Information On Sickle-Cell Anemia
inherited disorder, primarily seen in African Americans and others of
African descent, sickle cell anemia is a serious but increasingly
manageable disorder. This article is a comprehensive look at the
genetics and diagnosis of, and treatments for Sickle-Cell Disease.
Is Sickle-Cell Disease?
is carried within the red blood cells by hemoglobin, a complicated
molecule composed of proteins and iron. Sickle-cell disease is caused
by a genetic defect in this important hemoglobin molecule. A normal
red blood cell contains a molecule called hemoglobin A; in a sickle red blood cell, a variant of this molecule
exists and is called hemoglobin
S (S for sickle). The difference between hemoglobin A (HbA) and
hemoglobin S (HbS) lies in only one protein out of about three hundred
that are common to both. This protein lies along an amino-acid chain
called beta-globin, where even a tiny abnormality has disastrous
sickle-cell disease process is triggered when red blood cells become
deprived of oxygen. In everyone -- both those with and without the
disease -- hemoglobin loses its oxygen in a number of ways. To sustain
life, oxygen regularly passes from red blood cells to the tissues
where it is needed to perform vital functions. Hemoglobin loses oxygen
if blood cells become too acidic, for example, after strenuous
exercise. Going to high altitudes or any stressful activity or
situation that increases the body's demand for oxygen depletes its
supply in red blood cells. Such situations do not affect normal red
blood cells that contain hemoglobin A. Oxygen loss from hemoglobin S,
however, causes the molecules to form rigid rods called polymers
that distort the red blood cell into a sickle or crescent shape. The
sickle cell also has a chemical on its surface that sticks to blood
vessel walls. As a result, these abnormally sickle-shaped, rigid, and
sticky blood cells cannot squeeze through the capillaries. They block
the flow of blood, depriving tissues and organs of oxygen. Loss of
oxygen contributes to episodes of pain called sickle-cell crises and
to both short- and long-term organ damage. Excessive acidity and the
abnormal shape of the sickle cell also cause water and potassium loss
from the cell, resulting in dehydration -- another destructive outcome
of this process. Fortunately, because it takes a relatively long time
to form the sickle-cell shape, most blood cells have traveled out of
the capillaries before they have time to be affected. Only about 20%
of all red blood cells polymerize and become sickle-shaped. Sickle
cells also have a shorter life span (10 to 20 days) than that of
normal red blood cells (90 and 120 days). Every day the body produces
new red blood cells to replace old ones, but sickle cells become
destroyed so fast that the body cannot keep up. The red blood cell
count drops, which results in anemia; this gives sickle-cell disease
its more common name -- sickle-cell anemia.
severity of sickle-cell disease generally depends on three factors:
the extent of oxygen loss; the concentration of hemoglobin within the
cell (the lower the better); and the presence of a protective molecule
called hemoglobin F (for fetal). Hemoglobin F is produced in everyone during fetal
development and for a short time after birth. Some persists throughout
life. In sickle-cell patients, hemoglobin F does not polymerize and
form sickle-shapes, so its red blood cells continue to function
normally. People with the sickle-cell gene who continue to carry some
fetal hemoglobin are better protected, therefore, from severe forms of
Gets Sickle-Cell Disease?
80,000 Americans have sickle-cell disease. About 9% of African
Americans have the trait, and an estimated one in 500 African American
and one in every 1,000 to 1,400 American Hispanic children are born
with sickle-cell disease itself. The high incidence of the sickle-cell
gene in these and other specific populations is due to its ability to
make red blood cells resistant to the malaria parasite. This natural
protection has made the HbS gene common in malaria-infested areas,
particularly Africa and parts of India and the Mediterranean. (About
40% of people in certain parts of Africa have the trait.) The
sickle-cell gene occurs also in people from South and Central America,
the Caribbean, and the Middle East. This protection against malaria,
however, is bestowed only on people who have the sickle trait and have
inherited just a single gene. Those who inherit both copies of the HbS
gene and develop sickle-cell disease are not even protected from
malaria; in fact, malaria is more serious in these individuals.
Are the Symptoms of Sickle-Cell Disease?
of Sickle-Cell Crisis
first day of the crisis is usually the worst, with pain in the arms,
legs, and back that is described as sharp, intense, and throbbing.
Shortness of breath is common. Children also often experience pain in
the abdomen, which is probably caused by spasm or gas. Pain in the
bones is common because blood obstruction can directly damage bone and
because bone marrow is where red blood cells are manufactured. Sudden
attacks of pain also commonly occur in the fingers or toes and in
other bones and joints. The liver may become enlarged, causing pain in
the upper right side of the abdomen. Nausea, abdominal pain, low-grade
fever, and increasing jaundice may occur when the liver is affected.
Males of any age may experience prolonged, sometimes painful
erections, a condition called priapism. Acute chest syndrome is a
particularly serious complication of sickle-cell crisis. Symptoms may
include rapid or labored breathing. Acute chest syndrome is usually
accompanied by infections in the lungs, which can be caused by
viruses, bacteria, or fungi; pneumonia is often present. Acute pain
often lasts for several days. A dull, aching pain usually follows,
which most often ends after several weeks, although it may persist
between crises. Generally, people can resume a relatively normal life
patients have few painful events; others may need to hospitalized many
times a year. Some patients can go months without a crisis and then
have a cluster of severe attacks. Painful episodes sometimes become
less frequent with increasing age.
Serious Is Sickle-Cell Disease?
damage and durability of sickle-cell disease occurs because the log
jam that sickle cells cause in the capillaries slows the flow of blood
and reduces the supply of oxygen to various tissues. Not only does
pain occur when body tissues are damaged by lack of oxygen, but
serious and even life-threatening complications can result from severe
or prolonged oxygen deprivation. Sickle-cell disease has a wide
spectrum of effects, which vary from patient to patient. In some
people, the disease may trigger frequent and very painful sickle-cell
crises that require hospitalization; in others, it may cause less
frequent and milder attacks.
Problems in Infants and Young Children with Sickle-Cell Disease
in Older Children and Adults
Acute Chest Syndrome. Acute chest syndrome, a very dangerous
component of the sickle-cell crisis, is associated with the highest
risk for death in older patients. The longer a patient survives, the
greater is the damage done by repetitive sickle-cell crises in the
chest and lungs. Blockage of blood vessels cuts off oxygen to the
bones and tissues in the chest and lung. Injuries in the bone can
cause severe pain. The airways in the lungs may narrow, causing severe
reductions in oxygen delivery. Destructive changes in the chest area
increase susceptibility to invading infectious agents, such as
viruses, bacteria, fungi, and parasites. Acute chest syndrome can be
fatal, particularly if the patient is not immediately given
supplementary oxygen. Infections frequently clear up if they are
limited to small areas of the lung, but if they spread, they can
progress very quickly and become life threatening.
Stroke. After acute chest syndrome, stroke is the most common
killer of patients with sickle-cell disease who are older than three.
Between 8% and 10% of patients suffer strokes, typically at about age
seven. Transfusions are proving to prevent a first stroke as well as
recurrence. Strokes are usually caused by blockages of vessels
carrying oxygen to the brain. Studies indicate that sickle-cell
patients are also at high risk for stokes caused by aneurysm, a
weakened blood vessel wall that can rupture and hemorrhage. Multiple
aneurysms are common in sickle-cell patients, but they are often
located where they can be treated surgically. Some experts, therefore,
believe that any patients who have neurologic symptoms should undergo
angiography, an invasive diagnostic technique useful for detecting
Complications from Anemia. Because of the short life span of
the sickle red blood cells, the body is often unable to replace red
blood cells as quickly as they are destroyed. This causes the anemia
that gives this disease its more common name. Although the anemia may
occasionally become severe and require transfusions, it is usually
manageable. Chronic anemia, however, reduces oxygen and increases the
demand on the heart to pump more oxygen-bearing blood through the
body. Eventually, this can cause the heart to become dangerously
enlarged, with an increased risk for heart attack and heart failure.
Kidney Failure. The kidneys are particularly susceptible to
damage from the sickling process. Kidney failure is another major
danger in older patients and accounts for 10% to 15% of deaths in
Infections. Infections are also common in older children and
adults with sickle-cell disease, particularly respiratory infections
such as pneumonia and osteomyelitis, a serious infection in the bone.
The organisms causing them, however, tend to differ from those in
young children. The incidence of pneumococcal infections decrease and
those caused by E. coli and
bacteria known as gram negative
organisms increase, which can still be extremely serious.
Problems in the Genital-Urinary Tract. Problems with
urination are very common, particularly uncontrolled urination during
sleep. Patients may have blood in the urine, although this is usually
mild and painless and resolves without damaging consequences. Males,
including children, with sickle-cell disease may also suffer from
priapism, which is a prolonged and painful erection. If priapism is
not treated, partial or complete impotence can occur in 80% of cases.
Problems in the Liver. Enlargement of the liver occurs in over
half of sickle-cell patients, and acute damage to this organ occurs in
up to 10% of hospitalized patients. People with sickle-cell disease
who receive transfusions may also contract viral hepatitis, an
infection of the liver, although screening of donated blood has
reduced this risk considerably.
Gallbladder Disease. About 30% of children with sickle-cell
disease have gallstones, and, by age 30, 70% of patients have them. In
most cases, gallstones do not cause symptoms for years. When symptoms
develop, patients may feel overly full after meals, have pain in the
upper right quadrant of the abdomen, or have nausea and vomiting.
Acute attacks can be confused with a sickle-cell crisis in the liver.
Ultrasound is usually used to confirm a diagnosis of gallstones.
Problems in the Bones and Joints. In some children with
sickle-cell disease, excessive production of blood cells in the bone
marrow causes bones to grow abnormally, resulting in long legs and
arms or misshapen skulls. Sickling can also cause bone loss --
particularly the top of the thigh bone -- and pain in the hands and
feet of children, which is known as the hand-foot syndrome.
Other Medical Complications. Patients who survive infancy are
subject to other medical problems, including impaired physical
development, gum disease, scarring of the retina, and leg sores.
and Social Impact
Is Sickle-Cell Disease Diagnosed?
Out Other D
Can Sickle-Cell Crises and Long Term Complications Be Prevented?
Measures for Children and Adults
help reduce the frequency and severity of a sickle-cell crisis,
patients and their caregivers should take constant precautions to
avoid oxygen loss and dehydration. Sufficient rest, warmth, and
increased fluid intake are the most important ongoing measures for
reducing pain and managing the disease. The patient should drink as
much water as possible each day to prevent dehydration. Female
patients may want to include cranberry juice to help prevent urinary
tract infections. Other conditions that contribute to crises include
illness, physical exertion, stress, increased oxygen needs (such as
from exercise, air travel, or being at high altitudes), and
environmental toxins and chemicals. When flying, the patient or
caregiver should be sure that the airline can provide oxygen.
Psychologic and Emotional Support. Stress reduction techniques
and relaxation methods appear to be helpful. One study showed that
when adult patients were trained in coping skills, they had less
negative thinking and reported less pain. Unfortunately, studies
indicate that most patients do not receive even basic supportive care
that could help reduce the anxiety and intensity of pain that occurs
when a sickle-cell crisis erupts.
Diet. Good nutrition is essential. It is important to have five
to nine daily servings of green, red, and yellow vegetables, fruits,
or juices that are rich in antioxidants and other important nutrients.
Studies on fish oil and soybean oil show they might make red blood
cell membranes less fragile, and possibly less likely to sickle,
although no studies have proven this definitively. Although the
benefits of vitamin and mineral supplements are also unproven, some
research indicates that zinc and magnesium may help. Patients should
take folic acid daily and may wish to take supplements of the
antioxidant vitamins E and C if the diet does not adequately supply
Relief for Mild Pain. For mild pain relief, common
medications such as acetaminophen (Tylenol) or the class of drugs
known as nonsteroidal anti*inflammatory drugs (NSAIDs) are often
sufficient. Aspirin is the most common NSAID, but there are many
others, including ibuprofen (Advil, Motrin) and naproxen (Naprosyn,
Aleve). Aspirin is not usually recommended for children because it can
aggravate abdominal pain.
Are Sickle-Cell Crises and Long-Term Complications Managed and
of Sickle-Cell Crisis
Treatment of Pain. Effective pain medications are available
to help reduce the severe pain of sickle-cell crises. Often, however,
patients are not given the treatment they require. Many patients,
their families, and even physicians are hesitant to use opioids
aggressively because of fear of addiction. This fear, however, is
nearly always unwarranted. Studies indicate that less than one in a
thousand people who take long-term narcotics to alleviate chronic pain
develop an addiction to the drug. A problem for adult patients is that
early phases of sickle-cell crisis can cause severe pain before test
results confirm the crisis. In such cases, health professionals may
question the patient's response and may withhold appropriate pain
medication and not repeat tests later on that would confirm the
crisis. Adult patients and parents of children with the disease should
insist on aggressive pain-relief treatment. If physicians show any
reluctance to administer medications after the onset of pain, they
should not hesitate to seek a more responsive health care
severe pain, the patient must be hospitalized and treated with strong
painkillers, usually opioids. Opioids are generally given orally to
adults and adolescents and intravenously to children, although older
patients with severe pain may also require intravenous administration.
Often the opioid meperidine (Demerol) is used for sickle-cell crises,
although some experts believe that it is not adequate and prefer
morphine for frequent or prolonged episodes of pain. Meperidine is not
as powerful as morphine, and, if used for prolonged periods, may cause
twitches, tremors, and disturbed mental states including seizures. The
most dangerous side effect of high doses of opioids, especially
morphine, is depression of breathing function. This can occur some
time after the drug has been administered, and so patients must be
watched closely and monitored during treatment. Other side effects
opioids are vomiting and nausea, itching, and problems urinating. If
the patient vomits or becomes nauseated, the physician may administer
prochlorperazine (Compazine). Devices are being tested to allow
patients to administer their own painkillers as needed.
of the potentially serious side effects of opioids, physicians are
constantly searching for safer and easier ways of reducing the
severity of pain of sickle-cell crises. Because experts believe that
inflammation is a major contributor to the pain of sickle-cell
disease, drugs that reduce inflammation are being studied.
Prescription-strength NSAIDs, including diflunisal (Dolobid) and
ketorolac (Toradol), have shown promise. Steroid hormone drugs are
commonly used to treat pain caused by inflamed muscles and joints, and
studies using these drugs along with opioids are reporting some
success with sickle-cell patients. Such drugs include
methylprednisolone (Medrol) and dexamethasone (Decadron, Hexadrol). In
one study, children who were given methylprednisolone and morphine had
a shorter period of severe pain and required less morphine to control
the pain than those given morphine alone. These children, however, had
more recurrent attacks after medication was withdrawn than those
treated with opioids alone. Because steroids can suppress the body's
infection fighters, they should not be given to patients with
bacterial infections or any serious medical complication.
Treatment of Acute Chest Syndrome. Acute chest syndrome is
associated with a partially collapsed lung and infection, both of
which can be dangerous and even life threatening. Blockage of blood
vessels in the chest wall causes injury to the bones, serious lung
infections, and loss of oxygen. Basic treatments include
administration of fluids, pain-relievers, and oxygen. Exchange
transfusion, which involves drawing out the patient's blood while
exchanging it for donor blood, may be used to reduce hemoglobin S
levels. This treatment might also reduce the risk of heart failure and
help prevent fat embolism, a rare life-threatening condition in which
fatty tissue from the bone marrow travels to blood vessels in the
lungs and cuts off oxygen. Transfusions may also be indicated for
patients with progressive lung damage from acute chest syndrome.
Regular transfusions are also proving to significantly reduce the risk
for a first stroke in high-risk children.
increase oxygen levels in children hospitalized for acute chest
syndrome, a simple breathing technique known as incentive spirometry
may be beneficial. A spirometer is a hand-held plastic device commonly
used by asthma patients to measure their lung capacity and by patients
after surgery to increase intake of oxygen. In one trial, children
with sickle-cell disease were asked to inhale and exhale into this
device every two hours during the day and when they were awake at
night until their chest pain subsided. This device forces more air
into the lungs, and researchers hoped it would prevent the serious
drop in oxygen levels and the risk for infection caused by acute chest
syndrome. Results were encouraging: children who used spirometry had
significantly lower rates of collapsed lung tissue and infections than
those who did not. This very inexpensive and simple treatment might
have beneficial long-term effects.
Treatment of Infection. When sickle-cell patients develop
infections, they are nearly always hospitalized immediately and
treated with high dose injections of antibiotics in order to prevent
septicemia -- the dangerous spread of the infection throughout the
body. Repeated hospitalizations are very disruptive for both children
and adults. Studies have found that older children whose fever is
below 38.5 degrees Celsius (101 degrees Fahrenheit) and who have no
serious infection or other complications may not need hospitalization.
Children who have more serious complications (higher fevers, severe
infection and pain, a history of pneumonia, and signs of dehydration)
should remain in the hospital. If osteomyelitis, an infection in the
bone, occurs, a six-week antibiotic course is needed, most of it
intravenous. An accurate diagnosis of osteomyelitis is sometimes
difficult to make, because bone damage from sickling can cause similar
symptoms. It is important, however, to confirm the presence of an
actual infection before administering antibiotics, because the
antibiotic treatment required for osteomyelitis is so intensive and
prolonged. Urinary tract infections may be difficult to manage and can
be a serious problem for pregnant women with sickle-cell disease.
Physicians should take a urine culture before beginning antibiotic
treatment and another culture one to two weeks after treatment to be
sure the infection has cleared up.
for Other Complications of Sickle-Cell Disease
physicians are concerned about giving continual transfusions to every
sickle-cell patient whose ultrasounds indicate risk. Because
ultrasound is not accurate enough to predict which patients will have
a stroke, many who would never experience one will endure transfusions
and iron chelation therapy for years. An automated procedure for
exchanging red blood cells called erythrocytapheresis may limit iron
overload and provide an alternative to transfusions in some patients.
More research on this procedure is needed, however. Until diagnostic
tests can be more precise in determining risk, or there are effective
alternative treatments to transfusions, patients and their caregivers
and physicians must make the best decisions they can.
children who have had a stroke, rehabilitation and rehydration are
extremely important. Transfusions are administered at regular
intervals to prevent further damage and recurrence.
Kidney Problems. ACE inhibitors are drugs commonly used to
control high blood pressure that have been known to slow progression
of kidney failure in people with diabetes. Studies are now reporting
that these drugs might be beneficial in preventing hypertension and
kidney failure in sickle-cell patients. Such drugs include captopril (Capoten),
enalapril (Vasotec), quinipril (Accupril), benazepril (Lotensin), and
lisinopril (Prinivil, Zestril).
Anemia. Folic acid is given to help treat the anemia that
occurs in patients with sickle-cell disease.
Leg Sores Leg sores occur in up to 10% of sickle-cell
patients and usually affect patients older than 10 years. They are
difficult to treat, and, at this time, simple treatment with a moist
dressing provides the best results. To treat mild ulcers, the leg
should be gently washed with cotton gauze soaked in mild soap or a
solution of one tablespoon household bleach to one gallon of water. A
dressing soaked in diluted white vinegar may be applied every 3 to 4
hours. The leg should be elevated and bed rest for a week or more is
sometimes required for severe ulcers. Topical antibiotics, saline or
zinc oxide dressings, or cocoa butter or oil are also used depending
on severity. Skin grafts and transfusions have been helpful in some
Priapism. Priapism -- prolonged and sometimes painful
erections -- must be treated to prevent partial or complete impotence,
which can result from erections that last several hours to days.
Exchange transfusions may be used to reduce the hemoglobin S and
sickling that cause this condition. A surgical procedure that implants
a shunt to redirect blood flow is sometimes performed. Inflatable
penile implants may help maintain potency without causing priapism.
One study suggests that treatment with the drug leuprolide can prevent
repetitive and prolonged episodes of priapism in severely affected
teenage boys with sickle-cell disease; further research is required,
Pregnancy. Women who are pregnant should be treated at a
high-risk clinic. They should take folic acid in addition to
multivitamins and iron. Standard treatment is given for sickle-cell
crises, which may occur more frequently during pregnancy.
Are the Treatments Aimed at Sickle-Cell Disease Itself?
stimulation of production of healthy fetal hemoglobin in order to
inhibit the sickling process
therapy is also being studied, although effective treatments of this
kind are still years away.
of Fetal Hemoglobin
Hydroxyurea. To date, the most promising drug is hydroxyurea
(Droxia), which is currently used to prevent acute sickle-cell crises,
though it does not help once pain has begun. One trial reported that
hydroxyurea reduced the intensity and frequency of sickle-cell crises
by nearly 50%. Small studies of patients who have been using the
treatment for several years indicate that the drug may also may
improve spleen function, which aids in the immune process,
particularly in children. Hydroxyurea also increases water content in
red cells, which may add to its beneficial qualities. The drug also
reduces the number of neutrophils -- the white blood cells that
contribute to the process causing sickled cells to stick to the blood
vessel walls. This effect may actually be more protective against
sickle-cell crises over time than an increase in hemoglobin F. In some
patients, the drug may cause dark discoloration of the nails.
Continued monitoring of hemoglobin F has been recommended by some
experts who believe that the drug should be discontinued if there is
no increase in hemoglobin F within six months. Successful results
appear to depend on a number of conditions: the ability of the bone
marrow's ability to withstand the stress of the treatment; genetic
factors that affect hemoglobin F production; patient compliance; and
other biologic factors.
currently recommend that hydroxyurea be limited to adults with
moderate to severe recurrent, painful crises and to those who have
experienced at least three crises during the last year. Although small
studies show promise for the drug's use in children, its long term
benefits, risks, and effects on longevity are not yet known.
Laboratory studies indicate that it causes genetic changes and so may
increase the risk for cancer and birth defects. It should be pointed
out that one five-year follow-up study found no difference in survival
rates between those taking hydroxyurea and those on placebo (dummy
pills). In addition, one survey reported that there was no difference
over one month in how patients on hydroxyurea and those on placebo
recalled their experiences of pain.
Butyrate. Another drug, arginine butyrate, induces expression
of a gene known as gamma-globin, which stimulates hemoglobin F.
Results of early trials have been conflicting. In one 1998 study,
administration of butyrate using intermittent pulses increased HbF
levels to over 20% from a starting point of 2% of baseline.
to Prevent of Dehydration
are studying the mechanisms behind cell membrane damage, dehydration,
and potassium loss in order to develop drugs that will inhibit these
processes. Clotrimazole, commonly used in ointments (Lotrimin, Mycelex)
to treat fungal skin infections, stops potassium from leaving red
blood cells and prevents the entry of calcium. Very early studies
using an oral form of clotrimazole have been promising, but much more
research is needed. Nitrendipine (Baypress), another drug being
studied, prevents dehydration by blocking calcium's entry to red blood
cells. In laboratory studies, magnesium protected against potassium
and water loss in sickle-cells; small patient and animal studies are
reporting promise for its use in preventing dehydration and increases
in the hemoglobin S concentration.
or Stem-Cell Transplantation
marrow transplant carries its own dangers and limitations. About 10%
of those treated die from the treatment. Drugs that destroy bone
marrow and suppress immunity must be administered before the procedure
so that the body's immune system does not attack the transplanted
tissue. Nonetheless, transplanted cells which come from a donor
(called allogenic grafts) may attack the patient's own tissues, a
potentially fatal condition called graft-versus-host disease (GVHD).
Other very serious complications include bleeding, pneumonia, and
severe infection. Those who live but are not cured face long-term
problems caused by the drugs used in transplantation and by the
disease itself. Even in those who are cured, long-term consequences
may include a higher risk for cancer and infertility. To be a
candidate for bone marrow transplant, patients must be under age
sixteen and have severe symptoms but no long term organ or neurologic
damage and genetically matched siblings who will donate their marrow.
At this time only 1% to 2% of all sickle-cell patients meet all these
criteria. Experts hope that better diagnostic techniques will identify
more patients at an early age who are at high risk for developing
serious sickle-cell disease and in whom the benefits of
transplantation would outweigh the risks.
use of umbilical cord blood and cells from placentas is showing
promise for providing healthy stem cells to patients who do not have
genetically matched donors for bone marrow transplant. Cord blood has
certain advantages over stem cell transplantation, including the
capacity to produce more cells quickly. Because immune factors in cord
blood are immature, the risk and severity of graft-versus-host disease
(GVHD) may be reduced.
Investigative Treatments for Sickle-Cell Disease
L-Glutamine. L-glutamine is an ordinary amino acid that is
heavily used by sickle cells. One study using supplements of this
substance reported that after a month it caused changes in the blood
that might prove to have benefits for sickle-cell patients.
Gene Therapy. Some researchers are focusing on therapies that
transfer certain genes to bone marrow that might prevent the sickling
process. One unique form of gene therapy for sickle-cell disease
involves actually repairing existing defective genetic material to
restore production of healthy hemoglobin. Even if any of these
therapies are successful, however, widely available treatments are
still years away.
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