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Humor
-- By Martin Burke
A "dunce" award goes to Spain's Paralympic basketball
team. The
Paralympic events were held in Sydney and were for athletes with
disabilities.
According to other athletes and journalists, Spain provided perfectly
healthy athletes so they could win the medals but who, none the less,
lost
the events to the truly disabled athletes.
The Olympic federation doesn't test Paralympic athletes to make sure
they
are truly disabled.
Ananova 24-Nov-00
<http://www.ananova.com/news/story/sm_125309.html?nav_src=newsIndexHeadline>
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Witty Words of Wisdom
Accept that some days you're the pigeon, and some days you're the statue.
Always keep your words soft and sweet, just in case you have to eat them.
Always read stuff that will make you look good if you die in the middle of it.
Be wary of strong drink. It can make you shoot at tax collectors, and miss.
Cooking lesson #1: don't fry bacon in the nude.
Drive carefully. It's not only cars that can be recalled by their maker.
Eat a live toad in the morning and nothing worse will happen to you for the rest of the day.
If life gives you lemons, squeeze the juice into a watergun and shoot other people in the eyes.
If you're not part of the solution, be part of the problem!
If you can't be kind, at least have the decency to be vague.
If you can't beat your computer at chess, try kickboxing.
If you lend someone $20, and never see that person again, it was probably worth it.
If you think nobody cares if you're alive, try missing a couple of car payments.
If you try and don't succeed, cheat. Repeat until caught. Then lie.
It may be that your sole purpose in life is simply to serve as a warning to others.
Never buy a car you can't push.
Never eat yellow snow.
Never pet a burning dog.
Never put both feet in your mouth at the same time, because then you don't have a leg to stand on.
Never try to teach a pig to sing. It wastes your time and annoys the pig.
Nobody cares if you can't dance well. Just get up and dance.
The early worm gets eaten by the bird, so sleep late.
There are very few personal problems that cannot be solved through a suitable application of high explosives.
There are very few problems that cannot be solved by orders ending with 'or die.' - Alistair J.R. Young
When everything's coming your way, you're in the wrong lane.
You are what you eat. So stay away from the jerk chicken.
Be nice to the nerds and geeks in high school -- you'll be working for
them in the future.
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The child comes home from his first day at school.
His mother asks, "Well, what did you learn today?"
The kid replies, "Not enough. They want me to come back tomorrow."
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Pregnancy Questions and Answers
Q. Should I have a baby after 35?
A. No, 35 children is enough.
Q. I'm two months pregnant now. When will my baby move?
A. With any luck, right after he finishes college.
Q. How will I know if my vomiting is morning sickness or the flu?
A. If it's the flu, you'll get better.
Q. What is the most common pregnancy craving?
A. For men to be the ones who get pregnant.
Q. My wife is five months pregnant and so moody that sometimes she's borderline irrational.
A. So what's your question?
Q. How long is the average woman in labor?
A. Whatever she says divided by two.
Q. My childbirth instructor says it's not pain I'll feel during labor, but pressure. Is she right?
A. Yes, in the same way that a tornado might be called an air current.
Q. When is the best time to get an epidural?
A. Right after you find out you're pregnant.
Q. Is there any reason I have to be in the delivery room while my wife is in labor?
A. Not unless the word "alimony" means anything to you.
Q. Does pregnancy cause headaches?
A. Pregnancy causes anything you want to blame it for.
Q. Do I have to have a baby shower?
A. Not if you change the baby's diaper very quickly.
Q. Our baby was born last week. When will my wife begin to feel and act normal again?
A. When the kids are in college.
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A distraught man went to a psychiatrist and exclaimed,-"Doctor, I believe
that I am possessed by an evil spirit!"
After talking to the patient at some length, the psychiatrist said, "You do appear to have a problem. I'd like to see you again next Wednesday."
After a second session of psychotherapy, the psychiatrist pronounced his patient cured.
For the next nine months, the psychiatrist sent the man a monthly statement
for his professional services, but the man wouldn't pay and refused to
acknowledge the
debt.
Finally, the psychiatrist had no choice and took the man to court. He
had him repossessed...
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As the family gathered for a big dinner together, the youngest son
had an announcement to make: He'd just signed up at an army recruiter's
office.
There were audible gasps around the table, then some laughter, as his older brothers shared their disbelief that he could handle this new situation.
"Oh, come on, quit pulling our legs," snickered one: "You didn't really do that, did you?"
"I'm positive you'd never get through basic training," scoffed another.
The new recruit looked to his mother for help; but she was just gazing at him.
When she finally spoke, it was to voice a single question: "Do you really
plan to make your own bed every morning?"
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It's is not, it isn't ain't, and it's it's, not its, if you mean it
is. If you don't, it's its. Then too, it's hers. It isn't her's.
It isn't our's either. It's ours, and likewise yours and theirs.
- Oxford University Press, Edpress News
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World's shortest blues song:"I didn't wake up this morning...
"I opened a veterinary clinic next door to a dentist's office.Afterward I received a card from my neighbor signed, "From someonewho treats canines to another.
"It's no use having a good memory unless you have something good to remember.
My mind contains many good ideas, but it is not always easy to squeeze one out.
There is a guaranteed way to get what you want: want less.
"I told the doctor I broke my leg in two places. He told me to quit
going to those places."
- Henny Youngman
Did you hear about the self help group for compulsive talkers? It's
called On & On
- Anon.
If you can't be kind, at least have the decency to be vague.
First National Bank of Dad. Sorry, Closed.
Don't drink and drive. Instead, the next time you get too drunk to drive, walk into a local Domino's and order a pizza. Then when they go to deliver it, ask for a ride home.
Did you know that it costs forty thousand dollars a year to house each prisoner? Jeez, for forty thousand bucks a piece, I'll take a few prisoners into my house.
I live in Los Angeles. I already havebars on the windows.
I have wondered at times what the Ten Commandments would have looked
like if Moses had run them through the US congress.
- Ronald Reagan
Waiter: Would you like your coffee black?
Customer: What other colors do you have? Sometimes I wonder whether
the world is being run by smart people who are putting us on or by imbeciles
who really mean it. It is well documented that for every mile that you
jog, you add oneminute to your life. This enables you at 85 years
old to spend an additional 5 months in a nursing home at $5000 per month.
If you don't know where you are going, you can never get lost.-Herb Cohen
The American Way:Using instant coffee to dawdle away an hour. When I finished
school, I took one of those career aptitude tests,and based on my verbal
ability score, they suggested I become a mime.- Tim Cavanagh If he asks
what sort of books you're interested in, tell him the checkbook. A great
way to lose weight is to eat naked in front of a mirror. Restaurants will
almost always throw you out before you can eat too much. Keyboard Not Found
- Press [F1] to Continue.
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Mid-life (for women) is....
Mid-life is when you go to the doctor and you realize you are now so
old, you have to pay someone to look at you naked.
Mid-life women no longer have upper arms, we have wingspans...we are no longer women in sleeveless shirts, we are flying squirrels in drag.
Mid-life has hit you when you stand naked in front of a mirror and can see your rear end without turning around.
You know you are getting old when you go for a mammogram and you realize it is the only time someone will ask you to appear topless in film.
You know you've crossed the mid-life threshold when you're in the grocery store and you hear a Muzak version of "Stairway to Heaven" in the produce department.
Mid-life is when you bounce (a lot), but you don't bounce back.
(It's more like Splat!)
Mid-life brings the wisdom that life throws you curves...and that you're now sitting on your biggest ones.
It's very hard to "get jiggy with it" in mid-life... jiggly, yes; jiggy, no.
Mid-life is when your 1970s Body-by-Jake now includes Legs-by-Rand McNally.(more red and blue lines than an accurately scaled map of the state of Wisconsin).
Mid-life is when you want to grab every firm young lovely in a tube top and scream, "Listen, honey, even the Roman Empire fell, and those things will too!"
Mid-life can bring out your angry, bitter side. You look at your latte-swilling, beeper-wearing know-it-all teenager and think, "For this I have stretch marks?"
Mid-life is when your memory really starts to go. The only thing you still retain is water.
You become more reflective in mid-life. You start pondering the "big"
questions-- what is life, why am I here...how much Healthy Choice ice cream
can I eat before it's no longer a healthy choice?
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Things you don't want to hear during surgery:
Better save that. We'll need it for the autopsy.
Someone call the janitor - we're going to need a mop
"Accept this sacrifice, O Great Lord of Darkness"
Spot! Spot! Come back with that! Bad Dog!
Wait a minute, if this is his spleen, then what's that?
Hand me that...uh...that...uh.....thingie
Oh no! I just lost my Rolex.
Oops! Hey, has anyone ever survived 500ml of this stuff before?
Damn, there go the lights again...
"Ya know, there's big money in kidneys. Hell, the guy's got two of
'em."
Everybody stand back! I lost my contact lens!
Could you stop that thing from beating; it's throwing my concentration
off.
What do you mean he wasn't in for a sex change...!
Anyone see where I left that scalpel?
This patient has already had some kids, am I correct?
Nurse, did this patient sign the organ donor card?
Don't worry; I think it's sharp enough.
What do you mean "You want a divorce"!
She's gonna blow! Everyone take cover!!!
FIRE! FIRE! Everyone get out of here!
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My arm started to hurt me so I asked the doctor to
examine it.
She looked at my arm and brought out a medical book
and studied it for 15 minutes. Then she said to me,
"Have you ever had that pain before?"
I said, "Yes."
She said, "Well, you've got it again."
A Frataxin article translation
-- By Fanny Chagnon
ROLE OF FRATAXIN IN FRIEDREICH’S ATAXIA
by Pierre Rustin
From Espoir no. 81
Frataxin:
a mitochondrial protein
The mitochondrial localization of frataxin was established by numerous experiments and is now well established. However, the analysis of the structure and composition of frataxin did not permit to elucidate its exact role in the mitochondria. Only proteins involved in frataxin maturation have been found to interact with it, potential partners in a metabolic pathway in the mitochondria have not been found.
Many hypotheses have been emitted regarding the role of frataxin in the mitochondria. Studies led in yeast, which has a frataxin counterpart, concluded that frataxin was implicated, one way or another, in the stocking or transport of iron atoms in the mitochondria. In addition, iron deposits have been found in the cardiomyocytes of FA patients.
The conclusions from the yeast studies have been generalized to superior organisms as well as the human pathology. However, it must be kept in mind that iron metabolism might be different among the organisms. The iron regulation mechanisms have changed throughout evolution with the apparition of new genes and new functions. For example, the molecule that stocks iron in the mammal’s cell’s cytosol, ferritin, does not exist in yeast. The very complex system that regulates iron import in the cells varies greatly from one organism to the next, and also from one organ to the next. All this shoes that the precise organization and the regulation of iron metabolism varies greatly from one organ and one organism to the next. Thus, it is wise to avoid generalizing too quickly the results obtained in yeast to the human situation.
As indicated above, frataxin is probably implicated in iron metabolism, and possibly in iron transport in the mitochondria. Since mitochondria play a very important role in numerous cellular functions, the transport of different substances in the mitochondria is very closely regulated. Depending on the imported substance, regulation mechanisms are very different and also vary from one organ to the next. The mitochondrion is particularly permeable to metallic cations, such as iron. The transport of iron depends on the activity of the mitochondrial respiratory chain. The import of iron has only been studied in rat liver mitochondria, and those studies suggest the existence of many iron transporters. Very little is known about those transporters, and the idea that frataxin might play a role in the regulation of iron transport in the mitochondria recently stimulated the beginning of many studies. Those studies enabled the discovery of a new function for mitochondria. It has long been known that all cells possess different proteins that use iron and sulphur to function, reunited in an iron-sulphur centre, thus their name, proteins with an iron-sulphur centre. Those proteins play different roles in the cell. There are many in the mitochondria, particularly in the respiratory chain. It has just been shown that the iron-sulphur centres are assembled in the mitochondrion, to be used within or outside (in the cytosol) the mitochondria. As we will see later, those iron-sulphur proteins are defective in certain cells of FA patients.
The idea that frataxin could play a direct role on the control of iron transport in the mitochondria comes from the observation that yeast mutated in the gene equivalent to frataxin accumulate iron, probably at the expense of iron normally present in the cytosol. In yeast, where there is no iron stocking system, this metallic cation could normally be stocked in the mitochondria to be later used by the cell. To explain abnormal iron accumulation, it has been proposed that the loss of frataxin leads to a blockage of iron export from the mitochondrion to the cytosol. In humans, since the mitochondria do not seem to be the iron-stocking place, that is ferritin’s role, it has been proposed that frataxin is responsible for iron import in the mitochondria. Whatever hypothesis is true, the absence of frataxin will lead to abnormal iron accumulation in the mitochondria, at the expense of the iron normally present in the cytosol. In humans, the lack of iron in the cytosol will cause a series of modifications in the state and activity of iron import systems, in the cell this time. The cytosol possesses a system that checks if iron quantities are sufficient. This system is in fact a protein called cytosol aconitase. This protein has two forms, aconitase and IRP (Iron Responsive Protein). When there is a lot of iron, the protein is under the form aconitase, and when there is little iron, it is under the form IRP. The IRP will bind to the IRE (Iron Responsive Element) present on the messenger RNA (mRNA) implicated in iron use in the cell. Depending on the localization of the IRE on the mRNA, IRP will stabilize the mRNA by protecting it from degradation enzymes (in the case of mRNAs coding for iron transporters«), or it will reduce the mRNAs utilization (in the case of iron stocking proteins). Thus, when iron is missing in the cytosol, aconitase is in the IRP form, and the cells will have a tendency to absorb more and more iron, and without frataxin, the iron will accumulate in big quantities in the mitochondria.
That idea that frataxin controls iron transport in the mitochondria comes from the observation that iron accumulates when frataxin is missing or is in reduced quantities. However, recent results could shatter this hypothesis. First, it is possible to accumulate even bigger quantities of iron in yeast by modifying other genes, without observing the same effect in the mitochondria. Inversely, some yeasts, in which frataxin has been inactivated, do not accumulate iron but their mitochondria are not working properly. Also, mice that do not have frataxin at all, the animal model for FA, die in utero without abnormal iron accumulation.
It seems that iron can accumulate in the mitochondria without leading to a deficiency in iron-sulphur proteins, which is what is observed when frataxin is absent. On the other hand, the absence of frataxin does not necessarily lead to iron accumulation. Apparently, there is not a simple relation between an absence of frataxin and iron accumulation in the mitochondria. This suggests that frataxin is not involved directly in iron transport, but that iron accumulation is a secondary phenomenon. The fact that iron-sulphur proteins have less activity could depend more on the iron state in the mitochondria than on iron quantities, and frataxin could be involved in the stocking and/or the usage of iron in mitochondria, to allow iron-sulphur protein synthesis.
The iron, whether free or bound to small molecules (iron chelators) is extremely toxic. In fact, it reacts directly with oxygen to produce free radicals, also very toxic for the cell. A decrease in the quantity of a protein involved in iron stockage could have harmful consequences for the cell, identical to what is observed in FA, thus the idea that frataxin could play such a role. Initial observations that frataxin does not have an iron-binding domain led to the rejection of that hypothesis. But recently, it has been demonstrated that frataxin could react to the presence of iron by forming spherical complexes (up to 60 frataxin molecules reunited) in which iron would accumulate. If that observation is confirmed, those frataxin complexes could act as a stocking room for iron, and the iron present would then be less toxic. The absence of frataxin could then lead to a decrease in the iron-sulphur proteins’ activity, without really leading to iron accumulation.
The loss of the iron-sulphur proteins is very specific and characteristic of the biochemical defect observed in FA. That is observed in particular in cardiomyocytes at the firsts stages of the disease. Many hypotheses can account for the specific defect in iron-sulphur proteins.
· First, by modulating iron transport in the mitochondria, thus its quantity, frataxin could control toxic reactions depending on iron presence, particularly free radical production. The iron-sulphur centres of proteins are very easily destabilises by free radicals, so a decrease in specific activity of those proteins will be observed. However, there is no simple relation between the quantity of iron present and the consequences of frataxin levels decrease so the first hypothesis is probably not true.
· Second, if frataxin plays a role in the stocking of iron, a decrease in frataxin could stop the production of free radicals, thus stop the destruction of iron-sulphur proteins.
· Third, frataxin could play a direct role in the synthesis of iron-sulphur proteins, by enabling a correct usage of iron in the mitochondria.
This last hypothesis is very attractive because it explains most of the observations made. So the iron imported in the mitochondria would not be stocked, but used for the synthesis of the proteins that need iron to function, such as the iron-sulphur proteins.
Frataxin is found in many organisms, from bacteria all the way to mammals, without major structural changes. This suggested that it could play the same role in all those organisms. However, inactivation of the frataxin gene does not always lead to the same consequence. In the bacteria Escherichia coli, the absence of frataxin does not lead to iron accumulation or to sensitivity to free radicals. In mutated yeasts though, we observe an iron accumulation, a decrease in mitochondrial enzymes activity (particularly iron-sulphur proteins), and a greater sensitivity to free radicals. Lastly, in human, a decrease in frataxin leads initially to a loss of iron-sulphur proteins’ activity. Then, as the disease progresses, more defects occur with the accumulation of iron in the mitochondria.
Surprisingly, the specific loss of iron-sulphur protein’s activity observed in cardiomyocytes and in the nervous system is not found in the muscles, nor in blood cells or in skin cells, and we do not really know why. The fact that the biochemical defect is observed only in the heart and nervous system explains why it took so long to elucidate the origins of the disease.
Now that the mitochondrial origin of the disease is known, and that the mechanisms are more or less understood, it is possible to look for strategies to stop the progression of the disease.
Whichever mechanism leads to iron toxicity in the cells in the disease, it is now known that iron plays a major role in the development of the disease. The simplest strategy would then be to decrease iron levels. This can be done by using iron chelators, such as desferrioxamin or desferal. However, such a strategy leads to many problems. First, if iron accumulates in the mitochondria, it seems it is missing in the cytosol. Nobody knows the consequence of this. The use of a chelator could increase this problem, and it is not even certain that chelators can reduce iron levels in the mitochondria. On the other hand, in has been shown in vitro that if chelators can protects membranes against iron toxicity, they can also increase the destruction of soluble proteins by iron. Aconitase, which is already low in FA patients, is one of those soluble proteins. So the idea of using chelators has been abandoned because of the possibly severe side effects.
Because of the increase in free radical, linked to iron accumulation, another strategy based on the use of anti-oxidants has been considered in France. The treatment does not target iron but aims at protecting the cells from iron’s toxic effects. It is interesting to note that a deficiency in vitamin E (a-tocopherol), a natural anti-oxidant present in the mitochondria) leads to a disease similar to FA. This similarity suggests that, in both cases, there is an overproduction of free radicals.
There are many substances that act as antioxidants. In vitro trial have shown that some of the could be dangerous. Iron is only toxic in the reduced form, because it can react with oxygen and produce free radicals. In the oxidized state, those reactions do not occur. Some of the anti-oxidants are able to reduce iron and increase its toxicity. We must choose anti-oxidants that will not reduce iron.
Among those, there is idebenone, a substance that is a cousin of Coenzyme Q10, naturally present men. Idebenone diffuses better in the body and has been selected for clinical trials after many in vitro tests. Initial results, obtained on three young patients, yielded promising results: after only a few weeks of treatment, a major improvement in cardiac function was observed, without any side effects. Those observations seem to be confirmed by a trial on more patients. In 52 treated patients, the cardiac hypertrophy decrease, and for certain patients, there was also an improvement of the voice and fine movement. Of course, we need more time to conclude as for the interest of using this medication, but hope is permitted to interfere with the progression of the disease. The use of molecules similar to idebenone could be more efficient in more patients in the future. Other strategies could be developed once we know better the function of frataxin. In the future, the development of gene therapy could also permit the replacement of the defective gene.