News 28 april 2009
Arterial Disease of The Leg
Frequently Overlooked in Patients with Heart Disease
Peripheral arterial disease (PAD) of the
legs, in which the arteries become blocked with plaque and blood supply to the legs is
reduced, affects eight million people in the U.S. Early detection of PAD is important
because it can limit the ability to walk and exercise, it may place patients at greater
risk for limb loss and it increases the chance of having a heart attack or stroke.
Coronary artery disease (CAD) is prevalent in patients with PAD and it is known that PAD
is under diagnosed in the primary care setting, but a new study found that it is often
overlooked even in patients with known heart disease who are under a cardiologist’s
care. The study was published in the May issue of Catheterization and Cardiovascular
Interventions, the official journal of The Society for Cardiovascular Angiography and
Interventions (SCAI). Led by Dr. Issam D. Moussa of New York Presbyterian Hospital/Weill
Cornell Medical Center, the study involved nearly 800 patients with ischemic heart disease
who were to undergo coronary angiography and/or intervention and were either at least 70
years old, or between the ages of 50 and 69 and had a history of diabetes mellitus and/or
tobacco use. Researchers determined if patients had PAD by calculating the Ankle-Brachial
Index, the ratio of the blood pressure in the lower legs to blood pressure in the arms,
which is normally the first test administered to patients in cases where PAD is suspected.
Patients also answered questionnaires on PAD awareness and functional status. The results
showed that approximately one out of six patients had previously unrecognized PAD, despite
being under the care of a cardiovascular specialist. The researchers point out that this
includes only those with previously undiagnosed PAD and does not represent the total
prevalence of PAD in patients with heart disease, which is actually much higher. Most
patients with PAD did not limp or have leg pain, two symptoms of the disease. “The
combination of physician lack of awareness and lack of symptoms among patients results in
failure to diagnose PAD, even in patients who are at high risk,” the researchers
state. “Furthermore, clinical evaluation alone often lacks the sensitivity and
specificity to optimally identify PAD particularly in less advanced stages and in
hospitalized patients with CAD.” The study also found that previously missed PAD was
more frequent in older patients and women, which goes against the conventional wisdom that
PAD is more prevalent in men and suggests that PAD is more frequently overlooked in women
than men in outpatient settings.
Findings uncover new details about
mysterious mimivirus
An international team of researchers has
determined key structural features of the largest known virus, findings that could help
scientists studying how the simplest life evolved and whether the unusual virus causes any
human diseases. The mimivirus has been called a possible "missing link" between
viruses and living cells. It was discovered accidentally by French scientists in 1992 but
wasn't confirmed to be a virus until 2003.
The virus infects amoebas, but it is thought to possibly be a human pathogen because
antibodies to the virus have been discovered in pneumonia patients. However, many details
about the virus remain unknown, said Michael Rossmann, Purdue University's Hanley
Distinguished Professor of Biological Sciences. Now a team of researchers from Purdue, the
University of California at Irvine and the University of the Mediterranean in Marseilles,
France, have thrown more light on the mimivirus' makeup. The scientists have determined
the basic design of the virus' outer shell, or capsid, and also of the hundreds of smaller
units called capsomeres making up this outer shell. Findings also confirmed the existence
of a starfish-shaped structure that covers a "special vertex," an opening in the
capsid where genetic material leaves the virus to infect its host, and an indentation in
the virus's genetic material itself is positioned opposite this opening, Rossmann said.
"The findings are important in terms of studying the evolution of cells, bacteria and
viruses," said Siyang Sun, a postdoctoral research associate working in Rossmann's
lab. "The mimivirus is like an intermediate between a cell and a virus. We usually
think of cells as being alive and a virus is thought of as being dead because it needs a
host cell to complete its life cycle. The mimivirus straddles a middle ground between
viruses and living cells, perhaps redefining what a virus is.”
Study examines radiation dose
estimates for pregnant women undergoing therapeutic ERCP
Pregnant women with gallstone disease may
require immediate endoscopic intervention because of potentially life-threatening
cholangitis (infection in the bile ducts) or gallstone pancreatitis (inflammation of the
pancreas). The radiation exposure in endoscopic retrograde cholangiopancreatography
(ERCP), which is used to treat these conditions, is a concern because fetal tissues are
more susceptible to radiation injury. Researchers from Greece found that the radiation
risks associated with ERCP procedures are not trivial and that accurate fetal dose
estimation is now available regardless of patient body size, operating parameters,
equipment used and gestational stage. The study appears in the April issue of GIE:
Gastrointestinal Endoscopy, the monthly peer-reviewed scientific journal of the American
Society for Gastrointestinal Endoscopy (ASGE). Endoscopic retrograde
cholangiopancreatography is a specialized technique used to study and treat problems of
the ducts that drain the liver and pancreas. To reach the ducts, an endoscope is passed
through the mouth, beyond the stomach and into the small intestine (duodenum). A thin tube
is then inserted through the endoscope into the common bile duct and pancreatic duct
connecting the liver and pancreas to the intestine. A contrast material (dye) is injected
through the tube outlining those ducts as X-rays are taken. The X-rays can show narrowing
or blockages in the ducts that may be due to a cancer, gallstones or other abnormalities.
Radiation exposure is of obvious concern as developing fetal tissues are more susceptible
to radiation injury. During pregnancy, the most common indication for ERCP is treatment of
choledocholithiasis (gallstones in the common bile duct). The occurrence of
choledocholithiasis can reach up to 12 percent of the pregnant population and increases
with gestational age. Given that symptomatic gallstone disease increases the risk of
morbidity and mortality of both the fetus and mother, medical intervention often cannot be
postponed pending delivery. Previous case series have demonstrated ERCP to be safe and
effective during pregnancy.
Depression linked with accumulation
of visceral fat
Numerous studies have shown that depression
is associated with an increased risk of heart disease, but exactly how has never been
clear. Now, researchers at Rush University Medical Center have shown that depression is
linked with the accumulation of visceral fat, the kind of fat packed between internal
organs at the waistline, which has long been known to increase the risk of cardiovascular
disease and diabetes.
The study is posted online and will be published in the May issue of Psychosomatic
Medicine. "Our results suggest that central adiposity – which is commonly called
belly fat – is an important pathway by which depression contributes to the risk for
cardiovascular disease and diabetes," said Lynda Powell, PhD, chairperson of the
Department of Preventive Medicine at Rush and the study's principal investigator. "In
our study, depressive symptoms were clearly related to deposits of visceral fat, which is
the type of fat involved in disease." The study included 409 middle-aged women, about
half African-American and half Caucasian, who were participating in the Women in the South
Side Health Project (WISH) in Chicago, a longitudinal study of the menopausal transition.
Depressive symptoms were assessed using a common screening test, and visceral fat measured
with a CT scan. Although waist size is often used as a proxy for the amount of visceral
fat, it is an inaccurate measure because it includes subcutaneous fat, or fat deposited
just beneath the skin. The researchers found a strong correlation between depression and
visceral fat, particularly among overweight and obese women. The results were the same
even when the analysis adjusted for other variables that might explain the accumulation of
visceral fat, such as the level of physical activity. The study found no association
between depressive symptoms and subcutaneous fat. The findings were the same for both
black and white women.Powell speculated that depression triggers the accumulation of
visceral fat by means of certain chemical changes in the body – like the production
of cortisol and inflammatory compounds – but said that more research is needed to
pinpoint the exact mechanism.
Are we cherry picking participants
for studies of antidepressants?
Findings from clinical studies used to gain
Food and Drug Administration approval of common antidepressants are not applicable to most
patients with depression, according to a report led by the University of Pittsburgh
Graduate School of Public Health. Published in the May issue of the American Journal of
Psychiatry, the study suggests only a small percentage of people with depression qualify
for these studies, and those who do not qualify are often treated with the same
medications but may suffer poorer clinical outcomes. A part of the National Institute of
Mental Health-funded Sequenced Treatment Alternatives to Relieve Depression (STAR*D)
project – the largest study of the treatment of depression conducted in the United
States – researchers compared symptoms and outcomes in depressed patients who met
phase III study inclusion criteria to those who did not. Phase III studies for
antidepressants determine the effectiveness of the drug in comparison to a placebo. The
inclusion criteria for these studies are not standardized nor subject to federal
guidelines, resulting in some variation from study to study in the profile of eligible
patients. Typically excluded are patients with milder forms of depression, who might be
more likely to respond to a placebo drug, and those who may have chronic depression or
psychiatric and medical co-morbidities – additional illnesses or conditions. After
assessing 2,855 patients treated with citalopram, a commonly prescribed selective
serotonin reuptake inhibitor for mood disorders, study authors concluded that fewer than
one in four, or 22.2 percent, of the patients met the usual criteria for inclusion in
phase III antidepressant trials.
"Only a small percentage of depressed patients in our study would have qualified for
inclusion in phase III efficacy trials of depression drugs," said study lead author,
Stephen Wisniewski, Ph.D., professor of epidemiology and co-director of the Epidemiology
Data Center, University of Pittsburgh Graduate School of Public Health. "This raises
major concerns about whether results from traditional phase III studies can be generalized
to most people with depression, who also often suffer from anxiety, substance abuse and
other medical and psychiatric problems." When Dr. Wisniewski and colleagues further
assessed how well patients did on treatment, they found that those who met the eligibility
criteria for phase III trials had better outcomes, including higher remission rates, less
severe side effects and serious adverse events. The depression remission rate in the
patients who met the criteria was 34.4 percent, compared to only 24.7 percent in the
ineligible group. Additionally, the drug response rate also was higher in the eligible
group – 51.6 percent compared to 39.1 percent of the ineligible group."Results
from research studies suggest more optimistic outcomes than may exist for real-world
patients receiving treatment for depression," said Dr. Wisniewski. Although phase III
eligibility criteria could be changed to include a broader population of patients, Dr.
Wisniewski cautions that this could come at the cost of more serious side effects in
patients who have co-morbidities and are generally sicker. These patients may not be able
to safely tolerate the drugs being tested. Instead, he suggests medical care providers who
treat patients with depression use their professional judgment by noting that most phase
III findings are based on patients who may be very different than those under their care.
WA discovery a key to blood cell
development
A West Australian research team has made
the world-first discovery a 'pied piper' molecule within blood cells, called Liar, that
leads other molecules into the nucleus of the cell, and could offer a key in treating
prostate, breast and colon cancers as well as leukemia. Uncovered by two research groups
at the Western Australian Institute for Medical Research (WAIMR) led by Associate
Professor Evan Ingley and Director Professor Peter Klinken, they have also identified the
function of a known cellular enzyme, Lyn, as a switch that 'turns on' blood cell
development. The findings are published in the April 16 issue of Blood, the journal of the
American Society of Hematology, the world's premier hematology journal. Associate
Professor Ingley said the findings were a leap forward in the understanding of how blood
cells develop and divide, which could offer them a key to turning off cancerous cell
growth. "LIAR is like a key, which opens a pathway into the nucleus of a blood cell
for a number of other molecules, allowing them to flow in – and these molecules are
what signal the cell to develop and divide," he said. "From here, if we could
control Liar, the hope is that we could use it to switch off the growth of abnormal, or
cancerous, cells. "Because Liar is present in every blood cell, this knowledge could
help treat a huge range of conditions and diseases, but where it has most potential is in
cancers of the prostate, breast, colon and blood where activity of the enzyme Lyn is
heightened." The focus of the team's investigations, Lyn has now been identified as
an enzyme which modifies proteins that triggers the cell to develop further.
Alarming increase in drug affected
newborns
A new Australian study has found that the
number of newborns suffering serious drug withdrawal symptoms is now more than 40 times
higher than in 1980. The research, published in the latest edition of the international
journal Pediatrics, also found that these infants were at greater risk of neglect and of
being taken into care. The data analysis revealed that of 637195 live births in Western
Australia between 1980 and 2005, 906 were diagnosed with Neonatal Withdrawal Syndrome. For
every year, there was an average 16.4% increase in children born with the syndrome. Report
co?author, Professor Fiona Stanley from Perth’s Telethon Institute for Child Health
Research, said the study identified a range of factors that should assist with the early
identification of children at risk. “It is clear that if we are to reduce the number
of these children suffering from abuse and neglect, then there is a need to start working
with their mothers before these babies are born, and ideally, pre?conception,”
Professor Stanley said. “Our data show that the majority of the mothers had already
had contact with hospitals for mental health and substance use issues which suggests there
could have been numerous opportunities to intervene to prevent unplanned pregnancy and
provide intensive support with antenatal care and substance abuse treatment.”
Experimental drug shows promise
against head and neck cancer
A laboratory study by researchers at Albert
Einstein College of Medicine of Yeshiva University suggests that an anti-cancer compound
studied for treating blood cancers may also help in treating cancers of the head and neck.
The work is reported in the April 28th online edition of the Journal of Pathology. Head
and neck cancer refers to tumors in the mouth, throat, or larynx (voice box). Each year
about 40,000 men and women develop head and neck cancer in the U.S., making it the
country's sixth-most common type. Surgery, chemotherapy and/or radiation are the main
treatment options but can cause serious side effects. Better treatments are needed, since
only about half of patients with head and neck cancer survive for five or more years after
diagnosis. The Einstein study involved a new class of chemotherapy agents known as histone
deacetylase (HDAC) inhibitors, which affect the availability of genes that are transcribed
and translated into proteins. In many types of cancer, out-of-control cell growth results
from certain genes that are either too active or not active enough in producing proteins.
HDAC inhibitors appear to combat cancer by restoring the normal expression of key
regulatory genes that control cell growth and survival. The Einstein researchers focused
on a particular HDAC inhibitor known as LBH589 that has already shown some success in
clinical trials involving people with cancers of the blood. The researchers found that
LBH589 succeeded in killing tumor cells that had been removed from head and neck cancer
patients and grown in the laboratory. "This report shows that an HDAC inhibitor is
effective on head and neck cancer cell lines, and that is the first step toward use in
humans," said Richard Smith, M.D., the lead clinician involved in the study. Dr.
Smith is associate professor of clinical otorhinolaryngology-head & neck surgery and
associate professor of surgery at Einstein and is also vice-chair of
otorhinolaryngology-head & neck surgery at Einstein and Montefiore.
Autism genes discovered; help shape
connections among brain cells
A research team has connected more of the
intricate pieces of the autism puzzle, with two studies that identify genes with important
contributions to the disorder. One study pinpoints a gene region that may account for as
many as 15 percent of autism cases, while another study identifies missing or duplicated
stretches of DNA along two crucial gene pathways. Significantly, both studies detected
genes implicated in the development of brain circuitry in early childhood. "Because
other autism researchers have made intriguing suggestions that autism arises from abnormal
connections among brain cells during early development, it is very compelling to find
evidence that mutations in genes involved in brain interconnections increase a child's
risk of autism," said study leader Hakon Hakonarson, M.D., Ph.D., director of the
Center for Applied Genomics at The Children's Hospital of Philadelphia. He is on the
faculty of the University of Pennsylvania School of Medicine, as is his main collaborator,
neuroscientist Gerard D. Schellenberg, Ph.D. "This comprehensive research opens the
door to more focused investigations into the causes of autism disorders," said Philip
R. Johnson, M.D., chief scientific officer at The Children's Hospital of Philadelphia.
"It moves the field of autism research significantly ahead, similar to the way
oncology research progressed a few decades ago with the discovery of specific genes that
give rise to cancers. Our extensive pediatric genomics program has pinpointed particular
genes and biological pathways, and this discovery provides a starting point for
translating biological knowledge into future autism treatments." The hospital's
Center for Applied Genomics, launched in 2006, is the world's largest facility dedicated
to the genetic analysis of childhood diseases.Collaborating with researchers from more
than a dozen institutions, including members of the Autism Genome Project (AGP),
Hakonarson led both studies, which appear today in online publication in Nature. Autism is
the best known of the autism spectrum disorders (ASDs), a group of childhood
neurodevelopmental disorders that cause impairments in verbal communication, social
interaction and behavior. Currently estimated to affect as many as one in 150 U.S.
children, ASDs are known from family studies to be strongly influenced by genetics.
Previous studies have implicated several chromosome regions harboring rare variants in
raising the risk of ASDs, but until now, research has not been consistent in identifying
and replicating common genetic variants. One of the two studies by Hakonarson's team is
the first to identify common genetic variants associated with autism. By using highly
automated genotyping tools that scan the entire genome of thousands of individuals, the
researchers found that children with ASDs were more likely than healthy controls to have
gene variants on a particular region of chromosome 5. That region is located between two
genes, cadherin 9 (CDH9) and cadherin 10 (CDH10), which carry codes to produce neuronal
cell-adhesion molecules.
A longer lasting tumor blocker
On the heels of dismaying reports that a
promising antitumor drug could, in theory, shorten patients' long-term survival, comes a
promising study by a Japanese team of researchers that suggests a potentially better
option. The study appears in the May 11 issue of the Journal of Experimental Medicine
(online April 27).Many cancer treatments work by disrupting the formation of new blood
vessels that feed growing tumors. Agents that block a vessel-promoting factor called VEGF
have shown promise in human clinical trials. But recent studies in mice show that when
treatment stops, tumor growth rapidly resumes. Now, Yoshiaki Kubota and colleagues find
that blocking a different molecule, called M-CSF, suppressed tumor growth even after
treatment was stopped.Kubota and his team compared the efficacy of inhibitors against
M-CSF and VEGF in mice with a certain kind of bone tumor. Three weeks of anti-VEGF
treatment suppressed tumor growth but, similar to other recent reports, the tumors bounced
back when the drug treatment was curtailed. Tumor growth in mice on a similar regiment of
an M-CSF inhibitor remained suppressed in the absence of drug. Another distinction between
the two inhibitors was the type of vessel growth that was blocked. Blocking VEGF prevented
dangerous vessels from growing such as those that feed tumors. But it also stopped
beneficial vessels from growing, such as those that help injured tissues heal. Blocking
M-CSF, on the other hand, only impeded bad vessel growth. Most likely, the anti–M-CSF
treatment had a lasting effect because it resulted in damage to the scaffolding that
surrounds cancerous vessels, robbing the tumors of the structural support they need to
grow. Meanwhile, the scaffold of mice treated with anti-VEGF remained intact. M-CSF levels
soar in patients with osteosarcoma (a malignant bone cancer), breast cancer and prostate
cancer, making these cancers potentially the most responsive to M-CSF-blocking drugs
Whether or not other types of cancer rely more on M-CSF than on VEGF for their blood
supply remains unknown.
Risk of autism tied to genes that
influence brain cell connections
In three studies, including the most
comprehensive study of autism genetics to date, investigators funded in part by the
National Institutes of Health have identified common and rare genetic factors that affect
the risk of autism spectrum disorders. The results point to the importance of genes that
are involved in forming and maintaining the connections between brain cells. "These
findings establish that genetic factors play a strong role in autism spectrum
disorder," says Acting NIH Director Raynard Kington, M.D., Ph.D. "Detailed
analysis of the genes and how they affect brain development is likely to yield better
strategies for diagnosing and treating children with autism." Autism spectrum
disorders (ASD) comprise a group of disorders with core symptoms that include social
interaction problems, poor verbal and nonverbal communication and repetitive behaviors.
These disorders range from severe (autism) to mild (Asperger's syndrome), and in total
affect some 1 in 150 American children, about three-quarters of whom are boys. Researchers
theorize that the social parts of the brain are underdeveloped in ASD. "Previous
studies have suggested that autism is a developmental disorder resulting from abnormal
connections in the brain. These three studies suggest some of the genetic factors which
might lead to abnormal connectivity," says Thomas Insel, M.D., director of NIH's
National Institute of Mental Health (NIMH). The studies were funded in part by the NIMH,
the National Institute of Neurological Disorders and Stroke (NINDS), the Eunice Kennedy
Shriver National Institute of Child Health and Human Development (NICHD), the National
Institute on Deafness and Other Communication Disorders (NIDCD) and the National Center
for Research Resources (NCRR), all components of NIH. All three studies were genome-wide
association studies, which are undertaken to find clues about the causes of complex
disorders. Typically, these studies involve scanning the genome – the entire set of
DNA – for small differences between people who have a disorder and people who do not.
The largest study, reported in Nature, involved more than 10,000 subjects, including
individuals with ASD, their family members and other volunteers from across the U.S. The
study was led by Hakon Hakonarson, M.D., Ph.D., a professor at the University of
Pennsylvania School of Medicine and director of the Center for Applied Genomics at The
Children's Hospital of Philadelphia. Among other principal investigators on the study were
Gerard D. Schellenberg, Ph.D., also a professor at the University of Pennsylvania School
of Medicine; and Daniel Geschwind, M.D., Ph.D., a professor at the University of
California, Los Angeles and director of UCLA's Center for Autism Research and Treatment;
and Margaret Pericak-Vance, Ph.D., a professor at the University of Miami Miller School of
Medicine and director of the Miami Institute for Human Genomics, who also led an
independent study that generated similar results.
Novel role of protein in generating
amyloid-beta peptide
A defining hallmark of Alzheimer's disease
is the accumulation of the amyloid ? protein (A?), otherwise known as "senile
plaques," in the brain's cortex and hippocampus, where memory consolidation occurs.
Researchers at the University of California, San Diego School of Medicine have identified
a novel protein which, when over-expressed, leads to a dramatic increase in the generation
of A?. Their findings, which indicate a potential new target to block the accumulation of
amyloid plaque in the brain, will be published in the May 1 issue of the Journal of
Biological Chemistry. "The role of the multi-domain protein, RANBP9, suggests a
possible new therapeutic target for Alzheimer's disease," said David E. Kang, PhD,
assistant professor of neurosciences at UC San Diego and director of this study. The
neurotoxic protein A? is derived when the amyloid precursor protein (APP) is
"cut" by two enzymes, ?-secretase (or BACE) and ?-secretase (or Presenilin
complex.) However, inhibiting these enzymes in order to stop the amyloid cascade has many
negative side effects, as these enzymes also have various beneficial uses in brain cells.
So the researchers looked for an alternative way to block the production of amyloid beta.
In order for cleavage to occur, the APP needs to travel to cholesterol-enriched sites
within the cell membrane called RAFTS, where APP interacts with the two enzymes. It is
this contact that the researchers sought to block. Kang explains that the researchers
identified the RANBP9 protein by studying low density lipoprotein receptor-related protein
(LRP), a protein that rapidly shuttles A? out of the brain and across the blood-brain
barrier to the body, where it breaks down into harmless waste products. A small segment of
LRP can also stimulate A? generation, and the scientists narrowed this segment down to a
37-amino-acid stretch that can lead to changes in A?. "RANBP9 is one of the proteins
we identified that interacted with this LRP segment, but one that had never before been
associated with disease-related neuronal changes," said Kang. "We discovered
that this protein interacts with three components involved in A? generation – LRP,
APP and BACE1 – and appears to 'scaffold' them into a structure." Kang explained
that these three components must come together to result in the first cut or cleaving that
leads to production of A?. To test this, the scientists knocked out RANBP9 in the cell,
and discovered that 60% less A? was produced. "This unique factor enhances the
production of beta amyloid," said Kang. "Inhibiting the RANBP9 protein may offer
an alternative approach to therapy, by preventing contact between APP and the enzyme that
makes the cut essential to produce amyloid plaques." The researchers' next step is to
verify these findings in animal models.
Stem cell focus for IBD wound
healing
Scientists at The University of Nottingham
are investigating whether stem cell markers could have a role to play in speeding up wound
healing in patients suffering from inflammatory bowel disease (IBD). The study could
eventually lead to the development of new drugs which use natural molecules to spark the
recovery of patients suffering from ulcerative colitis and Crohn’s disease, reducing
their risk of associated complications such as scarring, bowel obstructions and tumour
growth. Funded with a £118,500 grant from the National Association for Colitis and
Crohn’s Disease (NACC), the two-year project is being led by Professor Mohammad Ilyas
in the University’s Division of Pathology. He said “The study will focus on the
molecule CD24 which is a stem cell marker and which plays a key role in cell proliferation
and the migration of healthy cells to a damaged area to restore normal tissue. “CD24
is a small molecule attached to the cell membrane which has been recently reported as a
marker of stem cells in the colon. It occurred to us that CD24 might have a role to play
in IBD and during further studies we found that it was indeed present in sections of
diseased bowel.”
