News 28 juli 2009
Protein excreted in urine may be
help in diagnosing kidney disease caused by HIV
New data collected at Columbia University Medical Center and by the Mount Sinai School of
Medicine are helping researchers understand the extent to which a certain protein –
NGAL – can play a significant role in marking chronic kidney disease resulting from
HIV while at the same time distinguishing nephropathy from more common causes such as
diabetes and hypertension. It's well-known that Human Immunodeficiency Virus-associated
nephropathy (HIVAN) is an important cause of kidney disease in HIV-infected patients.
Antiretroviral therapy plays an important role in the treatment of HIVAN, yet despite
advances in understanding HIVAN, current recommendations for treatment have largely been
based on observational data and can only definitively made after a kidney biopsy. The
current study, spearheaded by Columbia University's Jonathan Barasch, M.D., Ph.D., along
with Ali Gharavi M.D., Ph.D., Neal Paragas M.S., Thomas Nickolas M.D., M.S., and Vivette
D'Agati M.D., together with Paul Klotman, M.D., Christina Wyatt M.D., and Susan Morgello
M.D., of the Mount Sinai School of Medicine and Landino Allegri in Parma, Italy, and
Prasad Devarajan in Cincinnati Childrens Hospital, represents the examination of data from
human cohorts in New York and Parma, and from mouse models created by Dr. Klotman. The
team noted that NGAL, or Neutrophil Gelatinase Associated Lipocalin, a protein they
previously discovered in damaged kidneys, was prominently expressed in kidney tissue and
in the urine of humans and in mouse models of HIVAN. The high levels of the urine protein
were out of proportion to the degree of chronic renal failure, for example that typifies
patients with other types of chronic glomerular diseases of both mice and humans. Most
strikingly, Paragas, Barasch, and Gharavi noticed that the rise in urinary NGAL levels was
in conjunction with the development of a specific type of lesion, namely tubular cysts
that typify HIVAN. The association with these cysts consequently may justify their biopsy
or an aggressive treatment with antiretroviral drugs when high levels of urine NGAL are
discovered. "From what we can tell, NGAL is unexpectedly expressed in great abundance
by kidney cysts allowing the clinician to potentially identify HIVAN among other types of
chronic kidney diseases and hopefully to intervene to prevent a kidney from ultimately
dying from what physicians refer to as ESRD, or 'end-stage renal disease,'" Dr.
Barasch says. Dr. Barasch cautions that studying a much larger human cohort would be
needed in order to determine the precise relationship of NGAL to HIVAN and whether the
protein is a good enough predictor of tubular cysts, but he finds the results of the study
unexpected and intriguing.
Leukemia cells evade immune system
by mimicking normal cells, Stanford studies show
Human leukemia stem cells escape detection by co-opting a protective molecular badge used
by normal blood stem cells to migrate safely within the body, according to a pair of
studies by researchers at Stanford University Medical School."We call it the 'Don't
eat me signal,'" said Ravindra Majeti, MD, PhD, assistant professor of hematology at
the medical school and the co-first author of one of the studies, which focused on acute
myeloid leukemia. Patients whose cancer stem cells express higher levels of the molecule
have a poorer prognosis than those whose cells express lower levels, and masking its
presence makes the human cancer cells less deadly and more vulnerable to destruction when
injected into mice. The results indicate that the molecule may serve both as a prognostic
factor and a valuable therapeutic target for patients with the cancer. "When we
blocked this signal in mice with established human leukemia, the cancer cells were more
easily removed by the body's natural defenses," Majeti said. The researchers are now
moving ahead with plans to test a similar treatment in humans and have filed for a patent
for the potential therapy. Irving Weissman, MD, the Virginia & D.K. Ludwig Professor
for Clinical Investigation in Cancer Research at the medical school, is the senior author
of both studies, which will be published together in the July 24 issue of the journal
Cell. Majeti shares his first authorship with Mark Chao, an MD and PhD student in the
cancer biology program at the medical school. Both Majeti and Weissman are members of
Stanford's Cance Center.Together, the researchers of the studies found that the molecule,
CD47, protects the leukemia stem cells from macrophages — part of a roving cellular
army tasked with finding and engulfing diseased or dying cells — by binding to a
molecule on the macrophage's surface. The interaction between the two proteins inhibits
the macrophage's killing instinct and allows the marauding cancer cells to escape
unscathed. The current research sprang from an earlier study in Weissman's lab that showed
CD47 expression was expressed at significantly higher levels in mouse leukemia cells.
"At the time, we didn't know what role CD47 played in leukemia," said Siddhartha
Jaiswal, an MD and PhD student at the medical school who is the first author of the second
study. "But it was clearly important." It all fell into place, according to
Weissman, when another group showed that red blood cells expressing CD47 were bypassed by
macrophages, but those without CD47 were eaten. "Our discovery that leukemia cells in
mice also expressed CD47 led us to propose that this signal might be appropriated by the
leukemia stem cells as part of their leukemic progression," said Weissman.
New breast pumping approach helps
preemies' moms to improve milk supply, says Packard/Stanford study
Mothers of premature infants shouldn’t rely solely on breast pumps to establish and
maintain their breast milk supply, researchers at Lucile Packard Children’s Hospital
and the Stanford University School of Medicine have found. Moms already have a simple,
safe and free tool for assisting breast milk production: their own hands. In the study, 67
new mothers of premature infants learned how to combine an electric breast pump with
hand-expression techniques to extract milk. Unlike prior research showing poor milk
production in preemies’ moms, the subjects who used both hands and pump established
plentiful milk supplies. By the end of the eight-week study, their average milk production
exceeded the amount needed to feed a healthy 3-month-old, even though none of the women
studied could nurse when their babies were born. The findings could have implications for
women who have full-term infants, too. “When I saw the data, I realized, oh, my gosh,
this is impressive,” said Jane Morton, MD, who led the study. Morton was the director
of the breast-feeding medicine program at Packard Children’s when the study, which
appeared online July 2 in the Journal of Perinatology, was conducted. “We were
worried about mothers of preterm babies establishing any milk supply, much less an
average-or-better supply,” said William Rhine, MD, a neonatologist at Packard
Children’s and the study’s senior author. The findings contradict widely held
assumptions that premature delivery lessens the hormone signals needed to establish
breast-feeding.
New lab test helps predict kidney
damage
'Urine NGAL' gives clues to kidney injury in ICU patients and HIV-related kidney disease.
Acute kidney injury (AKI) is a frequent complication in patients in intensive care. A new
laboratory test called urine neutrophil gelatinase associated lipocalin (NGAL) helps
predict if patients will develop acute kidney injury, reports an upcoming study in the
Journal of the American Society of Nephrology (JASN). "As a stand-alone marker, urine
NGAL performed moderately well in predicting ongoing and subsequent AKI," comments T.
Alp Ikizler, MD (Vanderbilt University). Another study, also in JASN, indicates that urine
NGAL may also help in diagnosing HIV-related kidney disease affecting African Americans
and black Africans. "NGAL was very specifically expressed in renal
cysts—generating the new idea that NGAL may control the development of cysts in
HIV-associated nephropathy," says Jonathan Barasch, MD, PhD (Columbia University, New
York). He adds, "We and Prasad Devarajan, MD, identified NGAL in the kidney 10 years
ago and its translation into a clinical entity in such a short time is quite a story.
Almost every paper is positive for the association of NGAL and renal
dysfunction/disease." In the ICU study, patients with higher urine NGAL levels were
more likely to develop acute kidney injury, even after adjustment for other factors. The
rise in NGAL was present before any change in the standard test for AKI (serum creatinine
level). Without other information, however, urine NGAL was no more effective in predicting
AKI than clinical risk factors. Ikizler notes the study was limited by a lack of
information on incidence of death or the need for dialysis, and by a lack of information
on the patients' initial kidney function level. In the HIV study, levels of urine NGAL
were much higher in patients with HIV-associated nephropathy (HIVAN) than in patients with
other forms of kidney disease, with or without HIV. HIVAN is an important complication of
HIV, occurring mainly in patients of African descent. Studies in mice suggested that NGAL
may play an important role in the development of tubular disease and microcysts, which are
specific features of HIVAN. Barasch notes that the human component of their study was
limited by its small size but highlights the need for larger studies that definitively
measure the NGAL monomer. He adds, "If our results are confirmed, measuring urine
NGAL might help triage patients into different risk categories."
Fluoride can Harm Kidney Patients
The National Kidney Foundation withdrew its support of water fluoridation citing the 2006
National Research Council (NRC) fluoride report (A) indicating that kidney patients are
more susceptible to fluoride’s bone and teeth-damaging effects forcing the American
Dental Association (ADA) to admit on its web site that fluoride is a concern to kidney
patients. The kidney-impaired may retain and store more fluoride in their bones. High
bone-fluoride-levels are linked to skeletal fluorosis (a bone weakening disease),
fractures and severe tooth damage (enamel fluorosis) which can increase the risk of dental
decay, reports the NRC. Chronic kidney disease and bone fracture is already a growing
concern. Fluoride is added to US water supplies ostensibly to reduce tooth decay. Fluoride
is also in foods, beverages, (1) common antibiotics and dental products. The National
Kidney Foundation’s (NKF) (2) former fluoridation position statement also carried
surprising cautions. The NKF advised monitoring children’s fluoride intake along with
patients with chronic kidney impairment, those with excessive fluoride intake, and those
with prolonged disease. But NKF now admits, “exposure from food and beverages is
difficult to monitor, since FDA food labels do not quantify fluoride content.”
LSUHSC research shows for 1st time
infant inhalation of ultrafine air pollution linked to adult lung disease
Stephania Cormier, PhD, Associate Professor of Pharmacology at LSU Health Sciences Center
New Orleans, has shown for the first time that early exposure to environmentally
persistent free radicals (present in airborne ultrafine particulate matter) affects
long-term lung function. She recently presented her latest research data at the 11th
International Congress on Combustion By-Products and Their Health Effects at the
Environmental Protection Agency Conference Center in Research Triangle Park, N.C.Dr.
Cormier, a 2006 National Institute of Environmental Health Sciences Outstanding New
Environmental Scientist awardee, is conducting research to determine how inhalation
exposure to environmental factors such as allergens, pollutants, and respiratory viruses
during infancy leads to pulmonary inflammatory diseases, such as chronic obstructive
pulmonary disease (COPD) and asthma later in life. Using protein profiling techniques, Dr.
Cormier’s lab was able to determine that early exposure to these ultrafine pollutants
caused genes to produce a number of proteins, including one associated with COPD and
steroid-resistant asthma, and also caused proteins to misfold, rendering them
dysfunctional. These genetic defects are linked to structural changes in the lung, airflow
limitations, and permanent changes in immune responses. “It is no surprise that
elevations in airborne particulate matter (PM) are associated with increased hospital
admissions for respiratory symptoms including asthma exacerbations,” notes Dr.
Cormier. “What has come as a surprise is that early exposure to elevated levels of PM
elicits long-term effects on lung function and lung development in children.” These
results could be especially important because the US Environmental Protection Agency does
not currently regulate ultrafine PM emissions.
Fresh meats often contain additives
harmful to kidney disease patients
Uncooked meat products enhanced with food additives may contain high levels of phosphorous
and potassium that are not discernable from inspection of food labels, according to a
study appearing in an upcoming issue of the Clinical Journal of the American Society
Nephrology (CJASN). This can make it difficult for people to limit dietary phosphorous and
potassium that at high levels are harmful to kidney disease patients. Kidney disease
patients on dialysis must watch their intake of dietary phosphate so that their blood
phosphate levels do not rise. This is important because high blood phosphate levels may
cause premature death in dialysis patients. Kidney disease patients also must limit their
intake of potassium, because high blood potassium levels can cause sudden death. One
growing source of dietary phosphorous and potassium is through "enhanced" fresh
meat and poultry products. These foods are injected with a solution of water with sodium
and potassium salts (particularly phosphates) as well as antioxidants and flavorings.
While ingesting phosphates and potassium can be dangerous for dialysis patients, there is
no requirement that these ingredients be included in nutrition labels. There also have
been no studies on the levels of phosphates and potassium contained in fresh meat and
poultry products that have been "enhanced."
HIV infection and chronic drinking
have a synergistic, damaging effect on the brain
More than half of clinic patients infected with the human immunodeficiency virus (HIV)
report they also drink heavily. While highly active antiretroviral therapy has helped to
reduce HIV-related cognitive and motor deficits, neuropsychological deficits may continue
and even be exacerbated by alcohol. A study of memory deficits has found that HIV
infection and chronic alcoholism have synergistic, damaging effects on brain function.
Results will be published in the October issue of Alcoholism: Clinical & Experimental
Research and are currently available at Early View. "It has been consistently
documented that chronic heavy drinking results in cognitive and motor deficits,
particularly impairments in component processes of executive functions, memory,
visuospatial abilities, and speed of cognitive processing and motor movements," said
Edith V. Sullivan, professor in the department of psychiatry and behavioral sciences at
Stanford University School of Medicine and corresponding author for the study.
"Chronic heavy drinking co-occurring with HIV infection is highly prevalent, and the
separate and combined untoward effects on the brain and its processes can be significant
and disruptive of activities of daily living." This prevalence exists despite
considerable educational and prevention programs regarding both HIV and alcoholism, added
Sara Jo Nixon, a professor in the department of psychiatry at the University of Florida.
"Furthermore, their comorbidity constitutes an even greater health concern with
implications for treatment adherence, work and interpersonal skill maintenance."
Sullivan and her colleagues examined working and episodic memory in four groups (n=164)
– 40 individuals with HIV (28 men, 12 women), 38 with chronic alcoholism (24 men, 14
women), 47 with both HIV and chronic alcoholism (38 men; 9 women), and 39
"normal" controls (22 men, 17 women) – at baseline and then again at a
one-year follow-up. Measures included accuracy scores, response times, and rate of
information processing. "Individuals who are both positive for HIV and have a history
of chronic heavy drinking are at greater risk than individuals with only one of these
conditions to have trouble learning new information," said Sullivan. "This
difficulty in new learning can affect an individual's ability to use information important
to the successful completion of personal and work-related activities."
UTMB study identifies women at risk
of gaining excessive weight with injectable birth control
Researchers at the University of Texas Medical Branch at Galveston have identified women
who are likely to gain weight while using depot medroxyprogesterone acetate, more commonly
known as Depo-Provera or the birth control shot. These findings dispel the myth that all
women who use DMPA will gain weight and will help physicians to counsel patients
appropriately. DMPA users whose weight increased by 5 percent within the first six months
of use, called “early gainers,” are at risk of continued, excessive weight gain.
While 75 percent of users gained little or no weight, the early gainers averaged weight
gain of 24 pounds over three years. “DMPA-related weight gain is linked to increased
abdominal fat, a known component of metabolic syndrome, which raises the risk of
obesity-related conditions such as cardiovascular disease, stroke and diabetes,” said
corresponding author Dr. Abbey Berenson, professor in UTMB’s department of obstetrics
and gynecology.
Airway cells use 'tasting'
mechanism to detect and clear harmful substances
The same mechanism that helps you detect bad-tasting and potentially poisonous foods may
also play a role in protecting your airway from harmful substances, according to a study
by scientists at the University of Iowa Roy J. and Lucille A. Carver College of Medicine.
The findings could help explain why injured lungs are susceptible to further damage. The
study, published online July 23 in Science Express, shows that receptors for bitter
compounds that are found in taste buds on the tongue also are found in hair-like
protrusions on airway cells. In addition, the scientists showed that, unlike taste cells
on the tongue, these airway cells do not need help from the nervous system to translate
detection of bitter taste into an action that expels the harmful substance. The hair-like
protrusions, called motile cilia, were already known to beat in a wave-like motion to
sweep away mucus, bacteria and other foreign particles from the lungs. The study is the
first to show that motile cilia on airway cells not only have this "clearing"
function, but also use the receptors to play a sensory role. The researchers also found
that when the receptors detect bitter compounds, the cilia beat faster, suggesting that
the sensing and the motion capabilities of these cellular structures are linked.
Protein That Promotes Cancer Cell
Growth Identified
Scientists at Burnham Institute for Medical Research (Burnham) have found that the
Caspase-8 protein, long known to play a major role in promoting programmed cell death
(apoptosis), helps relay signals that can cause cancer cells to proliferate, migrate and
invade surrounding tissues. The study was published in the journal Cancer Research on June
15. The team of scientists, led by Kristiina Vuori, M.D., Ph.D., professor and director of
the Cancer Center at Burnham, showed that Caspase-8 caused neuroblastoma cancer cells to
proliferate and migrate. For the first time, Caspase-8 was shown to play a key role in
relaying the growth signals from epidermal growth factor (EGF) that cause cell division
and invasion. The researchers also identified an RXDLL amino acid motif that controls the
signaling from the EGF receptor through the protein kinase Src to the master cell
proliferation regulator protein, MAPK. This same signaling pathway stimulates
neuroblastoma cells to migrate and invade neighboring tissues--a critical process in
cancer metastasis. “Caspase-8 has a well defined role in promoting apoptosis,
especially in response to activation of the so-called death receptors on the outside of
cells,” said Darren Finlay, Ph.D., first author on the paper. “Although
Caspase-8 is involved in apoptosis, it is rarely deleted or silenced in tumors, suggesting
that it was giving cancer cells a leg up in some other way. Our studies suggest that
Caspase-8 does so by activating the MAPK pathway through Src.” Using immuno-blot
assays, the scientists showed that EGF signaling was absent in a cancer cell line that is
deficient in Caspase-8 and that EGF signaling can be restored by reconstituting the cells
with wildtype Caspase-8. Sequence homology studies helped to identify a RXDLL motif in the
protein, a sequence that has been shown in other proteins to function in cell signaling.
The researchers also used immune-blot assays to demonstrate that reconstituting the
Caspase-8 deficient cells with Caspase-8 with mutations in the RXDLL domain did not result
in EGF signaling. This suggests that Caspase-8 mediates signaling through the RXDLL
domain. The scientists had previously shown in another study that Caspase-8 associates
with Src, a protein known to be involved in cancer cell proliferation. In this study they
showed that interruption in this association disrupts EGF signaling indicating that
Caspase-8 exerts EGF signaling through Src.
Knee injuries may start with strain
on the brain, not the muscles
New research shows that training your brain may be just as effective as training your
muscles in preventing ACL knee injuries, and suggests a shift from performance-based to
prevention-based athletic training programs. The ACL, or anterior cruciate ligament, is
one of the four major ligaments of the knee, and ACL injuries pose a rising public health
problem as well as an economic strain on the medical system. University of Michigan
researchers studying ACL injuries had subjects perform one-legged squats to fatigue, then
tested the reactions to various jumping and movement commands. Researchers found that both
legs—not just the fatigued leg—showed equally dangerous and potentially
injurious responses, said Scott McLean, assistant professor with the U-M School of
Kinesiology. The fatigued subjects showed significant potentially harmful changes in lower
body movements that, when preformed improperly, can cause ACL tears. "These findings
suggest that training the central control process—the brain and reflexive
responses—may be necessary to counter the fatigue induced ACL injury risk," said
McLean, who also has an appointment with the U-M Bone & Joint Injury Prevention
Center.
Emphysema severity directly linked
to coal dust exposure
Coal dust exposure is directly linked to severity of emphysema in smokers and nonsmokers
alike, according to new research from the National Institute for Occupational Safety and
Health (NIOSH). "In this study we have shown that coal mine dust exposure is a
significant predictor of emphysema severity," said Eileen Kuempel, Ph.D., a senior
scientist at NIOSH and lead author of the study. The findings, which were reported in the
August 1 issue of the American Thoracic Society's American Journal of Respiratory and
Critical Care Medicine (AJRCCM), highlight a health problem related to a growing industry.
In the past 25 years, coal production has nearly doubled worldwide. Dr. Kuempel and
colleagues compared lung autopsy results from 722 individuals, including 616 coal miners
from West Virginia and 106 non-miners from West Virginia and Vermont. Those from West
Virginia were collected from consecutive autopsies from 1957 and 1973 at the Beckley
Southern Appalachian Regional Hospital as part of a black lung study. Those from Vermont
were taken from consecutive autopsies performed at the University of Vermont between 1972
and 1978. Age at death, race, miner/non-miner status and smoking history were established
where possible, and individual exposure to coal dust was estimated using work history data
and job-specific dust exposure estimates. Pathologists Francis Green, M.D., and Val
Vallyathan, Ph.D., two of the coauthors on this study, examined sections of the lungs to
determine the presence and extent of emphysema. A smaller subset of the study group had
their lung tissue analyzed for dust content. Emphysema was graded for type and severity.
Limited data suggest possible
association between Agent Orange exposure
A new report from the Institute of Medicine finds suggestive but limited evidence that
exposure to Agent Orange and other herbicides used during the Vietnam War is associated
with an increased chance of developing ischemic heart disease and Parkinson's disease for
Vietnam veterans. The report is the latest in a congressionally mandated series by the IOM
that every two years reviews the evidence about the health effects of these herbicides and
a type of dioxin -- TCDD -- that contaminated some of the defoliants. A finding of
"limited or suggestive evidence of an association" means that the evidence
indicates there could be a link between exposure to a chemical and increased risk for a
particular health effect, though conflicting results from studies, problems with how the
studies were conducted, or other confounding factors limit the certainty of the evidence.
Until now, the cumulative evidence had been inadequate to draw conclusions about whether
these two conditions may be associated with veterans' exposures to herbicides or TCDD.
Ischemic heart disease -- a condition characterized by reduced blood supply to the heart,
which can lead to heart attack and stroke -- is the foremost cause of death among people
in industrialized countries. Major risk factors include buildup of cholesterol in the
arteries, age, smoking, high blood pressure, and diabetes. The committee that wrote the
report reviewed several studies investigating TCDD exposure and heart disease, many of
which showed that higher TCDD exposure correlated with greater incidence of disease. The
studies had weaknesses; for instance, it is difficult to adjust entirely for the impact of
smoking, age, weight, and other common risk factors. But based on the preponderance of the
evidence as well as biologic data beginning to show how TCDD can cause this toxic effect,
the committee concluded
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