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2. disease

Progressnotes
MUSC’s Medical Magazine // November 2013
Chronic Blues:
The Link Between Depression and
Chronic Disease Outcomes
Rewiring the Brain’s Circuits to Relieve Depression
Journeying With tinman to the Heart of
Congenital Cardiac Malformations
Regenerating Skeletal Muscle for
Surgical Applications
Changing What’s Possible®
Watch for the MUSC Health Year in Review in January!
Regular issues of Progressnotes will begin again in March of 2014.
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Executive Editor
Etta D. Pisano, M.D.
Vice President for
Medical Affairs
Dean, College of Medicine
Editor
Patrick J. Cawley, M.D., MHM, FACHE
Executive Director/
Chief Executive Officer
MUSC Medical Center
Managing Editor
Kimberly McGhee, PhD
Upcoming CME Conferences
The following conferences, sponsored by the Medical University of South Carolina, will be held in
Charleston unless otherwise noted. Visit www.musc.edu/cme for a complete list of CME conferences.
November 11–13, 2013
Neonatal Pharmacology Conference 2013
Incorporating Evidence-Based Practice into Clinical Decision Making
Francis Marion Hotel
November 15, 2013
Comprehensive Stroke and Cerebrovascular Update
Doubletree Guest Suites Hotel
December 6–8, 2013
16th Annual Frontiers in Pediatrics
Francis Marion Hotel
February 13–15, 2014
Bridge to Hope: Contemporary Strategies for Debilitating Heart Failure
The Sanctuary
February 22, 2014
11th Liver Disease and Transplant Symposium
Crowne Plaza Hotel
March 31–April 2, 2014
45th Annual OB/GYN Spring Symposium
Doubletree Guest Suites Hotel
May 19–20, 2014
Society for Pediatric Sedation Conference
Francis Marion Hotel
May 22–24, 2014
Evidence-Based Drug Therapy Update
Crowne Plaza Hotel
July 21–26, 2014
Intensive Review of Family Medicine
Kiawah Island Golf Resort
On the cover: Gogh, Vincent van (1853–1890). Doctor Paul Gachet (1828–1909). 1890. Oil on canvas,
68 × 57 cm. Photo: Erich Lessing / Art Resource, NY
Medical Science Writers
Lindy Keane Carter, ABJ
Kimberly McGhee, PhD
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Progressnotes
November 2013
2
In Short
Feature Articles
6
Restringing the Heart’s Cords
Down the Stretch: Wireless Technology Enables Physicians to Assess the Entire Gastrointestinal Tract
An Entirely Subcutaneous Implantable Cardioverter-Defibrillator
Opening a Portal to the Spine
Journeying with tinman to the Heart of Congenital Cardiac Malformations
10 Leaving No Trace: Moving From Scar to Regeneration in Wound Healing
14 Chronic Blues
20 Rewiring the Brain’s Circuits to Relieve Depression
Digital Exclusive
Breaking Down Barriers to Health Care for the Hispanic Community:
The Office of Hispanic Health Initiatives in the MUSC College of Nursing
24 Welcome
Patrick J. Cawley, M.D., MHM, FACHE
New MUSC Physicians
The digital edition of Progressnotes can be accessed at MUSChealth.com/progressnotes
or by scanning the code to the left with your smart phone
1
Restringing the Heart’s Cords
ABOVE: FIGURE 1. Gore-tex® loops
(W. L. Gore & Associates, Inc., Flagstaff, AZ)
LEFT: Dr. Mario Castillo-Sang, performing
minimally invasive cardiac surgery
T
he mitral valve allows passage in a one-way direction from the
upper left chamber of the heart (left atrium) to the lower left
chamber of the heart (left ventricle). Two crescent-shaped flaps of
tissue called leaflets open to allow blood to pass from the left atrium
into the left ventricle during a contraction and then close between
contractions to prevent blood in the left ventricle from flowing back
into the left atrium. The chordae tendineae are fibrous strings that
attach the leaflets to the ventricle and control its opening and closing, ensuring a tight fit. According to Mario A. Castillo-Sang, M.D.,
Assistant Professor in the Division of Cardiothoracic Surgery at
MUSC, who specializes in minimally invasive cardiac surgeries, the
cords and leaflets act like “a parachute with the cords (parachute
strings) holding the leaflets (canopy)—if you break one or more
cords, then there is regurgitation of blood or leakage.” The main
symptoms of mitral regurgitation (ie, the flow of blood back into the
left atrium) are fatigue and shortness of breath upon exertion and,
in severe cases, even at rest. Not everyone who has mitral regurgitation requires an operation
as the severity of the regurgitation can be mild, moderate, or severe. Candidates for surgery include patients with severe mitral regurgitation who are manifesting symptoms, who have no symptoms but
who are showing silent damage to the heart on echocardiography,
and who are without symptoms and without silent damage to the
heart but who are deemed to have over a 90% chance of having a
successful mitral repair (as opposed to replacement). Many surgical techniques can be used for mitral valve repair, a
procedure that has as much art as it has science. At MUSC, mitral
valve repairs are performed in a standard approach via median
sternotomy and via right minithoracotomy, all dictated by the adequacy of the approach for each individual patient. According to Dr.
Castillo-Sang, what is new about right minithoracotomy is “not the
2
Progressnotes November 2013
access through the right chest but the much smaller incision.” The
smaller incision reduces the likelihood of infection, speeds recovery,
and causes less scar tissue around the heart. Because it does not
require the lower sternum to be separated, right minithoracotomy
does not disrupt the breathing mechanism, as can happen after the
lower sternum has been split in two.
A preferred technique at MUSC for minimally invasive mitral
valve surgery via right minithoracotomy is the “Leipzig Loop”
technique. Originated in Leipzig, Germany, by Professor Frederick Mohr, one of the pioneers in mitral valve repair, this technique
conserves the original tissue of the mitral valve leaflets and seeks
to replace the ruptured cords that caused the regurgitation using
Gore-tex® loops (Figure 1). “You leave everything the patient has,
but you are reinforcing and putting the Gore-tex loops into sites
where the cords were ruptured to make them competent again,”
explains Dr. Castillo-Sang. In essence, the Gore-tex loops are used
to restring and reinforce the chordae tendineae to improve closure
of the mitral valve (Figure 2), preventing regurgitation.
FIGURE 2. The mitral valve after “restringing” of the chordae tendineae
MUSC’s Medical Magazine
Down the Stretch: Wireless Technology Enables Physicians
to Assess the Entire Gastrointestinal Tract
By Lindy Keane Carter
F
or many people, eating means problems, not pleasure. One
third of the population has some form of digestive disorder,
such as irritable bowel syndrome, gastritis, acid reflux disease, gastroparesis (delayed emptying of the stomach), functional dyspepsia,
and chronic constipation.1 In treating these conditions, gastroenterologists seek to identify the site of the problem in the gastrointestinal (GI) tract. But until recently, they could monitor only the
stomach and beginning of the small bowel with upper endoscopy
and the colon and last part of the small bowel with colonoscopy.
That left twenty-odd feet of small bowel a mystery, explains
Donald O. Castell, M.D., MACG, a Professor in the Division of
Gastroenterology and Hepatology at MUSC. “We people in gastroenterology like to put tubes in one end or the other, but what lies
between is hard to access,” he says.
But now, Dr. Castell and his colleagues at MUSC’s Digestive Disease Center are using a new diagnostic tool that assesses
the rest of the small bowel: an ingestible wireless motility capsule
(WMC) called the SmartPill (SmartPill Corporation, Buffalo, NY).
Its sensors measure the GI tract’s pH, temperature, and pressure as
food moves through, data that reveal the food’s transit time. “So we
have gastric emptying time, small bowel transit time, and then large
bowel emptying time,” Dr. Castell says. “It’s pretty smart” (Figure).
Undiagnosed GI problems affect a large number of people.
Worse, many diagnoses—of irritable bowel syndrome, for example—are made by specialists on suspicion only. “Everyone gives
medications—the primary physician, the gastroenterologist, the
psychiatrist—resulting in side effects and cost,” Dr. Castell explains.
The SmartPill data enable physicians to locate the problem, make a
diagnosis, and recommend the best drug therapy.
Since the U.S. Food and Drug Administration’s approval of
the SmartPill in 2006, several studies have evaluated the device
FIGURE. The sensors of
the SmartPill measure the
GI tract’s pH, temperature,
and pressure as food moves
through, data that reveal the
food’s transit time.
against radio-opaque marker studies and scintigraphy. In a study
of 86 patients with either lower or upper GI symptoms who were
assessed with the WMC vs conventional tests, the WMC provided
new diagnostic information in 53% of those with lower GI symptoms
and 47% of those with upper GI symptoms.2 Other advantages:
the WMC is radiation-free, the patient is ambulatory, and recordings can be done at home.1 Disadvantages include the fact that the
patient must swallow the large capsule and wear the data receiver
for five days. In addition, there is a risk of capsule retention (0.33%),
which may require endoscopic removal or even surgery. “[The
WMC’s] getting stuck is rare but surgical removal may be necessary,” Dr. Castell says.
Contraindications include suspected mechanical obstruction,
gastrointestinal surgery within three months, and Crohn’s disease.3
Dr. Castell uses the SmartPill primarily with patients with chronic
constipation, inexplicable lack of appetite, early satiety, or those with
suspected irritable bowel syndrome (after other diagnostic tests).
For many, he has been able to hone in on the relevant therapies and
discontinue those that are contributing to the problem, resulting in
less frustration, lower healthcare costs, and improved quality of life.
References:
¹ Rao SS, et al. Evaluation of gastrointestinal transit in clinical practice:
position paper of the American and European Neurogastroenterology and
Motility Societies. Neurogastroenterol Motil 2011;23(1):8-23.
² Rao SS, et al. Diagnostic utility of wireless motility capsule in gastrointestinal
dysmotility. J Clin Gastroenterol. 2011 Sep;45(8):684-90.
³ Szarka, LA, et al. Methods for the assessment of small-bowel and colonic
transit. Semin Nucl Med 42: 113-123.
For more information, call MEDULINE at 1-800-922-5250 or 843-792-2200 or visit the digital edition at MUSChealth.com/progressnotes
3
An Entirely Subcutaneous Implantable Cardioverter-Defibrillator
FIGURE. Placement of the subcutaneous ICD. Illustration courtesy of Boston Scientific
P
atients at risk for dangerous arrhythmias and sudden cardiac
death have long relied on transvenous implantable cardioverterdefibrillators (ICDs) to detect an abnormal heart rhythm and deliver
a shock to restore a normal heart beat. Although the ICD has saved
many lives, its leads, which are connected to the heart’s chambers,
can fail or otherwise lead to serious complications. According to
Michael R. Gold, M.D., Ph.D., Director of the Division of Adult
Cardiology and Michael E. Assey Chair of Cardiology at MUSC,
“Leads are placed inside the heart with the heart beating several
million times a year, resulting in a high rate of leads wearing out,
fracturing and becoming seriously infected. Within five to ten years,
at least 20% of leads will fail.”
The subcutaneous ICD (S-ICD System®; Boston Scientific,
Natick, MA) is the first ICD in which the leads are placed under
the skin of the chest and are not connected to the heart (Figure). It
was approved on September 28, 2012, by the US Food and Drug
Administration (FDA) for select patients following the demonstration of the safety and efficacy of the device.1 Dr. Gold was one of
the lead investigators presenting data supporting the efficacy and
safety of the S-ICD to the FDA panel. Although the distance of the
lead from the heart initially raised concerns that it might fail to detect
dangerous heart arrhythmias or misinterpret extracardiac signals that
would cause it to deliver unnecessary shocks, the START trial (Subcutaneous vs Transvenous Arrhythmia Recognition Testing; Clinical Trial Registration: NCT01161589), for which Dr. Gold served as
4
Progressnotes November 2013
a principal investigator, provided evidence that, though both types
of ICDs (traditional and subcutaneous) accurately detected ventricular arrhythmias, S-ICDs detected supraventricular arrhythmias
with more accuracy than did traditional ICDs.2 No lead failures have
occurred in the more than 1000 S-ICDs implanted worldwide.
The relative ease with which the S-ICD is implanted and
accessed offers a number of safety advantages. Because it is not
implanted in the bloodstream, the S-ICD is less likely to lead to
vascular damage or to systemic infection than the traditional ICD;
when infections do occur, they are typically localized and can be
treated effectively with antibiotics. Fluoroscopy is not required to
guide S-ICD placement, sparing the patient exposure to radiation.
Subcutaneous leads are not subject to the stresses of the cardiac
contraction and so are much less likely to fail or need replacement.
Should they fail, they are far easier to access and to extract with far
less risk of morbidity and mortality for the patient.
S-ICDs are particularly appropriate for younger patients and
those with previous infections. For these patients, who may require
an ICD for decades to come, the risk of lead failure and lead extraction, which carry significant morbidity and mortality, is much higher
when implanted with a traditional ICD, subject to the stresses of the
cardiac environment, than with the more durable S-ICD.
S-ICD is also a good choice for chronic renal failure patients,
because it spares them the risk of vascular damage that can occur
with transvenous ICDs and thus does not threaten venous access
for future dialysis. Patients with congenital heart disease, previous
cardiac surgery, or certain anatomic constraints that could obstruct
placement of a transvenous ICD are also good candidates.
Despite its many advantages, the S-ICD has a number of limitations and so is not appropriate therapy for many patients requiring
ICDs. Because it provides no significant pacing support and, unlike
the traditional ICD, cannot be used in combination with biventricular pacing, the S-ICD is not recommended for patients with
congestive heart failure who would benefit from pacing. The S-ICD
also offers no anti-tachycardia pacing, which has been shown to
terminate monomorphic ventricular tachycardia without resorting to
shock, and so is not the best choice for patients with this condition.
The S-ICD will be rolled out first to medical centers like MUSC
that participated in the clinical trials. MUSC is among the first hospitals in the country and the first in South Carolina to offer this next
generation of ICD technology to patients. According to Dr. Gold,
“S-ICD provides South Carolinians access to the latest technology
to help combat sudden cardiac arrest.”
References
¹ Weiss R, Knight BP, MD, Gold, MR, et al. The safety and efficacy of
a totally subcutaneous implantable-defibrillator. Circulation 2013 Aug
27;128(9):944-953.
² Gold MR, Theuns DA, Knight BP, et al. Head-to-head comparison of
arrhythmia discrimination performance of subcutaneous and transvenous
ICD arrhythmia detection algorithms: the START study. Journal of
Cardiovascular Electrophysiology 2012; 23(4): 359-366.
MUSC’s Medical Magazine
Opening a Portal to the Spine
T
raditionally, correcting problems with the spine has necessitated
open back surgery, requiring a large incision (5-6 inches or
longer), muscle dissection, and retraction to expose the spine. Surgeons had full access and visualization of the spine, but at the cost
of significant tissue trauma and long recovery times. Many of the
spinal procedures once done via open surgery are now being performed, with comparable outcomes, using minimally invasive surgical (MIS) techniques that require smaller incisions, resulting in less
blood loss and disruption of muscle tissue. In addition to speeding
recovery times, these techniques are associated with less scarring
and a reduced risk of infection or wound breakdown.
Bruce M. Frankel, M.D., Professor of Neurological Surgery
and Radiation Oncology in the Departments of Neurosciences and
Radiation Oncology at MUSC, has helped pioneer the application
of these MIS techniques, now almost commonplace for the surgical treatment of degenerative disk conditions, to the treatment of
patients with metastatic spinal tumors (Figure) or with traumatic
fractures to their thoracolumbar spine.
Dr. Frankel specializes in MIS techniques for the spine. Instead
of exposing the spine to gain visualization and access, Dr. Frankel
opens a limited portal, through which the exact spinal region of
interest can be visualized with the aid of a microscope and through
which specialized surgical instruments can be passed to perform the
procedure. He makes a small incision off the midline of the back,
much smaller than that which would be required for open surgery,
and establishes a channel to the spine not by dissecting muscle but
by dilating it. Once access to the appropriate region of the spine
has been achieved using fluoroscopic guidance, an 18- to 24-mm
port is inserted. The posterior approach minimizes complications by
avoiding the transabdominal region and the chest.
The more rapid recovery times made possible by MIS techniques are particularly critical for cancer patients with tumors that
have metastasized to the spine. These tumors can put pressure
on the spine, leading to extreme pain as well as loss of mobility
and neurological function. Surgery is one palliative option in these
patients, helping to relieve some of these symptoms by removing
or debulking the tumor. However, many of these patients are in
the last months of their lives, and physicians and patients alike have
had to weigh the benefits that could be gained through surgery
(lessened pain, better ambulation) against the long recovery times
required after open surgery. The availability of an MIS option tips
that balance, because the same gains can be achieved with dramatically shortened recovery times. New approaches to minimally
invasive spine surgery are being pioneered at MUSC to positively
affect the outcomes of patients with complicated conditions involving the spine.
In a series of 72 patients with metastatic spinal tumors at
MUSC, those treated using MIS techniques had shorter hospital
stays, as well as decreased blood loss and wound breakdown, and
the quality of their lives increased, in part due to decreased pain
and better ambulation (data unpublished but presented at national
meetings). The surgery does not prolong survival, but it could affect
FIGURE. Dr. Frankel using a minimally invasive surgical technique (posterior approach)
to remove a metastatic tumor of the spine
it indirectly by making it possible for patients to restart chemotherapy or radiotherapy sooner and to stay ambulatory, staving off
immobility-associated complications.
This same MIS technique can be used to stabilize the spine or
fuse vertebrae in patients who have sustained thoracolumbar fractures, which are caused by high-velocity accidents like car crashes.
Such fractures can result in severe pain, spinal instability, as well as
lack of mobility and neurological function. In a cohort of 61 patients
(MIS technique, n=45; open, n=16), those undergoing an MIS technique vs open surgery lost less blood (mean: 518 mL vs 1800 mL),
had shorter hospital stays (6.5 vs 20.2 days), and had fewer complications (hardware failure: 6.6% vs 12.8%; wound infection: 3.3% vs
6.4%; data unpublished but presented at national meetings).
MUSC specializes in tissue-sparing minimally invasive surgery
for the brain and spine. For example, MUSC is the first in the state
to offer transforaminal endoscopic microdiscectomy for herniated
disk repair. This repair, which adopts a unique approach through
the intervertebral foramen (the opening formed by a neural arch
through the spinal cord), requires only an 8-mm incision and has a
far shorter recovery time than more traditional discetomies.
For more information, call MEDULINE at 1-800-922-5250 or 843-792-2200 or visit the digital edition at MUSChealth.com/progressnotes
5
REGENERATIVE MEDICINE
Journeying With tinman
to the Heart of Congenital
Cardiac Malformations
In the digital edition: Drs. Lee and Atz discuss current and potential
future treatments for children with congenital cardiac anomalies
“I am a Woodman, and made of tin. Therefore I have no heart, and
cannot love. I pray you to give me a heart that I may be as other men
are.” —The Tin Woodman from L. Frank Baum’s The Wonderful
Wizard of Oz
W
hen the Tin Woodman in L. Frank Baum’s The Wonderful
Wizard of Oz is ushered into the presence of the great and
terrible Oz, who is thought to have the power to grant any wish,
he asks for a heart so that he can be “as other men are.”
Children with congenital heart anomalies have much the same
wish—to be like any other child.
Ironically, the tinman gene, a homeobox (HOX) gene that
helps drive embryonic heart development in the fruit fly and that
has homologs in vertebrates such as the human and the mouse,
could well hold the key to future gene therapies for some of these
children. “Understanding the factors and genes that control cardiac development opens up new opportunities for addressing
some forms of congenital heart disease through a genetic rather
than surgical therapy. We envision someday treating a hole in the
heart by turning on a gene that makes heart tissue around the
hole grow and close the defect,” explains Andrew M. Atz, M.D.,
Chief of the Division of Pediatric Cardiology at MUSC Children’s Hospital.
Understanding the part played by the tinman gene and its
vertebrate homolog Nkx2-5 in embryonic heart development is the
focus of the research of Kyu-Ho Lee, M.D., PhD, a developmental biologist who holds a dual appointment in the Department of
Pediatrics, Division of Pediatric Cardiology, and the Department
of Regenerative Medicine and Cell Biology at MUSC. He is particularly interested in the splitting of the common outflow tract
(the vascular structures associated with movement of blood from
the ventricles) into a left side of the heart responsible for systemic
circulation and a right side primarily dedicated to pulmonary circulation (Figure 1). The tinman gene appears to regulate progenitors in the second heart field that develop into the right ventricle,
pulmonary artery, and aorta, all of which play important roles in
balancing the pulmonary and systemic circulation.
6
Progressnotes November 2013
Almost a third of congenital heart defects in children who
survive birth occur as a result of improper splitting of the outflow
tract. These defects, according to Dr. Atz, are among the most
challenging for surgeons: “Many of the complex anomalies pediatric surgeons deal with are related to the defects in the development of the outflow of blood from the heart, and in particular to
the separation of the outflow tract into a left and right side.” Of
these anomalies, perhaps the most common is the tetralogy of Fallot, characterized by four defects in the side of the heart associated
with pulmonary circulation that result in inadequately oxygenated
blood entering systemic circulation. This set of defects often results
in blue baby syndrome, in which infants have a blue tinge to their
skin because of the poorly oxygenated blood.
Controlling the body’s genetic signaling to trigger the regrowth
of heart tissue to repair defective hearts would seem to be the stuff
of miracles. And yet, such therapy is now realistically in reach in
the foreseeable future. What has brought such a miracle into the
realm of reality is not scientific hubris but a revolution in our
understanding of genetics and development and evolution that has
brought with it some sobering lessons in humility.
Lessons in Humility
Science has dealt humans a couple of hard blows to their collective
ego. When Galileo found that the sun did not revolve around the
earth and its inhabitants, it came as quite a shock to our human
sensibilities and understanding of our position as central to the
universe. When Darwin traced our lineage to the apes, he shattered
the long-held notion that we had been created as the dominant
species in the image of God. Even today’s scientists, chastened
by such discoveries, were shocked to have another assumption of
human superiority challenged—that our intelligence and other
special human traits must mean that we have many more genes
than other species.
The sequencing of the human genome brought this generation’s lesson in humility—instead of the 90,000-120,000 genes
predicted by many scientists, we actually only have about 23,000,
no more than some insects or other “lower forms” of life. And
MUSC’s Medical Magazine
KEY POINTS
•A
ll species descended from a common ancestor share a similar genetic toolkit for development.
•D
iversity results not from the addition of new genes but via regulation of the timing, duration, and intensity of the expression of proteincoding genes by gene switches and homeobox genes (the “master genes” throwing the genetic switches).
•T
he tinman gene and its homolog Nkx2-5 regulate embryonic heart development in fruit flies and vertebrates like humans and mice,
respectively, by throwing the gene switches that in turn control expression of protein-coding genes and their synthesis of proteins needed
to build anatomic structures.
• If adequate Nkx2-5 is not expressed, the right-sided structures of the heart associated with pulmonary circulation (ie, right ventricle,
pulmonary artery) do not develop properly, leading to congenital anomalies like the tetralogy of Fallot.
•S
urgery is currently the best option for children with such anomalies, but, once Nkx2-5’s regulatory role in gene expression is better
understood, gene therapies could be developed that could conceivably trigger the body to prevent or repair congenital heart defects like
holes in this part of the heart.
common
outflow tract
right ventricle
left ventricle
FIGURE 1. Dr Lee’s laboratory tests gene switch function. Pieces of regulatory DNA
direct color gene expression in the right-sided heart of mouse embryos.
many of the genes are the same, surprisingly conserved across what
seem to be widely divergent species.
As it turns out, most creatures with a common ancestor (ie, all
tetrapods) share a common genetic toolkit that drives their development. What then accounts for difference, say between a mouse and
a human, if we all start with the same or a very similar set of genes?
Drivers of Diversity
Increasing diversity results not from an increasing number of genes,
each charged with creating a protein with a specific biological function or the building of a specific tissue, but from the regulation of
the timing, intensity, and duration of the expression of genes shared
by species with a common toolkit. While on Galapagos, Darwin
collected several species of finches, which he later surmised had
descended from a common ancestor. He attributed the wide diversity in the beaks of these different finch species to adaptations to
their environment—finches on islands where seeds were abundant
developed tough beaks able to crack them while those on islands
where flowers and their nectar were the main foods developed long
and probing beaks. The same gene controlled beak formation in
each of these species, but the type of beak that developed depended
on the timing, intensity, and duration of that gene’s expression.¹
What, then, controls when and whether a gene is expressed?
Only about 2% of the human genome is made up of proteincoding genes. Other genes do not code proteins but regulate the
expression of the genes that do. Gene switches, also known as transcription factor binding sites, are pieces of regulatory DNA that
flank the protein-coding parts of the gene and control whether and
when the gene is turned on. A specific protein called a transcription factor binds to that site to tell that gene how much protein
to make and when to make it, determining the direction development will take. Because the same protein-coding genes are associated with similar function across a genetic toolkit—for example,
the distal-less/DLX gene with a variety of animal appendages—such
switches are key to ensuring the integrity of a species’ developmental program. They control the timing, extent, and duration of the
gene’s expression to ensure that a human develops an arm and not
a wing or a claw.
If diversity across the members of a given taxon is driven by the
regulation of the timing and intensity of gene expression by gene
switches, it is not surprising that switch-regulated gene expression
is also responsible for the embryonic development of diverse tissues
and structures within a species. For instance, the decapentaplegic
gene, which is reported to activate tinman expression in the fruit
fly,² is also responsible for the body axis, epidermal patterning, gut
formation, and patterning of wings, legs and other appendages.³
Dr. Lee thinks that this “makes sense evolutionarily—if you had
to have a separate and unique signal for each gene, your genome
would be huge, but this way, by using common elements over and
over again, but in slightly different contexts, you minimize the
number of genes needed to establish compartmental or cellular
identities.”
But what regulates the gene switches? The discovery of the
HOX genes in 1984 began to provide an answer to this question.
These “master genes,” which help determine the axis and body plan
of tetrapods (ie, what will be head, trunk, arms, fingers, legs, toes
and where these develop), also regulate the gene switches so that
the right genes are expressed at the right time at the right intensity
to ensure that a given species develops according to program.¹ If
something goes wrong and the switches do not turn on or silence
For more information, call MEDULINE at 1-800-922-5250 or 843-792-2200 or visit the digital edition at MUSChealth.com/progressnotes
7
REGENERATIVE MEDICINE
the correct genes, then a body part can suddenly appear in an inappropriate place. Most famously, if there are loss-of-function mutations in the HOX gene Antennapedia that controls leg development
in the fruit fly, the set of legs that should have appeared on the fly’s
thorax instead manifest where its antennae should be.
Nkx2-5 and Human Embryonic Heart Development
The patterning of the embryonic heart is complete early, usually by
ten to twelve weeks of gestation. The segments of the heart developing out of the second heart field are last to develop, well after
the left-sided structures of the heart, suggesting that separate regulatory systems drive the development of the left and right sides of
the heart.
Dr. Lee’s work focuses on the regulation by Nkx2-5, the vertebrate homolog of the tinman gene in the fruit fly, of right-sided
heart development (Figure 2). Studies have shown that the rightsided heart structures associated with pulmonary circulation fail to
develop properly in embryos deficient in Nkx2-5: the outflow tract
is hypoplastic and, instead of well-differentiated left and right ventricles, a single amorphous chamber develops that has some characteristics of the left ventricle.⁴,⁵ Restoring some Nkx2-5 expression
results in less severe defects, showing that there is a directly proportionate relationship between the degree of Nkx2-5 expression and
proper right-sided heart development. Dr. Lee has shown that this
critical regulation of Nkx2-5 expression in second heart field cells
is quite intricate, with its initial expression controlled by SMAD
transcription factors activated by bone morphogenetic protein
(interestingly a homolog of fruit fly Decapentaplegic) and its later
expression sustained by other members of a complex genetic network of other heart-specific transcription factors interacting with
the same control element.⁶
How does Nkx2-5 regulate right-sided heart development? It
is a HOX gene that produces a transcription factor that throws the
appropriate gene switches at the right time, telling other proteincoding genes when and how much protein to make. For example,
Dr. Lee has identified 11 genes showing sensitivity to variations in
the levels of Nkx2-5 in the pharyngeal arches of the second heart
field, which appear to be under direct control of Nkx2-5 during
right-sided heart development, and whose protein products may
play multiple roles in the specification, growth, and structural
Dr. Kyu-Ho Lee
development of embryonic right heart cells.⁷,⁸ Nkx2-5 is very likely
to control many other gene targets, the identity and role of which
are still being elucidated.
Nkx2-5 illustrates another of the tenets of modern genetics:
that the same genes can be used to drive development in different
body compartments depending upon the intensity and timing of
their expression. A surprise finding by Dr. Lee and his colleagues
in Obstetrics & Gynecology, including Eugene Y. Chang, M.D.,
Associate Professor in the Division of Maternal-Fetal Medicine at
MUSC, implicated Nkx2-5, which drives the development not
only of the right-sided heart but also of amniotic structures, in
the genesis of preeclampsia. Intriguingly, this finding also extends
to the expression of Nkx2-5 target genes that Dr. Lee found to be
regulated in the developing heart; these target genes may also be
relevant to preeclampsia.⁹ While these studies are still in the early
stages, their preliminary findings raise intriguing questions not
only about the conservation of genetic pathways, but also regarding previously unknown linkages between maternal health and
child development.
The Children’s Heart Program of South Carolina
The Children’s Heart Program of South Carolina is a collaborative effort by all children’s
hospitals in South Carolina to provide the state’s children with the best clinical cardiac
care while at the same time fostering research that could revolutionize the treatments of
tomorrow. Local pediatric cardiologists’ offices serve as the medical home for these children, ensuring consistency of care and follow-up, but all procedures and catheterizations
take place at the MUSC Children’s Hospital. As a result of this concentration of surgical
volume, MUSC’s pediatric cardiac surgeons have vast experience in treating a variety
of congenital heart anomalies and other pediatric heart conditions, allowing them to
achieve an impressive 99% survival rate for pediatric cardiac surgery in each of the past
five years (as recognized by U.S. News and World Report), especially impressive as the
MUSC Children’s Hospital treats some of the most challenging and complex of cases.
8
Progressnotes November 2013
MUSC’s Medical Magazine
FIGURE 2. Dr. Lee’s research focuses on second heart field development. Reprinted from the Journal of Clinical Investigations, Online, with permission.
Potential Clinical Applications
Regulation by Nkx2-5 is crucial to right-sided heart development,
and children in whom it is inadequately expressed are prone to
defects that involve improper splitting of the outflow tract and
underdevelopment or abnormal development of the right ventricle,
pulmonary artery, and aorta. Inadequate expression of other genes
regulating the formation of other areas of the heart would likewise
lead to different sets of cardiac malformations. Better understanding which gene networks are associated with which malformations
will help predict the course of disease and provide the basis for
tailored gene therapies that could begin to heal or prevent some of
those defects without the need to resort to invasive surgery.
Unlike the Wizard of Oz who proved powerless to grant the
wishes of the Tin Woodman and his companions, cardiovascular
developmental biology research, informed by the principles of
modern genetics, promises to one day offer new hope to children
with some congenital heart anomalies who want nothing more
than to be as other children are.
References
¹ NOVA. “What Darwin Never Knew,” NOVA website, http://www.pbs.org/
wgbh/nova/evolution/darwin-never-knew.html (accessed September 9, 2013).
² Frasch M. Induction of visceral and cardiac mesoderm by ectodermal Dpp in
the early Drosophila embryo. Nature 1995 Mar 30;374(6521):464-7.
³ Carroll SB. Evo-devo and an expanding evolutionary synthesis: a genetic
theory of morphological evolution. Cell 2008; 134:25-36.
⁴ Lints TJ, Parsons LM, Hartley L, et al. Nkx-2.5: a novel murine homeobox
gene expressed in early heart progenitor cells and their myogenic descendants.
Development 1993; 119(3):969.
⁵ Tanaka M, Chen Z, Bartunkova S, et al. The cardiac homeobox gene Csx/
Nkx2-5 lies genetically upstream of multiple genes essential for heart
development. Development 1999; 126:1269-1280.
⁶ Barth JL, Clark CD, Fresco VM, Knoll EP, Lee B, Agraves WS, Lee K-H.
Jarid2 is among a set of genes differentially regulated by Nkx2-5 during
outflow tract morphogenesis. Developmental Dynamics 2010; 239:2024-2033.
⁷ Prall OW, Menon MK, Solloway MJ,et al. An Nkx2–5/Bmp2/Smad1negative
feedback loop controls heart progenitor specification and proliferation. Cell
2007;128:947-959.
⁸L
ee KH, Evans S, Ruan TY, Lassar AB. SMAD-mediated modulation of
YY1 activity regulates the BMP response and cardiac-specific expression
of a GATA4/5/6-dependent chick Nkx2-5 enhancer. Development 2004
Oct;131(19):4709-23.
⁹ Lee K-H, Robinson CJ, Rivers E, Horton AJ, Clark CD. Molecular basis for
racial disparity in preeclampsia. Pediatric Academy Societies Annual Meeting.
Washington, DC. May 7, 2013. Abstract number 4503.112.
MUSC’s Cardiovascular Developmental Biology Center
Over the course of the past 20 years, the Cardiovascular
Developmental Biology Center (CDBC) has promoted
institutional, statewide, national, and international research
collaborations on fundamental studies of heart and vascular
birth defects that have evolved to include two translationally relevant missions: the developmental basis of adult cardiovascular diseases and the application of the principles of
developmental biology to stem cell–based, cardiovascular
tissue engineering. The CDBC is a home to a cadre of
world-class researchers in the field, including Roger Markwald, PhD, a pioneer of heart valve development and extracellular matrix protein biology who serves as the Chair of
the Department of Regenerative Medicine and Cell Biology
at MUSC; Arno (Andy) Wessels, PhD, an internationally
known expert in morphological heart development, and
Corey H. Mjaatvedt, PhD; as well as scientists who study
the embryonic formation of blood vessels, such as Chris
Drake, PhD, and the biochemistry of extracellular matrix, like
W. Scott Argraves, PhD. This ground-breaking research is
facilitated by MUSC’s expertise in immunohistochemistry (ie,
knowing which antibody to use to look for embryonic myocytes) and a strong molecular morphology and imaging core,
the Josh Spruill Imaging Facility, headed by Tom Trusk,
PhD, which includes a large confocal microscopy facility that
allows for digital analysis and quantification of small structures (needed for embryonic research).
For more information, call MEDULINE at 1-800-922-5250 or 843-792-2200 or visit the digital edition at MUSChealth.com/progressnotes
9
REGENERATIVE MEDICINE
In the digital edition: Drs. Fakhry and
Yost discuss how tissue engineering
could revolutionize trauma care
Dr. Michael J. Yost conferring with a colleague
Leaving No Trace
Moving From Scar to Regeneration in Wound Healing
“After injury, a scar is what makes you whole.”
—China Miéville, The Scar
T
rauma, meaning “physical wound” in the original Greek, has
always left a trace, a mark to remind us that the body’s boundaries have been breached and its integrity compromised. And yet,
those on the vanguard of tissue engineering research are challenging the notion that scar is the inevitable result of severe injury and
are seeking to move us beyond scar and toward regeneration.
Forward-thinking surgeons are looking to regenerative medicine to engineer a living, growing tissue that can replace or repair
tissue damaged by trauma and do so while leaving little or no scar.
Such tissue engineering could revolutionize trauma care, affording surgeons the opportunity to “replace tissue, repair tissue, cover
defects, and do certain operations we couldn’t otherwise do,”
according to Samir Fakhry, M.D., Chief of the Division of General Surgery, who leads the Level I MUSC Trauma Center as the
Medical Director for Surgical and Acute Critical Care.
Seeing the promise that tissue engineering holds for improving surgical care, the Division of General Surgery at MUSC
established a regenerative medicine laboratory in 2012 with
the recruitment of Michael J. Yost, PhD, Associate Professor in
the Department of Surgery and a bioengineer whose research
focuses on regenerating skeletal muscle. Dr. Fakhry is convinced
that the revolutionary treatments of tomorrow will spring from
10
Progressnotes November 2013
close collaboration between surgeons on the frontlines of treating trauma and scientists who are trying to equip them with better technology for doing so: “It is important to have a laboratory
where we can take questions and begin to develop solutions working with scientist colleagues.”
Why New Treatment Options Are Needed
Trauma can be caused by a violent assault (eg, gunshot or stabbing), a car crash, or by surgery. In each case, the body is penetrated and tissue is damaged or lost. Trauma surgeons, who witness
the effects of injury every day, currently have too few options
for addressing such tissue damage, and none of them is without
drawback. They can harvest skin or muscle flaps from elsewhere
on the patient’s body for grafting to the site of traumatic injury,
but sufficient tissue can sometimes be lacking for major injuries
and the donor sites can often become infected. They can graft tissue donated from human or animal donors, but those grafts can
be rejected by the patient’s immune system. Finally, they can use
commercially available synthetic (eg, polymers, plastic) materials to
close the wound, but these materials are expensive, easily become
infected, and are inert, ie, they do not adapt to the body’s needs,
limiting their functionality.
The body’s own response to trauma is scar. “The body will eventually replace most defects—fill in holes and bridge gaps—the body
has only one means of doing that and it’s very undifferentiated and
MUSC’s Medical Magazine
KEY POINTS
•S
car is the body’s response to wound healing but can disfigure or limit range of motion.
•R
egenerative medicine researchers like Michael J. Yost, PhD, Associate Professor in the Department of Surgery at MUSC, are trying to tip
the scales toward regeneration of normal tissue and away from scar.
•D
r. Yost’s research, which specifically targets the regeneration of skeletal muscle, shows that coadministration of satellite cells (the stem
cells of skeletal muscle) and an extracellular matrix to the trauma site signals the body to build skeletal muscle at that site.
•D
r. Yost is also researching ways to mute the initial inflammatory response to wound, both to minimize scarring and to improve the viability
and longevity of engineered tissue after implantation.
•B
ioprinter technology, a 3D printer with the capacity to print living tissue, will aid in producing sufficient engineered tissue for surgical and
medical applications.
it’s called scar—a very clever solution to a complex set of problems
but not the ideal solution,” explains Dr. Fakhry.
Scar tissue covers over the wound and allows for healing,
but it can also disfigure, lower self-esteem, and limit function
by causing contractures that restrict range of motion. Scar
tissue is also as much as 30% weaker than healthy tissue.
Scar may be the body’s natural response to trauma, but
it is in some ways an outmoded, even primitive one. “If in
prehistoric times I were bitten by a saber-toothed tiger, I’d
want the inflammatory response calling in neutrophils that
would blast everything so I could live. Today, I don’t want the
scar,” explains Dr. Yost.
Dr. Yost is working to offer a more sophisticated response
to trauma, one whose resolution is regeneration and not scar, by
taking a two-fold approach. First, he is working to engineer tissue
that can live and grow and function as normal tissue in the body.
Second, he is trying to learn to mute the body’s own inflammatory
response to such tissue so that it remains viable and so that scarring
can be minimized.
Regenerating Skeletal Muscle
Simple administration of satellite cells (the stem cells for skeletal
muscle) will not ensure the regeneration of skeletal tissue. A scaffold of some sort must be provided for the satellite cells to improve
their viability and preserve their orientation and architecture. Dr.
Yost’s laboratory has successfully regenerated skeletal muscle fibers
by administering satellite cells with an extracellular matrix (ie, collagen).¹ The co-administration of satellite cells and matrix to the
trauma site prompts the body to recognize the need to generate
skeletal muscle in that location and to initiate the events necessary
to do so, including the influx of additional satellite cells and the
creation of vasculature. Satellite cells grow together to form myocytes, the building blocks of muscle (Figure).
Although Dr. Yost and his team are able to obtain muscle fibers
with this method, they are not able to produce “nice, organized,
fascicular bundles of skeletal muscle” with good contractility,
and there is still some interstitial scarring, likely due to an initial
inflammatory response. “We have not seen a lot of good voluntary
contraction of the muscle—nobody has—but we are getting muscle in there and that is an important step.” In Dr. Yost’s opinion,
achieving organized bundles of muscle tissue will require better
“communication” between the regenerating muscle and neurons.
FIGURE. Illustration showing the steps of muscle repair and healing. Top circle: Macrophages
move to the injured area, cleaning up and removing the damaged muscle fibers. Middle circle:
Blood vessels deliver oxygen and other nutrients necessary for muscle repair. Bottom circle:
Specialized cells, called satellite cells, are activated and fuse together to regenerate a new
muscle fiber. Illustration by Elise Walmsley, Bsc, AAM, used with permission.
The regenerating skeletal muscle must provide cues to recruit
motor neurons, but innervation by those recruited motor neurons
is in turn necessary to cue the regenerating muscle to develop into
organized bundles. Dr. Yost has established the presence of activated motor neurons in the skeletal muscle he has regenerated;
however, that muscle does not yet seem to be able to take the cues
from the motor neurons. Further studies are needed to understand
how to make the regenerating muscle more receptive to those cues.
The advent of bioprinter technology will help realize the promise of such regenerated tissues by allowing medical centers to produce patient-specific tissue on site for surgical applications (see Box
to learn more about bioprinter technology).
The Inflammatory Response and Scar Formation
Engineering living, growing, functional tissue is only half the battle. The implanted tissue must then be protected from the body’s
For more information, call MEDULINE at 1-800-922-5250 or 843-792-2200 or visit the digital edition at MUSChealth.com/progressnotes
11
REGENERATIVE MEDICINE
innate defenses. The body assumes that all intrusions are hostile
ones and reacts to all the same, making no distinction between
stab wound and surgical incision, foreign toxin and bioengineered
tissue. As Dr. Yost notes, “the body has no plan for sterile surgical
trauma, and it has no plan for exogenous tissue to be implanted as
a repair material.” As a result, those seeking regenerative medicine
solutions to tissue damage find themselves battling the body’s own
first-line of defense—the inflammatory response that is an integral
part of innate immunity.²
Innate immunity is the body’s first line of defense, its emergency first responders. Inflammation helps to get the emergency
first responders to the area of damaged tissue, where they can begin
to clear up cellular debris and remove any noxious or foreign agents.
The initial step in inflammation, usually occurring within seconds to a few minutes of injury, is vascular: arterioles and venules
near the wound site contract and then dilate, allowing increased
blood flow to the site. At the same time, the walls of the vessels
become more permeable, allowing fluid to enter the damaged tissue. This increased blood flow and leakage of fluid from the blood
vessel into the surrounding tissue are responsible for the redness
and swelling associated with inflammation.
The next step in inflammation, occurring in the course of several hours, is cellular. Damaged cells leak adenosine triphosphate
(ATP) into the extracellular space, triggering migration of bloodborne leukocytes, especially neutrophils, to the site. The flow of
blood through the dilatated vessels becomes sluggish, providing
the opportunity for neutrophils and macrophages to accumulate in
the region of injury, move to the vessel walls, and eventually pass
through the walls into the damaged tissue. There, they phagocytize
any noxious or threatening agent as well as cellular debris and, on
occasion, healthy cells as well.
This “cleaning away” of damaged tissue is necessary before healing can begin. If the wound has been minor, the normal architecture of the tissue can be fully restored. However, in many cases, a
scar will form, as the body seeks to fill the gaps in tissue left by the
removal of the damaged cells by depositing fibroblasts and collagen.
From Scar to Regeneration
The goal of Dr. Yost’s research is to move healing away from scar
and toward regeneration. Although inflammation is essential to
protect the body against assaults and to remove toxins, pathogens,
and cellular debris, it can also damage healthy tissue (eg, through
the release of free radicals, through the phagocytosis of healthy
cells). How can the inflammatory response, necessary in order to
trigger regeneration, be attenuated so as to minimize damage to
healthy tissue and to lessen the likelihood that any engineered cells
that are implanted into the wound site will be attacked by neutrophils and other first responders?
Dr. Yost’s laboratory is trying to modulate the inflammatory
response by removing its trigger—the leakage of ATP from damaged cells into the extracellular space. ATP typically escapes from
cells via gap junctions, openings between adjacent endothelial cells
that are formed when the hemichannels of the two adjacent cells
come together. Each hemichannel is composed of six connexin
proteins. If the connexins can be prevented from forming hemichannels, then the ATP would have no means of escaping from
12
Progressnotes November 2013
the cell into the extracellular matrix to trigger inflammation. Two
peptides capable of disrupting formation of the hemichannels by
connexins have been identified by research done at MUSC.
The first, the α–connexin carboxyl-terminal (ACT1) peptide,
which was developed in the laboratory of former MUSC researcher
Robert Gourdie, PhD (who continues in an adjunct position at
MUSC), was shown to reduce scarring and promote wound healing in animal models by reducing the inflammatory response and
the area of scar progenitor tissue and to improve skin strength and
extensibility.³ MUSC licensed the rights to the peptide to First
String Research, which took a topical gel containing the peptide
into clinical trials. In July 2013 at the International Gap Junction
Conference in Charleston, SC, First String announced the promising results of phase 2 trials in three patient populations—those
with diabetic foot ulcers, those with venous leg ulcers, and those
who had undergone laparoscopic incisions. Significant increases
were reported in the mean percent of wound closure at four and
twelve weeks as well as the incidence of 100% wound closure. A
phase 3 trial of the topical gel is in the planning stages.
The second peptide, the development and testing of which has
been a collaborative effort between the laboratories of Dr. Yost and
Dr. Gourdie, has shown impressive anti-fibrotic, anti-inflammatory, and pro-regenerative activities in animal models. Like ACT1,
it disrupts formation of hemichannels by connexins, but via a
different mechanism. Preliminary results suggest a strong efficacy
in preventing scar formation and promoting regeneration of tissue
with normal architecture.
More Than a Cosmetic Benefit
Because the same mechanisms are involved in scar formation
throughout the body, therapies that prove effective in preventing or diminishing scarring could have broad applications. For
instance, such therapies could prevent tissue scarring that follows
myocardial infarction or results in macular degeneration. A standard therapy or set of therapies for reducing or preventing scar
formation could spare patients some of the most devastating consequences of these diseases.
And, of course, for those who have undergone traumatic
injury, regenerative therapies offer the hope of being made whole
without having to bear the lifelong scars of a past tragedy.
References
¹ Logan MS, Propst JT, Nottingham JM, Goodwin RL, Pabon DG,
Terracio L, Yost MJ, Fann SA. Human satellite progenitor cells for use in
myofascial repair: isolation and characterization. Annals of Plastic Surgery.
2010;64(6):794-799.
² Rhett JM, Ghatnekar GS, Palatinus JA, Quinn M, Yost MJ, Gourdie RG.
Novel therapies for scar reduction andregenerative healing of skin wounds.
Trends Biotechnol. 2008 Apr;26(4):173-80.
³ Ghatnekar GS, O’Quinn MP, Jourdan JL, Gurjarpadhye AA, Draughn RL,
Gourdie RG. Connexin43 carboxyl-terminal peptides reduce scar progenitor
and promote regenerative healing following skin wounding. Regen Med.
2009;4(2): 205-223.
MUSC’s Medical Magazine
Fabricating Living Tissue With Bioprinter Technology
Medical illustration by Rick Sargent Design
Could medical centers one day be able to print tissue and even
organs on demand to meet their patients’ needs, helping solve
the problems arising from today’s tissue and organ shortages?
That is the promise of bioprinter technology currently being
developed at the Advanced Tissue Biofabrication Center,
located on the MUSC campus.
A bioprinter is in essence a 3D printer capable of “printing” living tissue, using cells as “bioink.” An image is taken of
the desired type of tissue, and then, using specialized software,
translated to machine code that can be programmed into the
bioprinter, allowing the appropriate structure to be printed. Of
course, tissue is more difficult to print than plastic; it must be
sufficiently hydrated to remain alive, and the logistics of how
to do so during the printing process are still being worked out.
Once perfected, this technology would help realize the promise
of engineered tissues, allowing them to be produced in sufficient quantity for surgical and other medical applications.
Michael J. Yost, PhD, designed the Palmetto Bioprinter
housed at the Advanced Tissue Biofabrication Center and has
been leading the effort to make it operational and to optimize
its performance. According to Dr. Yost, “the vision is, much
like an imaging center for magnetic resonance imaging, that
there would be a biofabrication center at all the major medical institutions.” A week or two before a scheduled procedure,
the patient would undergo a biopsy, and then the biofabrication center could expand out cells obtained from that biopsy
specimen, print them with patient-specific microvasculature and
endothelial cells, and have them ready to implant at the time of
the patient’s procedure. Although the Advanced Tissue Biofabrication Center has a bioreactor that can simulate physiological
conditions in vitro, the goal would be to implant such “printed”
tissue into the patient as soon as possible. According to Dr.
Yost, “you as the patient are really the best place for these tissues to get the cues to become you.”
Such biofabricated tissue would not have many of the drawbacks of current options for patients who have undergone a
trauma: unlike patient-donated tissue, there would be no limits
on the quantity of available tissue; unlike tissue from human or
animal donors, there would be no issue with rejection; and unlike
synthetic materials, biofabricated tissue would not be inert but
could adapt to cues given by the body.
The establishment of the Advanced Tissue Biofabrication Center and its ongoing research were made possible by a
$20 million grant from the National Science Foundation, which
was awarded in 2009 to an effort, led by Roger Markwald,
PhD, Professor and Chair of the Department of Regenerative
Medicine and Cell Biology at MUSC, to establish a statewide
alliance in South Carolina in the field of tissue biofabrication,
with the ultimate goal of producing human organs. Dr. Yost, an
Associate Professor in the Department of Surgery, also holds an
adjunct position at Clemson University as part of the ClemsonMUSC Bioengineering Program.
For more information, call MEDULINE at 1-800-922-5250 or 843-792-2200 or visit the digital edition at MUSChealth.com/progressnotes
13
DEPRESSION
14
cme
Date of Release: November 5, 2013
Date of Expiration: November 5, 2015
You can complete the steps necessary to receive your AMA PRA Category 1 Credit(s)™ by visiting MUSC Health’s Physician Portal at
MUSChealth.com/progressnotescme.
Credit Designation:
Physicians: The Medical University of South Carolina designates this enduring material for a maximum of .50 AMA PRA Category 1 Credits™.
Physicians should claim only credit commensurate with the extent of their participation in the activity.
Nursing Credit: Most states accept CMEs that apply to a specific nursing specialty as nursing continuing education. Please check with your respective
State Board of Nursing to ascertain the equivalent number of contact hours offered for .50 AMA PRA Category 1 Credits™.
All Participants: The Medical University of South Carolina will award .05 CEU (.50 contact hour) for reading the article and passing the posttest.
(1 contact hour equals .1 CEU)
Accreditation Statement: The Medical University of South Carolina is accredited by the Accreditation Council for Continuing Medical Education
(ACCME) to provide continuing medical education for physicians.
Disclosure Statement: In accordance with the ACCME Essentials and Standards, anyone involved in planning or presenting this educational activity is
required to disclose any relevant financial relationships with commercial interests in the healthcare industry. Authors who incorporate information about offlabel or investigational use of drugs or devices will be asked to disclose that information at the beginning of the article.
Robert J. Malcolm, Jr, M.D., Mark B. Hamner, M.D., and Kimberly McGhee, have no relevant financial relationships to disclose.
A telepresentation by Dr. Hamner entitled “The Management of Depression in the Elderly Population” will be broadcast on November 20, 2013, from 3:00-4:00 pm
by South Carolina AHEC to its member sites (more details at the end of the article). The live activity has been approved for AMA PRA Category 1 Credit.TM
The session will be recorded as enduring material and made available at MUSChealth.com/Progressnotes for those who could not attend the live session.
Chronic Blues
Upon completion of this article, readers should better be able to:
•R
ecognize the importance of collaborative care for improving treatment adherence and outcomes in patients with chronic
disease with comorbid depression
• I ntegrate depression assessment questions into the interview of complicated patients with multiple chronic diseases
•P
rovide guideline-recommended care for depression and resist the temptation to discontinue antidepressant treatment
prematurely because of minor side effects
• I dentify the warning signs for suicide and characterize the increased likelihood of suicide in depressed patients with
concurrent substance abuse or in patients with bipolar disorder
How weary, stale, flat, and unprofitable
Seem to me all the uses of this world!
—from Shakespeare’s Hamlet
H
amlet, literature’s most famous melancholic character,
describes in this quotation how colorless life feels when hope
drains away. All action seems devoid of meaning, and favorite pastimes no longer bring pleasure.
Healing requires hope, a belief that one’s actions of today
will lead to a better, healthier tomorrow. Without it, patients are
unlikely to take the necessary measures to get better, whether that
be modifying their lifestyle or adhering to their treatment regimen.
The most severely depressed may even struggle to carry on with
activities essential to their well-being, like showing up for work or
even getting out of bed.
Such inaction carries a heavy price, not only for those who are
depressed but for the country. Depression cost the United States an
estimated $83.1 billion in 2000 due to direct medical expenses and
lost productivity and is predicted to be the leading cause of overall
disease burden by 2030.¹
Depression hits the Southeast the hardest, closely shadowing
the path of chronic disease.² The stroke belt is also a blues belt.
Primary care physicians, especially those in the Southeast, are
on the front lines of the battle against both chronic disease and
depression. In addition to managing their patients’ hypertension,
diabetes, and other chronic conditions, they treat a third to half of
the cases of depression in those younger than 65 and two-thirds
of those in the elderly.¹ And yet, a recent study found that, of the
12.5% of primary care patients who had major depressive disorder in the previous year, less than half were recognized clinically
and less than a quarter received any depression-related treatment.
Adequate treatment was provided to only 9% of these primary care
patients, and remission was achieved in only 6%.¹
Why is it critical for the primary care physician to note the
linkage between depression and chronic disease and provide
adequate treatment for depression that is comorbid with chronic
disease?
Patients with a chronic disease are two to three times more
likely to be depressed than the general population, and, amid the
complex symptomatology of their chronic disease, their depression is more likely to go undiagnosed.³,⁴ In addition, patients with
chronic disease and comorbid depression utilize more health care
resources, lose more time from work, and are more likely to have a
functional disability.⁵
Simply put, depressed patients, those who see little hope for
the future and have little faith that their actions can change their
fate, are far less likely to be motivated to pursue a healthier lifestyle
or to follow their treatment regimens. In patients with diabetes,
Title page from Robert Burton’s Anatomy of Melancholy. Courtesy of the Waring Historical Library, MUSC, Charleston, SC.
15
DEPRESSION
those with comorbid depression are less likely to adhere to diet,
exercise, and monitoring of blood glucose levels and more likely
to have high hemoglobin A1c levels than diabetic patients without depression.⁶ Not surprisingly, their outcomes are worse than
patients with chronic disease who are not depressed. For example,
two-thirds of those with both diabetes and depression have poorer
glycemic control (necessitating insulin therapy) than do their nondepressed counterparts.⁷
Screening and Assessing High-Risk Populations for
Depression
Screening for depression is especially critical in high-risk patients,
such as the elderly, those with chronic pain, or those with chronic,
debilitating and/or terminal illnesses, because it could improve
quality of life and potentially lead to better treatment adherence
and outcomes. Physicians should realize that depression is not a
natural part of aging, that controlling depression can lead to better overall outcomes, and that depression can be an early indicator
of Alzheimer’s disease. Patients with chronic pain should also be
carefully screened. Some patients with chronic pain, wishing to
find a physiological reason for their pain, may resist a diagnosis of
depression. If physicians take care not to stigmatize depression and
to explain to patients that the treatments for pain and depression
are often the same (ie, antidepressants can bring those with chronic
pain some relief from pain) because their underlying mechanisms
are similar, most patients are willing to be treated for depression. As
already discussed, depression is often comorbid with chronic disease and can lead to worse outcomes if not diagnosed and treated.
Primary care physicians, who may feel they have less and less
time to spend with their patients, many of whom have multiple
complicated medical disorders, may balk at devoting a portion
of that time in assessing a patient’s mental health state. However,
investing a few moments to screen at-risk patients for depression
can pay long-term dividends throughout the patient’s course of
care, potentially leading to better outcomes.
Asking just two questions has been shown to catch the majority
of cases of depression seen in primary care practice (Table 1). These
two questions were shown to have a sensitivity of 97% (95% confidence interval [CI], 83%-99%) and a specificity of 67% (95% CI,
62%-72%) for diagnosing depression in primary care patients not
currently taking antidepressants.⁸ If patients answer “yes” to one
of the questions, they should be further screened using the Patient
Health Questionnaire-9 (available at http://www.phqscreeners.com)
TABLE 1. Two Questions That Can Identify
Most Cases of Depression
•O
ver the past 2 weeks, have you felt down, depressed,
or hopeless?
•O
ver the past 2 weeks, have you felt little interest or
pleasure in doing things?
16
Progressnotes November 2013
or other validated measure that includes a question to assess suicide
risk in order to determine the extent of their depression and serve
as a baseline against which to measure their progress.
In assessing the severity of depression, it is important not only
to count the number of depressive symptoms (Table 3) but also to
consider their duration and effect on occupational and social function. Depression is classified as sub-threshold when there are fewer
than five symptoms and little functional impairment, as mild when
there are five or six symptoms that slightly affect function, and as
moderate when there are both more symptoms and more functional impairment. For a diagnosis of major depressive disorder,
the fifth edition of the Diagnostic and Statistical Manual of Mental
Disorders (DSM-5) requires at least five of the symptoms listed in
Table 3, at least one of which must be depressed mood or loss of
pleasure, as well as significant functional impairment.⁹
Knowing When to Seek Specialty Psychiatric Care
Although the primary care physician has a central role to play in
managing depression, some patients, such as those deemed at high
risk for suicide, those with bipolar disorder, and/or those with a
substance abuse disorder, require more immediate and more intensive specialty care.
The first concern for a patient deemed at high risk of suicide
is ensuring his or her safety, through inpatient hospitalization
if necessary. Among the risk factors for suicide are a profound
depression affecting the ability to carry out activities of daily living,
a history of suicide attempts, a preoccupation with death or dying
and interest in specific means for committing suicide, sudden
dramatic changes in behavior, and recent changes in patterns of
eating, sleeping or alcohol/drug use. Those who have undergone a
recent loss and those who live alone or are without a social support
network are also at increased risk.
The prevalence of substance abuse is high among those with
mood disorders, with an estimated 30% to 55% of those with
major depressive disorder and 30% to 50% of those with bipolar
disorder having a comorbid substance abuse problem.¹⁰ Because
suicide risk is elevated in those with a mood disorder with comorbid substance abuse,¹¹ such patients are best referred for specialty
care. The CAGE questionnaire can be used to quickly and effectively identify those with a substance abuse disorder (Table 2).
Although patients with bipolar disorder often first present to
their primary care provider with depression, they should be referred
for specialty psychiatric care because the treatment for bipolar
disorder differs substantially from that for depression and because
they are at an increased risk for suicide. Taking a good mental
health history, one that includes questions about previous episodes
of mania or impulsiveness as well as depression, can help identify
these patients. Patients with bipolar disorder can respond in unexpected ways (eg, manic or psychotic episodes, impulsive behavior)
to antidepressant therapy, and such an aberrant response, whether
current or past, should arouse suspicion of bipolar disorder.
Risk for suicide increases substantially in bipolar patients who
also have a substance abuse disorder. In one study, 25% of those
with both bipolar and substance abuse disorders had attempted
suicide, compared with 15% of those with bipolar disorder without a problem with drug/alcohol abuse.¹¹
MUSC’s Medical Magazine
TABLE 2. Screening for Substance Abuse:
the CAGE Questionnaire
**It can also be adapted for other drugs.
•H
ave you ever felt you needed to Cut down on your
drinking?
•H
ave people Annoyed you by criticizing your drinking?
•H
ave you ever felt Guilty about drinking?
•H
ave you ever felt you needed a drink first thing in the
morning (Eye-opener) to steady your nerves or to get rid
of a hangover?
From Ewing JA. Detecting alcoholism: the CAGE
questionnaire. JAMA. 1984;252(14):1905-1907
Stepped-Care Treatment for Depression
The primary care physician can effectively treat patients with mild
or moderate depression and can serve as an essential team member
in treating those with major depressive disorder.
The two broad approaches to depression are psychological
interventions and antidepressant medications.
The psychological intervention with the most evidence to support its efficacy is cognitive behavioral therapy (CBT). Cognitive
behavioral therapy focuses on helping patients identify negative
thought patterns and to replace them with more positive ones.
Negative thought patterns lead to low mood and to lack of positive action, creating a vicious circle that keeps the patient mired in
depression. Depressed patients tend to think in negative absolutes
and to express irrational guilt (“No one will ever love me”; “I am a
loser and will never be able to find another job”; “Anything I touch
goes bad”). Cognitive behavioral therapy helps move the patients
from the absolute into the quantitative through reality testing.
The certainty of these thoughts is challenged by having the patient
acknowledge evidence to the contrary (“I do have some friends and
family who love me”; “I have successfully held down jobs in the
past”; “I have made positive contributions to projects”). Patients
gradually become less sure of their negative absolutes and more
likely to engage in positive thought processes. For patients who
choose not to undergo CBT or who do not improve with CBT
therapy, other forms of psychological intervention (eg, interpersonal therapy) should be considered.
The most frequently prescribed antidepressants are selective serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs). Both delay reuptake
of neurotransmitters known to improve mood (eg, serotonin,
norepinephrine), allowing them to remain longer in the synapse, thereby improving neurotransmission. In patients taking
SSRIs/SNRIs, especially more than one, clinicians should remain
vigilant for serotonin syndrome, which can be characterized by
headache, agitation, mental confusion, hallucinations, shivering, nausea, diarrhea, tachycardia, muscle twitching, and tremor.
Once popular, tricyclic antidepressants and monoamine inhibitors, which are associated with a large number of side effects and
drug interactions, respectively, have fallen out of favor and, when
used in select patients who do not respond to first-line SSRI/SNRI
therapy, should be administered under the care of a psychiatrist.
As a rule, antidepressants should not be prescribed for patients
with mild depression because the benefits do not outweigh the
risk. These patients should be actively monitored and depressive
symptoms checked at each visit and compared against baseline to
identify any worsening of symptoms. These patients could also
benefit from learning about CBT and working through self-help
CBT exercises, using either a manual or computerized programs.
For patients with moderate or severe depression, or those with
persistent sub-threshold depressive symptoms or mild to moderate depression that does not respond to the above interventions,
antidepressant therapy or higher-intensity in-person CBT should
be considered. Clinicians should follow up regularly with patients
(usually within two weeks of beginning an antidepressant and
every two to four weeks thereafter for the first three months) to
determine whether the chosen antidepressant is working and to
identify and treat any side effects. Taking the time to help the
patient treat mild side effects with over-the-counter medications
can go a long way toward improving adherence. If an antidepressant is not having the desired effect, the clinician should ensure
that the patient has been taking the medication at the right dosage
and time intervals before stepping up the dosage or switching to a
different antidepressant. If the patient has been adherent but has
not improved or if side effects make it difficult for the patient to
tolerate the medication, the clinician should consider switching the
patient to another antidepressant.
Because side effects of antidepressants, particularly gastrointestinal ones, can hit the elderly harder, clinicians should “start low
and go slow” when prescribing the medications to these patients.
Polypharmacy is likely in elderly patients and patients with chronic
illness, and so clinicians should take care to prescribe an antidepressant that does not have negative interactions with the patients’
other medications, consulting other specialists treating the patient
Dr. Robert J. Malcolm, Jr., Professor, Department of Psychiatry & Behavioral Sciences
17
DEPRESSION
TABLE 3. Diagnostic Criteria for Major Depressive Disorder from DSM5
1. Five (or more) of the following symptoms have been present during the same 2-week period and represent a change from
previous functioning; at least one of the symptoms is either (1) depressed mood or (2) loss of interest or pleasure.
Note: Do not include symptoms that are clearly attributable to another medical condition.
•D
epressed mood most of the day, nearly every day, as indicated by either subjective report… or observation made by others
•M
arkedly diminished interest or pleasure in all, or almost all, activities most of the day, nearly every day
•S
ignificant weight loss when not dieting or weight gain (eg, a change of more than 5% of body weight in a month), or decrease or
increase in appetite nearly every day
• Insomnia or hypersomnia nearly every day
•P
sychomotor agitation or retardation nearly every day
•F
atigue or loss of energy nearly every day
•F
eelings of worthlessness or excessive or inappropriate guilt nearly every day (not merely self-reproach or guilt about being sick)
•D
iminished ability to think or concentrate, or indecisiveness, nearly every day
•R
ecurrent thoughts of death, recurrent suicidal ideation without a specific plan, or a suicide attempt or a specific plan for committing suicide.
2. The symptoms cause clinically significant distress or impairment in social, occupational, or other important areas of functioning.
3. The episode is not attributable to the physiological effects of a substance or to another medical condition.
From the Diagnostic and Statistical Manual of Mental Disorders (5th ed).9
as necessary (to learn more about the management of depression in
the elderly population, register for Dr. Mark Hamner’s telepresentation; see Box at bottom of the reverse page).
A collaborative care approach to treating depression has proven
efficacy and is particularly recommended in complicated patients
with chronic diseases with associated functional impairments and
comorbid moderate to severe depression. Collaborative care is
a coordinated approach to mental and physical health care that
typically involves the establishment of a multidisciplinary team of
physicians (primary care physician, mental health specialist, specialists in the patient’s chronic disease), who agree on a treatment
course for the patient and remain in close contact throughout the
course of that treatment. Also key to collaborative care is a midlevel provider, usually a nurse, who acts as a case manager, coordinating care for the patient, fostering communication between the
patient and providers and communication among the providers,
and offering education and follow-up for the patient. Typically,
the case manager would work under the supervision of a mental
health professional. Studies have shown that such collaborative
care interventions can significantly improve patient outcomes.⁶,¹²
Improved quality of life, increased patient satisfaction with care,
decreased levels of depression, and better treatment adherence
have been reported using collaborative care models,⁶,¹² and significant improvements in measures of chronic disease have also
been reported (eg, improved hemoglobin A1c levels in diabetic
patients).⁶
Treatment-Resistant Depression
Although a combination of antidepressant therapy using SSRIs/
SNRIs and psychological interventions can successfully treat many
cases of depression, as many as 30%-50% of patients treated with
18
Progressnotes November 2013
one or two antidepressants at a standard dose over six months do
not improve and are considered to have treatment-resistant depression. At ten to fourteen weeks, less than 40% of patients have
achieved remission.
Clearly, new therapies are needed that act more quickly against
depression and that can help those who do not respond to current
front-line therapies like SNRIs/SSRIs.
Pharmacological Approaches: Ketamine
Today, scientific consensus is that the etiology of depression can
be traced to dysfunction in the glutamatergic system, and drugs
that target this system are showing some of the most promising
results in clinical trials. For example, intravenously administered
ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist typically used as an anesthetic, can lead to rapid and remarkable improvements in mood in patients who do not respond to
traditional treatments. Ketamine often improves quality of sleep
in depressed patients, thereby elevating mood. An early placebocontrolled study showed significant improvement in mood 72
hours after a single ketamine infusion,¹³ and the efficacy of a single
dose of ketamine for short-term depression relief has since been
confirmed.¹⁴ To achieve a more durable response, repeated doses
of ketamine may be necessary; a recent study showed that patients
receiving six infusions of ketamine over twelve days saw a reduction of 85% from baseline in their score on the MontgomeryÅsberg Depression Rating Scale (MADRS).¹⁵ Side effects were
mild and not seen as bothersome by patients. Although repeateddose ketamine was acutely efficacious and caused minimal side
effects, its mood-elevating effect was not sustained long after termination of the ketamine injections. The Medical University of South
Carolina is currently one of the sites of a multicenter trial (clinical
MUSC’s Medical Magazine
trial identifier: NCT01627782) whose objective is to ascertain
the optimal dosing of ketamine for treatment of major depressive disorder (ie, 2 vs 3 times weekly) and to monitor symptoms
of depression using validated depression scales for up to 47 days.
To maximize the promise of ketamine therapy, other investigators
are developing analogues for ketamine that could be administered
orally, improving their practicability for clinical applications.
Non-pharmacological Approaches
Strong evidence supports that rapid relief from treatment-resistant
depression can also be achieved in some patients by electroconvulsive therapy (ECT). Passing electrical currents through the brain
triggers a seizure and causes changes in brain chemistry that can
quickly reverse depressive symptoms. Also promising is transcranial magnetic stimulation, approved by the U.S. Food and Drug
Administration in 2008 for the treatment of resistant depression,
which delivers magnetic stimulation to the areas of the brain
thought to regulate mood (for more information on these techniques, see “Rewiring the Brain’s Circuits to Relieve Depression”).
Restoring Hope
Few disorders can have a more profoundly debilitating effect on
patients than depression. When coupled with chronic disease, its
effects can be truly devastating. Despite the hopelessness felt by
those who experience it, depression is in fact very treatable, and
controlling depression can dramatically improve patients’ quality of life and health outcomes. Treating depression can restore
patients’ hope and motivation to work toward a healthier future
and could provide primary care physicians a much-needed strategy
for beginning to turn the tide against chronic disease.
References
¹ Centers for Disease Control and Prevention Data & Statistics. An estimated 1
in 10 U.S. adults report depression. Available at http://www.cdc.gov/features/
dsdepression/. Accessed August 11, 2013. Page last reviewed: April 20, 2012.
Page last updated: March 31, 2011.
² Pence BW, O’Donnell JK, and Gaynes BN. The Depression Treatment
Cascade in Primary Care: A Public Health Perspective. Curr Psychiatry
Rep (2012) 14:328–335. Available at http://dx.doi.org/10.1007/
s11920-012-0274-y.
³N
ational Institute for Health and Clinical Excellence (NICE).
Depression in adults with a chronic physical health problem: treatment
and management. NICE Clinical Guidelines 91; 2009. Available at
http://guidance.nice.org.uk/cg91
⁴ Huot KL, Lutfiyya MN, Akers MF, et al. A population-based cross-sectional
study of health service deficits among U.S. adults with depressive symptoms.
BMC Health Services Research 2013, 13:160. Available at http://www.
biomedcentral.com/1472-6963/13/160.
⁵ Egede, LE. Major depression in individuals with chronic medical disorders:
prevalence, correlates and association with health resource utilization, lost
productivity and functional disability. General Hospital Psychiatry 2007;
29:409-416.
⁶ Katon WJ, Von Korff M, Lin EHB, et al. The Pathways Study: a randomized
trial of collaborative care in patients with diabetes and depression. Arch Gen
Psychiatry 2004;61:1042-1049.
⁷ Egede LE, Hernández-Tejada MA. Effect of comorbid depression on quality
of life in adults with type 2 diabetes. Expert Rev Pharmacoecon Outcomes Res
2013; 13(1), 83-91.
⁸ Arroll B, Khin N, Kerse N. Screening for depression in primary care with two
verbally asked questions: cross sectional study. BMJ 2003;327:1144-1146.
⁹ American Psychiatric Association. (2013). Diagnostic and statistical manual of
mental disorders (5th ed.). Arlington: American Psychiatric Publishing; 2013.
¹⁰ Kenneson A, Funderburka JS, Maistoa SA. Substance use disorders increase
the odds of subsequent mood disorders. Drug and Alcohol Dependence.
Published ahead of print July 29, 2013. Available at http://dx.doi.
org/10.1016/j.drugalcdep.2013.06.011.
¹¹ Oquendo MA, Currier D, Liu S, et al. Increased risk for suicidal behavior in
comorbid bipolar disorder and alcohol use disorders. J Clin Psychiatry. 2010;
71(7): 902-909. Available at http://dx.doi.org/10.4088/JCP.09m05198gry.
¹² Katon WJ, Lin EHB, Von Korff M, et al. Collaborative care for patients with
depression and chronic illnesses. N Engl J Med 2010;363:2611-20.
¹³ Berman RM, Cappiello A, Anand A, et al. Antidepressant effects of ketamine
in depressed patients. Biol Psychiatry 2000;47:351–354.
¹⁴ Zarate CA Jr, Singh JB, Carlson PJ, et al. A randomized trial of an
N-methyl-D-aspartate antagonist in treatment-resistant major depression.
Arch Gen Psychiatry 2006; 63:856–864
¹⁵ aan het Rot M, Collins KA, Murrough JW, et al. Safety and efficacy of
repeated-dose intravenous ketamine for treatment-resistant depression. Biol
Psychiatry 2010; 67(2):139–145
Statewide Broadcast...
“Management of Depression in the Elderly Population”
November 20, 2013
3:00pm-4:00pm
Mark Hamner, M.D.
View a variet� of prog�ams at a location near you. You
can interact with nationally recog�ized ex�er�s, t�ack
your own CE credit, and register online - all at your
own convenience! For more infor�ation, visit our
website at www.scahec.net/schools.
19
DEPRESSION
Rewiring the
Brain’s Circuits
to Relieve Depression
In the digital edition: Dr. George discusses TMS therapy
for depression.
“Electricity is the real currency of the brain.” —Mark S. George, M.D.
N
europlasticity, the brain’s capacity to reorganize itself by
forming new neural connections throughout life, is a novel
paradigm in brain research studies, one that is replacing a longheld belief that the brain’s circuits are hard-wired by adulthood and
that little can be done to change them. If specific circuits involved
in psychiatric disorders can be identified, rewiring them could offer
hope for patients who thought they had run out of options.
“If we know the circuit, and can modify it, we can potentially
come up with a new treatment for any disease of the brain,” says
Mark S. George, M.D., McCurdy Endowed Distinguished Professor in the Departments of Psychiatry, Radiology, and Neurology and Director of the Brain Stimulation Laboratory at MUSC’s
Institute of Psychiatry. “With sophisticated brain imaging, we can
more accurately identify and target those circuits.”
What are the faulty circuits responsible for major depressive
disorder? How can those circuits be reset in the 30% to 50% of
patients who do not respond to or cannot tolerate pharmacological
therapy with antidepressant agents like selective serotonin reuptake
inhibitors and serotonin and norepinephrine reuptake inhibitors?
Electroconvulsive therapy (ECT) has been the workhorse for
treating severe depression since its development in the 1930s, and
new developments have reduced the likelihood of side effects like
memory loss. Transcranial magnetic stimulation (TMS), pioneered
by Dr. George and other scientists at MUSC and approved by the
U.S. Food and Drug Administration for treatment of this patient
population in 2008, more specifically targets the faulty circuits
specific to depression, achieving impressive response rates with few
side effects and without the need to anesthetize the patient.
Electroconvulsive Therapy
The exact mechanism by which ECT works is unknown, but
it is believed that passing currents through specific regions and
then producing a seizure “resets” the brain circuitry and chemistry, allowing for a reduction in depressive symptoms. It has
20
Progressnotes November 2013
FIGURE 1. The right hemisphere of the brain. Arrows represent the communication
(dysfunctional in the depressed) between the frontal cortex (pink) and the limbic system.
Illustration by Emma Vought.
demonstrated efficacy in treating patients with refractory depression; the vast majority of these patients—as many as 65% to
80%—show improvement after ECT treatment.
Although ECT still arouses concern in some patients because
of its early negative portrayal in the media, treatment delivery has
evolved significantly since its invention. It is used only in patients
with severe drug-refractory conditions. ECT involves anesthetizing the patient (with methohexital or etomidate), administering a
muscle relaxant (succinylcholine), and using an electrical stimulus
transmitted through electrode patches on the head to induce a
seizure. Studies have found ECT to be equally effective in treating bipolar disorder.¹ Other indications for ECT include mania,
schizophrenia, and catatonia.
ECT remains the most effective acute treatment for severe
major depression. “Advances in ECT, including better equipment,
more experienced and better trained physicians, changes in the
placement of electrodes, and changes in the pulse-width of the current have all helped significantly reduce the cognitive side effects
associated with ECT,” notes Baron Short, M.D., M.S., Director
of the MUSC Institute of Psychiatry’s Brain Stimulation Service.
“The Brain Stimulation Laboratory is further refining ECT methods so that we can maintain efficacy while dramatically reducing
side effects,” continues Dr. Short.
A 2013 article in Brain Stimulation (May-June 2013) reports
the initial results of a study conducted jointly at MUSC and
Columbia University in New York to assess the efficacy of a novel
form of precise ECT called FEAST (Focal Electrically Administered Seizure Therapy).² This new form of ECT uses pulsed direct
current stimulation, with the bulk of the electrical charge delivered directly under one electrode that is placed about two inches
above the right eye. Traditional ECT uses alternating current,
which flows in both directions and is thus harder to direct and
target. Patients undergoing FEAST became fully oriented just five
minutes after they first opened their eyes, an important finding
since longer orientation times typically predict longer-term cognitive effects. After an average of ten sessions over the course of four
MUSC’s Medical Magazine
KEY POINTS
•T
he brain’s circuits are not completely hard-wired in adults, and so faulty circuits can still be rewired.
•S
ophisticated brain imaging has helped to identify the faulty circuits responsible for a variety of psychiatric and neurological disorders.
•E
lectroconvulsive therapy has long been used to “reset” the brain’s circuits, and recent advances have minimized the likelihood of side
effects like memory loss.
•T
ranscranial magnetic stimulation (TMS), approved by the U.S. Food and Drug Administration for the treatment of patients who have
failed to respond to treatment with at least two separate antidepressants, delivers focused magnetic stimulation directly to the area of the
brain thought to be involved with regulating mood.
• In real-world clinical settings, 50% to 60% of patients with treatment-resistant depression respond to TMS, and early studies suggest that
the response is more durable than that achieved with ECT, with fewer side effects.
weeks, 8 of 17 study patients saw a reduction in their depressive
symptoms, and five patients were largely symptom free.
Identifying the Faulty Circuit in Depression
Early in his career, Dr. George, a pioneer in biomedical imaging,
set out to identify the regions of the brain associated with depression, comparing imaging studies of the brain in patients who were
depressed and those who were not. In depressed patients, far less
activity was observed in the frontal cortex. This is not surprising,
given that this area of the brain is associated with cognition, motivation, and executive function such as planning.
“What do we do with the frontal cortex? We think about our
role in the future, we plan, we hope, we understand how we fit
into the world. If you think about depression, it’s hopelessness (I
can’t see any future), helplessness (I’m not empowered to change
the world), and worthlessness (I am not worth anything), so the
normal role of the prefrontal cortex in realistically evaluating where
you are is totally gone,” explains Dr. George.
The frontal cortex submits the sensory and emotional stimuli
from the limbic system to a reality test (Figure 1). The limbic
system is a primitive region of the brain associated with primal
emotions like fear and anger that are integral to the fight or flight
response and so key for survival. Is a noise in the night a sign
of real danger that should provoke flight, or can it be rationally
traced to an unthreatening cause? It is the frontal cortex that runs
through the possible scenarios to decide whether action is required.
When this portion of the brain is not functioning properly,
our interpretation of sensory and emotional stimuli can become
irrational and inflexible. Whereas an “undepressed” person might
be able to entertain any number of plausible explanations for the
failure of a coworker to greet him or her (eg, the coworker was
having a bad day, was under the pressure of a deadline, was not
feeling well that day), the depressed person immediately assumes
it is evidence of that colleague’s anger toward and dislike of him or
her. The capacity to reason and think of alternative interpretations
is compromised, leaving the depressed person with an overly negative and reductive perspective on the world.
Transcranial Magnetic Stimulation
As early as 1995, Dr. George wondered whether we “might be
able to tickle or stimulate this part of the brain that is not working
FIGURE 2. Dr. Mark George, demonstrating transcranial magnetic stimulation therapy,
which he helped pioneer to treat depression.
in depressed people, and whether, if we could restore this regulatory system, we could get people undepressed.” From that germinal idea developed TMS, now available in more than 500 clinics
nationwide. In open-label clinical trials, one in two patients suffering with depression improved significantly after undergoing
TMS targeted to the frontal cortex, known to be underactive in
depressed patients, and one in three patients was completely free of
depressive symptoms after six weeks of treatment. TMS is proving
even more effective in real-world clinical settings, with a reported
response rate of 50% to 60%.³ As evidence of its efficacy and
effectiveness grows, insurers are becoming more willing to cover
the procedure. In South Carolina, Medicare and Blue Cross Blue
Shield are currently writing for coverage.
During TMS, a small curved device, about the size of a cupped
hand, rests lightly on the head of a patient reclining comfortably
in a spa chair, delivering focused magnetic stimulation directly to
the area of the brain thought to be involved with regulating mood
(Figures 2 and 3). The magnetic field pulses are the same strength
as those used in magnetic resonance imaging (MRI) machines—on
the order of 1.5 T—but very brief. Unlike ECT, which must be
given under anesthesia and which induces a seizure, TMS can be
For more information, call MEDULINE at 1-800-922-5250 or 843-792-2200 or visit the digital edition at MUSChealth.com/progressnotes
21
DEPRESSION
“If we know the circuit, and can modify
it, we can potentially come up with a
new treatment for any disease of the
brain.” —Mark George, M.D., Director of
the MUSC Brain Stimulation Laboratory
performed while the patient is awake and is targeted only at those
areas of the brain thought to be involved in depression.
Typically, patients receive four to six weeks of daily treatment,
each session lasting 30 to 45 minutes, and some patients receive
regular intermittent treatments thereafter to alleviate low mood.
Patients are awake, can read or listen to music during the treatment, and can even return to work after treatment, an advantage
over ECT, after which patients need time to recover.
TMS also has an attractive side effect profile, and early studies suggest better durability than that obtained with ECT.⁴ Unlike
pharmacological therapies that can result in weight gain and sexual
dysfunction, TMS has few side effects, and those are typically
minor (ie, mild scalp irritation, a very slight risk of seizure). Its
response rate of 50% to 60% may be somewhat lower than that
achieved in ECT, but the durability of that response may be superior (80% for TMS at one year vs 50% for ECT). The only real
disadvantage posed by TMS is the need to undergo treatments for
a period of several weeks. To address this issue, Dr. George and
his team are currently experimenting with shorter, more intensive
protocols (such as that described in “Reducing Suicidal Thinking
With TMS”), which thus far have proven to have similar efficacy
with no additional burden of side effects.
Reducing Suicidal Thinking With TMS
New evidence suggests that TMS can reduce suicidal thinking, an
important finding because few therapeutic options exist for this
22
Progressnotes November 2013
population. According to Dr. George, “We don’t have a treatment
for when someone comes off of the bridge. We can talk with them
or change medicine, but that takes time. There has been little available in the way of an acute treatment.”
In a study led by Dr. George and conducted jointly at the
Ralph H. Johnson VA Medical Center in Charleston, SC, and
Walter Reed National Military Medical Center in Bethesda, MD,
veterans in immediate danger of committing suicide received
TMS, using a shortened protocol of nine treatments over the
course of three days. TMS was found to halve the incidence of suicidal thinking in these patients in the first 24 hours of treatment.
When asked at the end of the nine treatments whether they were
currently bothered by thoughts of suicide, study patients receiving
TMS reported 40% less depression than at baseline.
The availability of an acute treatment for these patients could
revolutionize the management of suicide, mirroring the evolution
seen in the management of patients experiencing stroke or myocardial infarction once acute treatments— like tissue plasminogen
activator for ischemic stroke and cardiac catheterization for heart
attack—became available. Educational campaigns were launched
to teach the public how to recognize the warning signs, and protocols were developed to ensure the timely administration of treatment, greatly improving outcomes. Likewise, more suicides may
be prevented with the advent of an acute treatment for suicide and
educational campaigns reminding people that suicidal crisis is a
brain disease and can be treated.
MUSC’s Medical Magazine
p
Other Potential Research and Clinical Applications
The potential applications of TMS extend beyond treatmentresistant depression and suicide. TMS is a valuable research tool as
well as an important clinical advance. Because it can turn on or off
certain regions of the brain, or dial down or dial up the intensity of
their activity, TMS can be used, together with sophisticated brain
imaging, to identify the faulty circuits that characterize a range of
disorders. Once those faulty circuits have been identified, TMS can
be used to help repair that wiring. “We are not wedded to any one
7/21/03
7:00
Page 69
disease,”
saysPM
Dr. George.
“Researchers here at the MUSC Brain
Stimulation Lab are experimenting with TMS as a treatment for
chronic and acute pain management and addiction disorders in the
hopes of better understanding the circuits in the brain and targeting them for new treatments.”
To learn more about the Brain Stimulation Service at MUSC,
visit http://academicdepartments.musc.edu/psychiatry/research/
bsl/index.htm. To enroll a patient in a clinical trial, contact
research assistant Jkeonye Moss at [email protected]
References
¹ Daly JJ, et al. ECT in bipolar and unipolar depression: differences in speed of
response. Bipolar Disorders 2001;3(2):95-104.
² Nahas Z, et al. A feasibility study of a new method for electrically producing
seizures in man: focal electrically administered seizure therapy [FEAST].
Brain Stimul 2013;6(3):403-8.
³C
arpenter LL, et al. Transcranial magnetic stimulation (TMS) for major
depression: a multisite, naturalistic, observational study of acute treatment
outcomes in clinical practice. Depress Anxiety 2012;29(7):587-96.
⁴M
antovani A, et al. Long-term efficacy of repeated daily prefrontal
transcranial magnetic stimulation (TMS) in treatment-resistant depression.
Depress Anxiety 2012;29(10):883-890. dx.doi.org/10.1002/da.21967.
TRANSCRANIAL MAGNETIC STIMULATION
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field depth
Pulsed
magnetic
field
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brain region
Magnetic field
Positioning frame
Activated
neurons
Resting
neurons
FIGURE 3.succession,
Transcranial Magnetic
Stimulation.
Illustration bypression
Bryan Christie
Design,which
used withdiminishes
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23
FIGURE 1. College of Nursing Hispanic Health Initiative staff Romina McCandless (left) and Anna Tecklenburg Patton (right) conduct health outreach at a migrant camp on
Wadmalaw Island, SC
Breaking Down Barriers to Health Care for
the Hispanic Community
The Office of Hispanic Health Initiatives in the MUSC College of Nursing
T
he Hispanic population in South Carolina has grown rapidly
in the past 20 years, faster than the health care system has
been able to adapt to its needs. According to 2010 Census data,
South Carolina’s overall population grew by 15.3% in the past 10
years, but its Hispanic population grew by 148%, in part because
Hispanic workers were drawn to jobs in the agricultural and construction industries.
Health care workers, most of whom do not speak Spanish and
many of whom have little knowledge of Hispanic culture, have
struggled to know how to best serve this population, and the Hispanic community can find it challenging to navigate the American health care system. Language barriers are not the only factor
limiting access to health care for the Hispanic community; lack of
transportation, lack of insurance or other monies to pay for care,
immigration status, and misinformation (ie, the documentation
Digital Exclusive Progressnotes November 2013
that is required) can all play a role in preventing the Hispanic
populace from receiving adequate care. Many do not understand
where they “plug into” health care and are not familiar with the
American notions of primary care and the medical home, making
it more likely that they will wait to seek care until they are very
sick and then show up in emergency rooms.
To help address these needs, Deborah C. Williamson, DHA,
MSN, RN, Associate Dean for Practice and Associate Professor
in the MUSC College of Nursing, established the Office of Hispanic Health Initiatives (HHI), which has received grant funding
from The Duke Endowment and other private funding sources.
The original impetus for the founding of the HHI Office was a
request to Dr. Williamson, a long-time midwife, for help providing prenatal services to Hispanic women on Johns Island, whose
many farms have attracted a large Hispanic community. One of
MUSC’s Medical Magazine
the programs that has been sponsored by HHI, PASOs, is specifically charged with improving access to prenatal care and in general
to improving the reproductive health of Hispanic women. Abrazos,
a school-based program, aims to help Hispanic children integrate
into the school system while helping their mothers improve their
health literacy. While working to educate the Hispanic community
about how to navigate the U.S. healthcare system, the HHI Office,
through its HHI Scholars Program, is simultaneously seeking to
improve the cultural competence of health care workers, specifically nurses, by involving them in projects that help them learn
more about the challenges faced by the Hispanic community and
the barriers that can prevent them from receiving needed care.
Economic Barriers to Care
Hispanic children born in this country are U.S. citizens and can
qualify for Medicaid, meaning that they can be treated almost anywhere. Many of their mothers are not so lucky. Hispanic women
who are U.S. citizens can obtain prenatal and other care through
Medicaid, but undocumented workers cannot. Since 1996, those
legally residing in the U.S. for fewer than five years have also been
ineligible for Medicaid-covered care. Thus, many Hispanic women
do not receive regular care or preventive screenings and have a
much higher than average rate of diseases like cervical cancer.
When pregnant, Hispanic women not otherwise eligible for
care have a few more options, depending on their state of residence. The labor and delivery themselves may be covered by
Emergency Medicaid. Some states (fifteen as of 2009) have taken
advantage of a proviso in the Department of Health and Human
Services State Children’s Health Insurance Program (SCHIP) to
pay for prenatal care by enrolling fetuses in the program (since the
children, once born, will be U.S. citizens), though the postpartum
or other care of the mother is not included, and others have taken
advantage of an amendment in the 2009 SCHIP Reauthorization
Act that allowed states to be reimbursed for coverage of health care
for pregnant women and children who have been legally residing
in the U.S. for less than five years. South Carolina has not availed
itself of either option, and so Hispanic women legally residing
in the U.S. for less than 5 years are not eligible for Medicaid- or
SCHIP-funded prenatal care in this state.
The PASOs program, founded to improve the reproductive
and overall health of Hispanic women and their children, was able
to partner with the Arnold School of Public Health at the University of South Carolina to expand its program offerings after the
two jointly received a Duke Endowment Grant in 2008. It is now
available in 15 counties in South Carolina. In 2012, PASOs was
recognized as the “Promising Practice of the Year” by the National
Association for Maternal and Child Health Programs, meaning
that it could become a model for similar programs nationwide.
The PASOs program at MUSC’s College of Nursing, coordinated by Romina B. McCandless, MPH (Figure 1), opened in
2010 to serve the Tricounty region. According to 2011 data from
the South Carolina Department of Health and Environmental
Control, Hispanic women in Charleston are more than seven times
as likely to receive no prenatal care as white women (a marked
improvement compared with 2010 data, when they were sixteen
times as likely to receive no prenatal care). The MUSC College of
PASOs
The PASOs (steps in Spanish) Program was founded in 2005 as a
response to a study showing that babies in the Latino population
in South Carolina were at greater risk because of their mothers’
limited access to health care. Lack of prenatal care leads to higher
rates of preterm deliveries, which are associated with developmental and indeed lifelong health complications. Nearly one in eight
Hispanic births in the U.S. in 2004 was premature, in part because
of lack of prenatal care (March of Dimes, Peristats),and the rate of
preterm births has been increasing among Hispanic women relative to other ethnic groups (March of Dimes, 2009). Given that
the Hispanic population is growing rapidly, this failure to cover
prenatal care for future citizens is putting a whole generation of
U.S. citizens of Hispanic origin at risk, which could result in a far
greater burden on the health care system down the road than paying for prenatal coverage now.
FIGURE 2. MUSC Children’s Care offers culturally competent care for the Hispanic
community, including a bilingual patient navigator (top) and bilingual providers (bottom) and
front office staff
For more information, call MEDULINE at 1-800-922-5250 or 843-792-2200 Digital Exclusive
FIGURE 3. MUSC College of Nursing students at a migrant camp outreach
Nursing PASOs program works one-on-one with members of the
Hispanic community, particularly pregnant women, helping them
better understand and navigate the American health care system.
PASOs refers Hispanic families to culturally competent clinics like MUSC’s Children’s Care Clinic in North Charleston,
where all health care providers and many of the front office staff
speak Spanish and where patient navigator Martha Lucia Gomez,
CHW, acts as their advocate, whether that be explaining how to
administer medications or helping them find resources to pay the
next month’s electric bill (Figure 2). This clinic offers bilingual
case management, the opportunity to apply for Medicaid on site,
a family literacy program, screenings for trauma, as well as a crime
victims representative on site and referrals for human services
resources that can meet nutritional and other needs.
PASOs refers Hispanic adults without insurance to local free
clinics like the Harvest Free Medical Clinic in North Charleston,
the MUSC student-run Cares Clinic in Mount Pleasant (limit 10
patients per night), and the Barrier Island Free Medical Clinic on
Johns Island. Prenatal care is available at Our Lady of Mercy Community Outreach (free) or at the Franklin C. Fetter Family Health
Center, Inc, a federally qualified health center serving Berkeley,
Charleston, Colleton, and Dorchester counties (sliding-scale fees).
Partnering with community organizations, PASOs organizes
health fairs and screenings that are staffed by MUSC nursing students and other volunteers, provides monthly educational classes
on rotating maternal/child health topics (eg, nutrition, contraception, the importance of folic acid supplementation for women of
child-bearing age), and participates in a local migrant outreach
program during the migrant season (Figures 3 and 4). PASOs
also facilitates a weekly Spanish-language radio show on WAZS
El Sol 980/1480 am (http://www.elsol980.com/), the only one in
Digital Exclusive Progressnotes November 2013
FIGURE 4. A migrant worker participating in a health screening
Charleston, to help communicate with and educate the local Hispanic community on various maternal/child health topics.
Through its Promotores Initiative, PASOs also encourages Hispanic adults to become resources for their neighbors. Promotores
are community health workers who promote cultural competence
among health care workers and help members of the Hispanic
community learn how to access medical care. “Promotores have
learned how to identify services in the area and get into doctor’s
offices and they take that information back to the community,
becoming grassroots leaders,” says Ms. McCandless.
ABRAZOS
Like the health care system, the school system was not ready to
serve the needs of the growing Hispanic community. Dr. Williamson of the MUSC College of Nursing, Midland Park Ministries,
and the Trident Literacy Association joined together to found the
MUSC’s Medical Magazine
Abrazos Program (Spanish for hugs) to help better prepare Hispanic children for entry into the school system by offering child
development classes for three-year-olds (Figure 5). In recent years,
the Charleston County School District, seeing the benefits of the
program, applied for and was awarded a grant to continue the program, which is now entering its eighth year. The program, located
at the Midland Park Primary School in North Charleston, focuses
not only on readying Hispanic children for school but also on providing their mothers classes in English as a second language as well
as in health. Testing by the Charleston County School System has
shown that the English skills of both mothers and children have
improved dramatically due to the program.
The Abrazos program tries to be as responsive to the needs and
interests of the mothers as possible, asking them to suggest topics
for the health information sessions on the first day of class (popular
topics include reproductive health and domestic abuse) and providing an on-site nursery. Locating the program in the Midlands
Park region of North Charleston, where almost 50% of residents
are of Hispanic origin, means that Hispanic families do not have
to travel great distances to attend the classes, eliminating lack of
transportation as a barrier to participation. The program also helps
women and children apply for benefits for which they are eligible
(eg, Medicaid, SNAP) through the Benefit Bank so that they can
buy adequate food for their families. In this population struggling
with high rates of obesity and chronic disease like diabetes and
heart disease, the women are encouraged to adapt favorite recipes
to control calories and maximize vegetable and fruit intake. Last
year these recipes were collected into a cookbook for community
dissemination. In the words of Anna Tecklenburg Patton, MA,
the coordinator of the health component of the program (Figure
1), “We really do encourage their input throughout the whole year,
and so it’s a participatory process. It’s one small way to address
their health needs and questions, as well as greater social needs.”
Hispanic Health Initiative Scholars
The HHI Office was founded not only to help the Hispanic community better navigate the health care system but also to help teach
heath care workers more about that community so that they could
provide more culturally competent care. That is precisely the mission of the HHI Scholars Program, which engages third-semester
College of Nursing students (who apply in their second semester)
in projects to benefit the Hispanic community. HHI Scholars meet
almost every week to hear presentations by speakers on a host of
issues relevant to the Hispanic community, from immigration law
to food insecurity, and then discuss how these issues relate back to
health. As enlightening as these programs are, some of the most
dramatic learning experiences occur when the HHI scholars engage
in community projects, participate in outreach efforts at migrant
camps, to see working and living conditions and work with safety
net providers. According to Zachary Childress, a nursing student
at MUSC who just completed his semester as an HHI scholar, it
was quite eye opening “to see at migrant camps this hidden side of
food production down a dirt road in the country.” Another recent
HHI Scholar, Shanice Strobhart, appreciates the program because
“it put us in the community and helped us to see health care
from a different perspective and not just from inside a hospital.”
FIGURE 5. Children in the Abrazos Program learn the skills they will need when they
enter the school system while their mothers learn about important health topics and
improve their English
Through community engagement, she learned that “many factors
contribute to one’s health and it’s not just one’s personal decisions
that affect health but things that are not in one’s control.”
One of those factors is access to healthy foods. As their group
project, this year’s HHI scholars chose to focus on food insecurity
in the Hispanic community, which they thought only appropriate given the high rates of food insecurity in this population. They
also wanted to ensure that governmental programs like WIC and
SNAP helped the Hispanic community obtain nutritious food
like fruits and vegetables and not empty calories that contribute to obesity and chronic disease. They focused on encouraging
the Coastal Carolina Flea Market in Ladson, South Carolina, to
accept WIC and SNAP. The flea market, which includes a number
of fresh produce vendors, is located near Hispanic neighborhoods,
many of the residents of which frequent the market. Working
with Crop Up, a nonprofit organization that promotes access to
fresh produce in urban areas, the Scholars conducted an informal
survey of Hispanic customers at the flea market and found that
they would buy more fruits and vegetables if WIC and SNAP
were accepted, helped educate local farmers about how accepting WIC and SNAP could double their sales, and researched how
similar programs had been set up in California. This project supported community efforts to provide Hispanic customers greater
access to fresh foods.
Through these programs, the HHI Office at MUSC’s College
of Nursing is working with community members to break down
the barriers that prevent the Hispanic population from receiving
care and to encourage cultural competency among health care professionals so that they can better understand and meet the needs of
this population. It is not surprising that this effort took root in the
College of Nursing because, according to Dr. Williamson, “Historically, nurses have served as advocates for their patients, working
for individual-, system-, and policy-level changes.” The programs
supported by the HHI Office are collaborative efforts with community members, local agencies, and other MUSC departments to
improve the health and well-being of the Hispanic community by
promoting health equity and social justice.
For more information, call MEDULINE at 1-800-922-5250 or 843-792-2200 Digital Exclusive
Welcome
MUSC Welcomes Patrick J. Cawley, M.D., MHM, FACHE, as New Physician-CEO
“There is nothing wrong in
change, if it is in the right
direction. To improve is to
change, so to be perfect is to
change often.”—Winston
Churchill
In a time of rapid changes
in health care brought about
by health care reform on the
one hand and ever advancing scientific and information
technology on the other, physician-CEOs, who combine
a vision for the way forward
with instant credibility with
the clinical staff, will be in
greater demand.
With the appointment of Patrick J. Cawley, M.D., MHM,
FACHE, as Executive Director and Chief Executive Officer, the
MUSC Medical Center joins the ranks of the 5% of medical centers that are fortunate to have a physician-CEO at the helm. A
paradigm shift is under way in medicine, from fee-for-service to
pay for performance, from a focus solely on treating disease to a
concern for improving population health, and from competition
to collaboration to deliver affordable and coordinated care. Change
is never easy, but health care workers are more likely to adapt to
change if it is presented to them by a trusted colleague with a history of concern for patient care and an understanding of what it is
like to be on the frontlines.
As a practicing physician with an impressive record of leading successful quality and safety improvement initiatives and as
a nationally recognized physician leader, Dr. Cawley is uniquely
equipped to lead the MUSC Medical Center through these
changes. He is a certified physician executive through the American College of Physician Executives, a fellow of the American
College of Healthcare Executives and of the Liberty Fellowship
Program, and a member of the Aspen Global Leadership Network.
Dr. Cawley earned his medical degree at Georgetown University
before completing an internal medicine residency at Duke University, where he co-founded the first hospital medicine program.
He has since served as a consultant to both academic and nonacademic hospitals that were seeking to develop such programs
and was named a Master in Hospital Medicine by the Society of
Hospital Medicine. This impressive medical pedigree is enhanced
by a Master’s of Business Administration from the University of
Massachusetts-Amherst. As Chief Medical Officer at MUSC, a
position he held until appointed as Chief Executive Officer, he led
quality improvement and patient safety initiatives, which, in 2012,
culminated in MUSC being recognized as a Rising Star by The
University Healthsystem Consortium.
24
Progressnotes November 2013
Like Winston Churchill, Dr. Cawley believes that change in
the right direction can make us better. What are the changes he
sees coming, and how, if handled properly, can MUSC emerge a
stronger institution and an even greater asset to the state?
First, as payors, governmental and private alike, demand better health care value, the institutions that will survive and indeed
thrive are those which can engrain into their culture the will to
continuously improve quality and safety while identifying opportunities for cost-cutting. Such efforts will only succeed if physicians
and all members of the health care team are unified in their support, and they are more likely to garner such widespread clinical
support when a physician-CEO is leading the way, especially one,
like Dr. Cawley, with a successful track record with such initiatives.
Health care institutions will also be asked increasingly to
improve population health, intervening earlier with preventive
measures that can stave off the health and economic burdens that
come with chronic disease. Under Dr. Cawley’s leadership, MUSC
already has a number of pilot population health projects under
way, with more soon to follow.
At the same time as U.S. health care is held more accountable for population health, medicine as a whole will be grappling
with how our increasing knowledge of genomics will revolutionize
patient care. The new norm will be personalized medicine, where
medication and other therapies can be tailored to a person’s particular genetic profile. The growing availability of patient data,
including genetic information, via the electronic health record will
facilitate such personalized care. MUSC’s investments in establishing a genomics core and an electronic health record will position it
to be on the forefront of such personalized medicine.
The electronic health record will also identify opportunities
for quality improvement, provide clinical decision tools that can
help avoid costly medical errors, and promote the coordination of
patient care across all health care organizations.
Dr. Cawley has no doubt that MUSC is ready to meet the
challenges facing health care and that it will emerge even stronger than before. In his ten years at MUSC, he has been impressed
above all with the unquenchable curiosity of his colleagues: “All
members of our interprofessional teams have an insatiable curiosity
about patient care. They view things differently and constantly ask
questions. It is an invigorating environment!” That curiosity will
help ensure that MUSC remains at the forefront of clinical innovation and will motivate all members of its staff to work tirelessly to
move patient care ever forward.
MUSC’s Medical Magazine
Welcome
The Medical University of South Carolina Welcomes the Following New Physicians
Eric W. Angermeier, M.D. // Specialty: Orthopaedic Surgery // Special
Interests: Hand and upper extremity surgery, Microvascular surgery //
Medical School: Medical University of South Carolina // Residency:
Medical University of South Carolina // Fellowship: Duke University
Eric T. Kimchi, M.D. // Board Certification: Surgery // Specialty:
Surgical Oncology // Special Interests: Pancreatic cancer,
Neuroendocrine tumors, Bile duct cancer, Colon cancer metastatic
to the liver // Medical School: Pennsylvania State University
// Residency: Sinai Grace Hospital, Wayne State University //
Fellowships: Wayne State University, University of Chicago
Kyle P. Kokko, M.D. // Specialty: Orthopaedic Surgery // Special
Interests: Hand and upper extremity surgery, Microvascular surgery,
Hand disorders, Adult hand problems // Medical School: Medical
University of South Carolina // Residency: Medical University of
South Carolina // Fellowship: Hospital for Joint Diseases at NYU
Langone Medical Center
Bryan T. Kumiga, D.O. // Specialty: Physical Medicine &
Rehabilitation // Special Interests: Interventional spine care,
Musculoskeletal medicine, Electrodiagnostics, Epidural steroid
injections, Nerve blocks, Facet injections, Radiofrequency ablation
// Medical School: New York College of Osteopathic Medicine //
Residency: Long Beach Medical Center // Fellowship: University of
Massachusetts Medical School
Scott M. Lindhorst, M.D. // Board Certifications: Internal Medicine,
Internal Medicine: Hematology, Internal Medicine: Medical
Oncology // Specialties: Hematology & Oncology, Neurosurgery
// Special Interests: Neuro-oncology, Primary brain tumors, Central
nervous system lymphomas, Head and neck cancers, Lymphomas
// Medical School: University of South Alabama // Residency:
University of Alabama // Fellowships: University of Alabama,
Duke University
Linda M. Meyers, M.D. // Board Certification: Internal Medicine //
Specialty: Endocrinology // Special Interests: Endocrine disorders
including pituitary and thyroid and parathyroid, Diabetic medical
conditions // Medical School: University of Texas Medical School
// Residency: Medical University of South Carolina // Fellowship:
Medical University of South Carolina
Satish N. Nadig, M.D., PhD // Board Certification: Surgery //
Specialty: Transplant Surgery // Special Interests: Liver/kidney/
pancreas transplant, Pediatric multi-organ transplant, Laparoscopic
donor nephrectomy, General surgery in organ failure patients,
Translational research in transplant immunology // Medical School:
Medical University of South Carolina// Graduate School: University
of Oxford // Residency: Beth Israel Deaconess Medical Center at
Harvard // Fellowship: University of Michigan
Ryan H. Nobles, M.D. // Specialty: Anesthesia-Pain Management
// Special Interests: Pain management // Medical School: Medical
University of South Carolina // Residency: Medical University of
South Carolina // Fellowship: Emory University
Megan E. Redfern, M.D. // Specialty: Pediatrics General // Special
Interests: Pediatric urgent care // Medical School: Medical College
of Georgia School of Medicine // Residency: Medical University of
South Carolina
Elizabeth M. Wallis, M.D. // Board Certification: Pediatrics //
Specialty: Pediatrics General // Special Interests: Chronic illness,
Transition from pediatric to adult healthcare, Adolescent medicine,
Adolescent family planning // Medical School: Warren Alpert
Medical School of Brown University // Residency: Children’s
Hospital of Philadelphia // Fellowship: // Children’s Hospital of
Philadelphia
internationaL syMPosiuM on tHe MedicaL and surgicaL treatMent of cHronic Pancreatitis
February 6-8, 2014
Kiawah Island, South Carolina
HigHLigHts:
48 International Speakers
Free Paper Concurrent Sessions
Submitted Manuscripts Eligible for Publication in The American Surgeon
Benefit Charleston Style Oyster Roast
Charity Golf Tournament at Turtle Point
Learn More at our Website @ PancreatitissyMPosiuM.org
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25
MEDICAL UNIVERSITY OF SOUTH CAROLINA
Progressnotes
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Charleston SC 29425
MUSC has developed online tools for you and your office staff to provide easy
access to information and to help streamline the referral process.
Visit physicianportal.muschealth.com to:
• Access MUSC electronic medical records
• Make online referrals
• Access MUSC clinical trials
• Register for CME conferences and online CME activities
• Find resources for you and your staff
• Access the digital edition of Progressnotes
For technical questions or comments regarding the physician portal,
call MEDULINE at 1-800-922-5250 or 843-792-2200.
Visit www.musc.edu/cme for a complete list of CME conferences.
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