Loose Connections, Autumn 2007

AUTUMN 2007 “I must rise above the culture of perfection and remember that I can be even if I can no longer do.”

L O O S E CONNECTIONS

Richard M. Cohen

DARWIN EVOLVES THROUGH THE PAIN

BY Cory J. Mageors, Staff Writer, STAR COMMUNITY NEWSPAPERS This story was filed on Friday, August 3, 2007 6:26 PM CDT, and is copyright by Star Community Newspapers, Texas. It and similar stories about Nikki Darwin were carried first in Plano, and a month later the Dallas Morning News. In this issue, we’re focusing on individual efforts, carrying another piece run elsewhere, “Brooke’s Story” on Page 15 , and our “Golden Thread” stories on pages 8 and 10. At the end of Nikki’s story, you can find her mother (and EDNF Board Member) Michele Darwin’s accompanying notes, “News Blitz Ideas.” — Ed.

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his fall, John Paul II graduate Nikki Darwin, 18, will call Creighton University home for her first semester of college.

She plans to study nursing; a commendable career, but a far cry from her dream of playing basketball. But that dream came to a sudden halt during her junior year of high school.

After years of living a healthy and active lifestyle, the 6-foot-1 center began to experience back pains so unbearable she didn’t think she could continue playing. Her parents, Scott and Michele Darwin, became concerned because their daughter never complained. But suddenly she was contemplating ending her love affair with basketball.

TABLE OF CONTENTS AUTUMN 2007 FEATURES Book Review: How Doctors Think................... 5 Delayed Gratification........ 8 Musing About Fundraising..................... 10 News Blitz Ideas............. 14 Brooke’s Story................. 15

At the age of 16, Darwin was diagnosed with Ehlers-Danlos syndrome, which is a defect in the connective tissue throughout the entire body.

As a result of a lack of a protein called collagen, which acts as “glue” adding strength and elasticity to the connective tissue, Darwin does not receive the proper support in her muscles and ligaments. This tends to cause extreme cases of flexibility in the joints and can be very painful due to impact on the joints.

MEDICAL

While sensitive skin problems are also a concern for EDS patients, Darwin’s main area of concern is in her spine, near her neck.

President’s Award............. 3

“Her brain stem droops down a little,” said Mrs. Darwin “Sometimes, if she moves her head in a certain direction, her spinal vertebrae put pressure on her brain stem which can cause problems in her neurosystem. Her spine is

Local Groups................... 17

(continued on page twelve, third column)

FDA & Fibromyalgia......... 7 Self-association of Collagen.......................... 16

MEMBERSHIP & NEWS Board of Directors............. 2 Submissions Guidelines.... 3 Kids & Teens..................... 6 EDNF Research Results.. 11 Membership Form........... 18

www.ednf.org

L O O S E CONNECTIONS PAGE TWO • AUTUMN 2007

PUBLISHERS INDEX Published Quarterly by Ehlers-Danlos National Foundation FOUNDER Nancy Hanna Rogowski 1957 – 1995 President & CEO Cindy Lauren Board of Directors Richard Blouse Robin Coppi Michele Darwin Richard Goldenhersh Jeanne Kingsbury Cindy Lauren Charlotte Mecum David Specht Professional Advisory Network Patrick Agnew, DPM Peter Byers, MD Edith Cheng, MD Joseph Coselli, MD, FACC Joseph Ernest III, MD Clair Francomano, MD Tamison Jewett, MD Mark Lavallee, MD Howard Levy, MD, PhD Nazli McDonnell, MD, PhD Dianna Milewicz, MD, PhD Anna Mitchell, MD, PhD Raman Mitra, MD, PhD Linda Neumann-Potash, RN, MN Terry Olson, PT Mary F. Otterson, MD, MS Melanie Pepin, MS, CSG Elizabeth Russell, MD Ulrike Schwarze, MD Karen Sparrow, PhD Brad Tinkle, MD, PhD Mike Yergler, MD Editor Barbara Goldenhersh, PhD Graphics/Type Mark C. Martino

DIRECTOR OF LOCAL GROUPS LAST REPORT

BY CHARLOTTE MECUM

I

will be resigning my role as Director of Local Groups as of December 31, 2007. It has been an honor and a privilege to work with the dedicated volunteers who have served as Local Group Leaders and Regional Coordinators (RC) during the past five years.

Local Groups are a vital part of EDNF; the volunteers who take on the task of organizing, leading, serving as officers of Local Groups, as well as the individuals who participate as members of the Local Groups, are playing an invaluable part in making it possible for EDNF to carry out its mission.

I have always been passionate about the importance of our Local Groups. They are essential in spreading awareness of EDS, educating medical professionals and communities about the disorder, and in providing support to individuals and families dealing with EDS. My feelings about the necessity of Local Groups will not change and I will continue to work in my own Local Group.

I am very proud of our Organization and the resources and services it provides, and I am pleased to remain involved in it. I will have time to focus on other areas of EDNF’s work that are important to me. I urge each EDNF member, likewise, to find an area of interest in which you can volunteer your particular talents and skills. If you are interested in organizing a local group in your community, please contact Troy Winkels, wintr@hiwaay. net, or you can contact me at charlotte@ We have tried new structures and new ednf.org through the end of 2007. programs for Local Groups during my time as Director. The increasing number My thanks to each of you involved in the of Local Groups and EDNF members work of Local Groups and best wishes for and the progress of the Foundation have your continued success.

■■■ necessitated changes and adjustments to meet the changing needs. We have never LOCAL GROUP LISTINGS CAN BE FOUND ON PAGE 18. lost sight of the fact that our Group Leaders are volunteers and have tried to make it as easy on them as possible, while abiding by the regulations EDNF must follow as a non-profit organization. I appreciate the acceptance and cooperation of Local Group Leaders as these changes have been made.

“I am still determined to be

cheerful and happy, in whatever

We will be establishing a new structure once again, with the beginning of 2008. All reports and paperwork for Local Groups will be handled by the National office. The Regional Coordinator program was discontinued as of July 15, 2007. Troy Winkels, previously an RC, will assist as new groups are organized and when groups apply for charter. Group Leaders will receive additional information about the structure for 2008 before the end of the year.

It is my hope that our Local Groups will continue to grow in number and accomplishments, making life better for those who live and deal with EDS.

situation I may be; for I have also learned from experience

that the greater part of our

happiness or misery depends

upon our dispositions, and not upon our circumstances.”

— Martha Washington(1731-1802)

L O O S E CONNECTIONS AUTUMN 2007 • PAGE THREE

EDNF TO RECOGNIZE VOLUNTEERS THROUGH PRESIDENT’S AWARD

BY MICHELE DARWIN

E

hlers-Danlos National Foundation has a proud history of volunteer service and we want to reward your efforts. In recognition of these outstanding achievements, EhlersDanlos National Foundation is proud to announce the availability of the President’s Volunteer Service Award, a prestigious national honor offered in recognition of volunteer commitment. Established in 2003, this new Award is given by the President of the United States and honors individuals, families and groups who have demonstrated a sustained commitment

to volunteer service over the course of twelve months.

Our goal is to register all of our volunteers for this program. Our award year will run from July 1, 2007 through July 1, 2008. That means that any volunteer work done on behalf of EDNF since July 1, 2007 will be recorded. In order to participate you must register. Once you are registered you will receive a log to be completed monthly; you will receive reminders. For more information, or to register, please e-mail staff@ednf.org.

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To be eligible to receive the President’s Volunteer Service Award, Applicants’ service hours must be confirmed by a registered Certifying Organization.

There are three levels of the Award varying by hours of service completed within a 12-month period: Kids 14 and younger

Adults Ages 26 and up

Bronze Award

50 - 74 hours

Bronze Award

100 - 249 hours

Silver Award

75 - 99 hours

Silver Award

250 - 499 hours

Gold Award

100 or more hours

Gold Award

500 or more hours

Young Adults Ages 15 - 25

Families & Groups

(two or more people, each contributing at least 25 hours to total)

Bronze Award

100 - 174 hours

Bronze Award

200 - 499 hours

Silver Award

175 - 249 hours

Silver Award

500 - 999 hours

Gold Award

250 or more hours

Gold Award

1,000 or more hours

President’s Call to Service Award Individuals who have completed 4,000 or more volunteer service hours over the course of their lifetime are eligible to receive the President’s Call to Service Award.

Between September 1 and December 31, 2007

$25 Donation to EDNF

for Active CarePages created at http://www.carepages.com/ednf And the Organization Generating the Most NEW Active CarePages between September 1 and December 31, 2007

Receives an Added $5,000

GUIDELINES FOR SUBMISSIONS TO LOOSE CONNECTIONS 1. For text documents, use Helvetica or Times of at least 10 points (preferably 12 to 16) in size, so our editors can easily read your document and prepare it for publication.

Attach the text document in either Word (.doc) or Rich Text Format (.rtf) to an e-mail sent to editor@ednf.org that also tells us how to reach you for more information.

2. For photographs, attach them to an e-mail to editor@ednf. org; send three to five images that are at least 2400 x 3000 pixels (300 dpi resolution & 8 x 10 inches) and without compression beyond that performed by the camera when it was taken. In the e-mail, please identify the event or cause for the photographs, including any relevant identification (persons involved, date, photographer’s name if needed) and how to reach you for more information.

3. Following are the deadlines for the next year of four issues; special arrangements can be made with the editors before these dates, but not afterwards.

PUBLISHED FEATURES ON DUE WINTER ’07

DEC 7

OCT 19

COLUMNS DUE NOV 5

SPRING ’08

MAR 14

JAN 25

FEB 15

SUMMER ’08

JUNE 23

MAY 16

MAY 30

FALL ’08

SEPT 5

JULY 25

AUG 8

Text articles, photographs, or any other submissions to Loose Connections are accepted only on condition that publication of that material is not under copyright or other restrictions on its publication. EhlersDanlos National Foundation reserves all and final editorial privileges, including the right to choose not to print a submitted story; submissions may be edited at the discretion of the editorial staff.

The opinions expressed in Loose Connections are those of the contributors, authors, or advertisers, and do not necessarily reflect the views of Ehlers-Danlos National Foundation, Inc., the editorial staff, Professional Advisory Network, or the Board of Directors.

EDNF does not endorse any products.

L O O S E CONNECTIONS PAGE FOUR • AUTUMN 2007

This year, EDNF will be printing a special insert in our December 2007 edition of Loose Connections. This special section will be dedicated to those who have done so much for EDNF this year, a listing of our donors and supporters. Now, we offer a chance to acknowledge our volunteers and share the dedication of our families with the entire membership.

Want to say thanks for a supportive voice, good advice or just a soft place to fall? Do you want to share someone’s memory? Let our members and friends know how much those people have helped. Below are samples of tributes that will be published in the next Loose Connections.

Ty Beca

Mr. & Mrs. Tom Kruschev

Claire Blanca

In memory of

special research volunteeR, PAN HINGE EDITOR, EDNF/PAn LIAISON You have done and outstanding job. thank you so very much!

EDNF Staff & Board of Directors John Sebastian Brook J. & R. Carter Queen Columbia Johan Corigliano Frank Lynn DeLano Mr. T. Eseliot Bill Finn Triale B. Fire John Galt Frances Gedroyce P.R. Gilt Tim & Ray Gunn Philip Hafer Clint Hilary

Don Lee

Lorraine H. Lieberson Mrs. Ronald McDougal Ironic Mensa A.Lias Moniker Guido O’Malley Jean O’Martin

Have a great year!

Bama Ono Connie Powers Mr. & Mrs. L.W. Priestley

I.Q. Public J.D. Salinger A. Ron Sorekin Mr. Gary Scullin Stevie Songmeister

Half column-inch . . . . . . . . . .

(1.4 in x 0.5 in, no picture) One column-inch . . . . . . . . . .

(1.4 in x 1 in, no picture) One column-inch . . . . . . . . . .

(1.4 in x 1 in, W/picture) Eighth-page . . . . . . . . . . . . .

(4 in x 2.5 in, W/PICTURE) Quarter-page . . . . . . . . . . . .

(4 in x 5 in, W/PICTURE) Half-page . . . . . . . . . . . . . .

(8 in x 5 in, W/PICTURE)

$9.00 $12.50 $17.50 $24.50 $47.50 $85.00

SEND PAYMENT TO EDNF (3200 WILSHIRE BLVD, STE 1601 S TOWER, LOS ANGELES CA 90010) AND AN E-MAIL TO EDITOR@EDNF.ORG BEFORE NOVEMBER 15, 2007.

INCLUDE IN E-MAIL YOUR DESIRED TEXT; YOUR CHOICE OF TYPEFACE A, B OR C; AND IF APPLICABLE ATTACH PICTURE AT LEAST 1,200 PIXELS x 1,500 PIXELS IN SIZE.

Typeface A Typeface B Typeface C

Campbell B. Superior E.D. Syndromes Gertrude Steinmart Ms Chiara Stemme Alice K. Tablas

Dr. Sol Tardis Jed Tate IV Capt. A. Tenille Sam Whiting Bryan Wingo

�ou are sti� �� in�iration, �o� � mi� �o�

L O O S E CONNECTIONS AUTUMN 2007 • PAGE FIVE

BOOK REVIEW HOW DOCTORS THINK

BY JEROME GROOPMAN, MD • Reviewed by TRACY HORSTMANN

W

hen you hear hoofbeats, benefit of having a medical background. think about horses, not How could they begin to navigate through such issues, especially when zebras. they had problems that needed time and investigation to reach the heart of the Common things are common. diagnosis?

In his book, How Doctors Think, Dr. Jerome Groopman challenges these maxims With incredible openness, Dr. Groopman that interns are made to internalize discusses what is taught in medical during their training. In a poignantly- school, and what is not. He shows how written chapter about a mother trying to doctors learn from the doctors before understand the reasons for her adoptive them, including surgical technique or daughter’s life-threatening illness, I was types of medications prescribed. And surprised to read these sentences, and he reminds us that if the doctors before Dr. Groopman’s request that doctors stop have not learned or encountered obscure relying on them. He even states that the illnesses or disorders, then the interns phrase “zebra retreat” describes when a and residents do not really learn much doctor shies away from a rare diagnosis. about these issues, either.

He then postulates why doctors are Additionally, Dr. Groopman opens the reluctant to be “zebra hunters.” curtain and sheds light about a variety of Given that the phrase adopted by the people involved in the diagnostic process.

Ehlers-Danlos National Foundation is He discusses radiologists and how they asking doctors to be zebra hunters, it was read x-rays, and how lab results are refreshing to know there is a physician interpreted. He speaks about doctors who who sees problems with diagnostic may be too quick to prescribe surgeries, processes. For Dr. Groopman, it is and how pharmaceutical companies important that this message be brought influence some doctors. What emerges is a book to which anyone who has ever to the public dialog. had difficulty finding a diagnosis can The idea for this book came about when relate, and because of the information he was on rounds with his students. He presented, this can lead to any number noticed that they were not as engaged of feelings. in diagnosing their patients or looking beyond the familiar as they could be. Each person who reads this book is Students were taught to use algorithms going to react differently; some may for diagnosing, and those were relied find it a validation, and some may find on without any further attention. He it frustrating — especially if they are still questioned his own teaching skills, looking for a doctor or specialist to listen wondering how to get them to go beyond and understand what they are going the first impression. This is when he first through. Those of us, or our loved ones, asked himself, “How do doctors think?” who have finally been diagnosed with This meta-analysis took on new meaning EDS may find ourselves thinking, “Have when he was having difficulty with his I got a story for him!” But Dr. Groopman wrist. Within three years’ time he saw has taken the first step. He has given us six doctors and was given four different the background and the tools to talk to opinions, including four different surgery our doctors. The focus then needs to be options. He wondered how the same on to taking that energy or anger and issue could warrant so many different forming it into a positive device, using diagnoses and solutions. He wondered the suggestions in the book to help you about lay-people who did not have the

or your loved ones navigate through the medical establishment.

While Dr. Groopman does not think patients doing research is a bad thing, he reminds us that doctors spend years and years in medical school and many feel more than slightly put-off when a patient comes in with printouts and information about what they think they have. A contentious doctor may ask to keep the papers to look over and then do their own exam, perhaps scheduling another visit to go over both sets of information.

Finding a doctor who will go that extra step may not be easy to do. However, in lieu of presenting the information straight out, he also recommends asking the doctor questions to help open up the communication of diagnosis.

He gives many examples on how to open this dialog, including practicing speaking about the symptoms and issues, keeping a calm head, and asking questions that go beyond yes or no answers. To facilitate appointments, write questions down, and highlight at least two or three you know you want answers to so you have direction. The key is to be calm, not intimidated or demanding. Dr. Groopman suggests to practice in front of a mirror (or with your best friend), and if you anticipate a brush-off, to have a followup question or statement ready.

Dr. Groopman stresses how patients and doctors must work together and that if an interaction is not a good fit initially, not to waste too much time trying to make it work. Ultimately, the doctor/patient relationship needs to be one of trust and communication. If these elements are not present with a doctor, perhaps when you decide not to see them anymore you can send the book as food for thought.

How Doctors Think, by Jerome Groopman, MD, was published by Houghton Mifflin Company, March, 2007.

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L O O S E CONNECTIONS PAGE SIX • AUTUMN 2007

KIDS & TEENS Teenagers from Low Income Families at Greater Risk of Migraine MEDICAL ALERT BRACELETS

should be an important part of the daily wardrobe for people with EDS, especially children and teens. There are obvious reasons for those with the vascular form of EDS but many with hypermobility form seem to think it isn’t necessary. In the case of an emergency it is vitally important that emergency rooms are aware of pre-existing medical conditions. We never plan for emergencies, but if they happen please be prepared and allow the medical staff the opportunity to know what they are dealing with. When noting Ehlers-Danlos on a medical alert, an emergency response team can call ahead so staff can be better prepared. Some medical alert companies offer computer thumbdrives which can make your medical history instantly available to a doctor with a computer.

According to a study published in the July 3, 2007, issue of Neurology, the medical journal of the American Academy of Neurology. For more information about the American Academy of Neurology, visit http://www.aan.com.

experiencing migraine. The study also found most teenagers have one to four migraine attacks per month and most are severely impaired or require bedrest.

Bigal says the study is consistent with past studies which have found a strong relationship between migraine and low income in adults, but there are limitations. “Psychiatric factors, such as depression, anxiety, and substance abuse, were not measured in this study. It may be that these factors could explain the association between migraine and low income, which is why we need to better For the study, researchers surveyed 18,714 explore these factors,” said Bigal. adolescents and their parents. A total of 1,178 adolescents had migraine.

The study was supported by the National Headache Foundation.

In households with an annual income lower than $22,500, the rate of migraine The American Academy of Neurology, in teens without a parental history of an association of more than 20,000 migraine was 4.4 percent. In families n e u r o l o g i s t s a n d n e u r o s c i e n c e earning $90,000 or more, the rate was professionals, is dedicated to improving 2.9 percent. patient care through education and research. A neurologist is a doctor “Possible factors associated with low with specialized training in diagnosing, socioeconomic status, such as stress, treating and managing disorders of the poor diet or limited access to medical care brain and nervous system such as stroke, may be responsible for this increase,” Alzheimer’s disease, epilepsy, Parkinson’s said study author Marcelo E. Bigal, disease, and multiple sclerosis. ■ ■ ■ MD, PhD, with Albert Einstein College of Medicine in Bronx, NY. “We plan to further investigate the role of nutrition, stress and treatment patterns since migraine may interfere with education, making it a public health concern.”

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eenagers from low income households with no family history of migraine are more likely to suffer migraine than children from upper income families, according to a study published in the July 3, 2007, issue of Neurology®, the medical journal of the American Academy of Neurology.

In families with a history of migraine, the rate of migraine among adolescents was nearly the same between both income groups. “It’s possible that in those with family history of migraine, the biological predisposition dominates and household income does not have a strong effect,” said Bigal.

The study found that overall 6.3 percent of teens experience migraine per year, with more girls than boys and more Caucasians than African Americans

CRANIUM (FRONT)

L O O S E CONNECTIONS AUTUMN 2007 • PAGE SEVEN

NIHSENIORHEALTH.COM TIPS

FDA’S EFFORTS

H

We include these reports from news releases because many EDSers a re a l s o d i a g n o s e d a s h a v i n g Fibromyalgia — Ed.

ON TALKING WITH YOUR DOCTOR HELP FIBROMYALGIA FROM NEWS RELEASES FROM NEWS RELEASES ow do you talk about a sensitive subject with your doctor? What if you forget to ask an important question? What if you feel rushed during your visit?

How can you get the most out of your visit with your health care provider?

Being able to communicate openly, comfortably and assertively with your doctor can help you make good health decisions and stay well. But some older people shy away from this approach and hesitate to ask questions or take the doctor’s time.

The best patient-doctor relationships are more of a partnership, with both sides taking responsibility for good communication. To guide older patients in speaking with their doctors, the National Institutes of Health (NIH) offers Talking with Your Doctor, a newly released topic on NIHSeniorHealth.gov, a web site developed by NIH with the needs of older people in mind. The NIHSeniorHealth.gov web site is a joint effort of the National Institute on Aging (NIA) and the National Library of Medicine (NLM), which are components of the NIH.

says are among the many helpful tips older adults can find on the site.

One of the fastest growing age groups using the Internet, older Americans increasingly turn to the World Wide Web for health information. In fact, 68 percent of wired seniors surf for health and medical information when they go on-line.

NIHSeniorHealth.gov is based on the latest research on cognition and aging. It features short, easy-to-read segments of information that can be accessed in a variety of formats, including various large-print type sizes, open-captioned videos and an audio version. The site also links to MedlinePlus (http://www.nlm.nih. gov/medlineplus/), the National Library of Medicine’s premier, more detailed site for consumer health information.

NIA leads the federal effort supporting and conducting research on aging and the health and well-being of older people. NLM, the world’s largest library of the health sciences, creates and sponsors web-based health information resources for the public “Most people know that communicating and professionals. with their doctor is important to their health care, especially as they age The National Institutes of Health and are more likely to have health (NIH) — The Nation’s Medical conditions and treatments to discuss,” Research Agency — includes 27 says Judith A. Salerno, M.D., NIA Institutes and Centers and is a deputy director. “The key is to know component of the U.S. Department of Health and Human Services. It is the how to have that conversation.” primary federal agency for conducting Older adults can turn to this newest and supporting basic, clinical and feature on the NIHSeniorHealth web translational medical research, and it site for information on managing investigates the causes, treatments, conversations with their doctor. How and cures for both common and rare to prepare for a doctor visit, what to diseases. For more information about ask, what information to provide, and NIH and its programs, visit www.nih.

■■■ how to understand what the doctor gov.

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he U.S. Food and Drug Administration (FDA) recently announced the approval of its first drug to treat Fibromyalgia. This announcement is one more step towards increasing recognition and validation by U.S. government health officials and others in the healthcare community of the seriousness of Fibromyalgia.

With the number of Americans suffering from this debilitating condition having risen in recent years to nearly 12 million, Fibromyalgia represents a population of nearly 4%, and can no longer be ignored by the medical community. While the need for continued research and studies still exists, the importance of the FDA announcement represents a change in acceptance as well as thinking.

As the FDA announcement permeates through the community of Fibromyalgia suffers, it is essential to understand the medical management required in treating this illness. Fibromyalgia treatment is not accomplished in a single short visit with a physician and a comprehensive approach is essential for successful results.

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“I am fond of only what comes from the heart.”

— Martha Washington

L O O S E CONNECTIONS PAGE EIGHT • AUTUMN 2007

SHARING OUR GOLDEN THREAD STORIES

DELAYED GRATIFICATION

BY OLIVIA M KENNETT

I

most certainly would have been in intensive care had I not worn my seatbelt; I may have ended up on the hood of the Jeep, or worse yet, melded together with the semi stacked high with two-by-fours. The sounds of colliding metal can be roughly compared to a crushing coke can, only a hundred times louder, and with enormous force.

Surely, I was injured; luckily, I didn’t suffer even one cut. However, deep within my joints, I began to ache, and muscles in my neck and back tensed up as tightly as a guitar string. I had deeply and profoundly injured the soft tissue surrounding my shoulder, spine, knees and neck. I tore ligaments, tendons, and strained various muscles throughout my body.

After fours years of dealing with this new entity in my life, I awoke one January morning to a stabbing pain running the length of my spine as I sat up in bed. Two days later, I was diagnosed with long-term, progressive and degenerative damage to my lumbar spinal disc. I was twenty-three years old at the time. I would need fusion surgery, or at best, be the guinea pig for a new spinal device. I chose the device. As I sit typing, an artificial metal alloy disc sits between two lumbar vertebrae.

Amazingly, it only feels slightly different from the real thing.

Days after this car accident, to deal with the stewing, mounting and erupting pain, I poured my heart out writing journal page after journal page. I tried, futilely, to explain my pain away, to act as though it were short-term, fleeting, and minimal. I wrote poetry, scribbled pictures, doodled endlessly, and even took up painting to occupy my mind; I had to deny this endless, throbbing pain; it was consuming my daily thoughts.

my ankles in buckets of near frozen water; but when constant, burning pain continues, you have to at least try to help someone else comprehend and share those feelings, or you’ll go crazy. Discussing subjective pain with family, friends, and colleagues became tiresome; I tried explaining aspects and technicalities of my complicated health issues to those who inquired. It’s tough trying to convince another person how pain has become your constant companion.

I desperately wanted to know why suddenly, at times, I couldn’t do simple things such as brush my hair without pain. I’ve experienced eight orthopedic surgeries. Throughout four years of college, I only played two years of my scholarship sport—golf. The rest of the time, I was on the surgery table, in therapy, icing my joints, and taking pain medication to control the aching. I was trying, without success, to do what I used to do the way I used to do it. No matter how often I thought I was healed, I began to ache with only a few days’ activity. I desperately wanted back the healthy, strong, injury-free body of my high school days that I painfully realized was forever changed. I was mourning the health that prompts grandparents to sigh in reflection, “Youth is wasted on the young.”

Ironically, or perhaps because of my humbling experiences, I continued my studies in the field of Exercise Science — a field not entirely suited for an individual in bodily pain, as the field depends largely upon daily exercise.

Driven by an inner persistence to remain at least somewhat connected with the athletic field I had for so long been a part of, I became both an expert in the field of exercise techniques as well as a licensed teacher. I also completed I have a high pain tolerance — I played graduate school to enhance and refine years of basketball and religiously iced my knowledge.

I know about my body, I try to listen to it. I know how to tailor exercise for others so that they may become healthier or recover from injury. As a personal trainer and fitness advisor, I teach clients how to take care of their bodies.

The satisfaction I would have received from excelling athletically or from the competition of sport is now equaled by a smile and a kind word from clients. In some small way, their accomplishments are my accomplishments.

I’ve often experienced fatigue, impatience, frustration and exacerbation of my own pain helping clients.

Stretching a person’s legs or arms can be taxing on your own joints.

Repeatedly lifting dumb bells can pull on scar tissue and inflame injuries. I knew I would have to cut my client load or stop altogether to maintain my own health. Deep down, I did not want to stop giving to others that which gave me joy, but I knew it was going to have to end sooner or later.

This spring, feeling at the end of my rope — physically, emotionally, and mentally, I learned something so cathartic that the anger I felt from years of painful injuries dissipated, like fog on a summer day. I was diagnosed on May 4, 2007 with Ehlers-Danlos syndrome, Hypermobile Type. It’s a long name for a simple syndrome. It gives cause,

L O O S E CONNECTIONS AUTUMN 2007 • PAGE NINE

as my doctor explained, as to why I’ve had so many recurring joint problems throughout the years. It also lends explanation as to why surgery has been ineffective at stabilizing my shoulder.

The moment the doctor said, “I think we have a diagnosis for you; you have EDS, and I think we’ve found a cause for your symptoms,” it was as if a weight rolled off my shoulders. I tried to subdue the upwelling of tears, but I started crying uncontrollably. The physician’s honestly expressed tenderness, so often unseen in the medical field, is perhaps partially explained because he also has EDS. He was the only person whom I had ever met who intimately understood how I was feeling. Even before he stated his diagnosis, his precise, accurate questions and observations of my physical and emotional condition made me hope he had some answer. It was as if he could read my mind. He could read the physical signs I unknowingly displayed. After his personal disclosure of living with EDS, I left his office numb, emotionally fatigued, but mentally refreshed. The uncertainty that was eroding my will to continue through pain had now been met with a reason and an answer.

Today, even as I write, I have a new outlook on things. No longer do I have to wonder why nothing is working to make me feel better — surgery, heavy pain medication, and physical therapy.

I can now accept that because of EDS, coupled with exacerbation from the vehicle accident, my body will recover as best as the syndrome allows. The mental catharsis this diagnosis has given me is unbelievably reassuring. EDS is incurable; however, I am learning how to manage the chronic joint pain; I know it will never subside completely. I know I have EDS. Some things you just have to accept. This condition is one of those things. It is so much easier to face your foe, to know what he looks like.

He said that if I did have EDS, it would explain the recurring surgeries. Knowing the true origin of the pain conditions, I sometimes wonder, “Why didn’t anyone tell me? Why couldn’t they at least have mentioned this as a far-fetched answer?

How can well-educated orthopedists miss this?” The diagnosis could have prevented a lot of pain, anxiety, and frustration.

Ehlers-Danlos can be difficult to diagnose because those with Hypermobile Type are often healthy looking. The EDS specialist told me many of his patients are women; he even treats a few models.

It is easier for some people, even doctors, to think patients could be exaggerating symptoms — even hypochondria. Many times, patients with EDS — Hypermobile Type are misdiagnosed as having Fibromyalgia or Chronic Fatigue syndrome; they do not necessarily show the more severe manifestations of the syndrome.

My relief at being diagnosed with a genetic syndrome may appear contradictory. However, one has to realize that for me, it is a piece of knowledge; it is an answer to an arduous journey and burning questions. Knowing the why enables me to grasp and justify past, present, and future pain. Before this diagnosis, I could only question, “Why isn’t anything helping?” Now, I am at peace with my lot in life. I don’t resent the pain any longer. I am useful, content, and enlightened.

I still have pain, but medication controls it. I am learning how to exercise and treat my body with extreme care so I don’t further weaken my joints. I’m becoming educated about the syndrome.

There will be many more doctor visits and numerous tests. Granted, I will have to give up some things: personal training, contact sports, jump rope, running, and any sport that involves throwing or subjects my joints to lessI wonder how none of the previous than-favorable positions. For a person physicians identified the parallels in whose life is about fitness and sports, my symptoms. For example, about two this is hard … but not impossible. ■ ■ weeks before I was diagnosed, a surgeon I’ve seen for years asked me to “let him know” about the results from my consultation with the EDS specialist.

L O O S E CONNECTIONS PAGE TEN • AUTUMN 2007

SHARING OUR GOLDEN THREAD STORIES

MUSING ABOUT FUNDRAISING

BY JUDY SOBEL

I

h av e always hated fundraising. Luckily, at PS101 in Brooklyn we did no fundraising that required us to go door-todoor selling wrapping paper. There were a few exceptions however. We did collect pennies for UNICEF on Halloween but we were in costume so could not be identified (or so we believed). We collected dimes for the March of Dimes; money went to research a cure for polio. We also had punch boards; I cannot remember much about them, except that for 10¢ you could punch a spot on the board and receive a slip of paper informing you if you had won the jackpot. I cannot remember where the money went or if it was even a charitable fund raising. Since I lived in “Mafia Land” (part of The Godfather was filmed at a house on my corner), it is possible that it was a mob related activity. Even when my own children were in school, I would buy whatever they were selling, so they would not have to peddle their wares.

After being diagnosed with EDS at the ripe old age of 55, I joined EDNF and started a local group here in Atlanta. We did little fundraising, so I personally contributed whatever I could spare. Since I was actively employed at the time, I found it easier to make donations myself than to solicit others. Our group did decide to do fundraising by selling note cards with copies of pictures by a local artist — if anyone wants a box, please contact me as I have many left.

participated in national and local EDNF projects. But I still could not bring myself to activity solicit funds. I worked hard on preparing for the conference in Houston which was a great success, I think due mainly to Michele Hegler’s unceasing work in making it all happen. On the way home from the conference, my husband and I decided to take the long road home and vacation along the way. Everything was wonderful until we hit Jasper, Texas where I contracted a life-threatening case of e-coli.

I started to have severe stomach pain. Since I had already lost my appendix, I couldn’t imagine what was causing the excruciating pain.

We stopped at a motel for the night on the Texas/Louisiana border.

The next morning, I couldn’t wake up; I was in a coma. My husband frantically called 911, and the ambulance took me to the nearest hospital, Our Lady of Lourdes in Lafayette, Louisiana. I didn’t come out of the coma until the next day, and I found myself in the ICU. It was determined that I had e-coli and aspiration pneumonia.

That was the sickest I had ever been. The severity of the attack was exacerbated by EDS. At my suggestion, Dr. Nazli McDonnell was called to confer on treatment. She was in the airport at the time bound for Turkey. She was able to speak with the staff and give them helpful hints on how to handle some of the When I retired from teaching, my problems I developed. I was moved income was cut drastically. I could no to a regular room after about ten days longer fund our local group by myself. I in ICU. did have more time to volunteer and

We were getting ready to resume our journey back to Atlanta when I develpoped uncontrolled diarrhea and a grand mal seizure that lasted for eight hours. Back to ICU and many more tests: I now had moderate to severe neurological defects including loss of motor coordination, speech aphasia and apraxia and hearing loss. A wonderful neurologist who, in consultation with my neurologist in Atlanta, put me on a program of medication to control the seizures. Rehab was planned for me and begun in the hospital. I would not be released from the hospital, however, until an EEG showed that brain agitation had ceased. It took another ten days in ICU and three more EEGs until I was declared fit to travel. My son flew down to help my husband drive home so they could do the trip in one day.

After months of rehab, I have recovered some of the skills I lost. I still have a hearing loss, and — I who ran a computer training program for seniors — am slowly regaining my computer skills. I still have no balance and cannot step down off a curb without falling.

Why am I telling you all of this? A little self-analysis is called for at this point.

Losing my father at an early age made me very independent. I hated asking anyone for help for anything. We were left almost penniless, and no family member stepped forward to help us. Not only did I not want to ask for help, I was also afraid of being turned down. Although I went out of my way to aid others, I still found it difficult to ask anyone for help for myself. I think the general consensus at the hospital was that the various

L O O S E CONNECTIONS AUTUMN 2007 • PAGE ELEVEN

and sundry EDS problems turned what should have been a painful but manageable illness into a lifethreatening experience.

I realized that I could no longer send in my few dollars and expect EDNF to accomplish its very important goals which might have prevented or mitigated my problems. So I bit the bullet and launched into direct fundraising. I started by setting up a First Giving page and a goal of $600. I am proud to announce that I have already reached that goal and will now set another one.

You never know who is out there willing to help until you ask. This is from a letter I received from an old, but not very close, friend: However, we will send the contribution of $500.00 in a day or so. Good luck.

I know you pour your heart and soul into the organization.

If I can do it, so can you.

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EDNF RESEARCH PRODUCES RAPID RESULTS STAFF REPORTS

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DNF is proud to announce the results of new research directed toward gaining understanding of EDS. These two projects were sponsored

by EDNF and administrated through National Organization for Rare Disorders (NORD) using EDNF member donations of $70,000 and have come to fruition in an amazingly short two years. Margaret Casal, DVM, PhD and Anton Persikov, PhD each received a grant and both have completed their research projects. We include here the abstracts of their research.

Establishing Molecular Basis of Ehlers-Danlos Syndrome

by Bioinformatics and Biophysics Approaches Anton Persikov, PhD • Lewis-Sigler Institute for Integrative Genomics Princeton University

Dr. Persikov reports: Glycine mutations in type III collagen gene often lead to the vascular type of Ehlers-Danlos syndrome. My study showed that these substitutions result in destabilization of collagen triple helix, which varies depending on the amino acid residue replacing for glycine, as well as amino acid environment of the mutation site. The level of this destabilization may determine whether mutation will or will not lead to disease. In particular, when proline residue is found next to the mutated glycine, the triple helix destabilization is more dramatic, leading more frequently to pathological EDS phenotypes. The least destabilizing mutations, when glycine is replaced by alanine, cysteine or serine, and these residues are not followed by proline, lead to minimal destabilization of the collagen and normal phenotypes.

I will continue studying how mutations observed in EDS affect collagen ability to bind other molecules in extracellular matrix.

Understanding of molecular basis for EDS together with modern machine learning methods will allow prediction of phenotype from the knowledge of genotype. In another words, from DNA analysis it will be possible to predict whether alterations in collagen gene will or will not lead to disease.

Dr. Persikov has used the results of this study in two published research articles, available in whole on the EDNF Website: Self-association of Collagen Triple Helix Peptides into Higher Order Structures Y-Position Cysteine Substitution in Type I Collagen (a1(I) R888C/p.R1066C) Is Associated with Osteogenesis Imperfecta/Ehlers-Danlos Syndrome Phenotype

THE FOOT

L O O S E CONNECTIONS PAGE TWELVE • AUTUMN 2007

A Canine Model of Autosomal Dominant Ehlers-Danlos Margaret Casal, DVM, PhD • Section of Medical Genetics Veterinary Hospital of the University of Pennsylvania

The primary goal of this project was to provide a large animal (canine) model of the Ehlers-Danlos syndrome (EDS) to mechanism of disease. A female Labrador retriever with an autosomal dominant form of EDS was donated to the Section of Medical Genetics at the Veterinary Hospital of the University of Pennsylvania for characterization and expansion of this canine model. Initial studies included the identification of the defective gene and characterization of the disease to further strengthen the EDS dog as a model for the human disorder. To this end, skin biopsy samples were obtained from each dog under local anesthesia (as is routinely done in the clinical setting for canine patients), radiographs (X-rays) of all limbs were taken, and breeding studies are still being performed to confirm the mode of inheritance. Skin biopsy samples were examined by routine microscopy and electron microscopy. The biopsy samples were also examined for elasticity (tensile strength) and fragility.

The hearts of all dogs were examined routinely by auscultation (stethoscope), EKG, and echocardiography (ultrasound of the moving heart).

In summary, our dogs show not only the same clinical and pathological features as humans with EDS but they also have the same problems with medical management such as placing IV catheters and local lidocaine application. Future experiments are directed at developing better methods for placing IV catheters, more effective local anesthetics and understanding reasons why the skin does not react to local anesthetics as it does in normal dogs.

The ultimate goal is to use the EDS dog for treatment trials that would be curative rather than just palliative. We are in the process of establishing collaborations with the research dermatologists at The Thomas Jefferson University in Philadelphia, that have been using iRNAs (interfering RNAs) in mice with EDS. The iRNAs are designed to interfere with the production of the abnormal collagen molecule, so that only the normal fibers are generated.

The funding received from EDNF through the NORD Foundation has enabled us to generate results that have led to submission of an NIH grant to further study clinical care and treatment of this and the other genetic skin diseases we work with.

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(continued from front cover) unstable at the top and she has three herniated disks in her neck.”

Nikki is prone to imbalance in vision and range; sometimes waking up with one eye completely dilated while the other remains normal. At times even walking down a hallway can pose a challenge.

“I walk into walls and fall down sometimes,” Darwin said with a laugh. “I bruise really easily and tend to walk into a lot of things. My brother (John) has very sensitive skin; when he falls he gets some serious scars.”

EDS affects 1 in 5,000 people and has been found in Darwin’s 16-year-old brother John. Eleven-year-old brother Peter is involved in a clinical study at the National Institute of Health in Baltimore, Md., along with Nikki and John to better understand the inherited tissue disorder.

Playing for Meger Nikki’s height was an obvious genetic advantage for her in most athletic sports, so before Darwin went to John Paul, Plano Senior head coach Lynn Meger saw visions of a future low-post dominator. “(Darwin) was going to be one of my starters her junior and senior year,” Meger said. “As a coach you get a little excited about a player like that.”

Darwin was moved up to the varsity level early on and received a few minutes of playing time; enough to get some experience. But towards the end of Darwin’s sophomore season with the Lady Wildcats, back problems made it more difficult to practice and play.

“I told coach Meger and at first she asked me if I could fight through it,” Darwin said. “I would play a little and then I just couldn’t handle it. That’s when she realized something was really wrong and got worried.”

Meger couldn’t question Darwin’s toughness as she was a hard worker who gained the respect of her teammates.

After practices, Darwin would come home and lay flat out on the floor in pain that would last for days, sometimes weeks. Nikki saw a variety of doctors who were unable

L O O S E CONNECTIONS AUTUMN 2007 • PAGE THIRTEEN

to diagnose her with anything specific, and With her teacher standing at the front of the being left in limbo became difficult. class, Darwin didn’t want anybody to think she was complaining, but she had to reach “It was frustrating for me as her coach to somebody. know that she was in the amount of pain she was in,” Meger said. “On top of that, no “I didn’t know what to do,” Mrs. Darwin doctors were able to help her and she was said. “I asked her ‘How am I supposed to becoming frustrated as well.” help you right now?’ But she didn’t want anybody to think she was complaining.

The educated mother That’s been the toughest part is getting her to realize that she’s not complaining if she As any caring mother would do, Mrs. Darwin needs help. She doesn’t want anybody to became as educated as possible, in hopes of feel sorry for her; but if she needs help, she finding a solution for her daughter’s ailments. needs help.”

She took notes and researched nearly every clinical word the doctors threw her way.

Initially, the doctors thought Darwin could have Marfan syndrome, which is a major cause of deaths among young athletes.

“She was a very inspirational person for us as a player and as an assistant coach,” Dinkins said. “Nikki was right there beside me during home and away games, and we named her honorary co-captain of the team. She’s a very mature person for her age and I knew it was painful for her when she found out she couldn’t play. But she never got upset in front of the girls and never let it show.”

The National Honor Society and PAL’s took on a project with Darwin to sell John Paul crest charms at sporting events and throughout her senior year with all of the Still, Darwin’s passion for basketball was proceeds going to Nikki’s Charm Project indescribable. While she played through the Fund. She has already raised nearly $6,000 pain, her face never winced, but her body and continues to devote time to educating showed all of the signs. people about EDS.

“During one game, the team called a timeout As Darwin heads to college, she will still and when Nikki came to the bench, she was be faced with challenges along the way. just shaking,” Mrs. Darwin said.

Maintaining a healthy lifestyle and a proper exercise routine will be important Afterwards, Dinkins suggested to Mrs. for her body. Darwin does workouts that Darwin that she send her information to her focus on her core, tightening her abs to brother who is an emergency room doctor support her back. in Chicago. With tons of notes and a journal “Some days I feel like I worked out forever but never accomplished anything,” Darwin said. “Then other days I will wake up, not having done anything the day before and However, after running tests, the doctors kept as a file of her daughter’s symptoms, my muscles feel like I was hit by a dump found no problems with Darwin’s heart and she forwarded the information along. truck.” cleared her to play basketball again as long as she could deal with the pain. Some of Within two hours they received a reply.

One of the more imposing tests will be the doctors suggested that it was possible making friends as Darwin will be faced with Darwin was seeking attention and maybe “Almot instantly, he called and said he an entire group of new people to befriend at that she even needed to see a psychiatrist. thought she had Ehlers-Danlos,” Mrs. Creighton.

Darwin said. “He suggested we see Dr. “As her mother, seeing her go through this Mark Lavallee, a sports medicine specialist “I’ll let them know what they need to know pain and knowing my daughter as well as in South Bend, Indiana. He himself had EDS as they need to know it,” Darwin said. “I I do, it hurt to hear them say that,” Mrs. and we took her to see him.” don’t want to just spill my life story onto Darwin said. “And for Nikki, as a teenager, people right when I meet them, but as they it was hard for her to handle because she felt Dr. Lavallee looked at her mouth, her legs and need to find things out I will tell them.” like people didn’t believe her.” judged her flexibility. He did no brain scans or MRIs and diagnosed Nikki with EDS. At the age of 18, Darwin’s maturity is Thinking that she would be unable to abundant. Her hope is that more people continue playing basketball, Darwin “I was sort of relieved because there was become aware of EDS and that she can transferred to John Paul during her finally an answer,” Darwin said. “But he still become a spokesperson, bringing a shred of junior year, where she thought she could wasn’t quite sure how to fix the pain in my optimism to those who are down. concentrate more on her studies. back. I found out that a lot of the things I had done, I wasn’t supposed to do and I “Yes I have it, but it is something that I After doctor’s decided that she could still find out things that I am not supposed can live with,” Darwin said. “I see some continue to play, Darwin worked herself back to do.” spokespeople who want others to feel sorry in to playing mode under the instruction of for them, but I want to let people know they head coach Lara Dinkins. But the pain still During her senior year, Darwin was unable can still enjoy life.” affected her on a daily basis. to handle the pain any longer but still wanted to be part of the John Paul team. So she took For more information on Ehlers-Danlos One day sitting in class, Darwin sat silently a spot on the bench as a student assistant syndrome, visit: www.ednf.org. More and sent a text message to her mother coach and helped the Lady Cardinals with information on Nikki’s Charm Project Fund telling her that she was in so much pain she an eye of inspiration. can be found at: www.firstgiving.com/ was unable to get up and out of her desk. nikkidarwin.

■■■ “If you ever see a kid just drop dead on the basketball court, often times it’s due to Marfan,” Mrs. Darwin said. “If Nikki was hit the wrong way or bumped or received the wrong impact of any sort that would have been it. So, she wasn’t going to be able to play anymore.”

“I want to let people know they can still enjoy life.”

L O O S E CONNECTIONS PAGE FOURTEEN • AUTUMN 2007

NEWS BLITZ IDEAS

BY MICHELE DARWIN

You will notice we have included a number of media pieces in this issue. Many of us with EDS have tried unsuccessfully to obtain media coverage. Along with the published items, we share this overview of how it might be accomplished. — Ed.

newspapers and magazines have paid writers so it is unlikely they will publish your story as written, but if you can grab their attention, they will be interested in pursuing the story. Be very positive!

Emphasize awareness and ngaging the media fundraising work related to in our mission to raise the subject: awareness for EhlersDanlos can be a daunting task. If the subject in your story has It can involve phone calls that been raising money for EDNF go unreturned and e-mails with or has been involved in anything no replies, or the dreaded “auto relating to EDS and EDNF in reply” that leaves us to wonder your community then both briefly if the e-mails are ever even read. include that, as well as the link There are, however, some tips that a FirstGiving or CarePage so the may lead to a successful media media can see the proof of the awareness campaign but it takes work being done. time to organize and patience on Consult your physician: your part.

E

Begin by writing your story: Try to keep your thoughts clear and concise. Your goal in writing your story is to get the attention of the readers by pulling on their heartstrings and show them you have some outcome you wish to reach: awareness, education, fundraising, etc. You want to get their attention! Remember that

your list with the large paper that covers your area. Don’t forget the free magazines that may be published locally. If you aren’t sure what these might be, the Chamber of Commerce can be a great resource. As you look through the publications, you want to find the e-mail contact information for as many writers as you can. If you can’t find this information in the actual printed paper, go to their website to find them.

Create a Press Release:

Draft an e-mail that serves as a press release. It needs to be brief and effective! Compile an e-mail with the full list of recipients that you have found. Blind copy all of the recipients with the only e-mail address in the “to” line being your Consult your physician and ask own. Include your press release, him/her to read your story to any relevant photos and your check for accuracy in your medical attached story. facts and ask permission to share their contact information with the The final step is to simply be media. Any story written about patient and wait to see if you get EDS that includes current and any interest.

■■■ accurate medical references is far better than leaving it to the reader to fill in the blanks. Our doctors are very busy with other patients, “The most difficult but do try to see if they will at thing I have ever least critique your story before you distribute it.

Find the resources in your community: Make a list of the print media in your town and surrounding neighborhoods. Start at the small community newspapers and end

had to do is follow the guidance I prayed for.”

— Albert Schweitzer

L O O S E CONNECTIONS AUTUMN 2007 • PAGE FIFTEEN

BROOKE’S STORY:

A DOUGLAS STUDENT FIGHTS A RARE DISORDER

BY EMILY MOORHOUSE Contact Brooke Friedman at cure4eds@aol. com. Emily Moorhouse is an intern studying journalism at University of Florida at Gainesville.

D

ealing with a life-altering condition is distressing enough, but not knowing what that condition is or what its effects are can be downright scary. For 14 years, this was the reality of Marjory Stoneman Douglas High School sophomore, Brooke Friedman, and her family. Brooke endures tremendous pain caused by the daily dislocations of her joints including her hands, wrists, ankles, knees, neck, fingers, and hips.

Her parents began taking her to doctors at age two, and, throughout the years, she’s frequented the offices of eight different doctors. Each time, she was treated for the dislocations, but sent home with no firm diagnosis.

Not knowing what precautions were necessary for her “mystery” condition, Brooke and her family tried to go on with life normally. At five, Brooke began playing sports including T ball, softball, flag football, basketball, tennis, and bowling.However, as she got older Brooke’s dislocations increased to 12 to 15 times a day and her pain worsened, especially in her wrists and knees.When she went to camp in the mountains last summer, excessive walking caused her knees to buckle. “I was in pain the entire two weeks of camp and did not know why,” Brooke says. Thankfully, by August, she and her family had finally found a group of doctors who knew exactly that her pain was because of one of the six major types of Ehlers-Danlos syndrome (EDS), Hypermobility. A doctor of genetics and a pediatric orthopedics group at Joe Dimaggio hospital in Pembroke Pines provided the long-awaited confirmation.

Ehlers-Danlos syndrome is a genetic condition with, as yet, no cure. People with EDS have a defect within the collagen in their connective tissue, which normally works like “glue,” to support skin, muscles and ligaments and provide strength and elasticity.

These individuals usually suffer from unstable joints, frequent dislocations, and joint pain, as well as fragile skin prone to tearing, bruising, slow healing, and severe scarring. EDS affects 1 in 5,000 people and life expectancy is usually normal, except for cases of the potentially deadly Vascular type, which thankfully, Brooke does not have.

at Riverglades Elementary School from which she raised over $1200.

She helped to administer the collection and spoke about EDS on the Riverglades television station. Brooke collects donations for the EDS National Foundation on her website,www. firstgiving.com/edsdonation. Her goal is $10,000 and, currently, she has raised nearly $2,100, with more expected.

Brooke also started a recycling drive for cell phones and ink/laser cartridges at Parkland’s public schools, as well as some local businesses.

Brooke is determined With these drives, Brooke has put in over 150 volunteer hours and has to bring awareness to already collected over $600 for EDS. others, educate people “Stoneman Douglas has been very supportive... students are so wonderful on EDS, and raise and receptive to helping with donating money for research. their old cell phones,” Brooke says. “I plan to continue this collection drive for I n a d d i t i o n t o f r e q u e n t d a i l y the next school year and, if it goes well, dislocations, Brooke is easily injured, continue on through high school.” resulting in “black and blue” marks that do not go away for months. Her Brooke’s family has been extremely muscles tire easily, and she has a very supportive. “My mom is very active low pain tolerance. “When I go to the with the national foundation and the dentist, regular Novocaine doesn’t EDS local chapter,” explains Brooke. work,” she says. “I can exercise in the Mrs. Friedman speaks to local groups pool, that is about it… I can’t walk about EDS and has even hosted some for long distances or for more than meetings in their home. ten to fifteen minutes, I can’t walk up or down stairs [and] I can no longer Although EDS has put a significant play sports.” Yet, Brooke feels lucky, strain on Brooke’s daily life and she “some patients with EDS are confined is saddened that she cannot partake in to wheel chairs, no longer able to walk sports or much physical activity, she or use their hands to write.” contends, “I don’t feel any different, I feel like a normal 10th grader, a very Since her diagnosis, Brooke is normal teenager. I love life and I love determined to bring awareness to living in Parkland. I have a wonderful others, to educate people on EDS, and group of close friends and we have a raise money for research. She gives EDS great time together. Nothing stops us presentations at schools and at doctor’s from having fun…I have decided to offices. This March, she arranged make a difference and turn this into a a “Change for Change” fundraiser positive situation.”

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L O O S E CONNECTIONS PAGE SIXTEEN • AUTUMN 2007

FUNDED IN PART BY THE NIH

SELF-ASSOCIATION OF COLLAGEN TRIPLE HELIC PEPTIDES INTO HIGHER ORDER STRUCTURES*

BY KARUNAKAR KAR1, PRIYAL AMIN1, MICHAEL A. BRYAN2, ANTON V. PERSIKOV3, ANGELA MOHS , YUH-HWA WANG, AND BARBARA BRODSKY 4

This is extracted with permission from the full paper. We urge you to read the complete text, available at www.ednf.org (Medical Professionals section under Medical Reports and Findings) or at http://www.jbc.org.

To respond, write editor@ednf.org; always consult your doctors before making changes in your treatment. * This work was supported in part by National Institutes of Health (NIH) Grant GM60048 (to B.B.). The on-line version of this article (available at http://www.jbc.org) contains Figs. 1-12.

These authors contributed equally to this work.; Supported by NIH Predoctoral Research Fellowship Award F31 GM072149; 3Supported by a grant from the National Organization for Rare Disorders; 4Supported by a Deutsche Forschungsgemeinschaft postdoctoral fellowship; 5 To whom correspondence should be addressed: Dept. of Biochemistry, UMDNJ-Robert Wood Johnson Medical School, 675 Hoes Lane, Piscataway, NJ 08854. Tel.: 732-235-4397; Fax: 732-235-4783; E-mail: brodsky@umdnj. edu; 6The abbreviations used are: DSC, differential scanning calorimetry; DLS, dynamic light scattering; PBS, phosphate-buffered saline. — Ed. 1

2

Introduction There is increasing interest in the ability of proteins and peptides to self-associate into aggregates, both in normal and pathological processes. Normal selfassociation processes include fibril formation of collagen and polymerization of actin, whereas pathological aggregation of amyloid peptides, -synuclein, and prions is implicated in neurodegenerative diseases. Interest has focused on the nature of protein aggregation and the molecular and environmental determinants of the self-association process. The study of the ability of collagen-like peptides to aggregate offers an opportunity to characterize a unique system, which may relate to the

5

physiological self-association of collagen been characterized from thermodynamic molecules. and kinetic approaches. In addition, the assembly of type IV collagen into Collagen, the major structural protein networks in basement membranes and in the extracellular matrix, has a charac- the organization of type VII collagen teristic triple helical conformation, association in anchoring fibrils of skin consisting of three polyproline II-like are beginning to be defined. chains that are supercoiled around a common axis. The close packing of Studies of model peptides have the three chains near the central axis contributed much to the understanding generates a requirement for Gly as every of the structure, stability, conformation, third residue, (Gly-X-Y)n, whereas the and dynamics of the collagen triple high content of imino acids Pro and helix. The sequence Gly-Pro-Hyp is the hydroxyproline (Hyp) stabilizes the most stabilizing and common triplet individual polyproline II-like helices. in collagen and the peptide (Pro-HypAlthough imino acids are highly Gly)10 forms a highly stable triple helix. favorable for the triple helix, the post- The molecular structure of (Pro-Hyptranslational modification of Pro to Hyp Gly)10, determined to high resolution by in the Y position confers an additional x-ray crystallography, confirms the basic stabilizing contribution. This further triple helical structure and shows an stabilization of Hyp is likely to result extensive hydration network. Recently, from steroelectronic promotion of the there have been several reports of more favorable exo ring pucker for the collagen-like peptides that self-associate Y position and Hyp involvement in to higher molecular weight structures, solvent-mediated hydrogen bonding. including studies on poly(Pro-HypThe favorable enthalpy of collagen Gly)10, staggered arrangements of (Proindicates that hydrogen bonding is a Hyp-Gly)10 chains, and liquid crystalline major contributor to stability. One direct arrays of triple helical peptides. Crossinterchain peptide hydrogen bond is linked, high molecular weight forms of formed for each Gly-X-Y unit, together (Pro-Hyp-Gly)10, but not the (Pro-Hypwith an extensive water-mediated Gly)10 molecule itself, have previously hydrogen bonding network. The ordered been shown to function as strong inducers water network seen in crystal structures of platelet aggregation. Thus, peptide links the available backbone carbonyls of studies may increase our understanding the triple helix and Hyp groups. of the formation and biological activity of the polymeric collagen structure as well The family of collagens consists of 28 as giving information at the molecular distinct genetic types with a range of level. tissue distributions and diverse functions.

For most collagens, the molecules Here, self-assembly of the collagen model self-associate to form a higher order peptide (Pro-Hyp-Gly)10 is characterized structure, such as fibrils and networks, by a range of biophysical techniques, and the supermolecular structure is including turbidity, CD spectroscopy, responsible for mechanical and binding differential scanning calorimetry (DSC),6 properties critical to function. The most dynamic light scattering (DLS), and abundant collagens are types I, II, and electron microscopy. The peptide is III, which are found in characteristic shown to self-associate with increasing fibrils with an axial D = 670 Å period in temperature, following a nucleationtendon, skin, bone, cartilage, and other growth mechanism, from a simple trimer tissues. The process of association of to a higher molecular weight form. This type I collagen molecules into fibrils has process is promoted by high concen-

L O O S E CONNECTIONS AUTUMN 2007 • PAGE SEVENTEEN

tration, neutral pH, increasing peptide length, and increasing temperature and is a reversible process. The self-association properties of this triple helical peptide are discussed in the context of collagen fibril formation.

MATERIALS AND METHODS The peptide (Pro -Hyp-Gly)10 was obtained from Peptides International (Louisville, KY). The peptides (Pro-HypGly)7, (Pro-Hyp-Gly)8, and (Pro-HypGly)12 were synthesized by the Tufts University Core Facility (Boston, MA) and were purified on a reverse-phase high pressure liquid chromatography system (Shimadzu) with a C-18 column.

Purity of all peptides was ensured by mass spectrometry using matrix-assisted laser desorption ionization time-of-flight (MALDI-TOF). Peptide concentrations of starting solutions were measured by monitoring the absorbance at 214 nm using 214 = 2200 cm-1·M-1 per peptide bond. D-Glucose and D-fructose were obtained from Merck. Buffers used included 20 mM PBS (10 mM NaH2PO4, 10 mM Na2HPO4, 150 mM NaCl) for pH 7; acetate buffer (20 mM sodium acetate, 150 mM NaCl) for pH 3.0-4.5; and phosphate buffers (20 mM Na2HPO4, 150 mM NaCl) for pH 9-11.

DISCUSSION The triple helical peptide (Pro-HypGly)10 is reported here to self-associate under defined conditions of concentration, temperature, and pH. The turbidity curve monitoring self-association is similar to that seen for collagen fibril formation and the polymerization of other proteins, in having a lag or nucleation phase followed by a rapid growth phase and a plateau.

A nucleation-growth mechanism was confirmed by seeding experiments, which eliminated the lag phase. Consistent with this mechanism is the concentration dependence of the aggregation of (Pro-Hyp-Gly)10, which shows a critical concentration of about 1 mM.

gave a linear Arrhenius plot with a negative slope. The promotion of selfassociation with increasing temperature suggests the energetically unfavorable formation of a nucleus during the lag phase is entropically driven. Increasing temperature could loosen the triple helix and its associated water, which may promote self-association. A schematic diagram of the self-association process for (Pro-Hyp-Gly)10 is shown in Fig. 7, suggesting an intermediate loosened state of the triple helix, which has a propensity for association. This is reminiscent of the temperature dependence of assembly of collagen into fibrils, which has been analyzed in terms of forces. Leikin et al. showed this “temperature favored” process of collagen fibril formation is largely because of hydrophilic interactions, which could relate to release of structured water or increasing mobility of side chains. In the case of (Pro-HypGly)10, it is possible that a small increase in mobility of the rigid imino acids could play a role, but it is more likely that loosening of the ordered hydration shell due to increasing temperature is an important factor. Leikin’s laboratory has shown that sugars inhibit fibril formation of collagen by disrupting water mediated hydrogen bonds between triple helices, and the inhibitory effect of sugars on the self-association process of (Pro-Hyp-Gly)10 seen in our present work indicates a similar importance of hydration related hydrogen bonding for the peptide association.

A strong length dependence is observed for peptide association. An increase in peptide length could either lead to a larger number of cooperative interactions or promote a molecular crowding effect because of the larger hydrodynamic radius of a longer rod-like molecule. Consistent with molecular crowding, it has been reported that aggregation of several collagen-like peptides can be induced by very high concentrations (>10 mM).

Higher molecular weight peptides and cross-linked trimers of staggered chains with the sequence Gly-Pro-Hyp form The lag phase decreases, whereas the aggregates with a morphology similar to rate of fibril growth is enhanced with that reported here. increasing temperature, with a maximum rate occurring somewhat below the Self-association also depends on pH, Tm of (Pro-Hyp-Gly)10. The effect of with an optimum near neutral pH and temperature on the rate of association no aggregation at low and high pH

values. The pH dependence of the selfassociation could be related to water activity, or association could be promoted by lower thermal stability and a resultant loosening of the triple helix, because the melting temperature of (Pro-Hyp-Gly)10 shows a small decrease near neutral pH. The observation that a homologous triple helical peptide (Pro-Pro-Gly)10 does not come out of solution under the conditions used in this study suggests that all triple helical peptides do not have the same propensity for self-association.

The differences observed between (ProPro-Gly)10 and (Pro-Hyp-Gly)10 suggest a role for Hyp in promoting self-assembly, which is supported by the observation that recombinant collagen without Hyp does not undergo fibril formation under physiological conditions. The role of Hyp in triple helix association could relate to its involvement in the hydration network or to direct intermolecular hydrogen-bonding interactions between triple helices as observed in the crystals of collagen-like peptides or as proposed

by Gustavson in the 1950s. Preliminary observations in our laboratory on various triple helical peptides with diverse sequences sandwiched between terminal Pro-Hyp-Gly repeats indicate that selfassociation is negatively influenced by the presence of charged residues, a Gly substitution, or an imino acid-deficient zone, in contrast to the positive influence of Hyp residues.

The aggregation of (Pro-Hyp-Gly)10 is reversible. The triple helical peptide comes out of solution as the temperature is increased, forming some supramolecular structure of triple helices.

However, at temperatures higher than 80 °C, the aggregate fully dissolves into denatured monomeric chains. When cooling the unfolded monomers, the triple helix can re-form in a reversible manner, and while in the aggregation temperature range (37-60 °C) there is again aggregation of these refolded triple helices. Interestingly, both the monomertrimer transition and the trimer-aggregate transition appear close to equilibrium.

The results reported here indicate that the triple helical (Pro-Hyp-Gly)10 (continued on next page)

L O O S E CONNECTIONS PAGE EIGHTEEN • AUTUMN 2007

(continued from previous page) molecules are self-associating to form a higher order structure, which is more stable than the individual triple helices and which is fully reversible.

For the peptide, interacting triple helical molecules give rise to branched, fibrillar structures with no long-range order, which contrasts with the highly ordered axially periodic fibrils formed by type I collagen molecules. The short length of the model peptides and the uniformity of sequence are likely to contribute to its less ordered, branched structure and its high critical concentration value. Similar to the peptide association, collagen selfassociation into fibrils is reversible unless aldehyde-mediated covalent cross-links are formed. We suggest that the lateral self-assembly of triple helices may exhibit similar properties because of their common Hyp-mediated hydration networks. These hydrogenbonding hydration networks involving Hyp are inherent in the molecular structure of the triple helix and serve to provide regular hydrogen bonding with the two available backbone carbonyl groups within each Gly-X-Y unit. Such hydration forces have been implicated as critical to the lateral fibril organization.

Physiological interactions often depend on collagen being present in fibrillar or other higher order structures. For example, platelets are activated by collagen via glycoprotein VI; this activation can be mimicked by a crosslinked higher molecular form of (GlyPro-Hyp)10 but not by the triple helical (Gly-Pro-Hyp)10 molecule. Similarly, binding to certain integrins may involve collagens in a fibrillar form.

The ability to study the association of triple helical peptides may provide a tool for investigating interactions that require higher order structure as well as clarifying the principles of triple helix self-association. Elucidation of the principles of triple helix selfassociation may also be important in the design of biomaterials and tissue engineering scaffolds.

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