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The Addicted Brain: to Food to Booze… or to Anything Else…




Enviado por Felix Larocca



  1. Drugs
    to Die For
  2. Rheostat of Reward
  3. Dopamine, Please
  4. An
    Addiction Is Born
  5. Road
    to Relapse
  6. Learning Addiction
  7. A
    Common Cure?
  8. Freud
    had it right: Psychotherapy is the magic
    bullet!
  9. We
    just don"t have an answer
  10. Bibliography

White lines on a mirror. A needle and
spoon. For many users, the sight of a drug or its associated
paraphernalia can elicit shudders of anticipatory pleasure. Then,
with the fix, comes the real rush: the warmth, the clarity, the
vision, the relief, the sensation of being at the center of the
universe. For a brief period, everything feels right. But
something happens after repeated exposure to drugs of
abuse–whether heroin or cocaine, whiskey, sugar food, or
speed.

The amount that once produced euphoria
doesn't work as well, and users come to need a shot or a snort
just to feel normal; without it, they become depressed and,
often, physically ill. Then they begin to use the drug
compulsively. At this point, they are addicted, losing control
over their use and suffering powerful cravings even after the
thrill is gone and their habit begins to harm their health,
finances and personal relationships.

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Neurobiologists have long known that the
euphoria induced by drugs of abuse arises because all these
chemicals ultimately boost the activity of the brain's reward
system: a complex circuit of nerve cells, or neurons, that
evolved to make us feel flush after eating or sex–things we need
to do to survive and pass along our genes. At least initially,
goosing this system makes us feel good and encourages us to
repeat whatever activity brought us such pleasure.

But new research indicates that chronic
drug use induces changes in the structure and function of the
system's neurons that last for weeks, months or years after the
last fix. These adaptations, perversely, dampen the pleasurable
effects of a chronically abused substance yet also increase the
cravings that trap the addict in a destructive spiral of
escalating use and increased fallout at work and at home.
Improved understanding of these neural alterations should help
provide better interventions for addiction, so that people who
have become prey to habit-forming drugs or behaviors can reclaim
their brains and their lives.

Drugs to Die
For

The
realization that various drugs of abuse ultimately lead to
addiction through a common pathway emerged largely from studies
of laboratory animals that began about 40 years ago. Given the
opportunity, rats, mice and nonhuman primates will
self-administer the same substances that humans abuse. In these
experiments, the animals are connected to an intravenous line.
They are then taught to press one lever to receive an infusion of
drug through the IV, another lever to get a relatively
uninteresting saline solution, and a third lever to request a
food pellet. Within a few days, the animals are hooked: they
readily self-administer cocaine, heroin, amphetamine and many
other common habit-forming drugs. Others windup being just
fat.

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What is more, they eventually display
assorted behaviors of addiction. Individual animals will take
drugs at the expense of normal activities such as feeding
normally and sleeping–some even to the point that they die of
exhaustion or malnutrition. For the most addictive substances,
such as cocaine, animals will spend most of their waking hours
working to obtain more, even if it means pressing a lever
hundreds of times for a single hit. And just as human addicts
experience intense cravings when they encounter drug
paraphernalia or places where they have scored, the animals, too,
come to prefer an environment that they associate with the
drug–an area in the cage in which lever pressing always provides
chemical compensation — like the forays to the refrigerator in
the middle of the night searching for sugary things.

When the substance is taken away, the
animals soon cease to labor for chemical satisfaction. But the
pleasure is not forgotten. A rat that has remained clean–even
for months–will immediately return to its bar-pressing behavior
when given just a taste of cocaine or placed in a cage it
associates with a drug high. And certain psychological stresses,
such as a periodic, unexpected foot shock, will send rats
scurrying back to drugs. These same types of stimuli–exposure to
low doses of drug, drug-associated cues or stress–trigger
craving and relapse in human addicts. That"s exactly the trigger
that makes us fat.

Using this self-administration set-up and
related techniques, researchers mapped the regions of the brain
that mediate addictive behaviors and discovered the central role
of the brain's reward circuit. Drugs commandeer this circuit,
stimulating its activity with a force and persistence greater
than any natural reward.

A key component of the reward circuitry is
the mesolimbic dopamine system: a set of nerve cells that
originate in the ventral tegmental area (VTA), near the base of
the brain, and send projections to target regions in the front of
the brain–most notably to a structure deep beneath the frontal
cortex called the nucleus accumbens. Those VTA neurons
communicate by dispatching the chemical messenger
(neurotransmitter) dopamine from the terminals, or tips, of their
long projections to receptors on nucleus accumbens neurons. The
dopamine pathway from the VTA to the nucleus accumbens is
critical for addiction: animals with lesions in these brain
regions no longer show interest in substances of
abuse.

Rheostat of
Reward

Reward pathways are evolutionarily ancient.
Even the simple, soil-dwelling worm Caenorhabditis
elegans
possesses a rudimentary version. In these worms,
inactivation of four to eight key dopamine-containing neurons
causes an animal to plow straight past a heap of bacteria, its
favorite meal.

In mammals, the reward circuit is more
complex, and it is integrated with several other brain regions
that serve to color an experience with emotion and direct the
individual's response to rewarding stimuli, including food, sex
and social interaction. The amygdala, for instance, helps to
assess whether an experience is pleasurable or aversive–and
whether it should be repeated or avoided–and helps to forge
connections between an experience and other cues; the hippocampus
participates in recording the memories of an experience,
including where and when and with whom it occurred; and the
frontal regions of the cerebral cortex coordinate and process all
this information and determine the ultimate behavior of the
individual. The VTA-accumbens pathway, meanwhile, acts as a
rheostat of reward: it "tells" the other brain centers how
rewarding an activity is. The more rewarding an activity is
deemed, the more likely the organism is to remember it well and
repeat it.

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Although most knowledge of the brain's
reward circuitry has been derived from animals, brain-imaging
studies conducted over the past 10 years have revealed that
equivalent pathways control natural and drug rewards in humans.
Using functional magnetic resonance imaging (fMRI) or positron
emission tomography (PET) scans (techniques that measure changes
in blood flow associated with neuronal activity), researchers
have watched the nucleus accumbens in cocaine addicts light up
when they are offered a snort. When the same addicts are shown a
video of someone using cocaine or a photograph of white lines on
a mirror, the accumbens responds similarly, along with the
amygdala and some areas of the cortex. And the same regions react
in compulsive gamblers who are shown images of slot machines,
suggesting that the VTA-accumbens pathway has a similarly
critical role even in no drug addictions.

Dopamine,
Please

How is
it possible that diverse addictive substances–which have no
common structural features and exert a variety of effects on the
body–all elicit similar responses in the brain's reward
circuitry? How can cocaine, a stimulant that causes the heart to
race, and heroin, a pain-relieving sedative, food and sugar
supposedly to help us live, be so opposite in some ways and yet
alike in targeting the reward system? The answer is that all
substances of abuse, in addition to any other effects, cause the
nucleus accumbens to receive a flood of dopamine and sometimes
also dopamine-mimicking signals.

When a nerve cell in the VTA is excited, it
sends an electrical message racing along its axon–the
signal-carrying "highway" that extends into the nucleus
accumbens. The signal causes dopamine to be released from the
axon tip into the tiny space–the synaptic cleft–that separates
the axon terminal from a neuron in the nucleus accumbens. From
there, the dopamine latches onto its receptor on the accumbens
neuron and transmits its signal into the cell. To later shut down
the signal, the VTA neuron removes the dopamine from the synaptic
cleft and repackages it to be used again as needed.

Cocaine and other stimulants temporarily
disable the transporter protein that returns the neurotransmitter
to the VTA neuron terminals, thereby leaving excess dopamine to
act on the nucleus accumbens. Heroin and other opiates, on the
other hand, bind to neurons in the VTA that normally shut down
the dopamine-producing VTA neurons. The opiates release this
cellular clamp, thus freeing the dopamine-secreting cells to pour
extra dopamine into the nucleus accumbens. Opiates can also
generate a strong "reward" message by acting directly on the
nucleus accumbens, sugar, fat and savory things act in the same
manner.

But drugs do more than provide the dopamine
jolt that induces euphoria and mediates the initial reward and
reinforcement. Over time and with repeated exposure, they
initiate the gradual adaptations in the reward circuitry that
give rise to addiction.

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An Addiction Is
Born

The
early stages of addiction are characterized by tolerance and
dependence. After a drug or food binge, an addict needs more of
the substance to get the same effect on mood or concentration and
so on. This tolerance then provokes an escalation of drug use
that engenders dependence–a need that manifests itself as
painful emotional and, at times, physical reactions if
access to
a drug is cut off. Both tolerance and dependence occur because
frequent drug use can, ironically, suppress parts of the brain's
reward circuit.

At the heart of this cruel suppression lies
a molecule known as CREB (cAMP response element-binding protein).
CREB is a transcription factor, a protein that regulates the
expression, or activity, of genes and thus the overall behavior
of nerve cells. When drugs of abuse are administered, dopamine
concentrations in the nucleus accumbens rise, inducing
dopamine-responsive cells to increase production of a small
signaling molecule, cyclic AMP (cAMP), which in turn activates
CREB. After CREB is switched on, it binds to a specific set of
genes, triggering production of the proteins those genes
encode.

Chronic drug use causes sustained
activation of CREB, which enhances expression of its target
genes, some of which code for proteins that then dampen the
reward circuitry. For example, CREB controls the production of
dynorphin, a natural molecule with opium like effects. Dynorphin
is synthesized by a subset of neurons in the nucleus accumbens
that loop back and inhibit neurons in the VTA. Induction of
dynorphin by CREB thereby stifles the brain's reward circuitry,
inducing tolerance by making the same-old dose of drug less
rewarding. The increase in dynorphin also contributes to
dependence, as its inhibition of the reward pathway leaves the
individual, in the drug's absence, depressed and unable to take
pleasure in previously enjoyable activities.

But CREB is only a piece of the story. This
transcription factor is switched off within days after drug use
stops. So CREB cannot account for the longer-lasting grip that
abused substances have on the brain–for the brain alterations
that cause addicts to return to a substance even after years or
decades of abstinence. Such relapse is driven to a large extent
by sensitization, a phenomenon whereby the effects of a drug are
augmented.

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Although it might sound counterintuitive,
the same drug can evoke both tolerance and sensitization. Shortly
after a hit, CREB activity is high and tolerance rules: for
several days, the user would need increasing amounts of drug to
goose the reward circuit. But if the addict abstains, CREB
activity declines. At that point, tolerance wanes and
sensitization sets in, kicking off the intense craving that
underlies the compulsive drug-seeking behavior of addiction. A
mere taste or a memory can draw the addict back. This
relentless yearning persists even after long periods of
abstention. To understand the roots of sensitization, we have to
look for molecular changes that last longer than a few days. One
candidate culprit is another transcription factor: delta
FosB.

Road to
Relapse

Delta
FosB appears to function very differently in addiction than CREB
does. Studies of mice and rats indicate that in response to
chronic drug abuse, delta FosB concentrations rise gradually and
progressively in the nucleus accumbens and other brain regions.
Moreover, because the protein is extraordinarily stable, it
remains active in these nerve cells for weeks to months after
drug administration, a persistence that would enable it to
maintain changes in gene expression long after drug taking
ceased.

Studies of mutant mice that produce
excessive amounts of delta FosB in the nucleus accumbens show
that prolonged induction of this molecule causes animals to
become hypersensitive to drugs. These mice were highly prone to
relapse after the drugs were withdrawn and later made
available–a finding implying that delta FosB concentrations
could well contribute to long-term increases in sensitivity in
the reward pathways of humans. Interestingly, delta FosB is also
produced in the nucleus accumbens in mice in response to
repetitious nondrug rewards, such as excessive wheel running and
sugar (?) consumption. Hence, it might have a more general role
in the development of compulsive behavior toward a wide range of
rewarding stimuli.

The latter explains, why nothing is as
unstoppable as addiction as sugar…

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Recent evidence hints at a mechanism for
how sensitization could persist even after delta FosB
concentrations return to normal. Chronic exposure to cocaine and
other drugs of abuse is known to induce the signal-receiving
branches of nucleus accumbens neurons to sprout additional buds,
termed dendritic spines that bolster the cells' connections to
other neurons. In rodents, this sprouting can continue for some
months after drug taking ceases. This discovery suggests that
delta FosB may be responsible for the added spines. Highly
speculative extrapolation from these results raises the
possibility that the extra connections generated by delta FosB
activity amplify signaling between the linked cells for years and
that such heightened signaling might cause the brain to overreact
to drug-related cues. The dendritic changes may, in the end, be
the key adaptation that accounts for the intransigence of
addiction.

Learning
Addiction

Thus
far we have focused on drug-induced changes that relate to
dopamine in the brain's reward system. Recall, however, that
other brain regions–namely, the amygdala, hippocampus and
frontal cortex–are involved in addiction and communicate back
and forth with the VTA and the nucleus accumbens. All those
regions talk to the reward pathway by releasing the
neurotransmitter glutamate (a distant sugar"s cousin). When drugs
of abuse increase dopamine release from the VTA into the nucleus
accumbens, they also alter the responsiveness of the VTA and
nucleus accumbens to glutamate for days. Animal experiments
indicate that changes in sensitivity to glutamate in the reward
pathway enhance both the release of dopamine from the VTA and
responsiveness to dopamine in the nucleus accumbens, thereby
promoting CREB and delta FosB activity and the unhappy effects of
these molecules. Furthermore, it seems that this altered
glutamate sensitivity strengthens the neuronal pathways that link
memories of drug-taking experiences with high reward, thereby
feeding the desire to seek the drug. Here think of sugar and you
will see what I mean.

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The mechanism by which drugs alter
sensitivity to glutamate in neurons of the reward pathway is not
yet known with certainty, but a working hypothesis can be
formulated based on how glutamate affects neurons in the
hippocampus. There certain types of short-term stimuli can
enhance a cell's response to glutamate over many hours sugar
seems to do the same at a hypothalamic level. Remember; behind
all this chemical activity remain an active hypothalamus. The
phenomenon, dubbed long-term potentiation, helps memories to form
and appears to be mediated by the shuttling of certain
glutamate-binding receptor proteins from intracellular stores,
where they are not functional, to the nerve cell membrane, where
they can respond to glutamate released into a synapse. Drugs of
abuse influence the shuttling of glutamate receptors in the
reward pathway. Some findings suggest that they can also
influence the synthesis of certain glutamate
receptors.

Taken together, all the drug-induced
changes in the reward circuit that we have discussed ultimately
promote tolerance, dependence, craving, relapse and the
complicated behaviors that accompany addiction. Many details
remain mysterious, but we can say some things with assurance.
During prolonged drug use, after becoming obese and hooked on
sugar, and shortly after use ceases, changes in the
concentrations of cyclic AMP and the activity of CREB in neurons
in the reward pathway predominate. These alterations cause
tolerance and dependence, reducing sensitivity to the drug and
rendering the addict depressed and lacking motivation. With more
prolonged abstention, changes in delta FosB activity and
glutamate signaling predominate. These actions seem to be the
ones that draw an addict back for more–by increasing sensitivity
to the drug's effects if it is used again after a lapse and by
eliciting powerful responses to memories of past highs and to
cues that bring those memories to mind.

Back to memories of the last
"hartura" (or gorge) as it is known by my Spanish
speaking followers…

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The revisions in CREB, delta FosB and
glutamate signaling are central to addiction, but they certainly
are not the whole story. As research progresses, neuroscientists
will surely uncover other important molecular and cellular
adaptations in the reward circuit and in related brain areas that
will illuminate the true nature of addiction.

A Common Cure?

Beyond
improving understanding of the biological basis of drug
addiction, the discovery of these molecular alterations provides
novel targets for the biochemical treatment of this disorder. And
the need for fresh therapies is enormous. In addition to
addiction's obvious physical and psychological damage, the
condition is a leading cause of medical illness. Alcoholics are
prone to cirrhosis of the liver, smokers are susceptible to lung
cancer, overeaters to obesity at any and all ages, and heroin
addicts spread HIV when they share needles. Addiction's toll on
health and productivity in the U.S. has been estimated at more
than $300 billion a year, making it one of the most serious
problems facing society. If the definition of addiction is
broadened to encompass other forms of compulsive pathological
behavior, such as overeating and gambling, the costs are far
higher. Therapies that could correct aberrant, addictive
reactions to rewarding stimuli–whether cocaine or cheesecake or
the thrill of winning at blackjack–would provide an enormous
benefit to society.

Today's treatments fail to cure most
addicts. Some medications prevent the drug from getting to its
target. These measures leave users with an "addicted brain" and
intense drug craving. Other medical interventions mimic a drug's
effects and thereby dampen craving long enough for an addict to
kick the habit. These chemical substitutes, however, may merely
replace one habit with another. And although nonmedical,
rehabilitative treatments–such as the popular 12-step
programs–help many people grapple with their addictions,
participants still relapse at a high rate.

Freud had it
right: Psychotherapy is the magic bullet!

Armed with insight into the biology of
addiction, researchers may one day be able to design medicines
that counter or compensate for the long-term effects of drugs of
abuse on reward regions in the brain. Compounds that interact
specifically with the receptors that bind to glutamate or
dopamine in the nucleus accumbens, or chemicals that prevent CREB
or delta FosB from acting on their target genes in that area,
could potentially loosen a drug's grip on an addict.

Can Prozac help you kick cocaine? Can
Ritalin? How about a blood pressure pill or medicine for muscle
spasms?

If you're an alcoholic, could you get help
staying sober by taking an anti-nausea drug used by cancer
patients?

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We just don"t
have an answer

However, scientists are exploring those
questions right now. In fact, in the field of addiction medicine,
one of the hottest sources of new drugs is … old
drugs.

Despite years of research, there is no drug
approved in the United States for treating cocaine dependence. To
find such a treatment, the National Institute on Drug Abuse is
sponsoring human studies of 21 medicines already on the market
for something else. That's about two-thirds of all the potential
cocaine drugs being tested in people, says Frank Vocci, director
of NIDA's pharmacotherapy division.

Over at the National Institute on Alcohol
Abuse and Alcoholism, nearly all the potential alcoholism drugs
tested in people under institute sponsorship over the past 10
years were previously approved for some other use, says Raye
Litten, co-leader of the institute's medications development
team.

While the strategy is hardly new, "it's
been going on maybe just a bit below the radar screen" for most
of the public, Vocci said.

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It can certainly work. In 1997, for
example, the government approved a stop-smoking pill called
Zyban, which was in fact the older antidepressant Wellbutrin —
its effectiveness is not proven.

To be sure, experts haven't given up on
developing new drugs. Most NIAAA-funded drug studies for
alcoholism that are in early stage testing — not yet tried on
people — are brand-new drugs, Litten said.

But the notion of examining current drugs
for addiction-breaking potential holds several advantages. It's a
lot cheaper to get federal approval for a new use of an old drug
than to bring a completely new medicine to market. And experience
with an existing drug gives an idea of its safety and dose range
for possible anti-addiction effects, Vocci said.

He and others caution that people who
happen to have medications on hand that show promise in such
studies shouldn't give them to friends and family with addiction
problems. That must be left to professionals. Experts also say
that even effective anti-addiction medicines usually can't work
by themselves, but must be used along with non-drug
therapy.

The most straightforward approach to
testing an existing drug is to follow its approved purpose, but
in a different way. For example, some scientists are studying how
to prolong the effects of naltrexone, now usually given as a
daily pill for treating dependence on alcohol or opiates like
heroin and morphine.

Dr. David Gastfriend of Massachusetts
General Hospital and Harvard Medical School and other researchers
recently reported that specially formulated naltrexone helped
alcoholic men cut down on their drinking for a month when they
received the drug as a shot in the buttocks.

Why is a monthly visit to a doctor better
than just taking a pill every day?

"The pill requires a daily awareness that
this is a dangerous disease and a rational decision to take the
pill," Gastfriend said. "The problem with this illness is that on
any given day, a person can feel, 'No, it would be better if I
could drink.' So you take the pill the first day and you have to
make 29 more decisions" the rest of the month. And that in itself
is psychotherapy, as anyone that has used, in expert hands, it
can tell…

"But if you received an injection the first
day, those 29 decisions have already been made," said Gastfriend,
a paid consultant to Alkermes Inc., which is developing the
formulation he studied, called Vivitrex.

Emerging knowledge guides search

More striking than just reformulating a
drug is finding a new and apparently unrelated use for it. Here,
scientists are guided by emerging knowledge about how addiction
hijacks the brain.

Addicts apparently suffer from a
combination of unusually strong desire for a drug and a weak
inhibition against using it, Vocci said.

"These people essentially have a revved-up
engine and thin brake pads," he said.

In the brain, scientists have found that
cocaine and sugar produce euphoria by stimulating nerve circuits
that communicate with a substance called dopamine. So they've
looked for medications that can affect the activity of this
dopamine system.

One is a decades-old old drug called
baclofen (pronounced BAK-loe-fen), used to treat spasms, cramps
and muscle tightness in people with multiple sclerosis or spinal
problems. Steven Shoptaw, a researcher at the University of
California, Los Angeles, recently published a preliminary,
federally funded study that suggested it can cut cocaine use in
addicts. A much larger study is now under way to confirm that,
but for now the drug looks promising, Shoptaw said.

Other drugs that work in a similar way and
that are being tested in cocaine addicts include the anti-seizure
medications tiagabine, topiramate and a drug sold overseas as
Vigabatrin.

Cocaine withdrawal symptoms might be eased
by boosting the brain's depleted dopamine levels. So scientists
are studying dopamine-boosting drugs like Ritalin, potentially
itself addictive, used for attention deficit hyperactivity
disorder, and amantadine, found in chocolate, and used for flu
and Parkinson's disease.

But addiction is complicated enough to
involve many brain circuits, which in turn provide many targets
for anti-addiction drugs. Inderal, a blood-pressure medicine, may
reduce cocaine craving during early abstinence by interfering
with the actions of another brain substance, norepinephrine. The
antidepressants Prozac and Effexor, which boost levels of yet
another brain chemical called serotonin, are also under study in
cocaine dependence.

Then there's ondansetron (pronounced
on-DAN-se-tron), which is normally used to prevent nausea and
vomiting after cancer chemotherapy or surgery. Scientists are
studying it for both cocaine and alcohol abuse, again for its
action in the serotonin circuitry.

Antabuse found to help cocaine addiction

It might seem logical that a single drug
could help in multiple kinds of addiction, but even that
situation can come with a twist. Consider Antabuse, the
anti-alcohol drug that works by making users sick if they drink
alcohol. Scientists recently found, unexpectedly, that Antabuse
also helps cocaine-dependent people cut back on cocaine, though
not by making them sick.

Just how it does that isn't clear, says
researcher Dr. Thomas Kosten of Yale University. Antabuse hampers
the normal breakdown of cocaine by the body, and boosts dopamine
levels while reducing norepinephrine levels, he said. The net
effect may be to reduce both withdrawal symptoms and desire to
seek sugar and cocaine, he said.

Shoptaw thinks that within the next five
years, some drug will win approval for treating cocaine
dependence. Baclofen, topiramate and Antabuse lead his list of
candidates. Each may find a use in a different phase of cocaine
and sugar dependence, such as getting off the drug or staying
off, he said.

And addiction specialists are eagerly
looking beyond today's medicine cabinet toward a drug that isn't
approved for anything in the United States yet. Rimonabant blazed
into the headlines in March when researchers reported evidence
that it might (just, might) help people battle
both cigarette smoking and obesity.

But why stop there?

Rimonabant blocks the brain's docking sites
for its own marijuana-like substances, part of the "cannabinoid"
system that might play a role in addictions beyond food and
nicotine, says Dr. Herbert Kleber of Columbia
University.

Once the drug is approved for either
smoking or obesity, he expects researchers will jump in and test
it for things like heroin and cocaine.

And the strategy of squeezing new uses of
out existing drugs may score another success.

Meanwhile, obesity goes
on…

Bibliography

Furnished by request.

 

 

Autor:

Félix E. F. Larocca
MD

 

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