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News - Week 19 - 2009
New doctors, teaching physicians
disagree about essential medical procedures to learn
Physicians teaching at medical schools and
doctors who have just completed their first year out of medical school disagree about
which procedures are necessary to learn before graduating, according to a new survey done
by researchers at Wake Forest University School of Medicine. Participating physicians were
asked to rate 31 basic clinical procedures – from throat culture to spinal tap –
based on their importance in the first year after graduation from medical school. Faculty
physicians rated 14 procedures as "must know," while new physicians agreed on
only six of those 14 clinical procedures and placed five additional, completely different
procedures in the "must know" category. The results of the survey appear in the
most recent issue of Medical Teacher, a peer-reviewed publication. The authors say the
results are understandable, given that the medical school curriculum often is based on
experience, not structured evaluation. "Like a lot of clinical education in most
medical schools, the third and fourth years are learning by doing – taking care of
real patients," said Michael T. Fitch, M.D., Ph.D., the lead author of the paper and
an assistant professor of emergency medicine at the School of Medicine. "So, the
procedures the patients need end up being the ones students learn." Interestingly,
Fitch said, the procedures rated as "must know" by new doctors were more
invasive – spinal taps, incisions and drainage, intubation and inserting a central
line, for example, than the more basic procedures identified as "must know" by
the experienced, faculty physicians. The study states that many of the procedures where
disagreement occurred are minimally invasive procedures such as drawing blood, which is
frequently completed by non-physician staff in many institutions – a fact that may
explain why new physicians felt that it was not essential to have known how to complete
those procedures during internship.
Study Suggests Buddhist Deity
Meditation Temporarily Augments Visuospatial Abilities
Meditation has been practiced for
centuries, as a way to calm the soul and bring about inner peace. According to a new study
in Psychological Science, a journal of the Association for Psychological Science, there is
now evidence that a specific method of meditation may temporarily boost our visuospatial
abilities (for example, the ability to retain an image in visual memory for a long time).
That is, the meditation allows practitioners to access a heightened state of
visual-spatial awareness that lasts for a limited period of time. Normally when we see
something, it is kept in our visual short-term memory for only a brief amount of time
(images will begin to fade in a matter of seconds). However, there have been reports of
Buddhist monks who have exceptional imagery skills and are able to maintain complex images
in their visual short-term memory for minutes, and sometimes even hours. Led by
psychologist Maria Kozhevnikov of George Mason University, a team of researchers
investigated the effects of different styles of Buddhist meditation on visuospatial
skills. The researchers focused on two styles of meditation: Deity Yoga (DY) and Open
Presence (OP). During DY meditation, the practitioner focuses intently on an image of
deity and his or her entourage. This requires coming up with an immensely detailed,
three-dimensional image of the deity, and also focusing on the deity's emotions and
environment. In contrast, practitioners of OP meditation believe that pure awareness
cannot be achieved by focusing on a specific image and therefore, they attempt to evenly
distribute their attention while meditating, without dwelling on or analyzing any
experiences, images, or thoughts that may arise.
Diminuendo – New Mouse Model
for Understanding Cause of Progressive Hearing Loss
Scientists of Helmholtz Zentrum München
have developed a new mouse model that can be associated with deafness. With this model
they succeeded for the first time in showing that microRNA, a new class of genes,
influences hearing loss. The respective microRNA seed region influences the production of
sensory hair cells in the inner ear, both in the mouse and in humans. The findings have
been published ahead of print in the current online issue of Nature Genetics. This study
represents a major step forward in elucidating the common phenomenon of progressive
hearing loss, opening up new avenues for treatment. Scientists of Helmholtz Zentrum
München, led by Professor Martin Hrabé de Angelis, director of the Institute of
Experimental Genetics, have developed a new mouse model with a genetic mutant in which a
single base of a specific microRNA seed region has been altered. Mice carrying this miR-96
mutation suffer progressive hearing loss as they get older. Moreover, if they carry two of
these mutants, their sensory hair cells are impaired from birth on. A number of genes
associated with hearing loss were already known. "However, we were very surprised
when with our new mouse model we discovered this new class of genes –microRNA –
as genetic cause for this clinical picture," explained Dr. Helmut Fuchs, who
conceived the idea of this mouse model and who is scientific -technical head of the German
Mouse Clinic at Helmholtz Zentrum München.
Different treatment options in
chronic coronary artery disease
Sometimes cardiologists and cardiac
surgeons can agree! There is often disagreement between the professions of cardiology and
cardiac surgery about the proper therapy for coronary artery disease (CAD)—and this
can harm the patient. In the current edition of Deutsches Ärzteblatt International, an
interdisciplinary team of authors consisting of cardiologists and cardiac surgeons
provides answers to the question of when a bypass operation (ACB) and when percutaneous
coronary intervention (PCI) is effective (Dtsch Arztebl Int 2009; 106(15): 253-61). Martin
Russ, Jochen Cremer and coauthors show that ACB and PCI are of equivalent value and can be
placed in a complementary treatment plan. The authors not only consider the results of
randomized controlled studies, but extend their overview to the analyses of registries,
which provide complementary data.
AUA counters mainstream
recommendations with new best practice statement on PSA testing
The American Urological Association (AUA)
today issued new clinical guidance – which directly contrasts recent recommendations
issued by other major groups – about prostate cancer screening, asserting that the
prostate-specific antigen (PSA) test should be offered to well-informed, men aged 40 years
or older who have a life expectancy of at least 10 years. The PSA test, as well as how it
is used to guide patient care (e.g., at what age men should begin regular testing,
intervals at which the test should be repeated, at what point a biopsy is necessary) is
highly controversial; however, the AUA believes that, when offered and interpreted
appropriately the PSA test may provide essential information for the diagnosis,
pre-treatment staging or risk assessment and post-treatment monitoring of prostate cancer.
The new Best Practice Statement updates the AUA's previous guidance, which was issued in
2000. Major changes to the AUA statement include new recommendations about who should be
considered for PSA testing, as well as when a biopsy is indicated following an abnormal
PSA reading. According to the AUA, early detection and risk assessment of prostate cancer
should be offered to well-informed men 40 years of age or older who have a life expectancy
of at least 10 years. The future risk of prostate cancer is closely related to a man's PSA
score; a baseline PSA level above the median for age 40 is a strong predictor of prostate
cancer. Such testing may not only allow for earlier detection of more curable cancers, but
may also allow for more efficient, less frequent testing. Men who wish to be screened for
prostate cancer should have both a PSA test and a digital rectal exam (DRE). The Statement
also notes that other factors such as family history, age, overall health and ethnicity
should be combined with the results of PSA testing and physical examination in order to
better determine the risk of prostate cancer. The Statement recommends that the benefits
and risks of screening of prostate cancer should be discussed including the risk of
over-detection, detecting some cancers which may not need immediate treatment "The
single most important message of this statement is that prostate cancer testing is an
individual decision that patients of any age should make in conjunction with their
physicians and urologists. There is no single standard that applies to all men, nor should
there be at this time," Dr. Carroll said. He also notes that the "panel
carefully reviewed the most recently reported trials of PSA testing in both the United
States and Europe before finalizing their guidelines. The strengths and limitations of
these trials are reviewed in the guideline."
Obesity associated with higer risk
for urinary tract infections
As body mass increases, so does a
patient’s risk of urinary tract infection (UTI), according to Baltimore researchers.
A new study, presented at the 104th Annual Scientific Meeting of the American Urological
Association (AUA) assesses and stratifies this risk. Researchers evaluated insurance
claims of 95,962 subjects over a five year period (from 2002 through 2006) to identify
whether obesity is associated with a UTI diagnosis. The results show that, as BMI
increased, the odds of being diagnosed with a UTI increased as well. This association was
strongest for morbidly obese patients. “The effect of the obesity epidemic in the
United States transcends any one medical specialty or condition,” said Anthony Y.
Smith, MD, an AUA spokesman. “Patients with elevated body mass index should be
vigilant about urologic health because even the most simple of urinary tract infections
can be deadly if left untreated.”
Early brain activity sheds new
light on the neural basis of reading
Most people are expert readers, but it is
something of an enigma that our brain can achieve expertise in such a recent cultural
invention, which lies at the interface between vision and language. Given that the first
alphabetic scripts are thought to have been invented only around four to five thousand
years it is unlikely that enough time has elapsed to allow the evolution of specialized
parts of the brain for reading. While neuroimaging techniques have made some progress in
understanding the neural underpinning of this essentially cultural skill, the exact
unfolding of brain activity has remained elusive. Now, a better understanding of the brain
basis of reading has been reported in research published in the open-access, peer-reviewed
journal PLoS ONE. The research was led by Piers Cornelissen, Morten Kringelbach, Ian
Holliday and Peter Hansen from the Universities of York, Oxford, Aston, and Birmingham UK,
and was funded by the Wellcome Trust. The authors showed very early interactions between
the vision and language domains during reading, with the speech motor areas of the brain
(inferior frontal gyrus) being active at the same time (after a seventh of a second) as
the orthographic word-form is being resolved within a brain region called the fusiform
gyrus. This finding challenges the conventional view of a temporally serial processing
sequence for reading in which letter forms are initially decoded, interact with their
phonological and semantic representations, and only then gain access to a speech code.
This finding has a potentially important clinical application in relation to developmental
dyslexia (affecting between 15-30 million people in the US alone) and those with acquired
reading disabilities through injury or disease. A better understanding of normal reading
processes could potentially help these individuals.
New study overturns orthodoxy on
how macrophages kill bacteria
For decades, microbiologists assumed that
macrophages, immune cells that can engulf and poison bacteria and other pathogens, killed
microbes by damaging their DNA. A new study from the University of Illinois disproves
that. The study, published in the journal PLoS ONE, shows that macrophages focus their
most potent poisons, known as reactive oxygen species (ROS), on targets outside the
cytoplasm. Macrophages are voracious eaters that "swallow" cellular debris and
invading organisms. They kill microbes with ROS. All aerobic cells inadvertently produce
ROS that can, if left unchecked, damage DNA and other cellular components and cause cell
death. Bacteria and animal cells contain special enzymes, called superoxide dismutases,
which neutralize an important ROS, called superoxide. Macrophages have harnessed these
lethal compounds, dumping large quantities of superoxide onto engulfed bacteria to kill
them. Although macrophages direct ROS against invading bacteria, Salmonella typhimurium,
the microbe used in the study, is adept at evading these defenses. The most virulent
strains of S. typhimurium can survive and even propagate inside macrophages, eventually
emerging to infect more cells. "It's been assumed that reactive oxygen species kill
the bacteria by going into the cytoplasm and causing DNA damage," said medical
microbiology professor James Slauch, who led the study. "You can find this idea over
and over again in review articles and many immunological textbooks, but with no real data
to back it up."
'Autoantibodies' may be created in
response to bacterial DNA
Autoimmune diseases have long been regarded
as illnesses in which the immune system creates autoantibodies to attack the body itself.
But, researchers at the California non-profit Autoimmunity Research Foundation (ARF)
explain that the antibodies observed in autoimmune disease actually result from alteration
of human genes and gene products by hidden bacteria. Not long ago, scientists believed
they had located all bacteria capable of causing human disease, But DNA discoveries in the
last decade have led the NIH Human Microbiome Project to now estimate that as many as 90%
of cells in the body are bacterial in origin. Many of these bacteria, which have yet to be
named and characterized, have been implicated in the progression of autoimmune disease. In
a paper published in Autoimmunity Reviews, the ARF team, under the guidance of Professor
Trevor Marshall of Murdoch University, Western Australia, has explained how Homo sapiens
must now be viewed as a superorganism in which a plethora of bacterial genomes – a
metagenome – work in concert with our own. Marshall and team contend that the human
genome can no longer be studied in isolation. "When analyzing a genetic pathway, we
must study how bacterial and human genes interact, in order to fully understand any
process related to the human superorganism," states Marshall. "Especially since
some of these pathways contribute to the pathogenesis of autoimmune disease." For
example, the team notes that the single gene ACE has an impact on myocardial infarction,
renal tubular dysgenesis, Alzheimer's, the progression of SARS, diabetes mellitus, and
sarcoidosis, yet recently ACE has been shown to be affected by the common species
Lactobacillus and Bifidobacteria. Found in yogurt, these species are often considered to
be innocuous or "friendly." "No one would argue that these species aren't
present in the human body, yet there has been inadequate study of how these 'friendly'
species affect disease," states Amy Proal, the paper's lead author. "What we
thought were autoantibodies generated against the body itself can now be understood as
antibodies directed against the hidden bacteria," states Marshall. "In
autoimmune disease, the immune system is not attacking itself. It is protecting the body
from pathogens."
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.
Potential Lung Disease Biomarkers
Yield Clues to COX-2 Inhibitor Side Effects
In searching for a simple way to identify individuals with smoking-related lung injury,
scientists at Weill Cornell Medical College have stumbled upon a potential explanation for
why the class of pain-relievers known as COX-2 inhibitors increases the risk of heart
problems among users. The findings are notable in two ways, explains Dr. Andrew J.
Dannenberg, director of the Weill Cornell Cancer Center and the Henry R. Erle,
M.D.–Roberts Family Professor of Medicine at Weill Cornell Medical College and a
leading gastroenterologist at NewYork-Presbyterian Hospital/Weill Cornell Medical Center.
"Not only could they lead to the development of a simple urine test to determine
which smokers are at increased risk of developing chronic obstructive pulmonary disease or
emphysema, but they might also pave the way for new drugs or combinations of drugs that
harness the benefit of COX-2 inhibitors, including cancer-fighting properties, with
reduced cardiovascular toxicity." Dr. Dannenberg is senior author of a new study
detailing the findings which appears in the April issue of Cancer Prevention Research. A
collaboration led by Weill Cornell Medical College and Memorial Sloan-Kettering Cancer
Center, the research study was funded by Weill Cornell's Clinical and Translational
Science Center (CTSC), an NIH-funded consortium for biomedical collaboration on New York's
Upper East Side, as well as by the Flight Attendant Medical Research Institute (FAMRI),
Pfizer Inc., and a Memorial Sloan-Kettering Cancer Center Prevention Control and
Population Research Program Pilot Project Award. COX-2 inhibitors were developed to
selectively target the cyclooxygenase-2 (COX-2) enzyme, which plays an important role in
inflammation. The idea was to treat pain and arthritis without the potentially dangerous
gastrointestinal side effects of other non-steroidal anti-inflammatory drugs (NSAIDs).
This class of drugs has also been shown to reduce colorectal polyps, a precursor to
colorectal cancer. But two blockbuster COX-2 inhibitors, Vioxx (rofecoxib) and Bextra
(valdecoxib), were pulled off the market after reports that they elevated the risk of
heart attack, stroke and death in users. Celebrex (celecoxib) is the only COX-2 inhibitor
still available.
First Neuroimaging Study Examining
Motor Execution in Children With Autism Reveals Brain Activation Differences, Decreased
Connectivity Between Brain Regions
In the first neuroimaging study to examine motor execution in children with autism,
researchers at the Kennedy Krieger Institute have uncovered important new insight into the
neurological basis of autism. The study, published online in the journal Brain’s
April 23 Brain Advanced Access, compared the brain activity of children with high
functioning autism and their typically developing peers while performing a simple motor
task—tapping their fingers in sequence. The researchers found that children with
autism relied more heavily on a region of the brain responsible for conscious, effortful
movement, while their typically developing peers utilized a region of the brain important
for automating motor tasks. Children with autism also showed less connectivity between
different regions of the brain involved in coordinating and executing movement, supporting
the theory that a decreased ability of distant regions of the brain to communicate with
each other forms the neurological basis of autism. Researchers used fMRI scans to examine
the brain activity of 13 children with high functioning autism and 13 typically developing
children while performing sequential finger tapping. The typically developing children had
increased activity in the cerebellum, a region of the brain important for automating motor
tasks, while children with autism had increased activity in the supplementary motor area
(SMA), a region of the brain important for conscious movement. This suggests children with
autism have to recruit and rely on more conscious, effortful motor planning because they
are not able to rely on the cerebellum to automate tasks.
Tufted bacteria cause infection in
premature babies
Bacteria that normally reside on the skin of healthy people can cause serious infections
in premature babies. A group of researchers at Karolinska Institutet have now found an
explanation for why a certain kind of staphylococcus can attach itself to the skin and
quickly develop dynamic ecosystems: the bacteria are like tufted, self-adhesive hairballs.
Staphylococcus establishes itself on the child's skin and mucous membranes directly after
birth. In healthy adults and children, these bacteria normally live in harmony with the
host organism. However, in sick adults or premature babies, they can cause blood
poisoning. The scientists believe that the hair-like protrusions on the surface of the
bacteria that have now been identified serve to adhere the bacteria to the host's cells,
whereupon they cause infection. They also found that the antimicrobial substance LL37,
which is found on the skin (amongst other places) can inhibit the growth of the bacteria,
and probably plays an important part in keeping the bacteria flora stable and inhibiting
their uncontrolled proliferation.
Topical Cream Studied as Way to
Treat Skin Cancer without the Knife
In a case study of a type of melanoma skin cancer typically found on chronically
sun-exposed skin, Saint Louis University researchers found that imiquimod, a topical
cream, produced good results for patients when used together with surgery to treat the
cancer, potentially helping doctors cut less. The study, published in Dermatologic
Surgery, looked at two cases of the most common type of melanoma of the head and neck,
lentigo maligna (LM), a type of "melanoma-in- situ", the earliest stage of
melanoma. This early form, known as LM, precedes the more invasive form, lentigo maligna
melanoma (LMM), and the progression of LM to LMM typically occurs after 10 to 15 years.
Though surgical removal of LM is most often used to treat the non-invasive form of the
cancer, it can have high local recurrence rates. In two patients who had both LM and LMM,
investigators used imiquimod in conjunction with surgery. In both patients, surgery was
first done to remove the area of known invasive disease, followed by the topical cream to
the outer area of LM. This approach was chosen with patients who did not want extensive
surgery due to the large size of the melanoma on their scalp and face. These cases, along
with other recent studies, suggest that imiquimod may help to reduce the area needing
surgery, manage the LM and hopefully minimize its recurrence.
New therapy based on magnetic
stimulation shows promise for non-drug treatment for migraine
A new UCSF study examining the mechanism of a novel therapy that uses magnetic pulses to
treat chronic migraine sufferers showed the treatment to be a promising alternative to
medication.The therapy is called transcranial magnetic stimulation, or TMS. Study findings
were presented today (April 29, 2009) during the annual American Academy of Neurology
scientific meeting in Seattle.In a previous randomized controlled clinical study by Ohio
State University Medical Center, TMS was used to treat patients who suffer from migraine
with aura, a condition in which a variety of mostly visual sensations come before or
accompany the pain of a migraine attack. The study showed that TMS treatment was superior
to the placebo given to the control group. Patients were pain-free at follow-up intervals
of 2, 24 and 48 hours.In the new study, conducted in rats, UCSF researchers focused on
understanding the mechanism of action of TMS therapy -- how the treatment interacted with
the brain to produce the pain-free outcomes of patients in the previous study.The UCSF
research identified potential opportunities to enhance treatment strategies in patients.
One example, the study team noted, was that factors such as time and peak intensity of
stimulation may be important components in the brain's response to TMS."The data
demonstrate a biological rationale for the use of TMS to treat migraine aura," said
Peter Goadsby, MD, PhD, lead investigator of the study, professor and director of the UCSF
Headache Center. "We found that cortical spreading depression, known as CSD and the
animal correlate of migraine aura, was susceptible to TMS therapy, with the wave of
neuronal excitation blocked on over 50 percent of occasions."The study findings
showed that migraine aura responds to magnetic stimulation because TMS therapy blocks the
wave of neuronal excitation, which is a biological system through which neurons become
stimulated to fire. TMS creates a focused magnetic pulse that passes noninvasively through
the skull, inducing an electric current to disrupt the abnormal brain waves believed to be
associated with migraine, including CSD. CSD in humans precedes migraine with aura.
Oxytocin - Love potion #1?
Relationships are difficult and most of us probably think at some point that communicating
positively with our partner when discussing stressful issues, like home finances, is an
impossible task. What if there was a safe way to take the "edge" off these
discussions? The biology of human social relationships is just beginning to emerge as
groundbreaking research on social cognition conducted in animals is now informing research
in humans. In its May 1st issue, Biological Psychiatry
(http://www.elsevier.com/locate/biopsychiat), published by Elsevier, includes a paper by
Swiss researchers that have investigated the effects of oxytocin, the "love
hormone," on human couple interactions. They recruited adult couples who received
oxytocin or placebo intranasally before engaging in a conflict discussion in the
laboratory. Oxytocin increased positive communication behavior in relation to negative
behavior and reduced salivary cortisol, i.e., their stress levels, compared to placebo.
"We are just beginning to understand the powerful effects of hormones and chemicals
released by the body in the context of important social interactions," commented John
Krystal, M.D., the editor of Biological Psychiatry. "As this knowledge grows, the
question of how to best use our developing capacities to pharmacologically alter social
processes will become an important question to explore." Author Beate Ditzen, Ph.D.,
noted that this was the first study of its kind and important because it evaluated
real-time natural couple behavior in the laboratory. "[Oxytocin] might help us to
pronounce the effects of a standard treatment, such as cognitive behavioral therapy, by
possibly making the benefits of social interaction more accessible to the individual. But
it probably will not replace these standard treatments." They clarify that this study
does not show that oxytocin should currently be used as a treatment itself and the effects
of repeated administration have not been evaluated in humans. In addition, important
ethical concerns will have to be addressed, such as to what extent it should be used as a
"treatment" and whether developed treatments could become drugs of abuse in the
form of "social enhancers."
Potential preventative therapy for
Type 1 diabetes
Scientists believe they may have found a preventative therapy for Type 1 diabetes, by
making the body's killer immune cells tolerate the insulin-producing cells they would
normally attack and destroy, prior to disease onset. Type 1 diabetes is an autoimmune
condition, where the body attacks its own insulin producing cells. It is very serious,
with a sudden and dramatic onset, usually in youth. People with Type 1 diabetes must
maintain an insulin-monitoring and insulin-injecting regimen for the rest of their lives.
PhD student Eliana Mariño and Dr Shane Grey, from the Garvan Institute of Medical
Research in Sydney, have demonstrated how a particular molecule may be used in future as a
preventative therapy. Their findings are published online in the international journal
Diabetes. The body's immune cells, or white blood cells, include B cells and T cells. B
cells make antibodies and present 'antigens' to T cells, allowing them to recognise, and
kill, invaders. In previously published studies about Type 1 diabetes, Mariño and Grey
showed that groups of B cells migrate to the pancreas and pancreatic lymph nodes,
presenting specific insulin antigen to T cells. In other words, B cells go to the disease
site and tell T cells to kill the cells that produce insulin. "Taking that work
further, our current study looks at different ways of subduing B cells, and how that
affects development of the disease," said Grey. Working with mice that spontaneously
develop Type 1 diabetes, Eliana Mariño found that if she blocked BAFF (a hormone that
controls survival of B cells) prior to onset, none of the mice developed diabetes.
"This is a remarkable finding, as other B cell depletion methods tested elsewhere
have just delayed or reduced disease incidence," said Eliana.
Mother-daughter breast density
study points way to earlier cancer risk assessment
A unique mother-daughter study that used magnetic resonance to measure breast density in
younger women shows that percent of breast water could be linked to the risk of breast
cancer in middle age and older. The findings, published online today in Lancet Oncology,
add another key piece to the puzzle of understanding more about breast density, an
inheritable characteristic known to be a cancer risk factor, that could aid in developing
prevention methods, says principal investigator Dr. Norman Boyd, a scientist at The
Campbell Family Institute for Breast Cancer Research at Princess Margaret Hospital. Dr.
Boyd initially verified breast density (mammographic density, or MD) as a strong risk
factor for breast cancer in middle aged and older women in a landmark study published in
the New England Journal of Medicine in 2007. Until now, little was known about the
development of breast density in early life, or how it relates to a young woman's height,
weight and age, and the breast density of their mothers. The findings of the current study
indicate that risk assessment using less harmful techniques such as magnetic resonance
imaging (MRI) instead of X-ray should start much earlier in life. Says Dr. Boyd "It
is known that the breast is most susceptible to the effects of carcinogens at early ages.
Our findings suggest that differences in breast tissue composition in early life may be a
potential mechanism for this increased susceptibility. By identifying the environmental
and genetic factors that influence breast tissue composition in early life we may be able
to develop safe and effective methods of prevention." In this study, between
2003-2006, the researchers recruited 400 mother-daughter pairs and used MRI to examine
breast tissue in daughters, aged 15-30-years, and a random sample of 100 of the mothers.
In the young women, MRI was used to measure breast water concentration to avoid exposure
to radiation from mammograms. Blood was obtained from each woman within 10 days of the
start of the most recent menstrual period. Mothers underwent mammography and a random
sample of 100 also consented to have a breast MRI.Results show that percent breast water
variation is higher in 15-19 year olds than in 20-30 year olds, and decreases with age, as
backed by analysis of the 100 mother-daughter pairs who both had MRI.
Glutamate identified as predictor
of disease progression in multiple sclerosis
UCSF researchers have identified a correlation between higher levels of glutamate, which
occurs naturally in the brain as a byproduct of metabolism, and greater disease burden in
multiple sclerosis patients. The study is the first to measure glutamate toxicity in the
brain over time and suggests an improved method for tracking the disease and predicting
its course. The research team employed a novel technique, developed by Radhika Srinivasan,
PhD, study author and assistant researcher in the UCSF Department of Radiology and
Biomedical Imaging, to measure glutamate levels in clinical trial patients. The technique
was based on a sophisticated form of imaging known as proton MR spectroscopy, which uses
simple radio-frequency pulses targeting specific brain chemicals. Study findings were
presented today (April 29, 2009) during the American Academy of Neurology annual
scientific meeting in Seattle. Glutamate, a neurotransmitter, in normal levels performs
fundamental processes like memory and sensory perception. In excess, it triggers a cascade
of negative reactions in the brain leading to many of the complications associated with
neurologic diseases such as MS, Parkinson's disease, stroke, ALS (amyotrophic lateral
sclerosis or Lou Gehrig's disease) and Alzheimer's disease by destroying nerve cells and
causing seizures, injury after stroke, and the perception of pain, among other problems.
Already a target for therapeutic drug development, the identification of the glutamate
pathway for MS suggests a new way for clinicians to monitor treatment of these drugs.
"This is the first time that we have had the ability to measure glutamate toxicity in
the brain in real time, which gives us a marker for monitoring disease progression as well
as our treatment of the disease," said Daniel Pelletier, MD, study author, associate
professor of neurology and a member of the Multiple Sclerosis Research Group at the
University of California, San Francisco. "For instance, we already have
anti-glutamate drugs, so now we can assess, with imaging, the impact of the therapy and
the progression of the disease," he said.Elevated levels of glutamate in the brain
are understood clinically as a cause of cell injury and death. Injury to neuro-axons,
which are the long fibers that extend from the cell body of a neuron cell toward other
nerve cells, is partly responsible for disability progression in MS. In a previous study
using proton MR spectroscopic imaging, the research team reported that MS brains have
significant elevation of glutamate concentrations. For this study, researchers looked for
levels of glutamate and levels of NAA (n-acteylaspartate), a marker of axonal integrity in
mature brains, to see if a relationship existed. The team scanned 265 MS patients annually
and followed them for an average of 1.8 years. Accounting for disease duration and age of
onset, researchers found that significant annual loss of NAA, which is a measure of
neurodegeneration, was associated with concentration of glutamate. This finding indicated
that the higher the level of glutamate, the greater the expected neuro-axonal loss over
time. According to the authors, the study is the largest clinical analysis to date of
metabolism byproducts in the brain, and the results strongly support the link between the
excess of glutamate and decline of neuro-axonal integrity in MS. The finding, Pelletier
says, goes beyond MS. "Now that we have those markers, we can quantify levels of
glutamate for other neurologic diseases, which could be another way to track disease
progression and therapeutic intervention."
Urine screening test may one day
predict coronary artery disease
Proteome analysis, a screening requiring only a patient's urine specimen, shows promise as
a reliable and noninvasive way to diagnose atherosclerosis and coronary artery disease in
the future, according to research presented at the American Heart Association's
Arteriosclerosis, Thrombosis and Vascular Biology Annual Conference 2009. Coronary
angiography, an X-ray examination of the blood vessels or chambers of the heart, is the
traditional way to diagnose atherosclerosis. To perform this procedure, clinicians insert
a small tube, or catheter, into a blood vessel in the groin area or arm and thread the
catheter to the coronary arteries of the heart. "Atherosclerotic disease results in
heart attack and stroke, which have major impacts on life and health in the Western
world," said Constantin von zur Muehlen, M.D., the study's lead author and
cardiologist at the University Hospital Freiburg, Department of Cardiology in Freiburg,
Germany. "We conducted this study to find new biomarkers for atherosclerosis and
determine whether this noninvasive screening could reliably recognize this disease."
Proteome analysis shows protein patterns in body fluids, such as blood or urine, Muehlen
said. Using two techniques to analyze specimens (mass spectrometry and capillary
electrophoresis), scientists can simultaneously characterize thousands of proteins in one
examination. Muehlen and colleagues determined that certain protein fragments can only be
found in coronary artery disease patients, and this patient group established the proteome
pattern. The 17 protein fragments that the researchers identified as being associated with
atherosclerotic disease were collagen fragments, known to be present on the surface of
atherosclerotic plaques. The researchers then applied the proteome pattern in another
group of patients with atherosclerotic disease of the coronary arteries. The investigators
compared the results of the urine proteome screenings from 67 patients presenting with
symptoms of coronary artery disease to patients' results from coronary angiography, the
current gold standard used to rule out or confirm coronary artery disease.
Migraine prevention by targeting
glutamate receptors?
When migraine strikes, because of severe pain, often accompanied by nausea and sensitivity
to light and sound, sufferers are effectively disabled for up to 72 hours. Since they are
forced to stop what they are doing until the pain and other symptoms subside, migraine
causes a significant loss in productivity at work and the personal lives of those
affected. Migraineurs – especially the 25% of migraineurs who experience more than
three migraine attacks per month – are looking to drug developers to provide new
drugs to prevent migraine attacks before they start. In the U.S. alone, approximately 30
million people suffer from migraines and the cost to employers has been estimated at $13
billion annually in lost productivity. Currently, several types of drugs, like generic
beta blockers, calcium channel blockers, tricyclic antidepressants and anti-epileptic
drugs, some of which are used off-label, are given to prevent migraines. However, many
patients have only a partial response to these products, many of which have troubling side
effects. Nevertheless, many migraine patients use existing drugs, illustrating how badly
new drugs are needed. Given the role of glutamate in the pathophysiology of migraine, the
future of migraine prophylaxis, may lie in modulating one of the receptors in the
glutamate system, mGluR5. At the forthcoming annual meeting of the American Academy of
Neurology in Seattle (April 25 – May 2), Addex Pharmaceuticals (SIX: ADXN) will
present Phase IIa data on ADX10059, a negative mGluR5 allosteric modulator, which shows
efficacy in treating acute migraine attacks and provides evidence that inhibition of this
glutamate receptor subtype could play a role in stopping migraine attacks before they
start. Preclinical experiments and small scale studies in migraineurs with drugs like
ketamine, which acts on glutamate signaling through NMDA receptors (functionally related
to mGluR5) and the NMDA antagonist memantine, suggest that mGluR5 could play a role in the
"migraine circuit," a positive feedback loop that generates the symptoms of a
migraine attack. The initial step to test this hypothesis was Addex' proof of concept
study in acute treatment of migraine attacks.
Combination of genetic and
environmental 'hits' required for Parkinson's disease
New research finds that a complex interaction between separate factors underlies the
pathology associated with Parkinson's disease (PD), reinforcing the concept that multiple
therapeutic targets should be considered when designing treatment strategies. The
findings, published by Cell Press in the April 30th issue of the journal Neuron, also help
to explain why known risk factors do not predict PD in a straightforward manner. PD is a
neurodegenerative disease that impairs movement and is characterized by a specific loss of
dopamine neurons in a region of the midbrain called the substantia nigra (SN).
Interestingly, dopamine neurons in neighboring brain regions are spared. Research has
shown that the SN neurons of PD patients contain ?-synuclein protein and exhibit elevated
levels of calcium and free intracellular dopamine (known as "cytosolic"
dopamine). However, the specific contributions and interplay of these factors are not well
understood. "Although a long-standing hypothesis of neuronal neurodegeneration in PD
postulates that elevated cytosolic dopamine underlies the selective cell death
characteristic of PD, it has never been directly studied," explains senior study
author, Dr. David Sulzer from the Department of Neurology at Columbia University. "To
better understand the pathology of PD, we used a new electrochemical approach to measure
cytosolic dopamine in neurons following various pharmacological and genetic
interventions." Dr. Sulzer and colleagues found that in midbrain neurons grown in
culture, elevated cytosolic dopamine was toxic to neurons. Genetic and pharmacological
interventions which decreased levels of cytosolic dopamine protected the neurons. The
characteristic increased susceptibility of SN neurons, and not neighboring neurons, to
cytosolic dopamine-related toxicity was dependent on the activity of calcium channels.
Further, neurons lacking ?-synuclein were resistant to cytosolic-dopamine-induced cell
death.
Parkinson's - Neurons destroyed by
3 simultaneous strikes
In a study that reveals the clearest picture to date of neuron death in Parkinson's
disease, researchers at Columbia University Medical Center have found that a trio of
culprits acting in concert is responsible for killing the brain cells. The study,
published in the April 30 issue of Neuron, showed that three molecules – the
neurotransmitter dopamine, a calcium channel, and a protein called alpha-synuclein –
act together to kill the neurons. The discovery gives researchers a new understanding of
how to save the neurons, say the study's authors, Eugene Mosharov, Ph.D., associate
research scientist, and David Sulzer, Ph.D., professor of neurology & psychiatry at
Columbia University Medical Center. "Though the interactions among the three
molecules are complex, the flip side is that we now see that there are many options
available to rescue the cells," says Dr. Mosharov. The symptoms of Parkinson's –
including uncontrollable tremors and difficulty in moving arms and legs – are blamed
on the loss of neurons from the substantia nigra region of the brain. Researchers had
previously suspected dopamine, alpha-synuclein and calcium channels were involved in
killing the neurons, but could not pin the deaths on any single molecule. The new paper,
along with previous studies with Dr. Ana Maria Cuervo at Albert Einstein College of
Medicine, shows that it is the combination of all three factors that kills the neurons.
The studies found that neurons die because calcium channels lead to an increase of
dopamine inside the cell; excess dopamine then reacts with alpha-synuclein to form
inactive complexes; and then the complexes gum up the cell's ability to dispose of toxic
waste that builds up in the cell over time. The waste eventually kills the cell.
New diagnostic advance seen for
head, throat cancer
Pharmacy researchers at Oregon State University today announced the discovery of a genetic
regulator that is expressed at higher levels in the most aggressive types of head and neck
cancers, in work that may help to identify them earlier or even offer a new therapy at
some point in the future. This "transcriptional regulator" is called CTIP2, and
in recent research has been demonstrated to be a master regulator that has important roles
in many biological functions, ranging from the proper development of enamel on teeth to
skin formation and the possible treatment of eczema or psoriasis. In the newest study,
published today in PLoS ONE, a professional journal, scientists found for the first time
that levels of CTIP2 were more than five times higher in the "poorly
differentiated" tumor cells that caused the most deadly types of squamous cell
carcinomas in the larynx, throat, tongue and other parts of the head. There was a high
correlation between greater CTIP2 expression and the aggressive nature of the cancer.
World's largest DNA scan for autism
uncovers new gene variant for disorder
UCLA scientists, in partnership with 30 research institutions across the country, have
identified a new gene variant that is highly common in autistic children. And when
researchers scrutinized the activity of the gene, known as CDH10, in the fetal brain, they
discovered that it is most active in key regions that support language, speech and
interpreting social behavior. Published April 28 in the advance online edition of the
journal Nature, the two findings suggest that CDH10 plays a critical role in shaping the
developing brain and may contribute to a prenatal risk of autism. A variant is a gene that
has undergone subtle changes from the normal DNA yet is shared by a significant portion of
the population. "While this gene variant is common in the general population, we
discovered that it occurs about 20 percent more often in children with autism," said
study author Dr. Daniel Geschwind, director of the UCLA Center for Autism Treatment and
Research. "A major change like this in the genetic code is too common to be a simple
mutation — it is a risk factor in the origin of the disease." Using the largest
population sample to date, the scientists systematically scanned the DNA of 3,100
individuals from 780 families nationwide. Each family had at least two autistic children.
The scan connected autism to a specific region of chromosome 5, which previous studies at
UCLA and collaborating institutions had pinpointed as a hub for genetic variations linked
to higher autism risk. To verify the findings, Dr. Hakon Hakonarson at the Children's
Hospital of Pennsylvania led the team in conducting a second scan on the DNA of 1,200
individuals from families affected by autism, as well as nearly 6,500 healthy controls.
All participants shared European ancestry. The scientists evaluated the relationship of
more than half a million gene variants to autism and consistently discovered six changes
that occurred more frequently in autistic children than in the control group. These
variants sat on chromosome 5 between two genes, CDH9 and CDH10.
OSU To Head Major National Program
to Study Health Risks of “PAH” Toxins
Polycyclic aromatic hydrocarbons are the natural result of many forms of combustion,
including diesel engines, automotive exhaust, coal burning, grilling of meat and even the
smoking of cigarettes. They’ve been studied for years and their impacts had been
thought to be declining until just lately, with the huge industrialization of Asia.
Prophylaxis fends off
life-threatening invasive fungal infections
Invasive fungal infection carries a mortality rate ranging from 50% to 90% in certain
patients. Infectious disease experts explain why offense in treatment is the best defense.
Gut Reaction - Environmental
Effects on the Human Microbiota
Living within our bodies is a vast population of bacteria and other microbes we rely upon
to keep us healthy. This population—known collectively as the microbiota—is
similar to an organ in that it performs functions essential for our survival. Just as with
the heart or the liver, when something goes wrong with the microbiota, the result can be
disease. This article (p. A198) takes a look at the complex relationship between our
health and our gut microbiota, and examines how environmental factors can influence the
makeup and activity of this inner garden.
Amplify, Amplify - Shotgun
Proteomics Boosts the Signal for Biomarker Discovery
In the last 10 years proteomics technologies involving mass spectrometry have made it
possible to quickly identify proteins and quantify adducts, down to the very amino acid
site of modification, so scientists can more quickly screen potential biomarkers. But the
list of candidates must still be narrowed by testing them in larger numbers of clinical
samples, such as blood samples from unexposed or exposed people. That testing requires
development of targeted immunoassays, which are difficult and expensive. This article (p.
A206) discusses shotgun proteomics, which now promises to streamline the discovery process
by identifying the most promising biomarkers for exploration.
Autoimmune Effects of TCE in Mice
and Humans
Trichloroethylene (TCE), an industrial solvent used for metal cleaning and degreasing, has
been the subject of multiple experimental and observational studies focused on potential
immune-related effects. Cooper et al. (p. 696) reviewed experimental and epidemiologic
research on this topic, including studies of MRL+/+ mice (used as a model of lupus in
humans) that have shown accelerated autoimmune responses after exposure to TCE or TCE
metabolites; they also reviewed mechanistic research on the role of oxidative stress in
TCE-induced autoimmune disease. Two studies have reported evidence of inflammatory immune
responses in humans with occupational or environmental TCE exposure; occupational exposure
has also been associated with a severe, generalized hypersensitivity skin disorder and
systemic sclerosis (scleroderma). The authors conclude that the overall consistency of
research findings provides support for an etiologic role of TCE in autoimmune disease, but
they suggest that multisite studies of specific autoimmune diseases and preclinical immune
markers are needed to further develop this field of research.
Nanoparticle-Induced Oxidative
Damage to DNA in Rats Exposed by Oral Gavage
Hazardous effects of nanoparticles may involve oxidative stress and oxidative damage of
DNA. Folkmann et al. (p. 703) measured oxidative DNA damage based on
8-oxo-7,8-dihydro-2´-deoxyguanosine (8-oxodG) levels in the colon mucosa, liver, and lung
of rats after intragastric administration of a single dose of pristine C60 fullerenes or
single-walled carbon nanotubes (SWCNT) at 0.064 or 0.64 mg/kg body weight. In addition,
they evaluated the expression of several genes involved in repair of oxidative DNA damage
and assayed 8-oxoguanine DNA glycosylase (OGG1) repair activity 24 hr after exposure.
Exposure to these relatively low doses of C60 fullerenes and SWCNT was associated with
oxidative damage to DNA in liver and lung cells, and OGG1 expression in liver cells
increased with exposure to C60 fullerenes. However, exposure did not appear to influence
expression of other DNA repair genes or DNA repair activity. The authors note that levels
of oxidative damage were lower than previously measured following exposure to comparable
doses of diesel exhaust particles but suggest that results may still be a cause for
concern given the potential for human exposure.
Environmental Cadmium and
Periodontal Disease in U.S. Adults
Periodontal disease is a chronic inflammatory disease that degrades periodontal
structures, including alveolar bone. Arora et al. (p. 739) hypothesized that environmental
Cd may promote periodontal disease through adverse affects on bone remodeling and
inflammation, and they used data from 11,412 adult participants in the Third National
Health and Nutrition Examination Survey (NHANES III) to determine whether
creatinine-corrected urinary Cd levels were associated with periodontal disease (defined
as attachment loss of at least 4 mm in > 10% of sites examined). Participants with
periodontal disease had a higher age-adjusted geometric mean urine Cd concentration than
other participants: 0.50 µg/g creatinine [95% confidence interval (CI), 0.45–0.56]
compared with 0.30 µg/g creatinine (95% CI, 0.28–0.31). After adjustment for
multiple measures of tobacco exposure (a risk factor for periodontal disease and important
source of Cd) and other confounders, a 3-fold increase in creatinine-corrected urinary
cadmium concentration [corresponding to a contrast between the 75th (0.63 µg/g) and 25th
(0.18 µg/g) percentiles of Cd exposure] was associated with a 54% increase in the
relative odds of prevalent periodontal disease (odds ratio = 1.54; 95% CI,
1.26–1.87).
Predictors of Endotoxin Levels in
U.S. Housholds
The relation between domestic endotoxin exposure and allergy and asthma has been widely
investigated, but few studies have evaluated predictors of household endotoxin, and none
have done so for multiple locations within homes on a national scale. Thorne et al. (p.
763) analyzed data from a nationwide study to identify factors that predicted household
endotoxin levels in dust samples collected from five different locations in 831
households. Weighted geometric mean endotoxin concentrations ranged from 18.7 to 80.5
endotoxin units (EU)/mg, and endotoxin loads ranged from 4,160 to 19,500 EU/m2. Factors
that predicted endotoxin concentrations included geographic location, poverty, low
educational attainment, numbers of household occupants and children, current dog
ownership, and evidence of cockroach infestations, food debris, and smoking. The authors
suggest that improving housing conditions, eliminating cockroach infestations, and
reducing indoor cigarette smoking would reduce exposure to endotoxins.
Traffic-Related Air Pollution and
Mortality
Chronic exposure to traffic-related air pollution (TRAP) may contribute to premature
mortality in people living near roadways; however, previous studies have relied on
distance from roadways as a proxy measure of TRAP exposure, and statistical models used to
estimate regional patterns of pollution may fail to capture fine-scale exposure gradients
near TRAP sources. Jerrett et al. (p. 772) report on a study of that used field
measurements of nitrogen dioxide (a marker of TRAP) and land-use regression models to
estimate fine-scale TRAP exposures in a Toronto, Ontario, Canada, cohort of 2,360
respiratory clinic patients followed for mortality from 1991 to 2002. The authors used
multilevel Cox proportional hazard models to estimate associations between TRAP and
mortality adjusted for age, sex, lung function, obesity, smoking, and a neighborhood
deprivation index. They report that TRAP was associated with increased all-cause and
circulatory mortality in the study cohort, which included a large proportion of patients
with preexisting cardiopulmonary disease.
Xenoestrogens Alter Dopamine
Transport and Trafficking
Xenoestrogens (XEs), including nonylphenol (NP), bisphenol A (BPA), and some chlorinated
pesticides, may disrupt estrogenic signaling. Previous research showed effects of
17??estradiol (E2) on dopamine transport in nerve growth factor–differentiated PC12
rat pheochromocytoma cells that were mediated by membrane estrogen receptors (ERs). Alyea
and Watson (p. 778) examined the influence of XEs on dopamine transport by measuring
dopamine transporter (DAT) activity in response to low concentrations of NP, BPA,
dieldrin, endosulfan, o´,p´?dichlorodiphenylethylene (DDE), and E2 based on the efflux
of 3H?dopamine in PC12 cells. All compounds caused dopamine efflux, inhibited efflux, or
both at 1 nM; all were active at some concentration < 10 nM; and all showed
nonmonotonic dose responses. The authors conclude that low levels of environmental
estrogen contaminants may act as endocrine disruptors via membrane ERs; potential effects
on neurotransmitter function could have important implications for Parkinson disease and
other neurologic disorders, particularly among women.
Antiandrogens and Feminization of
Wild Fish
Evidence that feminization in wild fish is associated with exposure to environmental
estrogens has contributed to concerns about environmental estrogens as a cause of
testicular dysgenesis syndrome and other reproductive disorders in human males. Jobling et
al. (p. 797) hypothesized that endocrine disruption in fish might result from exposure to
mixtures of estrogenic and antiandrogenic chemicals, based on evidence from rodent models
of testicular dysfunction. The authors explored this hypothesis using statistical models
to estimate associations between feminization responses in wild fish and modeled
concentrations and activities of estrogenic and antiandrogenic chemicals in the rivers in
which they lived. Both estrogenic and antiandrogenic substances were prevalent in most of
the treated sewage effluents tested, and feminizing effects in wild fish were best
predicted based on combined exposure to antiandrogens and estrogens or exposure to
antiandrogens alone. The authors conclude that results support a multicausal etiology for
feminization of wild fish resulting from exposure to steroidal estrogens, xenoestrogens,
and environmental contaminants with antiandrogenic properties.
Spontaneous Cytokine Production and
Environmental Exposures in Children
Environmental factors may have profound effects on the development of host immune
responses, and changes in infectious and microbial exposures associated with improved
hygiene may have important implications for the development of inflammatory disorders such
as asthma. Figueiredo et al. (p. 845) investigated associations between environmental
exposures and spontaneous cytokine production in unstimulated peripheral blood leukocytes
collected from 1,376 children 4–11 years of age living in a poor urban area of
Brazil. Children in households without tap water were more likely to produce interleukin
(IL)?10 than other children, and children living in households that never had a sewage
system were more likely to produce IL?10 and IL?5 than other children. The authors suggest
that their results indicate that hygiene in early life may have profound effects on immune
homeostasis in later childhood. However, they note that additional research is needed to
determine whether specific viral, bacterial, or parasitic exposures drive these
associations, and to clarify the implications of environmentally mediated immune
modulation for the development of asthma and other outcomes.
Prenatal Lead Exposure and
Schizophrenia: Further Evidence and More Neurobiological Connections
Schizophrenia is a neurodevelopmental disorder that is expressed later in life. Pb2+ is a
neurotoxicant that is known to cause developmental abnormalities. Animal models of
developmental Pb2+ exposure express a behavioral phenotype with features that overlap with
those in animal models of schizophrenia, including increased spontaneous activity,
decreased social interaction, and learning deficits (Moreira et al. 2001; Nihei et al.
2000). Also, some of the behavioral effects described in adolescents with early-life Pb2+
exposure are similar to those expressed in schizophrenia patients (Opler and Susser 2005).
Thus, although the environmental causes of schizophrenia have not evaluated environmental
toxicants, the emerging evidence from the human studies by Opler and colleagues and animal
studies suggest that prenatal Pb2+ exposure may be an environmental risk factor for
schizophrenia.
Methylation Links Prenatal PAH
Exposure to Asthma
Research suggests that a mother’s exposure to pollution during pregnancy may
predispose her child to asthma, and there is preliminary evidence implicating
transplacental exposure to polycyclic aromatic hydrocarbons (PAHs)—generated mainly
by the burning of fossil fuels and abundant in high-traffic areas. Until recently,
progress in the study of prenatal exposures to PAHs and other pollutants has been hampered
by a paucity of biomarkers for predicting asthmatic risk. Researchers from the University
of Cincinnati and Columbia University Mailman School of Public Health now report that
methylation of ACSL3, a gene expressed in lung and thymus tissue, may provide a possible
biomarker linking prenatal exposure to PAHs to childhood asthma.
Vitamin D Regulates MS Gene
Multiple sclerosis (MS), an autoimmune disease affecting some 2.5 million people
worldwide, is thought to arise from a confluence of genetic and environmental factors.
Dietary vitamin D intake has been associated with lower MS risk, and vitamin D deficiency
has been associated with increased risk, but direct links between vitamin D and MS have
not been identified. A team of Canadian and British researchers has now reported evidence
that vitamin D interacts with a variant form of the HLA-DRB1 gene, which has been
associated with MS. As reported in the 6 February 2009 issue of the online journal PLoS
Genetics, study leader George Ebers, a clinical neurologist at the University of Oxford,
United Kingdom, and colleagues examined cells with two copies of the HLA-DRB*15 form of
HLA-DRB1. They identified a vitamin D response element (VDRE)—a short stretch of DNA
that is a signature of genes regulated by vitamin D—next to the gene. When they
examined DNA from study participants they found the same VDRE sequence in each of 322
individuals with two copies of HLA-DRB1*15 (including people with and without MS), but
found different VDRE sequences in DNA samples from 168 study participants without
HLA-DRB1*15. The researchers also showed that the VDRE sequence found in people with
HLA-DRB1*15 could bind to the vitamin D receptor, and that the HLA-DRB1 gene responded
more strongly to vitamin D in cells with the HLA-DRB1*15 VDRE sequence than in cells
without it. “This is the first direct evidence that vitamin D regulates the
gene,” says Ebers. He says that whereas the general public has a 1 in 1,000 chance of
developing MS, the estimated risk of MS is 1 in 300 for people with one copy of the
HLA-DRB1*1501 gene variant, and 1 in 100 for those with two copies of HLA-DRB1*1501.
New Data Shed Light on Exposure,
Potential Bioaccumulation
Bisphenol A (BPA), an industrial chemical used in a variety of consumer products, is
ubiquitous in the modern environment, with residues found in the urine of an estimated 93%
of Americans over 6 years of age, according to data from the 2003–2004 National
Health and Nutrition Examination Survey (NHANES). Recent research indicates that BPA acts
as an endocrine disruptor and may increase the risk of heart disease, diabetes, and liver
problems in adults. Until now, most exposure was thought to occur through diet, and the
chemical was thought to clear the body quickly and completely. But a new study shows that
urine BPA levels of subjects who had fasted for several hours were not as low as expected,
suggesting either nondietary exposures or accumulation in fatty tissue, or both.
Contactin-2/TAG-1-directed
autoimmunity is identified in multiple sclerosis patients and mediates gray matter
pathology in animals
Gray matter pathology is increasingly recognized as an important feature of multiple
sclerosis (MS), but the nature of the immune response that targets the gray matter is
poorly understood. Starting with a proteomics approach, we identified
contactin-2/transiently expressed axonal glycoprotein 1 (TAG-1) as a candidate autoantigen
recognized by both autoantibodies and T helper (Th) 1/Th17 T cells in MS patients.
Contactin-2 and its rat homologue, TAG-1, are expressed by various neuronal populations
and sequestered in the juxtaparanodal domain of myelinated axons both at the axonal and
myelin sides. The pathogenic significance of these autoimmune responses was then explored
in experimental autoimmune encephalitis models in the rat. Adoptive transfer of
TAG-1–specific T cells induced encephalitis characterized by a preferential
inflammation of gray matter of the spinal cord and cortex. Cotransfer of
TAG-1–specific T cells with a myelin oligodendrocyte glycoprotein-specific mAb
generated focal perivascular demyelinating lesions in the cortex and extensive
demyelination in spinal cord gray and white matter. This study identifies contactin-2 as
an autoantigen targeted by T cells and autoantibodies in MS. Our findings suggest that a
contactin-2–specific T-cell response contributes to the development of gray matter
pathology.
Chlamydia May Play Role In a Type
of Arthritis
Spondylarthritis (SpA) represents a group of arthritidies that share clinical features
such as inflammatory back pain and inflammation at sites where tendons attach to bone. It
includes ankylosing spondylitis (AS), psoriatic arthritis, inflammatory
bowel-disease-related arthritis, reactive arthritis (ReA) and undifferentiated
spondylarthritides (uSpA). Since Chlamydia trachomatis or Chlamydia pneumoniae (which are
often asymptomatic) frequently cause ReA, a new study examined whether there was a
connection between these two infections and uSpA. The study was published in the May issue
of Arthritis & Rheumatism (http://www3.interscience.wiley.com/journal/76509746/home).
Led by John D. Carter of theUniversity of South Florida, the study involved blood and
synovial tissue analysis from 26 patients who had chronic uSpA or Chlamydia-induced ReA.
Synovial tissue samples from 167 osteoarthritis patients were used as controls. Samples
were analyzed to assess chlamydial DNA and the 26 subjects were asked if they had any
known exposure to Chlamydia trachomatis or Chlamydia pneumoniae and if so, the infection
was documented in relation to the onset of their uSpA. They also underwent a physical exam
that included evaluation of swollen and tender joints and other symptoms of SpA. The
results showed that the rate of Chlamydia infection was 62 percent in uSpA patients,
significantly higher than the 12 percent seen in control subjects.
Endoscopic surgery effectively
relieves sinusitis symptoms; large pooled study
Endoscopic sinus surgery can significantly relieve symptoms of chronic rhinosinusitis
– inflammation of the sinus cavities – according to a research team, led by a
Georgetown physician, which conducted the first large-scale analysis of surgical outcomes
from the procedure. In the May issue of Otolaryngology Head Neck Surgery, researchers
found that symptoms usually associated with the chronic condition, including nasal
obstruction, facial pain, postnasal discharge, headaches, and impaired smell, all
substantially improved after endoscopic sinus surgery. "This kind of surgery is
indeed beneficial to patients when standard medical treatment doesn't resolve the
condition," says the study's lead investigator, Alexander C. Chester, MD, a physician
and clinical professor at Georgetown University Medical Center. Two other physicians from
St. Louis University School of Medicine collaborated in the study. Endoscopic sinus
surgery is an extremely common procedure – about 200,000 procedures are performed
each year – yet this is the first meta-analysis of symptom relief following the
surgery, Chester says. It was conducted by examining 21 different published studies, which
included 2,070 patients, analyzing improvement for each symptom. "Reports of relative
symptom relief vary across studies, so it was important to pool the study results. We
wanted to know not only if symptoms improve overall, but if they improve to a similar
degree, and if these benefits last," says Chester. "Our findings offer
reassurance that, with minor exceptions, individual symptoms usually improve substantially
and similarly following surgery." Chester, an internist, says the study does not
attempt to prove the effectiveness of endoscopic sinus surgery compared with medical
treatment. "Only a randomized, controlled clinical trial testing surgery and medical
therapy could prove that point." But the findings will help patients weigh both the
benefits and the risks of a surgical intervention, he says. "We now have the
information we need to more accurately advise our patients," Chester says.
Fish may actually feel pain and
react to it much like humans
Fish don't make noises or contort their faces to show that it hurts when hooks are pulled
from their mouths, but a Purdue University researcher believes they feel that pain all the
same. Joseph Garner, an assistant professor of animal sciences, helped develop a test that
found goldfish do feel pain, and their reactions to it are much like that of humans. A
paper detailing the finding was published in the early online version of the journal
Applied Animal Behaviour Science. "There has been an effort by some to argue that a
fish's response to a noxious stimuli is merely a reflexive action, but that it didn't
really feel pain," Garner said. "We wanted to see if fish responded to
potentially painful stimuli in a reflexive way or a more clever way." Garner and
Janicke Nordgreen, a doctoral student in the Norwegian School of Veterinary Science,
attached small foil heaters to the goldfish and slowly increased the temperature. The
heaters were designed with sensors and safeguards that shut off the heaters to prevent any
physical damage to a fish's tissue. Half of the fish were injected with morphine, and the
others received saline. The researchers believed that those with the morphine would be
able to withstand higher temperatures before reacting if they actually felt the pain.
However, both groups of fish showed a response at about the same temperature. Because both
groups of fish wriggled at about the same temperature, the researchers thought the
responses might be more like a reflex than a cognitive reaction to experiencing pain. The
reflexive response is similar to a person involuntarily moving a hand off a hot stove with
which they had come into contact. The reaction happens before a person actually
experiences pain or understands that they have been hurt. Upon later observation in their
home tanks, however, the researchers noticed that the fish from each group were exhibiting
different behaviors.
Cancer-obesity link discovery by
MSU researchers could aid prevention efforts
A new link between body fat and cancer identified by a Michigan State University
researcher underscores obesity’s health risk and could lead to new cancer treatment
and prevention strategies. Jenifer Fenton, an MSU food science and human nutrition
researcher with the Michigan Agricultural Experiment Station, identified the connection
between obesity and colon cancer, the third-leading killer of Americans, in part by
examining tissue hormones. Working with MSU/MAES physiologist Julia Busik and biologist
Fay Hansen-Smith of Oakland University in Rochester, Mich., Fenton examined a key hormone
found in fat tissue and thought to promote cancer. Her conclusions are published in a
study today in the journal Carcinogenesis. Leptin – a fat cell-derived hormone
regulating body energy – is higher in obese individuals. Fenton’s study is the
first to demonstrate that, at higher levels, leptin induces precancerous colon cells to
produce more of a growth factor that can increase blood supply to early cancer cells
– promoting tumor growth and cancer progression. "Adipose tissue, or fat, is
recognized as a significant risk factor for diabetes and heart disease, but the role of
adipose tissue in cancer risk is less understood,” Fenton said. “Abdominal fat
in particular seems to be associated with the greatest risk for cancer. As your
waist-to-hip ratio increases, so does your risk for cancer, especially breast, colon and
endometrial cancers.” Some 149,000 Americans will be diagnosed with colon cancer and
50,000 will die from it this year, according to the American Cancer Society. More than a
million have been diagnosed with colon or rectal cancer in the U.S. as of 2006, the
National Cancer Institute reported.
Potentially harmful chemicals found
in forest fire smoke
Researchers have detected common plant toxins that affect human health and ecosystems in
smoke from forest fires. The results from the new study also suggest that smoldering fires
may produce more toxins than wildfires - a reason to keep human exposures to a minimum
during controlled burns. Finding these toxins -- known as alkaloids -- helps researchers
understand how they cycle through earth and air. Smoke-related alkaloids in the
environment can change aquatic and terrestrial ecosystems, as well as where and when
clouds form. The study, which was of Ponderosa pines, by scientists at the Department of
Energy's Pacific Northwest National Laboratory will appear June 1 in Environmental Science
and Technology. "Ponderosa pines are widespread in areas that are prone to forest
fires," said PNNL physical chemist Julia Laskin, one of the coauthors. "This
study shows us which molecules are in smoke so we can better understand smoke's
environmental impact."
BUSM researchers find prenatal
cocaine exposure may compromise neurocognitive development
Researchers at Boston University School of Medicine (BUSM) have found that heavier
intrauterine cocaine exposure (IUCE) is associated with mild compromise on selective areas
of neurocognitive development during middle childhood. The BUSM study appears in the May
issue of Neurotoxicology and Teratology. BUSM researchers evaluated whether the level of
IUCE or the interaction between IUCE and contextual variables was related during middle
childhood to executive functioning as measured by two neuropsychological assessments. The
Stroop Color-Word Test measures verbal inhibitory control while the Rey Osterrieth
Organizational score evaluates skills such as planning, organization and perception. BUSM
researchers classified subjects as either unexposed, lighter, or heavier IUCE by positive
maternal reports and/or biological assay. Examiners who did not know the children's
history or group status assessed 143 children at 9 and 11 years of age (74 with IUCE and
69 demographically similar children without IUCE). After controlling for contextual
variables including intrauterine exposures to other licit and illicit substances, level of
IUCE was not significantly associated with either assessment scores. However, the heavier
cocaine-exposed group of children had significantly lower Stroop scores compared to the
combined lighter/unexposed group.
Chemical found in medical devices
impairs heart function
Researchers at the Johns Hopkins University School of Medicine have found that a chemical
commonly used in the production of such medical plastic devices as intravenous (IV) bags
and catheters can impair heart function in rats. Appearing online this week in the
American Journal of Physiology, these new findings suggest a possible new reason for some
of the common side effects—loss of taste, short term memory loss—of medical
procedures that require blood to be circulated through plastic tubing outside the body,
such as heart bypass surgery or kidney dialysis. These findings also have strong
implications for the future of medical plastics manufacturing. In addition to loss of
taste and memory, coronary bypass patients often complain of swelling and fatigue. These
side effects usually resolve within a few months after surgery, but they are troubling and
sometimes hinder recovery. His personal experience with coronary bypass surgery propelled
his search for a root cause for the loss of taste phenomenon, reports principal
investigator Artin Shoukas, Ph.D., professor of biomedical engineering, physiology and
anesthesiology and critical care medicine at Johns Hopkins. "I'm a chocoholic, and
after my bypass surgery everything tasted awful, and chocolate tasted like charcoal for
months." Shoukas and Caitlin Thompson-Torgerson, Ph.D., a postdoctoral fellow in
anesthesiology and critical care medicine suspected that the trigger for these side
effects might be a chemical compound of some kind. To test their theory, Shoukas and his
team of researchers took liquid samples from IV bags and bypass machines before they were
used on patients. The team analyzed the fluids in another machine that can identify
unknown chemicals and found the liquid to contain a chemical compound called
cyclohexanone. The researchers thought that the cyclohexanone in the fluid samples might
have leached from the plastic. Although the amount of cyclohexanone leaching from these
devices varied greatly, all fluid samples contained at least some detectable level of the
chemical.
Chronic ankle pain may be more than
just a sprain
Ankle sprains are a common injury after a fall, sudden twist or blow to the ankle joint.
Approximately 40 percent of those who suffer an ankle sprain will experience chronic ankle
pain, even after being treated for their initial injury. A review article published in the
May 2009 issue of the Journal of the American Academy of Orthopaedic Surgeons (JAAOS)
explains that tendon injuries to the ankle can be a possible cause for this chronic pain.
In some cases, the condition is untreated or overlooked which prolongs the pain and the
problem. "When patients injure their ankles, the injury may not seem serious at
first," explains Terrence Philbin, DO, lead author of the article and Fellowship
Director of the Orthopedic Foot and Ankle Center in Columbus, Ohio. "People may not
seek medical attention and they can think it will just get better on its own. I think that
is why this condition often goes undiagnosed."
Massive fraud revelations stun
orthopaedics
Revelations about a well-known pain management researcher have hit orthopaedics,
anesthesia, and other medical fields, resulting in more than 20 scientific articles being
identified as containing fabricated data. Scott S. Reuben, MD, was one of the most
prolific investigators in the field of anesthesia and analgesia, particularly for
orthopaedic perioperative and postoperative pain management. His work on multimodal
analgesia appeared in numerous peer reviewed medical journals, and he was frequently
invited to speak on the subject. So when an investigation begun last year by Baystate
Medical Center in Springfield, Mass., recently found that Dr. Reuben had fabricated part
or all of the data used in 21 of his studies since 1996, the news surprised and shocked
both the anesthesia and the orthopaedic communities. Both The Journal of Bone and Joint
Surgery (JBJS) and Anesthesia &Analgesia, which were among the journals that have
published Dr. Reuben’s studies, have posted retractions on their Web sites.
Anesthesiologists and orthopaedists who had used Dr. Reuben’s treatment protocols
were left with many unanswered questions.
Maternal depression is associated
with significant sleep disturbance in infants
A study in the May 1 issue of the journal SLEEP suggests that babies born to mothers with
depression are more likely to suffer from significant sleep disturbances at 2 weeks
postpartum that continue until 6 months of age. Findings of the study are of particular
importance, as sleep disturbances in infancy may result in increased risk for developing
early-onset depression in childhood. Results indicate that infants born to mothers with
depression had significant sleep disturbances compared to low-risk infants; the high-risk
group had an hour longer nocturnal sleep latency, shorter sleep episodes and lower sleep
efficiency than infants who were born to mothers without depression. Although average
sleep time in a 24 hours did not differ by risk group at eight two or four weeks,
nocturnal total sleep time was 97 minutes longer in the low-risk group at both recording
periods. High-risk infants also had significantly more daytime sleep episodes of a shorter
average duration. Previous studies have found that levels of cortisol, a hormone that is
associated with stress, is increased during pregnancy and after delivery in depressed
mothers, indicating that the mother's hormone level may affect the infant's sleep.
According to the lead author, Roseanne Armitage, PhD, director of the Sleep and
Chronophysiology Laboratory at the University Of Michigan Depression Center, while
maternal depression does have a negative effect on infants' sleep, the damage may be
reversible.
Study links ADHD with sleep
problems in adolescents
A study in the May 1 issue of the journal SLEEP shows that adolescents with a childhood
diagnosis of Attention Deficit/Hyperactivity Disorder (ADHD) are more likely to have
current and lifetime sleep problems and disorders, regardless of the severity of current
ADHD symptoms. Authors suggest that findings indicate that mental health professionals
should screen for sleep problems and psychiatric comorbidities among all adolescents with
a childhood diagnosis of ADHD. Results indicate that adolescents with a childhood
diagnosis of ADHD, regardless of persistent ADHD were more likely to have current sleep
problems and sleep disorders such as insomnia, sleep terrors, nightmares, bruxism and
snoring. Of the total sample, 17 percent of children with ADHD were currently suffering
from primary insomnia, versus 7 percent of controls; lifetime primary insomnia occurred in
20 percent of children with ADHD, compared to 10 percent of controls. Nightmare disorder
affected 11 percent of children with ADHD and lifetime nightmare disorder affected 23
percent, versus 5 and 16 percent of controls. The presence of at least one psychiatric
comorbid condition increases the risks for insomnia and nightmares. According to principal
investigator Susan Shur-Fen Gau, MD, PhD, associate professor at the College of Medicine
and Public Health, National Taiwan University, symptoms and consequences of ADHD and sleep
problems in children often overlap. Some primary sleep disorders are found to be
associated with inattention, hyperactivity, behavioral problems and impaired academic
performance, which are often mistaken for symptoms of ADHD. "In some patients with
ADHD, symptoms are caused or exaggerated by primary sleep disorders, and therefore
treatment of the sleep disorder will improve ADHD symptoms," said Gau.
Study Shows Institution of a
Consistent Nightly Bedtime Routine Improves Sleep in Infants and Toddlers as well as
Maternal Mood
A study in the May 1 issue of the journal SLEEP demonstrates that the use of a consistent
bedtime routine contributes to improvements in multiple aspects of infant and toddler
sleep, bedtime behavior and maternal mood.Results indicate that the establishment of a
nightly bedtime routine produced significant reductions in problematic sleep behaviors for
infants and toddlers. Improvements were seen in latency and sleep onset and in the number
and duration of night wakings. Toddlers were less likely to call out to their parents or
get out of their crib/bed during the night. Sleep continuity increased and there was a
significant decrease in the number of mothers who rated their child’s sleep as
problematic. Maternal mood also significantly improved. According to the study, sleep
problems are one of the most common concerns of parents of young children; approximately
20 to 30 percent of infants and toddlers experience sleep difficulties. Previous studies
have found that successful treatment of children’s sleep problems with behavioral
interventions also result in improvements in parental well-being. According to principal
investigator, Jodi Mindell, PhD, professor of psychology at Saint Joseph's University in
Philadelphia, PA., creating a bedtime routine is an easy change that can significantly
improve both the child’s sleep and the mother’s quality of life. “There is
no question that maternal mood and children's sleep impact one another. The better a child
sleeps and the easier bedtime is, the better a mother's mood is going to be,” said
Mindell. ”In addition, a mom who is not feeling tense, depressed, and fatigued is
going to be calmer at bedtime, which will help a child settle down to sleep.” Data
were collected from 405 mothers and their infant or toddler,(206 infants between the ages
of 7 and 18 months and 199 toddlers between the ages of 18 and 36 months), who then
participated in two age-specific three week studies. Families were randomly assigned to a
routine or control group. The first week of the study served as a baseline, during which
the mothers followed their child’s usual bedtime routines. During the following two
weeks mothers were instructed to conduct a specific bedtime routine, while the control
group continued with their child’s normal bedtime procedure.
Popular diabetes treatment could
trigger pancreatitis, pancreatic cancer
A drug widely used to treat Type 2 diabetes may have unintended effects on the pancreas
that could lead to a form of low-grade pancreatitis in some patients and a greater risk of
pancreatic cancer in long-term users, UCLA researchers have found. In a study published in
the online edition of the journal Diabetes, researchers from the Larry L. Hillblom Islet
Research Center at UCLA found that sitagliptin, sold in pill form as Januvia, caused
abnormalities in the pancreas that are recognized as risk factors for pancreatitis and,
with time, pancreatic cancer in humans. Januvia is marketed by Merck & Co. Inc.
Sitagliptin is a member of a new class of drugs that enhance the actions of the gut
hormone known as glucagon-like peptide 1 (GLP-1), which has been shown to be effective in
lowering blood sugar in people with Type 2 diabetes. The study is available at
http://diabetes.diabetesjournals.org/cgi/content/abstract/db09-0058v1. "Type 2
diabetes is a lifelong disease — people often take the same drugs for many years, so
any adverse effect that could over time increase the risk for pancreatic cancer would be a
concern," said Dr. Peter Butler, director of the Hillblom Center and the study's lead
investigator. "A concern here is that the unwanted effects of this drug on the
pancreas would likely not be detected in humans unless the pancreas was removed and
examined." An observed connection between Byetta, a drug used to treat Type 2
diabetes that is related to Januvia in its intended actions, and pancreatitis has already
been reported, prompting a Food and Drug Administration warning. Amylin Corp., which
markets Byetta, has suggested that since there is no known mechanism linking the cases of
pancreatitis with Byetta, the association might be chance. The UCLA study suggests that
there may indeed be a link between drugs that enhance the actions of GLP-1 and
pancreatitis — by increasing the rate of formation of cells that line the pancreatic
ducts.
Scientists find the cellular on and
off switch for allergies and asthma
If you're one of the millions who dread the spring allergy season, things are looking up.
A research study appearing in the May 2009 issue of the Journal of Leukocyte Biology
(http://www.jleukbio.org) shows how a team of American scientists have identified a
previously unknown cellular switch that turns allergies and asthma both on and off.
Equally important, this study also suggests that at least for some people with asthma and
allergies, their problems might be caused by genes that prevent this switch from working
properly. Taken together, this information is an important first step toward new
medications that address the root causes of allergies, asthma and other similar diseases.
"This study uncovers some of the basic mechanisms that control whether or not people
have asthma and allergies and the severity of the symptoms," said John Ryan, Ph.D.,
Professor of Biology at Virginia Commonwealth University, and a senior scientist involved
in the research. "This understanding opens new avenues for treating these and other
related diseases." Ryan and colleagues made this discovery in mouse experiments that
examined cells from bone marrow and umbilical cord blood that ultimately help create a
type of immune cell (mast cells). Too many mast cells lead to an over-aggressive immune
response, which causes allergies and asthma. The scientists found that when chemicals
(cytokines IL-4 and IL-10) used to initiate an immune response (the "on switch")
are added to developing mast cells, the developing cells die. Because bone marrow makes
both mast cells and these cytokines, the researchers conclude that just as the cytokines
serve as the "on switch" for the immune system, bone marrow cells also use them
as the "off switch" to stop mast cells from getting out of hand. Further
supporting their discovery was the finding that strains of mice prone to allergies and
asthma had genes which affected the production of this chemical "off switch" in
their bone marrow. "The immune system has an incredible capacity for balance and
counterbalance to maintain optimal and properly tuned immune responses," said John
Wherry, Ph.D., Deputy Editor of the Journal of Leukocyte Biology, "The studies by
Ryan and colleagues are an excellent example of this inherent self-regulation of the
immune system and how an imbalance in mast cell regulation could contribute to allergy and
disease."
Genetic variant impairs
communication within the brain
For some time now it has been known that certain hereditary factors enhance the risk of
schizophrenia or a manic-depressive disorder. However, just how this occurs had remained
obscure. Researchers at the Zentralinstitut für Seelische Gesundheit in Mannheim,
Heidelberg University and Bonn University are now able to answer this question, at least
for one common genetic variant: this impairs the interoperation of certain regions of the
brain. The study is to appear on 1st May in the prestigious scientific journal Science. It
will also be suited to provide fresh stimuli for the search for cures. The scientists
examined test persons with whom a certain genetic trait had undergone a characteristic
mutation. A year ago, a research team had demonstrated that this mutation was, amongst
other things, associated with an enhanced risk of schizophrenia. In addition to this,
people carrying this variant were more susceptible to a bipolar malady also known as a
manic-depressive disorder. In the present case, however, our results were based on
examinations of 115 healthy subjects."At this point, no-one had the slightest idea of
what effect the genetic variant we had observed might have on the brain", declares
Professor Dr. Andreas Meyer-Lindenberg. The director of the Zentralinstitut für Seelische
Gesundheit was the initiator of the study. "We examined our test subjects in magnetic
resonance tomographs, which reveal how the various areas of the brain interoperate".
Result - persons suffering from this high-risk genetic variant exhibited a change in the
communication between their dorsolateral prefrontal cortex (DLPFC) and other regions of
their brains. The DLPFC plays an active role in the working memory and diverse
"higher" cerebral functions. It comprises a right-hand and a left-hand fraction,
and it was the communication between these two halves which had become impaired. In
contrast to this, the link between the DLPFC and the hippocampus, a further region of the
brain of importance for the memory, was improved. Both these noteworthy phenomena had
already been shown to exist in patients suffering from schizophrenia.
Low vitamin D causes problems for
acutely ill patients
A group of endocrinologists in Sydney have observed that very sick patients tend to have
very low levels of Vitamin D. The sicker they are, the lower the levels. Dr Paul Lee,
Professor John Eisman and Associate Professor Jackie Center, researchers at Sydney's
Garvan Institute of Medical Research, examined a cohort of 42 Intensive Care Unit (ICU)
patients. Forty-five percent turned out to be Vitamin D deficient. These findings will be
published as a letter in the April 30, 2009 issue of the New England Journal of Medicine.
"Until now, the medical community has thought of Vitamin D deficiency as a chronic
condition," said Dr Lee. "Little is known about its acute complications."
"Last year, we published several cases showing that Vitamin D deficiency can cause
acute complications in the intensive care unit." "Recently, Vitamin D has been
recognised for its many roles beyond the musculoskeletal system. It has been implicated in
diabetes, in the immune system, in cancers, in heart disease and in metabolic
syndrome." "Vitamin D appears to have roles in controlling sugar, calcium, heart
function, gut integrity, immunity and defence against infection. Patients in ICU suffer
from different degrees of inflammation, infection, heart dysfunction, diarrhoea and
metabolic dysregulation – so vitamin D deficiency may play a role in each of these
common ICU conditions." "So we did a preliminary study and found that 45% of
people in our ICU were Vitamin D deficient. There may be a bias, in that all patients were
referred to endocrinology, so the numbers may not reflect the prevalence in a standard ICU
cohort. However 45% is still a significant proportion. When the team correlated the
Vitamin D levels with a disease severity score, there was a direct correspondence between
sickness and Vitamin D deficiency. In other words, the sicker someone was, the lower the
levels of Vitamin D. Out of the 42 patients studied, there were 3 deaths. The 3 patients
who died all had the lowest level of Vitamin D in the cohort. "Perhaps when we are
well, we have ways to compensate for organ dysfunction if we run low on Vitamin D,"
said Lee.
White tea -- the solution to the
obesity epidemic?
Possible anti-obesity effects of white tea have been demonstrated in a series of
experiments on human fat cells (adipocytes). Researchers writing in BioMed Central's open
access journal Nutrition and Metabolism have shown that an extract of the herbal brew
effectively inhibits the generation of new adipocytes and stimulates fat mobilization from
mature fat cells. Marc Winnefeld led a team of researchers from Beiersdorf AG, Germany,
who studied the biological effects of an extract of white tea – the least processed
version of the tea plant Camellia sinensis. He said, "In the industrialized
countries, the rising incidence of obesity-associated disorders including cardiovascular
diseases and diabetes constitutes a growing problem. We've shown that white tea may be an
ideal natural source of slimming substances". After treating lab-cultured human
pre-adipocytes with the tea extract, the authors found that fat incorporation during the
genesis of new adipocytes was reduced. According to Winnefeld, "The extract solution
induced a decrease in the expression of genes associated with the growth of new fat cells,
while also prompting existing adipocytes to break down the fat they contain". White
tea is made from the buds and first leaves of the plant used to make green tea and the
black tea most commonly drunk in Western countries. It is less processed than the other
teas and contains more of the ingredients thought to be active on human cells, such as
methylxanthines (like caffeine) and epigallocatechin-3-gallate (EGCG) – which the
authors believe to be responsible for many of the anti-adipogenic effects demonstrated in
their study.
Folic acid may help treat
allergies, asthma
Folic acid, or vitamin B9, essential for red blood cell health and long known to reduce
the risk of spinal birth defects, may also suppress allergic reactions and lessen the
severity of allergy and asthma symptoms, according to new research from the Johns Hopkins
Children's Center. In what is believed to be the first study in humans examining the link
between blood levels of folate – the naturally occurring form of folic acid —
and allergies, the Hopkins scientists say results add to mounting evidence that folate can
help regulate inflammation. Recent studies, including research from Hopkins, have found a
link between folate levels and inflammation-mediated diseases, including heart disease. A
report on the Hopkins Children's findings appears online ahead of print in the Journal of
Allergy & Clinical Immunology. Cautioning that it's far too soon to recommend folic
acid supplements to prevent or treat people with asthma and allergies, the researchers
emphasize that more research needs to be done to confirm their results, and to establish
safe doses and risks. Reviewing the medical records of more than 8,000 people ages 2 to 85
the investigators tracked the effect of folate levels on respiratory and allergic symptoms
and on levels of IgE antibodies, immune system markers that rise in response to an
allergen. People with higher blood levels of folate had fewer IgE antibodies, fewer
reported allergies, less wheezing and lower likelihood of asthma, researchers report.
"Our findings are a clear indication that folic acid may indeed help regulate immune
response to allergens, and may reduce allergy and asthma symptoms," says lead
investigator Elizabeth Matsui, M.D. M.H.S., pediatric allergist at Hopkins Children's.
"But we still need to figure out the exact mechanism behind it, and to do so we need
studies that follow people receiving treatment with folic acid, before we even consider
supplementation with folic acid to treat or prevent allergies and asthma."
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.”
Autism may be linked to being
firstborn, breech births or moms 35 or older
Children who are firstborn or breech or
whose mothers are 35 or older when giving birth are at significantly greater risk for
developing an autism spectrum disorder, University of Utah School of Medicine researchers
have reported in a new study with Utah children. In the April 27, 2009, online issue of
the journal Pediatrics, the researchers showed that women who give birth at 35 or older
are 1.7 times more likely to have a child with an autism spectrum disorder (ASD), compared
with women between the ages of 20-34. Children diagnosed with ASD also were nearly 1.8
times more likely to be the firstborn child, the researchers found. Although they didn't
identify a causal relationship between breech births and autism, children diagnosed with
the disorder were more than twice as likely to have been a breech presentation, meaning
they were not born head first. "The results of this study give us an opportunity to
look more closely at these risk factors for children across the autism spectrum, and not
only those diagnosed with autism," said first author Deborah A. Bilder, M.D.,
assistant professor of psychiatry. "This shows that further investigation of the
influence of prenatal factors is warranted." Autism is a complex brain disorder that
impairs social, communicative, and behavioral development and often is characterized by
extreme behavior.
Inadequate sleep leads to
behavioral problems
A recent Finnish study suggests that
children's short sleep duration even without sleeping difficulties increases the risk for
behavioral symptoms of ADHD. During the recent decades, sleep duration has decreased in
many countries; in the United States a third of children are estimated to suffer from
inadequate sleep. It has been hypothesised that sleep deprivation may manifest in children
as behavioral symptoms rather than as tiredness, but only few studies have investigated
this hypothesis. The researchers at the University of Helsinki and National Institute of
Health and Welfare, Finland, examined whether decreased sleep leads to behavioral problems
similar to those exhibited by children with attention-deficit/hyperactivity disorder
(ADHD). 280 healthy children (146 girls and 134 boys) participated in the study. The
researchers tracked the children's sleep using parental reporting as well as actigraphs,
or devices worn on the wrist to monitor sleep. The children whose average sleep duration
as measured by actigraphs was shorter than 7.7 hours had a higher hyperactivity and
impulsivity score and a higher ADHD total score, but similar inattention score than those
sleeping for a longer time. In multivariate statistical models, short sleep duration
remained a statistically significant predictor of hyperactivity and impulsivity, and
sleeping difficulties were associated with hyperactivity, impulsivity and inattention.
There were no significant interactions between short sleep and sleeping difficulties.
"We were able to show that short sleep duration and sleeping difficulties are related
to behavioral symptoms of ADHD, and we also showed that short sleep, per se, increases
behavioral symptoms, regardless of the presence of sleeping difficulties", says
researcher Juulia Paavonen, MD, PhD. "The findings suggest that maintaining adequate
sleep schedules among children is likely to be important in preventing behavioral
symptoms. However, even though inadequate sleep seems to owe potential to impair behaviour
and performance, intervention studies are needed to confirm the causality," Paavonen
continues.
Packard/Stanford study suggests two
causes for bowel disease in infants
New research from Lucile Packard Children's
Hospital and the Stanford University School of Medicine is helping physicians unravel the
cause of a deadly and mysterious bowel disease that strikes medically fragile newborn
babies. The findings could lead to a better understanding of the disease and its medical
management, and also shed light on the causes of sepsis, a major killer of children and
young adults.
The bowel disorder, necrotizing enterocolitis, or NEC, is seen mainly among premature
infants, affecting about one in every 2,000 births. A similar constellation of symptoms,
also labeled NEC, is also seen in children born with congenital heart defects. The disease
causes massive intestinal inflammation and impairs nutrient uptake. Complications can
include perforation of the intestine and widespread infection of the abdominal cavity or
blood — sepsis — as well as lasting consequences such as the need for bowel
transplant or chronic intravenous feeding. The findings, which will appear in the May
issue of the journal Pediatrics, suggest that the diagnosis of NEC in premature infants
versus those with heart disease may actually encompass two distinct disease processes with
different origins. "If we start accepting that we are looking at two different
diseases, further research may be able to elucidate some differences in the disease
process and help us tailor management," said senior study author Sanjeev Dutta, MD,
assistant professor of surgery and pediatrics at Packard Children's and the School of
Medicine. Right now, because physicians have such a poor understanding of what causes the
disease, they can't tell which infants will be hardest hit, Dutta said. "At present,
we're managing all cases the same way without addressing the concept that the child with
heart disease may have a different underlying cause of NEC than the child with prematurity
alone. We're giving support, but not really curing the disease." To gain insight into
how necrotizing enterocolitis starts, Dutta and his collaborators investigated whether a
pre-existing medical problem — congenital heart defects — affected the course of
the disease. They reviewed medical records from 76 infants who had a congenital heart
defect together with necrotizing enterocolitis and 126 infants who had necrotizing
enterocolitis alone. All study subjects were patients at Packard Children's between May
1999 and August 2007. The researchers found that babies who had both necrotizing
enterocolitis and a congenital heart defect fared better than those who had necrotizing
enterocolitis alone. Even premature babies with heart defects did better than those who
were premature alone. Babies who had heart defects were less likely than other affected
infants to suffer intestinal perforation or abnormal narrowing of the bowel. They also
were less likely to need surgery to resolve infection, to require an artificial drain
through the abdominal wall for managing bowel perforation or to require removal of
portions of diseased intestine. The findings suggest that infants with heart defects may
be getting the disorder because of reduced blood flow to the bowel, while those with
normal hearts may get the disease for other reasons, such as a bad reaction to oral
feeding in premature infants with an underdeveloped gut. Both poor blood flow and gut
immaturity have been blamed for NEC before, but the relative importance of each factor has
been unclear.
Brain works best when cells keep
right rhythms, new Stanford study suggests
It is said that each of us marches to the
beat of a different drum, but new Stanford University research suggests that brain cells
need to follow specific rhythms that must be kept for proper brain functioning. These
rhythms don’t appear to be working correctly in such diseases as schizophrenia and
autism, and now two papers published online by the journals Nature and Science demonstrate
that precisely tuning the oscillation frequencies of certain neurons can affect how the
brain processes information and implements feelings of reward. “A unifying theme here
is that of brain rhythms and ‘arrhythmias’,” said Karl Deisseroth, MD, PhD,
associate professor of bioengineering and of psychiatry and behavioral sciences and senior
author of both papers. An arrhythmia is what cardiologists call a seriously irregular
heartbeat. The new findings suggest that, like the cells that keep the beat of the heart
(or the coxswain on a rowing team that calls out the rhythm of the strokes), certain brain
cells can orchestrate oscillations that ultimately help govern behavior of other cells
that are guided by those rhythms.
Prostate cancer therapy increases
risk of fractures and cardiovascular-related death
Prostate cancer patients who undergo
therapy to decrease testosterone levels increase their risk of developing bone- and
heart-related side effects compared to patients who do not take these medications,
according to a new analysis. Published in the June 1, 2009 issue of CANCER, a
peer-reviewed journal of the American Cancer Society, the study indicates that preventive
measures and careful scrutiny of patients' health can keep men from experiencing these
potentially serious consequences. While medical treatments that decrease testosterone
levels—called androgen deprivation therapy (ADT)—are important and effective
therapies for men with prostate cancer, they can cause a variety of side effects including
skeletal and cardiovascular complications, sexual dysfunction, periodontal disease, and
mood disorders. Bone and heart complications are among the most serious side effects
associated with ADT, but the actual risk patients have of developing these effects is
unknown. Lockwood Taylor, MPH, of the University of Texas Health Science Center and
colleagues conducted a study to assess this risk by analyzing all of the literature
related to side effects from ADT published between 1996 and mid-2008. They found 14
studies (8 bone-related, 6 heart-related) that were suitable for analysis. The
researchers' review revealed that men treated with ADT for prostate cancer had an
increased risk of bone fractures and heart-related death, although the absolute risk for
both was still low. For bone fractures, there was a 23 percent increased risk compared to
prostate cancer patients who did not undergo the treatment. The absolute risk of fracture
among ADT-exposed men was still only 7.2 per 100 person years. For heart-related death,
the increased risk among ADT-exposed men was 17 percent higher compared to other prostate
cancer patients. However, because the baseline risk is low, the increase translated to an
additional one-to-two deaths per 1,000 men who received ADT. Two large studies also
documented significant increases in diabetes risk associated with the therapy. "While
the absolute risks of fracture and cardiovascular mortality are low among men treated with
androgen deprivation therapy, preventive treatments may further reduce the risk of these
serious adverse outcomes related to androgen deprivation therapy," the authors wrote.
They also noted that because some patients may benefit from this therapy more than others,
physicians should consider each patient's overall health and prostate cancer status when
weighing treatment options.
Whiter laundry and a surprising new
treatment for kids' eczema
It's best known for whitening a load of
laundry. But now simple household bleach has a surprising new role: an effective treatment
for kids' chronic eczema. Chronic, severe eczema can mar a childhood. The skin disorder
starts with red, itchy, inflamed skin that often becomes crusty and raw from scratching.
The eczema disturbs kids' sleep, alters their appearance and affects their concentration
in school. The itching is so bad kids may break the skin from scratching and get chronic
skin infections that are difficult to treat, especially from methicillin-resistant
Staphylococcus aureus (MRSA). Researchers from the Northwestern University Feinberg School
of Medicine have discovered powerful relief in the form of diluted beach baths. It's a
cheap, simple and safe treatment that drastically improves the rash as well as reduces
flare-ups of eczema, which affects 17 percent of school-age children. The study found
giving pediatric patients with moderate or severe eczema (atopic dermatitis) diluted
bleach baths decreased signs of infection and improved the severity and extent of the
eczema on their bodies. That translates into less scratching, fewer infections and a
higher quality of life for these children. The typical treatment of oral and topical
antibiotics increases the risk of bacterial resistance, something doctors try to avoid,
especially in children. Bleach kills the bacteria but doesn't have the same risk of
creating bacterial resistance. Patients on the bleach baths had a reduction in eczema
severity that was five times greater than those treated with placebos over one to three
months, said Amy S. Paller, M.D., the Walter J. Hamlin Professor and chair of dermatology,
and professor of pediatrics, at the Feinberg School. Paller also is an attending physician
at Children's Memorial Hospital.
Building the lymphatic drainage
system
Our bodies' tissues need continuous
irrigation and drainage. Blood vessels feeding the tissues bring in the fluids, and
drainage occurs via the lymphatic system. While much is known about how blood vessels are
built, the same was not true for lymph vessels. Now though, Norrmén et al. have
identified two of the lead engineers that direct drainage construction in the mouse
embryo. The engineers are the transcription factors, Foxc2 and NFATc1. Foxc2 had been
implicated in lymph vessel development already, but Norrmén and colleagues have now found
that the factor specifically regulates a late stage of lymph development when large,
valve-containing vessels arise from more primitive capillaries. The study will be
published online April 27 (www.jcb.org) and will appear in the May 4 print issue of the
Journal of Cell Biology. Foxc2 built the lymph vessel valves with the help of NFATc1,
which was a known heart valve engineer. Norrmén and colleagues also showed that Foxc2 and
NFATc1 physically interact and that many DNA binding sites for the two transcription
factors are closely linked. This latter finding generated a long list of target genes that
might be controlled by the two factors. The team now plans to investigate these targets as
well as to work out the upstream molecular pathways controlling Foxc2 and NFATc1. Whatever
the mechanisms, if the team can show that Foxc2 and NFATc1 also prompt lymph vessel
regeneration in adults, boosting these factors could help patients with lymph drainage
problems – including those that have suffered extensive tissue injuries, or have had
lymph nodes removed as part of cancer treatment.
Scientists discover how to improve
immune response to cancer at Princess Margaret Hospital
A team of scientists at The Campbell Family
Institute for Breast Cancer Research (CFIBCR) at Princess Margaret Hospital and
international collaborators have discovered how to trigger an improved immune response to
cancer that could be included in new clinical trials that use a patient's own cells to
destroy tumours. The findings, published online today in Nature Medicine (DOI
10.1038/nm.1953), demonstrate the tantalizing potential of immunotherapy in cancer
treatment, says principal investigator Dr. Pamela Ohashi, co-director, CFIBCR. In the lab
study, the scientists combined interleukin-7 (IL-7) – a key component of the immune
system – with a viral vaccine to improve the ability of the cells of the immune
system to attack tumours. The result was clear: The combination boosted immunity to
tumours. "We are extremely excited because our research has revealed the unexpected
ways IL-7 works to break down barriers that naturally block the immune response to
tumours. This is important because current vaccine approaches for immune therapy induce a
response in just 1% to 3% of patients," says Dr. Ohashi, a senior scientist in
signaling biology who holds a Canada Research Chair in Autoimmunity and Tumour Immunity.
She is also a Professor, University of Toronto, in the Department of Medical Biophysics
and Immunology. " Dr. Tak Mak, co-author and CFIBCR director, says: "The promise
of using the body's own defenses to fight cancer is enormous. The day is coming when
immunotherapy may help spare cancer patients the toxic side effects of traditional
therapies and greatly improve their quality of life while treating the disease. This is
why we are planning to expand our immunotherapy research program at PMH." Dr. Mak is
also a Professor, University of Toronto, in the Department of Medical Biophysics and
Immunology.
Drinking diet soda may reduce the
risk of forming kidney stones
Patients with stone disease could benefit
from drinking diet soda. New research from the University of California, San Francisco
suggests that the citrate and malate content in commonly consumed sodas may be sufficient
to inhibit the development of calcium stones. The study was presented at the 104th Annual
Scientific Meeting of the American Urological Association (AUA). Increased alkalinity is
proven to augment citraturia, a known factor for calcium stones. Malate increases the
amount of alkali delivered. Researchers measured the citrate and malate content of 15
popular diet sodas. The researchers found that Diet Sunkist Orange contained the greatest
amount of total alkali and Diet 7-Up had the greatest amount of citrate as alkali.
"This study by no means suggests that patients with recurrent kidney stones should
trade in their water bottles for soda cans," said Anthony Y. Smith, MD, an AUA
spokesman. "However, this study suggests instead that patients with stone disease who
do not drink soda may benefit from moderate consumption."
Long-term complications of melamine
consumption in children
Children with a history of consuming
melamine-contaminated milk powder are at an increased risk of developing kidney stones and
other urological complications. Researchers presenting two studies at the 104th Annual
Scientific Meeting of the American Urological Association (AUA) found that melamine
calculus occurred mostly in infants at six months to 18 months after consuming
melamine-contaminated milk powder after birth but that the stones could be effectively
managed with noninvasive treatment. In the first study, researchers analyzed the clinical
data of 50 young children with double kidney stones who had a history of consuming
melamine-contaminated milk powder. Researchers studied ultrasound images from each child,
measuring kidney stone size, number, shape and location. Eighty-five percent of these
cases occurred in children ages six to 18 months. Of these 50 children, 42 formed kidney
stones in both kidneys; multiple stones were found in 18 children; and single stones were
found in nine of them. Eleven children experienced kidney failure, in which the stone
diameters of bilateral kidneys were significantly larger than those who did not experience
kidney failure. In 21 cases, the stone was passed after non-operative hospital treatment
in an average of eight days. Researchers in the second study analyzed the clinical data of
165 infants, aged 50 days to three years, with urinary stones who had a history of
consuming melamine-contaminated milk powder. The children were divided into mild (25
cases), moderate (122 cases) and severe (18 cases) groups. Researchers found that the peak
incidence of urolithiasis (urinary stones) was found in children aged six months to 12
months. Of these patients, 50.3 percent were asymptomatic, 16.9 percent experienced
dysuria (painful urination), 14.6 percent had infantile colic, 10.9 percent experienced
oliguria or anuria (decreased urine and absence of urine, respectively) and 7.3 percent
had hematuria (blood in the urine). Acute urinary retention (the sudden inability to
urinate) caused by urethral stones was found in five cases. The stone diameter ranged from
22mm to 16mm, and 63.5 percent of cases had 4-10 mm stones. All cases accepted
non-operative treatment, except those cases with a bilateral stone and obstruction. After
hospital treatment, the stone expulsion rate was 43 percent. "This study presents us
with the long-term complications for children who had been fed with melamine contaminated
products," said Anthony Atala, MD, an AUA spokesman. "Both parents and
physicians should be vigilant of these signs and symptoms in children who may have
consumed the contaminated milk powder."
Men treated for localized prostate
cancer could benefit from pomegranate juice consumption
Pomegranate juice may slow the progression
of post-treatment prostate cancer recurrence, according to new long-term research results
being presented at the 104th Annual Scientific Meeting of the American Urological
Association (AUA). Researchers found that men who have undergone treatment for localized
prostate cancer could benefit from drinking pomegranate juice. The two-stage clinical
trial followed a total of 48 participants over six years. Eligible participants had a
rising PSA after surgery or radiotherapy, a PSA greater than 0.2 ng/ml and less than 5
ng/ml and a Gleason score of 7 or less. These patients were treated by drinking eight
ounces of pomegranate juice daily. Currently, in the sixth year of treatment, active
patients who remain on the study have a median total follow-up of 56 months. These
participants continue to experience a significant increase in PSA doubling time following
treatment, from a mean of 15.4 months at baseline to 60 months post-treatment, with a
median PSA slope decrease of 60 percent, 0.06 to 0.024. Researchers compared active
patients, who remain on the study, with non-active patients, who no longer remain on the
study. Though these two groups demonstrated similar mean PSA doubling times at baseline,
both the PSA doubling time prolongation and the decline in median PSA slope were greater
in active patients when compared to non-active patients. "This study suggests that
pomegranate juice may effectively slow the progression of prostate cancer after
unsuccessful treatment," said Christopher Amling, MD, an AUA spokesman. "This
finding and other ongoing research might one day reveal that pomegranate juice is an
effective prostate cancer preventative agent as well." Parts of this ongoing study
suggest that some patients may be more sensitive to the effects of pomegranate juice on
PSA doubling time. Phase three of this study is currently underway to further evaluate the
benefits of pomegranate juice in a placebo-controlled manner.
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