), a facility that has benefited from millions of dollars worth of equipment upgrades in just the last few years. Headed by Professor of Pathology Douglas J. Taatjes, Ph.D., the MIC is a core facility of the College of Medicine, but it serves science and engineering departments all over the University as well as researchers from Middlebury College and nearby companies such as General Dynamics. “Because the cost of even a single advanced microscope can be prohibitive, they come to use equipment...that may not find its way into a single investigator’s laboratory,” says Taatjes. MIC staff first train researchers on the use of the equipment, which allows them to examine a wide range of experimental objects — everything from live cells to asbestos crystals to shrapnel. In addition to experienced scientists and physicians, some of those researchers are still in high school: participants in the Governor’s Institutes of Vermont collected the mosquitoes that were later sputtercoated and placed in the SEM, and they learned how to use the instrument from von Turkovich. “They left here in awe,” she recalled of the most recent class.

A fleet of scopes
Like the SEM, most of the imaging center’s fleet of microscopes are not the glass-slide-and-coverslip kind familiar to decades of students. The classical light microscope has its limitations, offering at best about a 200-nanometer resolution due to the fundamental properties of visible light. But there are ways around that barrier. For example, instead of visible light, the SEM bounces electrons off the specimen. The center’s transmission electron microscope (TEM) sends electrons straight through a sample, while the atomic force microscope physically probes the specimen to map out its topography. The electric cell-substrate impedance sensing system isn’t a microscope, but it provides submicroscopic information. The system cultures live cells on a slide that contains gold electrodes; these measure changes in a cell’s electrical processes, which allows a researcher to examine their physiology in real time — a little like checking an EKG on a patient in the clinic.

Then there is the confocal laser scanning microscope, which allows researchers to focus on an object at a specific depth, without interference from foreground or background. Like an advanced CT scanner, it “sees” deep into specimens and captures images of individual planes; researchers can opt to create three-dimensional reconstructions with imaging software. And like a CT scanner, it can examine live tissues and organisms — no slicing or fixation required.

The confocal microscope is central to Professor of Neurology Helene Langevin, M.D.’s research. Langevin studies connective tissue, the substance that fills the spaces between muscles, nerves, and other types of tissue. Connective tissue, which hitherto has been the subject of relatively little research, is difficult to slice into thin sections, as it tends to shear. “The confocal microscope allows you to look at the whole sample without cutting it, and it allows you to take optical sections,” she says; it also enables her to study how live connective tissue reacts over several minutes while being stretched. This is a key component of her research into acupuncture, in which she studies the possible effects caused by stretching of tissue around the needle insertion point. “We couldn’t do this research without the Microscopy Imaging Center,” Langevin says.

Professor of Chemistry Christopher Landry, Ph.D., a specialist in materials chemistry, has relied on the MIC for research into new systems of drug delivery he conducts in association with Professor of Pathology Brooke Mossman, Ph.D.’77. Landry and Mossman synthesize hollow, microscopic, silica spheres whose shells are full of holes, like a Wiffle ball. Guided by antibodies, the spheres carry chemotherapy drugs to tumors, releasing their cargo inside tumor cells soon after their arrival. Because it targets only problem cells, Landry and Mossman’s technique could allow for much lower doses of chemotherapeutic medications, many of which are more toxic in higher doses. On one study that involved students, the group used the confocal and transmission electron microscopes to prove that the spheres and their cargo, the drug doxirubicin, had reached the insides of tumor cells. These confocal images glow with color from fluorescent labels that track the spheres and cells.

The atomic force microscope was Taatjes’s instrument of choice to study antiphospholipid syndrome (APL), a disease that leads to blood clots and repeated miscarriages. Situated inside a metallic vibration-dampening shield, the microscope nudges its way along the surfaces of specimens, gently tapping them with a probe that can resolve textures some 1000 times smaller than the best light microscope can reveal. Taatjes and his colleagues used it to make images of an important protective protein called annexin, which crystallizes in a two-dimensional pattern like a chain-link fence. They then added the harmful antibodies found in APL and captured images of the antibodies as they disrupted the fence, thus providing the first visual evidence of the destructive interaction they suspect underlies the disease. These interactions could only have been followed with an atomic force microscope, said Taatjes, in part because it allowed them to occur in a live, hydrated state.

A broad focus
Along with basic scientists, clinical and translational researchers also make regular use of the MIC. Several times a week, the Fletcher Allen pathology department sends kidney biopsy specimens to Senior Laboratory Technician Janet Schwarz. She slices each specimen, adds a stain, embeds it in resin, then prepares sections to examine through a transmission electron microscope at magnifications of up to 50,000×. The best images are captured digitally and sent back to the hospital for diagnosis by pathologists; Schwarz and the physicians often go over the cases in person together. Because the MIC handles patients’ specimens, it is licensed by the College of American Pathologists, whose strict standards are listed in a dozen thick ring binders that line a shelf in the lab. Taatjes and his colleagues carry those standards over to research applications as well; their thorough record-keeping, he says, has impressed many a visiting researcher.

The MIC makes it a point to connect with the community. Schwarz leads Project MICRO events, in which she visits local middle schools to give many children their first look through a microscope (profiled in “You’re Never Too Young to Learn” in the Winter 2011 issue of Vermont Medicine). Some of the high school juniors who use the SEM during Governor’s Institutes are so entranced by its possibilities that they return to use the instrument for projects during their senior year. In partnership with the Vermont Health Department, the MIC has also signed on as a satellite lab in case a bioterrorist attack overwhelms government facilities; one of its technicians trained at the Centers for Diseases Control and Prevention in Atlanta to learn to spot pathogens like smallpox and anthrax. “We’re there in the background, just in case,” says Taatjes.

Two decades of service
Taatjes has run the MIC from its inception in 1993. Before college, he said, he liked science, but had no particular interest in microscopes. That changed in an instant after his undergraduate advisor invited him to do a project on an electron microscope. As Taatjes looked at the fantastically detailed images of cell structures for the first time, he recalls, “I knew then and there, ‘This is what I’m going to do.’”

After earning his Ph.D. from the University of Basel in Switzerland, Taatjes joined the UVM faculty in 1987, and was recruited to run the pathology department’s single-transmission electron microscope. Several years later, then-Associate Dean of Research John Evans, Ph.D., and Chair of Pathology Edwin Bovill, M.D., decided to centralize the university’s microscopy resources, so they bought a new electron microscope and made it the heart of a new facility. A confocal microscope arrived soon after, the first of many grant-funded acquisitions over the years. Thanks to shared instrumentation grants from the National Institutes of Health (NIH) — which go to fund equipment for at least three NIH-funded researchers who will share it — and funding from other sources, the MIC’s instruments now comprise a formidable lineup.

Landry recalls asking to visit the Cell Imaging Center during his 1996 job interview. (The Cell Imaging Center is the MIC’s former name; it was changed in 2001 because so many researchers were using it to study other objects.) Now, as a frequent search chair for new faculty members, Landry always arranges for candidates to tour the MIC. “In one way or another, most of the new chemists that we’re hiring in our department will be making some use of the imaging facility,” he said. “It’s rapidly becoming an important tool for departments outside medicine.”

Taatjes hopes soon to bring a groundbreaking new instrument to the MIC. The super resolution microscope is a light microscope that breaks the 200-nanometer limit, one which was thought for at least a century to be unbreakable. (200 nanometers is about 1/500th the width of a human hair.) The super-resolution microscope resolves objects ten times smaller than that without resorting to the fixing and staining that higher-resolution electron microscopes require. “What you’re seeing [with electron microscopes] is a snapshot of what the cell was doing when you dumped the fixative on it,” said Taatjes. With super resolution microscopy, by contrast, researchers can watch live cells in action at nearly the same scale. That’s thrilling, in part because so many cell organelles are smaller than 200 nanometers. “[We can] begin to look at dynamic interactions between molecules and cells,” said Taatjes. “Super resolution is really a revolution right now in cell biology, and we want to get this technology on campus.” Researchers are eagerly anticipating its arrival. During a recent seminar to discuss the super-resolution microscope, Taatjes recalled, the room was “unbelievably packed.... People were sitting in the aisles.”

If the grant he is writing is successful, the super resolution microscope will become the MIC’s eleventh microscopy-based imaging system, giving researchers the freedom to design entirely new experiments. “When I interview potential faculty members,” Taatjes said, “one of the things that I always hear is ‘Wow, you’ve got basically everything I need.’ ...We’re pretty unique, I think.”

It was a bright and bustling morning in Trivandrum, the capital of India’s southwesternmost state, Kerala. A third-year resident in family medicine, I had come here to work with the staff of an Indian nonprofit devoted to advancing palliative care services across India. Seema was a young, newly qualified junior doctor who had only recently joined the organization. We were traveling with five others — our driver, two nurses and two nursing trainees — into the mountains east of Trivandrum for the day.

“We don’t really speak about the weather like you do,” Seema gently chided. “In the West you spend lots of time talking about the weather.” As I silently ceded her point, she consoled me: “I think you have more variety to your weather. Here it is only hot, very hot, or cold and rainy. Most people carry an umbrella because it’s useful in any of those cases.”

I counted the passing umbrellas as our van carried us into the foothills on our way to Palode, a village where we would hold a small outpatient clinic before making home visits. After the clinic session, Seema looked tired. I asked what she was thinking.

“Sometimes I feel frustrated that we can’t do more for our patients,” she said. “Doesn’t this frustrate you?”
Of course, I thought. It frustrates all of us.

A bit tentatively, I asked, “Have you heard, Seema, about the idea of bearing witness?” She shook her head.

“It’s the idea that just being present with someone can be healing,” I went on. “In the Bronx, where I work, lots of our patients suffer from sicknesses and social ills that we can’t do much about. Sometimes, just being there is doing something; sometimes it’s the best we can offer.” Perhaps this notion was merely a salve for my feelings of helplessness. Still, I hoped that it was true. Seema’s answer was silence — whether thoughtful or skeptical, I couldn’t tell.

After lunch, we were joined by a beautiful ten-year-old girl named Paadini. A member of her school’s health club, she aspired to be a doctor and sometimes accompanied the palliative-care team on home visits.

As we drove deeper into the mountains, Paadini sang quietly to herself, and Seema told me about the patient we were going to see. Diagnosed at forty-eight with breast cancer, she’d had a left radical mastectomy and multiple rounds of chemotherapy and radiation therapy. The treatment had been unsuccessful, likely because of her late diagnosis — common in a country where most people don’t have access to primary care or the money to pay for it.

The woman’s alcoholic husband had left her years before, but had returned home a month or so back, Seema said. “He had nowhere else to go, and she could not, as his wife, turn him away.” He’d recently been found lying dead in the road. The woman’s son worked nearby, but was rarely home; a few months back, her daughter had fled with a boy. The patient, bed-bound and fed twice daily by a seventeen-year-old neighbor, was essentially alone.

The road’s jagged asphalt gave way to red dust. We passed government-owned bamboo and acacia farms, abandoned bus shelters and a painted cement statue of Shiva — the giver and taker of life — with his blue skin, dreadlocks, and trident. Crossing over a fast-flowing river, we reached the patient’s small village and stopped to buy biscuits and bananas to bring the patient.

We parked the van and descended into a shallow valley of rice paddies and palms. Led by Paadini in her pink dress, we walked single-file through the lush, green landscape to the sound of a gently trickling stream and goats bleating in the distance. Around us, white cranes swooped into placid ponds filled with blooming lotus flowers.
As we scrambled up a steep rise to a small, dark, mud-brick home, an eager puppy on a chain barked piercingly, announcing our arrival.

Our patient lay in the open front porch, naked except for a stained white sari blouse and the bright pink blankets that covered her. Eyes closed, she moaned quietly, grimacing between shallow, rasping breaths. Her head, covered with short wisps of hair, lay awkwardly on the pillow. Her cheekbones jutted over sunken cheeks, her lips were dry and cracked, her exposed arms were wasted. On a bench a package of steroids, unused since the team’s visit a week back, sat next to a tin of watery rice porridge — her unfinished breakfast.

Responding to our greeting, she seemed confused. She’d tried to bathe that morning, she said, but had fallen in the pool — an event that had actually taken place two weeks before. She complained of being in pain, and she looked it. When she rolled over, I saw bits of dry feces caked to her thigh. She seemed very close to death.

Hoping to relieve her pain and breathlessness, I asked Seema, “Can we give her morphine?”

“No,” Seema answered. “None of her family are here. If we give her morphine and then something happens, her family will say that she was fine when they last saw her and blame us for making her worse. Our hands are tied.” I suppressed a flash of anger. There must be something we can do.

We crushed the steroid pills into the rice milk, and the nurse spooned it into her mouth. We tried and failed to take her blood pressure; her weak, thready pulse told us that it was very low.

As a team member called the woman’s son on a mobile phone, we sat on a mat next to the woman’s bed. Looking around, she locked her eyes onto mine, then reached for my hand.

I clasped her hand in mine, and we sat for several minutes, looking at each other. As I had many times in my brief medical career, I moved past my own discomfort by acting as I thought a good doctor would. And though I wouldn’t generally use these words, I think that I prayed for her. I also wondered how she understood this strange situation, and wondered who was comforting who more.

“She doesn’t know us, but she knows that we’re here to help her, ” Seema said.

An idea occurred to me. Turning, I caught Paadini’s eye. “She’s very sick, Paadini,” I said gently. “Maybe it would make her feel better if you could sing her a song.” But Paadini shrank back shyly.

The son arrived, doe-eyed and bewildered. Seema explained that his mother was very close to death; that she needed to be cleaned and to have someone stay with her. The son promised to take care of these things.
Bending down, I took the woman’s hand again and smiled. Then Seema did the same.
Our earlier conversation came back to me. Our presence may be the best thing we have to offer.
We left and walked back through the forest.

I thought about how much suffering the woman had endured. I hoped that our presence had meant something to her. Quietly, I wished that her pain would go, that her breathlessness would cease, that she would die peacefully and soon.
Up ahead I could hear Paadini, leading us out of the green valley with a song. VM

Epilogue: The following week, I learned that the woman had died within an hour of our visit.

A cartoon from a 1995 New Yorker magazine depicts a physician sitting at his desk in a traditional, diploma-decorated office, speaking to a patient. The caption reads: “Mr. Wilkins, I believe your condition is going to get us both into the Journal of the American Medical Association.” Even after more than 15 years, the cartoon’s message isn’t dated; physicians and scientists continue to seek high-impact journal publication to disseminate new knowledge. In the process, they further their careers and, more important, they further the incremental improvement of understanding diseases and offering more successful treatments to patients worldwide. Unlike mainstream commercial publishing, which is heavily concentrated in a few major cities, scientific journals are headquartered throughout the country, and draw their contributions from any of the nation’s 135 medical schools and many independent clinics and institutes. At the UVM College of Medicine, faculty members from across a range of departments support the editorial process that keeps the peer-reviewed journal the dominant mechanism for the vetting and sharing of new medical information.

The scientific journal has been around since the very beginnings of the magazine as a medium. Prior to the mid-seventeenth century, physicians shared information through informal networks of correspondence. With the simultaneous appearance in the mid-1600s of both scientific societies and the newspaper, the stage was set for the appearance of the first steps in formal scientific publication, with the French Le Journal des Sçavans, and the English Philosophical Transaction of the Royal Society of London both premiering in 1665. More than a century later, in 1797, The Medical Repository became the first scientific journal published in the United States. It was printed in New York City, as its title page stated, for “the Faculty of Physic of Columbia College.” Throughout the nineteenth century the numbers of medical journals grew at a rapid rate, as did the concept of having submissions reviewed by peers in specific fields before publication. Today, between 4,500 and 5,500 biomedical journals are published worldwide, and a count by the journal Science Watch showed that nearly three million scientific papers were published by American investigators in the ten years between 1996 and 2006, of which a hefty portion were biomedical in theme.

With the rise of Internet publishing, smart phone and tablet applications, blogs, and online social media, information sharing among scientists has become more fluid and accessible. However, the hard copy, peer-reviewed journal is still the “gold standard” of publishing, even as new technology has changed the way many have accessed its information. The task of editing a journal — and determining article acceptances — remains a rewarding experience. Several College of Medicine faculty members have become intimately familiar with the challenges and rewards of serving as an editor-in-chief — including Lewis First, M.D., at Pediatrics, Jeffrey Klein, M.D., at RadioGraphics, Naomi Fukagawa, M.D., Ph.D., at Nutrition Reviews, and Burton Sobel, M.D., at Coronary Artery Disease; in addition, several faculty serve in the important role of associate editor, including Jason Bates, Ph.D., at the Journal of Applied Physiology, Mary Cushman, M.D.’89 at the Journal of Thrombosis and Haemostasis, James Hudziak, M.D., at the Journal of the American Academy of Child and Adolescent Psychiatry, and David Schneider, M.D., at Coronary Artery Disease. Here, we profile just a sampling of these editors.

Lewis First, M.D.
Editor, Pediatrics

At UVM, no one knows the burden of shouldering an editorial role on top of research, teaching, and patient care responsibilities better than Jerold Lucey M.D., professor emeritus of pediatrics. For 34 years, Lucey sat at the editorial helm of Pediatrics, the monthly journal of the American Academy of Pediatrics. His successor, Lewis First, M.D., professor and chair of pediatrics, became editor-in-chief in January 2009, adding the challenges of keeping a major journal up-to-date and constantly adapting to reflect changes in the field, while maintaining his duties as department chair, chief of pediatrics and physician leader at Vermont Children’s Hospital at Fletcher Allen Health Care, as well as his active service within the community.

Pediatrics operates out of several offices — one at UVM, where First, Associate Editors Jeffrey Horbar, M.D., and William Raszka, M.D., and Editorial Associates Martha Andreas and Deana Stoppler work; another in Houston, Texas, for Deputy Editor Virginia Moyer, M.D., Associate Editor Gordon Schutze, M.D., and Assistant Editor Claudia Kozinetz, M.D.; and at the AAP headquarters in Elk Grove, Illinois, occupied by the journal’s senior managing editor, managing editor, and an editorial associate.

“We receive more than 4,000 manuscripts from the U.S. and around the world each year,” says First, who credits Lucey with elevating Pediatrics to its current status as the most highly referenced pediatrics journal in the world, producing multiple translated editions and developing the journal’s online edition. “Jerry was a master at editing, article selection, judgment, and recognizing what readers need,” says First. “He is a great mentor for me.”

First describes Pediatrics as a team effort. He and Deputy Editor Moyer speak almost daily and each week, they have a “triage” call to determine which of the 100 newly reviewed articles on hand will be accepted. Horbar oversees the dozens of letters to the editor received each month. Raszka covers the office’s day-to-day operations when First is out, and has gained notoriety among Pediatrics readers as “the filler king” — he writes short one- to two-paragraph current news-related feature items that fill space at the end of articles in the hard-copy edition of the journal.

First believes the complexity of editorial responsibility nowadays precludes him from being sole decision maker. He holds a monthly conference call with his ten executive board members regarding policies, controversial papers, and the governance of the journal. And twice a year, he holds meetings with his 40-member editorial board, which is made up of pediatricians from all over the U.S. Two to three times each year, First convenes a meeting of other pediatric journal editors, who represent such publications as Clinical Pediatrics, Journal of Pediatrics, Pediatrics Research and Adolescent Medicine. Collectively, these leaders share and brainstorm about such issues as conflict of interest policies, pre-registration of clinical trials, and how to consider industrial pharmaceutical studies.

Since becoming editor-in-chief, First and his team have also revamped the look of the journal and increased the use of online technology and social media to make the journal more user-friendly. They also created a dynamic website with a blog, authored by First (and aptly titled “First Read”) that highlights new articles. In 2010, Pediatrics received two awards from Association Media & Publishing — a gold award in the journals category for “most improved,” and a silver award for design excellence.

Another recent accomplishment is the reduction of time from acceptance of a paper to its publication from almost a year to two to three months. Letters to the Editor — or e-letters — are posted online, usually within a day.

With an aim to be as accessible as possible, First devotes the second half of his work-day to addressing authors’ concerns and complaints, walking contributors through revisions. “It’s exciting to call people all over the world and help them write better manuscripts,” says First.

A combination of a tight page budget and sharp uptick in the number of submitted manuscripts means Pediatrics cannot publish all the submissions worthy of publication. “That’s a good indication that there is so much good work being done in our field,” he says.

Jeffrey Klein, M.D.
Editor, RadioGraphics

A. Bradley Soule and John P. Tampas Green and Gold Professor of Radiology Jeffrey Klein, M.D., recently embarked on a six-month transition period in preparation for assuming the editorship of RadioGraphics, the bi-monthly journal of the Radiological Society of North America (RSNA). Klein will be the journal’s third editor when, in January 2012, he succeeds University of Maryland radiologist William Olmsted, M.D., who served as the journal’s editor for 21 years.

RadioGraphics is unique in that it is almost exclusively educational. The journal’s articles are selected from accepted educational exhibits at RSNA’s Annual Meeting, which takes place in Chicago in late November each year. The editorial team identifies exhibits with high-quality content and images that will translate well into a journal article, then invites authors to convert their exhibits into a journal article format for peer review for inclusion in one of the six issues for that year. A seventh issue of the journal, published in October, focuses on a specific topic.

Klein, who previously served as the editor of the Journal of Thoracic Imaging, is a practicing radiologist, educator, and researcher. “It’s difficult to leave clinical practice at any point,” he says. Klein estimates he will dedicate about 70 percent of his time to editing, leaving about a third to care for patients and interpret studies. Two associate editors share the workload, and are responsible for quality improvement and informatics, editing regular articles in each issue. In addition, the journal has a managing editor at the RSNA headquarters in Oak Brook, Ill., an editorial associate in the Vermont office, and a 25-member editorial board support the effort.

On rare occasions, says Klein, RadioGraphics will publish an article not solicited from an Annual Meeting exhibit, if that topic isn’t addressed by an exhibit. “We try to match topics with what readers want and need,” says Klein, adding that members are solicited for a top ten list of what’s “hot” to determine topics.

While currently in the process of expanding from print to electronic — only two articles per issue are available online — Klein says RadioGraphics is widely considered the best educational journal in radiology. “It’s a real challenge to decide how the journal maintains its identity and evolves into its electronic version, and I have to shepherd it into that realm successfully,” Klein says.

Christopher Francklyn, Ph.D.
JBC Editorial Board

Some journals, like Pediatrics, publish monthly; others are bi-monthly, like RadioGraphics, but many are published weekly. Professor of Biochemistry Christopher Francklyn, Ph.D., who is nearing the end of a five-year term on the editorial board of The Journal of Biological Chemistry (JBC), a weekly publication focused on research that seeks to gain an understanding of the molecular and cellular basis of biological processes.

Francklyn possesses a distinct opinion about the gravity of editorial responsibility, influenced by a meeting early in his career with the late Sir John Maddox, former editor of the journal Nature. “You are a chief quality control officer — deciding what does and doesn’t go in the journal — responsible for standards of science and resolving conflicts,” he emphasizes, adding that “editors have to have the experienced-based judgment to know a paper’s good enough and the balance to not push for too much.”

He puts this philosophy into practice as a reviewer, a duty that entails evaluating about 30 papers per year, with an average two to three papers “in the queue” at all times. Each article has two reviewers and a third is added if the first two don’t reach agreement. Editors can operate at their discretion, such as recommending a third reviewer to get an opinion from a specific expert to solidify an opinion.

Francklyn subscribes to the “golden rule” of peer review: he reviews just as he wishes to be reviewed. On his fit-for-publication criteria checklist is evidence of interesting and important work, especially novel discoveries, and sufficient data to prove the study’s case. Determining what would make it a better paper is also part of the equation for Francklyn. “If someone discovers something important in the field, I want to get it out there and get people excited,” he says.

His willingness to help promising scientists get their work published has resulted in another editorial role as a regular contributor and editorial board member of Principal Investigator Advisor (PIA) and NIH & NSF Funding Advisor. This year-old opportunity landed in Francklyn’s lap after he posted a comment in response to a column about reviewing that appeared in The Scientist, a New York-based magazine that covers the latest developments in the life sciences. Leslie Norins, M.D., Ph.D., publisher of PIA, read the online comment and called him to be a contributor. “I figured I would pass it along, sharing more broadly those things I’d share with a junior colleague down the hall,” Francklyn says.

“When you are judged as a scientist, where you publish makes a difference,” he says. He considers issues like how to measure impact and standards that determine innovation some of the most critical discussions in the journal field. “You are a ‘custodian’ of your field, so it’s subjective judgment; you bring your own personal ethics to the table,” he admits. In the academic world, says Francklyn, “people put lots of time into reviewing that’s never compensated in the strictest sense. But all people involved in the process of producing a journal know that the work pays dividends for those who contribute today, and those who glean knowledge far into the future.”

To the average walking-around brain, the skull seems a simple thing — a sort of bony, custom-fitted helmet, personalized by a range of hairstyles. We slip it on sometime in utero, and it stays with us to our death, and beyond. It really has no choice in the matter. Your skull can’t escape you because, as the protective wrapper of the brain, it contains you — your approximately 100 billion brain cells and the less-easily-quantifiable concept known as your mind. It is the seat of most of your senses. And it adds structure to your face, that collection of muscle, cartilage, and skin by which the rest of the human brains in the world identify your unique self. The skull is special. Hamlet holding poor Yorick’s femur: a creepy desecration. The prince cradling the jester’s skull: a poignant meeting of old friends.

So, on a cold January afternoon, in a room on the third floor of the Given Building that is crowded with men and women in surgical scrubs, the scene, to a casual observer, has an added philosophical slant. Here, in the Skull Base Laboratory he founded after joining the faculty eleven years ago, Associate Professor of Surgery Michael Horgan, M.D., presides over the biggest educational event of the lab’s year, its annual course called “Surgical Approaches to the Skull Base: a Hands-On Cadaver Workshop for Neurosurgeons.” Residents and faculty members from neurosurgery departments across New England have packed into the surgical lab for a chance to practice a skill which must be performed perfectly every time: accessing the brain and its vascular and neurological supply and transmission lines. And here, the philosophical effect: a roomful of highly trained minds using their considerable knowledge and fine motor skills to explore ways to reach within the cranium — the brain learning to access itself.

“Maximal exposure with minimal disruption, that’s what we’re going for,” explains Horgan from a relatively quiet corner of the lab. Behind him, teams of residents and their teachers cluster around the six surgical stations in the lab’s main teaching area, a 30-by-30-foot room canopied by the branching arms of its six gray-and-black surgical microscopes. Under every scope is clamped the cadaver head upon which each team will practice surgical skills over the five-day run of the course. Two large flat-screen monitors mounted in opposite corners of the room give all the participants a live view from two of the surgical fields. High on one wall, in a place of honor, hangs the white coat of surgical pioneer R.M.P. Donaghy, M.D., who invented many of the techniques of microneurosurgery in this very room four decades ago.

The focus of the room’s attention, the human skull, is a tight collection of 22 bones, many of them wafer thin, and held together by the tightly-knit connections called sutures. For centuries, those physicians who dared operate in the region of the brain gained access from the top or sides of the head. Neurosurgeons give the name “skull base” to the part of the skull that the brain rests upon. Although the brain, with a tissue consistency somewhat like tofu, mostly floats within its enclosure, its lower portions do sit directly upon the bottom of the skull. Within this area is a maze of bony channels that house the arteries and veins and nerves that nourish the brain and allow it to communicate. For decades after surgeons began operating on the tumors, aneurysms, and other maladies that can afflict the upper brain, the areas in the underside of the organ and the cervical spine connection remained offlimits, the neurosurgical version of some unapproachable mountain escarpment. Indeed, neurosurgeons tend to veer into the parlance of mountain climbers or spelunkers when describing these challenges.

“Thirty or 40 years ago, it was almost impossible to access these areas,” says Horgan. “You would have to traverse the brain to get to them, or really pull upon the brain. You’d either have to move the brain — actually pushing it — or go through it in order to get to those spots. Or you just left them alone, and didn’t treat the problems in these areas — they were just considered inaccessible.” But slowly, and with increasing activity from the 1980s on, new routes to the base areas of the brain were plotted. “Having a knowledge of the anatomy of the base of the skull is very important,” says Horgan. “You need to know precisely which bones you can remove and how much you can drill without getting into trouble with nerves or arteries or veins.” To the lay observer, these routes are squirm-inducing — they often involve operating through the back of the mouth, or moving the eyeballs slightly and entering from the back of the eye sockets — but they are worth the effort if they give the surgeon access to a centimeter of open space under the brain. “A centimeter is an enormous amount of room for us, comparatively,” says Horgan.

When Neurosurgery Division Chief Bruce Tranmer, M.D., recruited Horgan to Vermont, the promise of having a skull base lab was a crucial part of the offer, Horgan says. It meshed with Horgan’s desire to teach and do research in addition to his many weekly hours of surgery, and it met a crucial need in the field. “It takes a long, long time to become a neurosurgeon,” he says. Neurosurgeons complete seven-year residencies after medical school. Most are approaching their mid-30s before their training is done. “Anything we can do to make the training more complete and up-to-date is worth it,” Horgan says.

As a regional resource, UVM’s lab is appreciated by neurosurgeons throughout New England. “The best way to learn this anatomy is through repeated cadaver dissection, “ says Carl Heilman, M.D., chair of the Department of Neurosurgery at Tufts Medical Center and president of the New England Neurosurgical Society, the professional group that underwrites the cost of residents’ tuition in the January course. “UVM’s Skull Base Laboratory has helped many neurosurgery residents, from Yale, Harvard, Tufts, and others to solidify their knowledge.”

At the same time, the lab gives UVM/Fletcher Allen residents the chance to pursue research into new surgical techniques. Fourth-year resident Richard Murray, M.D., was interested in the developing field of endoscopy — the use of an optical-fiber instrument to view and operate directly within cavities and organs. Murray’s research specifically looked at approaches to the cervical spine through both the mouth and the nose. “The Skull Base Lab offered the ideal setting for this research,” Murray says. He set up a complete endoscopic operative system in the lab, carefully measured and analyzed angles of exposure, and drew useful conclusions on the limitations of each approach, and ways to judge patient suitability. “This project offered me, as a junior researcher, the chance to engage in meaningful research, which I could then present at a national level,” he says. Murray presented his findings at this February’s North American Skull Base Society meeting in Arizona.

Medical students also benefit from the lab. William Ares, a third-year medical student with a deep interest in neurosurgery, calls his participation in the January workshop “an incredible opportunity for me. I had the chance to interact with world-renowned surgeons from some of the premier neurosurgery programs in the county. The workshop and the lab give me an avenue for hands-on learning that a medical student just couldn’t realistically get in the operating room.”

For Michael Horgan, standing in the corner of lab has its limitations. A course participant at one of the operative scopes needs a guiding hand, and he goes to join her. Lesson by lesson, the brain develops the collective memory of how to reach and repair itself.

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