Wednesday, December 19, 2012

CRPS: Neuropeptide deficient mice


thank you, brave and selfless mice of the research world.



Neuropeptide deficient mice have attenuated nociceptive, vascular, and inflammatory changes in a tibia fracture model of complex regional pain syndrome

Tian-Zhi Guo (wxtguo@yahoo.com)

Tzuping Wei (tzupingwei@yahoo.com)
Xiaoyou Shi (xyshi@stanford.edu)
Wen-Wu Li (wenwu.li@gmail.com)
Saiyun Hou (saiyunh@gmail.com)
Liping Wang (lipingwang05@yahoo.com)
Kazutake Tsujikawa (tujikawa@phs.osaka-u.ac.jp)
Kenner C Rice (kennerr@nida.nih.gov)
Kejun Cheng (kejunch@mail.nih.gov)
David J Clark (David.Clark5@va.gov)
Wade S Kingery (wkingery@stanford.edu)


Molecular Pain 2012, 8:85 doi:10.1186/1744-8069-8-85
Published: 28 November 2012

Abstract (provisional)

Background
Distal limb fracture in man can induce a complex regional pain syndrome (CRPS) with pain, warmth, edema, and cutaneous inflammation. In the present study substance P (SP, Tac1-/-) and CGRP receptor (RAMP1-/-) deficient mice were used to investigate the contribution of neuropeptide signaling to CRPS-like changes in a tibia fracture mouse model. Wildtype, Tac1-/-, and RAMP1-/- mice underwent tibia fracture and casting for 3 weeks, then the cast was removed and hindpaw mechanical allodynia, unweighting, warmth, and edema were tested over time. Hindpaw skin was collected at 3 weeks post-fracture for immunoassay and femurs were collected for micro-CT analysis.

Results
Wildtype mice developed hindpaw allodynia, unweighting, warmth, and edema at 3 weeks post-fracture, but in the Tac1-/- fracture mice allodynia and unweighting were attenuated and there was no warmth and edema. RAMP1-/- fracture mice had a similar presentation, except there was no reduction in hindpaw edema. Hindpaw skin TNFalpha, IL-1beta, IL-6 and NGF levels were up-regulated in wildtype fracture mice at 3 weeks post-fracture, but in the Tac1-/- and RAMP1-/- fracture mice only IL-6 was increased. The epidermal keratinocytes were the cellular source for these inflammatory mediators. An IL-6 receptor antagonist partially reversed post-fracture pain behaviors in wildtype mice.

Conclusions
In conclusion, both SP and CGRP are critical neuropeptide mediators for the pain behaviors, vascular abnormalities, and up-regulated innate immune responses observed in the fracture hindlimb. We postulate that the residual pain behaviors observed in the Tac1-/- and RAMP1-/- fracture mice are attributable to the increased IL-6 levels observed in the hindpaw skin after fracture.

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    Sunday, December 16, 2012

    orryvoyer:: to stem the endless tide::orryvoyer


    as the shell casings of dead children, educators, and gunman -- today of newtown, connecticut -- ricocheted around my brain, my hands strayed over the bookcases, and landed here. another occasion to contribute to the ruination of copyright protections.  i don't think white would have minded, much. if you're unfamiliar with his Book of Merlyn, please, go and buy a copy.


    here is the wikipedia "plot summary":  
    The book opens as King Arthur prepares himself for his final battle. Merlyn reappears to complete Arthur's education and discover the cause of wars. As he did in The Sword in the Stone, Merlyn again demonstrates ethics and politics to Arthur by transforming him into various animals.

    The last chapter of the book takes place only hours before the final battle between King Arthur and his son and nephew Mordred. Arthur does not want to fight after everything that he has learned from Merlyn. He makes a deal with Mordred to split England in half. Mordred accepts. During the making of this deal, a snake comes upon one of Mordred's soldiers. The soldier draws his sword. The opposing side, unaware of the snake, takes this as an act of betrayal. Arthur's troops attack Mordred's, and both Arthur and Mordred die in the battle that follows.


    Guenever joins a convent, and remains there till death. Lancelot becomes a hermit and dies a hermit. His last miracle was making the room that he died in smell like heaven.








    "Mv FATHER made me a wooden castle big enough to get into, and he fixed real pistol barrels beneath its battlements to fire a salute on my birthday, but made me sit in front the first night—that deep Indian night—to receive the salute, and 1, believing I was to be shot, cried."
    Throughout his life White was subject to fears: fears from without—a menacing
    psychopathic mother, the prefects at Cheltenham College "rattling their canes," poverty, tuberculosis, public opinion; fears from within—fear of being afraid, of being a failure, of being trapped. He was afraid of death, afraid of the dark. He was afraid of his own proclivities, which might be called vices: drink, boys, a latent sadism. Notably free from fearing God, he was basically afraid of the human race. His life was a running battle with these fears, which he fought with courage, levity, sardonic wit, and industry
    . -- Prologue, Sylvia Townsend Warner




    The magician stood up, looking at his ancient pupil in perplexity. He twisted his beard into
    several rat tails, put the corners in his mouth, twirled his moustachios, and cracked his finger
    joints. He was frightened of what he had done to the king, feeling as if he were trying to
    revive a drowned man with artificial respiration, who was nearly too far gone. But he was not
    ashamed. When you are a scientist you must press on without remorse, following the only
    thing of any importance, Truth.

    Later he asked quietly, as if he were calling somebody who was asleep: "Wart?"

    There was no reply.

    "King?"

    The bitter answer was: "Le roy s'advisera."

    It was worse than he had feared. He sat down, took the limp hand, and began to wheedle.

    "One more try," he asked. "We are not quite done."

    "What is the use of trying?"

    "It is a thing which people do."

    "People are dupes, then."

    The old fellow replied frankly: "People are dupes, and wicked too. That is what makes it
    interesting to get them better."

    His victim opened his eyes, but closed them wearily.

    "The thing which you were thinking about before I came, king, was true. I mean about
    Homo ferox. But hawks are ferae naturae also: that is their interest."

    The eyes remained closed.

    "The thing which you were thinking about... about people being machines: that was
    not true. Or, if it is true, it does not signify. For if we are all machines ourselves, then there
    are none to bother about."

    "I see."




    homo ferox, The Book of Merlyn, T.H. White




    "We know the objections," he said. "The idea that it is useful might be considered a little
    more. If there is some necessity for Might, why is the committee ready to stop it?"

    "Sir, the committee is attempting to trace the physiological basis, possibly of a pituitary or
    adrenal origin. Possibly the human system requires periodical doses of adrenalin, in order
    to remain healthy. (The Japanese, as an instance of glandular activity, are said to eat large
    quantities offish, which, by charging their bodies with iodine, expands their thyroids and
    makes them touchy.) Until this matter has been properly investigated the subject remains
    vague, but the committee desires to point out that the physiological need could be supplied
    by other means. War, it has already been observed, is an inefficient way of keeping down
    the population: it may also be an inefficient way of stimulating the adrenal glands through
    fear."

    "What other ways?"

    "Under the Roman Empire, the experiment of offering bloody spectacles in the circus was
    attempted as a substitute. They provided the Purgation which Aristotle talks about, and some such alternative might be found efficient.  Science, however, would suggest more radical cures. Either the glandular deficiency might be supplied by periodical injections of the whole population with adrenalin—or with whatever the deficiency may prove to be—or else some form of surgery might be found effective.  Perhaps the root of war is removable, like the appendix."

    "We were told that war is caused by National Property: now we are told that it is due to a
    gland."

    "Sir, the two things may be related, though they may not be consequent upon one another.
    For instance, if wars were solely due to national property, we should expect them to continue
    without intermission so long as national property continued: that is, all the time. We find,
    however, that they are interrupted by frequent lulls, called Peace, It seems as if the human
    race becomes more and more comatose during these periods of truce, until, when what you
    may call the saturation-point of adrenalin deficiency has been reached, it seizes upon the first handy excuse for a good shot of fear-stimulant. The handy excuse is national property.
    Even if the wars are dolled up as religious ones, such as crusades against Saladin or the
    Albigensians or Montezuma, the basis remains the same. Nobody would have troubled to
    extend the benefits of Christianity to Montezuma, if his sandals had not been made of gold,
    and nobody would have thought the gold itself a sufficient temptation, if they had not been
    needing a dose of adrenalin."

    "You suggest an alternative like the circus, pending the investigation of your gland. Have you
    considered it?"

    Archimedes giggled unexpectedly.

    "Merlyn wants to have an international fair, Sir. He wants to have a lot of flip-flaps and giant
    wheels and scenic railways in a reservation, and they are all to be slightly dangerous, so as
    to kill perhaps one man in a hundred. Entrance is to be voluntary, for he says that the one
    unutterably wicked thing about a war is conscription. He says that people will go to the fair of
    their own freewill, through boredom or through adrenalin deficiency or whatever it is, and that
    they are likely to feel the need for it during their twenty-fifth, thirtieth, and forty-fifth years. It is
    to be made fashionable and glorious to go. Every visitor will get a commemorative medal,
    while those who go fifty times will get what he calls the D.S.O. or the V.C. for a hundred
    visits."

    The magician looked ashamed and cracked his fingers.

    "The suggestion," he said humbly, "was more to provide thought, than to be thought of."

    "Certainly it does not seem a practical suggestion for the present year of grace. Are there
    no panaceas for war, which could be used in the meantime?"

    "The committee has suggested an antidote which might have a temporary effect, like soda
    for an acid stomach. It would be of no use as a cure for the malady, though it might alleviate
    it. It might save a few million lives in a century."

    "What is this antidote?'

    "Sir, you will have noticed that the people who are responsible for the declaration and the
    higher conduct of wars do not tend to be the people who endure their extremes. At the battle
    of Bedegraine Your Majesty dealt with something of the same sort. The kings and the
    generals and the leaders of battles have a peculiar aptitude for not being killed in them. The
    committee has suggested that, after every war, all the officials on the losing side who held a
    higher rank than colonel ought to be executed out of hand, irrespective of their war-guilt. No
    doubt there would be a certain amount of injustice in this measure, but the consciousness
    that death was the certain result of losing a war would have a deterrent effect on those who
    help to promote and to regulate such engagements, and it might, by preventing a few wars,
    save millions of lives among the lower classes. Even a Fiihrer like Mordred might think twice
    about heading hostilities, if he knew that his own execution would be the result of being
    unlucky in them."

    "It seems reasonable."

    "It is less reasonable than it seems, partly because the responsibility for warfare does not lie
    wholly with the leaders. After all, a leader has to be chosen or accepted by those whom he
    leads. The hydra-headed multitudes are not so innocent as they like to pretend. They have
    given a mandate to their generals, and they must abide by the moral responsibility."

    "Still, it would have the effect of making the leaders reluctant to be pushed into warfare by
    their followers, and even that would help."

    "It would help. The difficulty would lie in persuading the leading classes to agree to such a convention in the first place. Also, I am afraid that you will find there is always a type of maniac, anxious for notoriety at any price, or even for martyrdom, who would accept the pomp of leadership with even greater alacrity because it was enhanced by melodramatic penalties. The kings of Irish mythology were compelled by their station to march in the forefront of the battle, which occasioned a frightful mortality among them, yet there never seems to have been a lack of kings or battles in the history of the Green Isle."

    "What about this new-fangled Law," asked the goat suddenly, "which our king has been
    inventing? If individuals can be deterred from murder by fear of a death penalty, why cannot
    there be an international law, under which nations can be deterred from war by similar
    means? An aggressive nation might be kept at peace by the knowledge that, if it began a
    war, some international police force would sentence it to dispersal, by mass transportation
    to other countries for instance."

    "There are two objections to that. First, you would be trying to cure the disease, not to
    prevent it. Second, we know from experience that the existence of a death penalty does not
    in fact abolish murder. It might, however, prove to be a temporary step in the right direction."

    The old man folded his hands in his sleeves, like a Chinaman, and looked round the council
    table, doggedly, waiting for further questions. His eyes had begun to discharge their watch.

    "He has been writing a book called the Ubellus Merlini, the Prophecies of Merlyn," continued Archimedes wickedly, when he saw that this subject had been concluded, "which he had intended to read aloud to Your Majesty, as soon as you arrived."

    "We will hear a reading."

    Merlyn wrung his hands.

    "Sir," he said. "It is mere fortune-telling, only gypsy tricks. It had to be written because there
    was a good deal of fuss about it in the twelfth century, after which we are to lose sight of it
    until the twentieth. But, oh Sir, it is merely a parlour game—not worth Your Majesty's
    attention at present."

    "Read me some part of it, none the less."

    So the humiliated scientist, all of whose quips and quiddities had been knocked out of him
    in the last hour, fetched the burnt manuscript from the fender and handed round a collection
    of such slips as were still legible, as if it had been a parlour game in earnest. The animals
    read them out in turn, like mottos from crackers, and this is what they said:

    "God will provide, the Dodo will remark."

    'The Bear will cure his headache by cutting off his head—but it will leave him with a sore
    behind."

    "The Lion will lie down with the Eagle, saying, At last all the animals are united! But the Devil
    will see the joke."

    "The Stars which taught the Sun to rise must agree with him at noon—or vanish."

    "A child standing in Broadway will cry, Look mother, there is a man!"

    "How long it takes to build Jerusalem, the spider will say, pausing exhausted at his web on
    the ground floor of the Empire State Building."

    "Living-space leads to space for the coffin, observed the Beetle."

    "Force makes force."

    "Wars of community, county, country, creed, continent, colour. After that the hand of God, if
    not before."

    "Imitation before action will save mankind."

    "The Elk died because it grew its horns too big."

    "No collision with the moon was required to exterminate the Mammoth."

    "The destiny of all species is extinction as such, fortunately for them."

    There was a pause after the last motto, while the listeners thought them over.

    "What is the meaning of the one with the Greek word?"

    "Sir, a part of its meaning, but only a small part, is that the one hope for our human race
    must lie in education without coercion. Confucius has it that: In order to propagate virtue to the world, onemust first rule one's country. In order to rule one's country, one must first rule one's family. In order to rule one's family, one must first regulate one's body by moral training.  In order to regulate one's body, one must first regulate one's mind. In order to regulate the mind, one must first be sincere in one's intentions. In order to be sincere in one's intentions, one
    must first increase one's knowledge."

    "I see."

    "Have the rest any relevant meaning?" added the king.

    "None whatever."

    "One further question before we rise. You have said that politics are out of order, but they
    seem so closely tied to the question of warfare that they must be faced to some extent. At an
    earlier stage you claimed to be a capitalist. Are you sure of these views?"

    "If I said so, Your Majesty, I did not mean it. Badger was talking at me like a communist of
    the nineteen-twenties, which made me talk like a capitalist in self-defence. I am an
    anarchist, like any other sensible person. In point of fact the race will find that capitalists and
    communists modify themselves so much during the ages that they end by being
    indistinguishable as democrats: and so will the fascists modify themselves, for that matter.
    But whatever may be the contortions adopted by these three brands of collectivism, and
    however many the centuries during which they butcher each other out of childish ill-temper,
    the fact remains that all forms of collectivism are mistaken, according to the human skull.
    The destiny of man is an individualistic destiny, and it is in that sense that I may have implied
    a qualified approval of capitalism, if I did imply it. The despised Victorian capitalist, who did at least allow a good deal of play to the individual, was probably more truly futuristic in his politics
    than all the New Orders shrieked for in the twentieth century. He was of the future, because
    individualism lies in the future of the human brain. He was not so old-fashioned as the
    fascists and communists. But of course he was considerably old-fashioned for all that, and
    that is why I prefer myself to be an anarchist: that is, to be a little up-to-date. The geese are
    anarchists, you remember. They realise that the moral sense must come from inside, not
    from outside."

    "I thought," said the badger plaintively, "that communism was supposed to be a step
    towards anarchy. I thought that when communism had been properly achieved the state
    would wither away."

    "People have told me so, but I doubt it. I cannot see how you may emancipate an individual
    by first creating an omnipotent state. There are no states in nature, except among
    monstrosities like the ants. It seems to me that people who go creating states, as Mordred
    is trying to do with his Thrashers, must tend to become involved in them, and so unable to
    escape. But perhaps what you say is true. I hope it is. In any case let us leave these dubious
    questions of politics to the dingy tyrants who look after them. Ten thousand years from now it
    may be time for the educated to concern themselves with such things, but meanwhile they
    must wait for the race to grow up. We for our part have offered a solution this evening to the special problem of force as an arbiter: the obvious platitude that war is due to
    national property, with the rider that it is stimulated by certain glands. Let us leave it at that
    for the present, in God's name."

    The old magician swept his notes away with a trembling hand. He had been deeply
    wounded by the hedgehog's earlier criticisms, because, in the secrecy of his heart, he loved
    his student dearly. He knew now, since the royal hero had returned victorious in his choice,
    that his own wisdom was not the end. He knew that he had finished his tutorship. Once he
    had told the king that he would never be the Wart again: but it had been an encouraging thing to say: he had not meant it. Now he did mean it, now knew that he himself had yielded
    place, had stepped down from the authority to lead or to direct. The abdication had cost him
    his gaiety. He would not be able to rant any more, or to twinkle and mystify with the flashing
    folds of his magic cloak. The condescension of learning was pricked in him. He was feeling
    ancient and ashamed.

    The old king, whose childhood had vanished also, toyed with a slip left on the table. He was
    at his trick of watching his hands, when in abstraction. He folded the paper this way, that
    way, carefully, and unfolded it. It was one of Merlyn's notes for the card-index, which badger
    had muddled with the Prophecies: a quotation from a historian called Friar Clynn, who had
    died in 1348. This friar, employed as the annalist of his abbey to keep the historical records,
    had seen the Black Death coming to fetch him—possibly to fetch the whole world, for it had killed a third of the population of Europe already. Carefully leaving some pieces of blank parchment with the book in which he was to write no longer, he had concluded with the following message, which had once awakened Merlyn's strange respect. 

    "Seeing these many ills," he had written in Latin, "and as it were the whole world
    thrust into malignancy, waiting among the dead for death to come to me, I have put into
    writing what I have truthfully heard and examined. And, lest the writing should perish with the
    writer or the work fail with the workman, I am now leaving some paper for the continuation of
    it—in case by any chance a man may remain alive in the future, or any person of the race of
    Adam may escape this pestilence, to carry on the labour once begun by me."

    The king folded it neatly, measured it on the table. They watched him, knowing he was about
    to rise and ready to follow his example.

    "Very good," he said. "We understand the puzzle."

    He tapped the table with the paper, then got to his feet.

    "We must return before the morning."

    The animals were rising too. They were conducting him to the door, crowding round him to
    kiss his hand and bid farewell. His now retired tutor, who must conduct him home, was
    holding the door for him to pass. Whether he was a dream or not, he had begun to flicker, as
    had they all. They were saying "Good success to Your Majesty, a speedy and successful
    issue."

    He smiled gravely, saying: "We hope it will be speedy."

    But he was referring to his death, as one of them knew.

    "It is only for this time, Majesty," said T. natrix. "You remember the story of St. George, and
    Homo sapiens is like that still. You will fail because it is the nature of man to slay, in
    ignorance if not in wrath. But failure builds success and nature changes. A good man's
    example always does instruct the ignorant and lessens their rage, little by little through the
    ages, until the spirit of the waters is content: and so, strong courage to Your Majesty, and a
    tranquil heart."

    He inclined his head to the one who knew, and turned to go.

    At the last moment a hand was tugging at his sleeve, reminding him of the friend he had
    forgotten. He lifted the hedgehog with both hands under its armpits, and held it at arm's
    length, face to face.

    "Ah, tiggy," he said. "Us have thee to thank for royalty. Farewell, tiggy, and a merry life to
    thee and thy sweet songs."

    But the hedgehog paddled its feet as if it were bicycling, because it wanted to be put down.
    It tugged the sleeve again, when it was safe upon the floor, and the old man lowered his ear
    to hear the whisper.

    "Nay, nay," it mentioned hoarsely, clutching his hand, looking earnestly in his face. "Say not
    Farewell."

    It tugged again, dropping its voice to the brink of silence.

    "Orryvoyer," whispered the urchin. "Orryvoyer."

    WELL, WE HAVE REACHED IT AT LAST, the end of our winding story.
    Arthur of England went back to the world, to do his duty as well as he could. He called a
    truce with Mordred, having made up his mind that he must offer half his kingdom for the sake
    of peace. To tell the truth, he was prepared to yield it all if necessary. As a possession it had
    long ceased to be of value to him, and he had come to know for sure that peace was more
    important than a kingdom. But he felt it was his duty to retain a half if he could, and it was for
    this reason: that if he had even half a world to work on, he might be able still to introduce, in
    it, the germs of that good sense which he had learned from geese and animals.

    The truce was made, the armies drawn up in their battles, face to face. Each had a standard
    made from a ship's mast set on wheels, at the top of which a small box held the consecrated Host, while, from the masts, there flew the banners of the Dragon and the Thistle. The knights of Mordred's party were dressed in sable armour, their plumes were sable also, and, on their arms, the scarlet whip of Mordred's badge glared with the sinister tint of blood. Perhaps they looked more terrible than they felt.

    It was explained to the waiting ranks that none of them must make a hostile demonstration,
    but all must keep their swords in sheath. Only, for fear of treachery, it was told that they might
    charge to rescue, if any sword was seen unharnessed at the parley.

    Arthur went forward to the space between the armies with his staff, and Mordred, with his
    own staff in their black accoutrements, came out to meet him. They encountered, and the old
    king saw his son's face once again. It was taut and haggard.  He too, poor man, had strayed beyond Sorrow and Solitude to the country of Kennaquhair;  but he had gone without a guide and lost his way.

    The treaty was agreed on, to the surprise of all, more easily than had been hoped. The king
    was left with half his realm. For a moment joy and peace were in the balance.

    But, at that knife-edge of a moment, the old Adam reared itself in a different form. The feudal
    war, baronial oppression, individual might, even ideological rebellion: he had settled them
    all in one way or another, only to be beaten on the last lap now, by the episodic fact that
    man was a slayer by instinct.

    A grass-snake moved in the meadow near their feet, close to an officer of Mordred's staff.
    This officer stepped back instinctively and swung his hand across his body, his armlet with
    the whip shewing for a second's flash. The bright sword flamed into being, to destroy the so-called
    viper. The waiting armies, taking it for treachery, raised their shout of rage. The lances on
    both sides bowed to rest. 






    And, as King Arthur ran towards his own array, an old man with white hair trying to stem the endless tide, holding out the knuckled hands in a gesture of pressing them back, struggling to the last against the flood of Might which had burst out all his life at a new place whenever he had dammed it, so the tumult rose, the war-yell sounded, and the meeting waters closed above his head.

    Lancelot arrived too late...