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Christopher Pelant

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Nickname(s)

Hacktivist (himself)

Aliases

Bassam Alfayat
Justin Trimple

Occupation

IT instructor
Hacker
Waiter (alternative reality)

"Trying to make the system secure, we make it more complex. But the more complex we make it, the more insecure we actually are."
&#;Pelant in The Crack in the Code

Christopher Pelant or The Hacktivist&#;was&#;a serial killer introduced in the season seven episode "The Crack in the Code".

History[]

Christopher Pelant was an American citizen who, according to Booth in The Corpse on the Canopy, was officially&#;born in Denmark in and raised&#;in the town of Pitt Meadows, Virginia. According to Sweets in The Past in the Present, his parents divorced when he was young and he was close to his father, though they rarely saw each other afterward. He later used his distinctive hacking skills to erase his true identity, making it appear as though he was not an American but actually an Egyptian citizen, Bassam Alfayat, who had lived in Egypt until the age of six. He did this in order to escape arrest for a crime he committed during his teens that 'Christopher Pelant' could be tied to. By making it appear as though he wasn't Pelant, he evaded arrest.

During high school, Pelant had a guidance counselor by the name of Carole Morrissey. He asked&#;her to write him a letter of recommendation for Stanford but she refused. He&#;hacked into her computer and&#;wrote the recommendation himself. Pelant&#;then killed&#;her with a katana he "borrowed" from his grandfather, who obtained the weapon while serving in the Pacific theater during WWII.&#; He buried her hoping he would never get caught. &#;At the time of the murder, Pelant was rather obese, however, he later placed pictures on an online yearbook from his high school making it appear that he was slim, therefore distorting the proportions of the force of the fatal blow and the weight of the murder weapon. This distortion made it look like he was slim and using a heavier weapon, when in reality he was large and using a lighter weapon. He then&#;began rapidly losing the large weight he had at the time to further corroborate his story.

Before Pelant&#;became a serial killer, he was already a computer hacker who had a strong belief that the U.S. government was corrupt. He demonstrated his hacking skills twice by shutting down the Senate website in and hacking into the Pentagon security system to shut it down, endangering the lives of countless U.S. soldiers. He was eventually arrested, convicted of wire and computer fraud, and sentenced to house arrest. His personal calling card both times was leaving behind a question written in blood-like letters on the websites; on the Senate website he left the question "Where's the website?" and on the Pentagon's, he left behind "What are you defending?".

Pelant: I'm not a criminal. I'm a 'Hacktivist'.

--The Crack in the Code

His hatred was then directed towards the FBI for his arrest and conviction and resulted in him seeking revenge against them. He started by stealing the blood of five FBI agents and acquiring a bang stick (or as is suggested constructing one himself). He was then able to surreptitiously remove his ankle monitor and proceeded to kill a woman. He then placed her remains in various locations for the FBI to find, upon scanning the bones the Jeffersonian computers were infected with a worm that Pelant had intricately carved into their surface.&#;

It is possible that Pelant discovered the truth about Glen Durant and his shadow government and covered his tracks to avoid getting detected or killed by Durant. These actions could have led to his first crimes; hacking into the Senate website and the Pentagon security system. He must have decided to lead Brennan and Booth to the Ghost killer so they can inevitably discover the conspiracy through the McNamara's background hoping that Durant or his agents would kill them if he failed to make Brennan see him in a new light and/or kill them.&#;

Sweets mentioned that Gordon Wyatt wrote a book on the role of sexual sadism in female serial killers. Implying that Pelant may have reviewed Bones and Booth's Psychological Case Files from Dr. Wyatt to be even more thorough. He also may have read Dr. Wyatt's book and used its psychological information and his intelligence to find the serial killer he mentioned to Bones; The Ghost Killer.&#;

Throughout The Bones series[]

The Crack in the Code[]

In his first appearance, Pelant places the skull and spine of his victim in front of a statue of Abraham Lincoln and leaves the message "Where is the Rest of Me?." He then proceeds to leave the rest of the bones in a storage area where the FBI keeps information regarding its informants. After this, he reaches out to a reporter named Ezra Krane, who had previously covered his trial and gives him all the details of his crimes and the FBI's corruption. Later Pelant gets nervous and kills Krane in order to ensure the identity of his source remains a secret. Pelant then hacks various hospitals to have Krane's body cremated before an autopsy can be made. When brought in for interrogation, Pelant doesn't deny being responsible for the murders, but also points out that his ankle monitor gives him a solid alibi.

The Past in the Present[]

In the season seven finale, Pelant, who is up for the possibility of parole, frames Brennan for the murder of her friend, Ethan Sawyer, a schizophrenic mathematician whom she had asked for help with the case, exploiting the fact that his delusions included a belief that Brennan's new baby, Christine, was a 'demon'. Altering video footage and using supplies stolen from the Jeffersonian, he ensures that people who love Brennan and are capable of solving his crimes are removed from investigation one by one. Caroline recognizes this and her hope for bringing justice for Brennan and his victims lays with the Jeffersonian team still being on a case, aided by the fact that Camdidn't conceal crucial evidence of samples of Sawyer's hair in Brennan's car. Eventually, Brennan's fatherconvinces her that she shouldn't trust the system given Pelant's computer skills, thus making her go into hiding.

The Future in the Past[]

In the Season 8 opener, Bones is still on the run, still attempting to find a way to prove Pelant has framed her, while Pelant is currently teaching a night class in computer skills at a nearby college. She manages to uncover the bones of Pelant's former school counselor, whom he murdered in order to ensure his place at Stanford by forging her recommendation; Sweets is able to identify this as key passages of the recommendation later fit with Pelant's writing style rather than the guidance counselor's. It is revealed that Angela and Bones have also been communicating using flowers with various coded meanings. Cam tells Edison to send details of both the bones and the flowers to Booth via email, knowing it will draw Pelant out. Knowing of the flower's code Pelant waits at the next drop point for a flowered message and encounters Hodgins who he taunts into strangling him into unconsciousness. Hodgins reveals this fact to Sweets who realizes it uncovers the third aspect of Pelant's personality and gives this information to Angela, showing that it fits into Ethan's pyramid. Booth convinces Flynn (the agent who took over for Booth when Booth was taken off the case due to manipulation by Pelant) to arrest Pelant for hacking into the FBI email system just as Cam had hoped and he is detained. Meanwhile, Bones has snuck into the Jeffersonian and is using Cam and Edison's work to analyze the bones further; based on her observations of his gait, she determines that Pelant was in fact fat in high school and thus could have used a light weapon to deliver a heavy blow. The FBI discovers his grandfather's Japanese sword and it matches the killing blow to his high school counselor, he is finally arrested for at least one murder. Angela uses the explanation Sweets provided of Ethan's pyramid to find an encryption key that breaks some of Pelant's code and reveals how he superimposed Bones into security footage.

Just when things start to seem settled, Caroline reveals that the man they know as Pelant is in fact, according to DNA, fingerprints, and background records, Bassam Alfayat, an Egyptian diplomat who is being taken back to Egypt by their government, begging the question of which identity was real. As a final act, Pelant/Alfayat gives Bones a Marigold symbolizing pain and grief, and in return, Bones slaps him across the face. When Bones tells Booth what the flower means, Booth throws it into a nearby wastebasket and they both leave, only to have the camera zero in on the flower in the wastebasket, which is then retrieved by Agent Flynn.

The Corpse on the Canopy[]

Angela and Hodgins wake up with a skinned body above them. They figure out that it was Pelant who placed it there. They identify the victim as a private military contractor and track Pelant to his place of work. Pelant hacks into a security firm's firewalls and takes control of a drone and targets a school full of children in Afghanistan. At the same time, he hacks into Hodgins' bank accounts and starts draining all his money. He forces the team to make a choice between the school and the money and Hodgins' chooses the children while Booth and Flynn pursue Pelant. In pursuit of Pelant, Flynn is shot and injured by robotic machine guns while Booth opens fire on Pelant, grazing his face from behind, and causing severe damage to his right side. He drains all the money from Hodgins' account so now Hodgins is broke.&#;He is last seen stitching up his face with supplies he took from a dead veterinarian.

The Secret in the Siege[]

In the season 8 finale, Pelant, now bearing heavy scarring to the right side of his face after being wounded by Booth, manipulates a woman named Anna Samuels into killing FBI agents who were involved in a raid on a separatist religious cult that went wrong. He has been stalking Booth and Brennan since their last encounter. At the end of the episode, during which they had decided to get married, Pelant calls Booth and tells him that he changed the rules when he shot him. He also forces Booth to turn down Brennan's proposal, threatening to kill more innocent people and pinning them on him if he refuses or even if he tells her why he does it. Unwilling to let that happen, Booth tells Brennan that the relationship they have is enough. She accepts this, but is left heartbroken, although Booth still vows to kill Pelant one day.

The Secrets in the Proposal[]

Though not featured in this episode, after three months of trying to find him, Booth doesn't have any sort of leads on Pelant. Booth and Brennan are conflicted, because if Booth accepted Brennan's proposal then Pelant would kill five random people and send Booth to jail for the murders, and Brennan can't know it. The two become distant, but Brennan talks with an old friend of Booth and decides to have faith in Booth that he wouldn't have declined her proposal without a good reason. At the end of the episode, after the couple made up, the kitchen clock starts blinking the wrong time before going back to the right one, proving or at least implying that Pelant is spying on them.

The Sense in the Sacrifice[]

"You and I are destined to die together Someday. I hope not today, but that's up to you."
&#;Pelant to Brennan

As Angela installs more anti-hacking firewalls in the Jeffersonian computers, the Jeffersonian staff, Booth, and Flynn use a donated body to stage a Pelant-style crime scene to try to flush Pelant out. They send Flynn to pose the skinned body as Prometheus in a painting. Although the plan does work, Pelant, who has bugged Flynn's car, catches onto them, kills Flynn, and uses his body for the crime scene instead. Pelant tries to woo Doctor Brennan, thinking that he would be able to win her over based on his analysis of Sweets' research, which 'confirmed' that Brennan can change her mind about people. In the end, however, Brennan refuses Pelant, who thought that Brennan would pick him instead. Though he has the intelligence, Brennan still wants him dead, even if it means her death. Booth calls Pelant's bluff, shooting him in the neck, "disconnecting the computer", and ultimately killing him, and then proposes to Brennan, telling her the truth behind his refusal. She stated that she knew that it was something like that and that he made the right choice.

In this episode, Pelant reveals to Brennan that there is another serial killer still at large. Pelant may or may not know them personally, but he has "a reason to believe it's a woman."

The Ghost in the Killer[]

Brennan has nightmares about Pelant and his possible companion The Ghost Killer, becoming rather obsessed with this new killer.

The th in the 10th[]

In the alternate reality, Pelant makes a brief cameo as a waiter to tell Brennan she has a phone call.

The Next in the Last[]

When the Jeffersonian are investigating a corpse that had their hands cut off, on the obelisk with a flower and a message of "be warned", they start to investigate connections to Pelant. They discover links to his previous cases and discover a copycat murderer using the Modus Operandi of Pelant. They eventually reveal the killer to be Leelah Strawn and find evidence at her house including a newspaper clipping. They also recover Hodgins's money drained two years ago, and Pelant himself is later seen in a video but Brennan turns it off deciding to leave Pelant in the past where he belongs.

Modus Operandi[]

Pelant had no consistent method in his crimes, though his murders were usually very complex and involved severely mutilating the victims, sometimes in order to implant messages into their remains. When he manipulated Anna Samuels into killing, her victims were shot with a 9mm pistol, first once in the neck to kill them and then ten more times in the body. He also based some details of Samuels' crimes on research papers written by Sweets.

He used messages written in blood to sign his work on the Senate website and the Pentagon security system as well as Inger Johannsen's murder investigation during The Crack in the Code. Ever since he was put under arrest for Ethan Sawyer's murder after the team proved Brennan's innocence, he started to leave flowers next to some of his later victims similar to how Brennan communicated with Angela between Seasons 7 and 8.

His use of Sweets' psychological research on everyone he faced could indicate that he is the Anti-Sweets like how Heather Taffet is the Anti-Brennan and how Jacob Broadsky is the Anti-Booth. Some of the crimes he commits not only depends on computers and other forms of technology, but also on human behavior, such as the behavior of the people he faced during his crime spree. He uses the information he accumulated from Sweets' files to manipulate people into doing exactly what he wants them to do in order to use the criminal justice system against them. However, he was also the Anti-Sweets in his inability to truly understand this insight, believing that Sweets' observations about how Brennan had changed over time meant that he could convince Brennan to return his displays of 'affection,' as he was incapable of recognizing that Brennan had fallen in love with Booth due to their shared dedication to finding justice and protecting innocent people in the process of arresting and/or killing murderers like him.

Known Victims[]

  • June Carole Morrissey (snared, hung upside down and slashed to death and gutted with a katana)
  • Inger Johannsen (killed with a bang stick, dismembered and her spine and skull removed)
  • Ezra Krane (killed with a bang stick and hung from a flagpost)
  • Ethan Sawyer (drugged him with tubocurarine, cut his arteries and left him to be eaten by wolves; framed Brennan for the murder)
  • Xavier Freeman (tortured to the point of cardiac arrest with repeated needle punctures to the spine, then flayed and mutilated and posed like Vesalius)
  • Special Agent Hayes Flynn (shot with security Gatling guns; survived, was later killed and posed like Prometheus and his liver was removed while he was still alive)
  • The students of a girls' school in Afghanistan (threatened to kill with a drone strike; averted)
  • An unnamed veterinarian (apparently stabbed; killed for access to his office and supplies)
  • Alan Friedlander (shot once in the neck and shot ten more times post-mortem by Anna Samuels)
  • Jeff Stone (shot once in the neck and shot ten more times post-mortem by Anna Samuels)
  • Lance Sweets (attempted shooting by Anna Samuels)
  • Trivia[]

    • He is regarded as the most dangerous and recurring serial killer in the entire series.
    • He had a grandfather that served in WWII who was befriended by Max Keenan in order to gain information. He brought over many Japanese weapons from his time in WWII, including the Japanese katana Pelant used on his first victim.
    • The right side of his face was badly mutilated by a shot from Booth into Pelant's car's windshield, which Pelant had to sew up himself using tools from a veterinarian he killed.
    • Booth shot Pelant in the neck, severing his spinal column. While going after Jacob Broadsky, Booth mentioned in The Killer in The Crosshairs while investigating the death of Walter Coolidge that severing the head from the spinal cord is a gold standard for snipers. They call it "Disconnecting the Computer." It was the same method that Booth used to kill Pelant with his handgun.
    • The old computer Pelant owned in The Crack in the Code was an IBM Console Card Reader made in However, it was based on discrete transistors rather than old vacuum tubes which makes it questionable how there would be a vacuum tube missing from inside the computer. Although, Pelant may have possessed old vacuum tubes among his collection of obsolete electronics to build his bang stick.
    • The computer virus/worm delivered via the bone etchings, which Pelant personally devised and carved, could be considered a form of Arbitrary Code Execution (aka ACE exploit), a real-world method of computer security exploitation. While it may not be feasible to use carvings on bones to produce an&#;ACE exploit, the core concept of using seemingly random imputs to&#;generate&#;a series of code within a program&#;thus making&#;the program do something it normally shouldn't&#;remain a valid real-world technique.&#;(In this case, the imaging program which rendered the images of the scanned bone etchings gave Pelant remote access to the FBI computers.)
    • Pelant has the highest known I.Q. of all of the villains to appear on&#;the show,

    Notes[]

    • Due to his unparalleled hacker and computer skills and his appreciation of the fine arts (albeit for self-gratification) Pelant could be viewed as the Anti-Angela.
    • Since Pelant is quite adept at reading human psychology in order to unhinge and manipulate his enemies, Pelant also functions as the Anti-Sweets. Although he can be equally stubborn when it comes to bringing his patients' issues to the light, Lance Sweets refuses to push their personal boundaries, whereas Pelant would go through extremes to bring out their personalities' darkest aspects.
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    Amy Pond

    Fictional character in the TV series Doctor Who

    Amelia “Amy” Pond is a fictional character portrayed by Karen Gillan in the long-running British science fiction television series Doctor Who. Amy is a companion of the series protagonist the Doctor, in his eleventh incarnation, played by Matt Smith. She appears in the programme from the fifth series () to midway through the seventh series (). Gillan returned for a brief cameo in Smith's final episode "The Time of the Doctor".

    The Doctor first meets Amelia when she is seven years old (portrayed by Caitlin Blackwood) and disturbed by a crack in her wall. He promises to return to the lonely girl in five minutes and take her with him in the TARDIS, but accidentally arrives twelve years later, by which time adult Amy has become sceptical about her "imaginary friend". However, she eventually decides to travel with him, and the duo are later joined by her fiancé Rory Williams (Arthur Darvill). Amy and Rory marry at the end of the fifth series. In the sixth series, Amy gives birth to their daughter, Melody Pond, who is revealed to be recurring character (since the fourth series) River Song (Alex Kingston).

    Appearances[edit]

    Television[edit]

    Amelia Pond is introduced in the first episode of the fifth series (), "The Eleventh Hour", as a seven-year-old girl living with only her aunt when the Doctor (Matt Smith) crashes into her front yard one night. She asks him to investigate an unusual crack in her wall, but he is interrupted by an alert from the TARDIS. He promises Amelia that he will return in five minutes, but is inadvertently late by twelve years. In the intervening period, Amelia's family and friends believe the Doctor is just her imaginary friend; her insistence that he is real leads to her being treated by psychiatrists. When the Doctor returns, Amy is nineteen years old and working as a kissogram. She helps him save Earth from the galactic police force, the Atraxi, and when he returns two years later she begins travelling with him as his companion.[2] At the end of "Flesh and Stone", Amy reveals that they had left Earth on the eve of her marriage to Rory Williams (Arthur Darvill) and attempts to seduce the Doctor.[3] The Doctor finds Rory and takes him and Amy to 16th century Venice on an intended romantic date after which Rory continues travelling with them.[4] In "Amy's Choice", Amy is pressured to resolve her conflicted feelings for the Doctor and Rory and realises the depth of her love for Rory.[5] At the end of "Cold Blood", Rory is killed by a Silurian, then is erased from history by the cracks in the universe. Because he is part of Amy's own time-line, she ceases to remember him.[6] The Doctor takes Amy to 19th century France to lessen his guilt about Rory's loss and she forms a close friendship with famed painter Vincent van Gogh (Tony Curran).[7]

    In the fifth series finale, "The Pandorica Opens"/"The Big Bang", Rory reappears in AD as a Roman centurion. He triggers Amy's memories, but as she remembers, it is revealed that the centurion Rory is actually an Auton—a duplicate of living plastic—created from Amy's memories to help capture the Doctor. Rory's consciousness tries to fight his programming, but he is compelled to shoot and kill her.[8] Amy's body is kept alive in the Pandorica, a special prison intended to trap the Doctor. The Auton Rory protects it for years. The Doctor realises that Amy is connected to the cracks in the universe which originated from a temporal explosion on her wedding day. He tells her that her parents had been erased by the crack in her wall and urges her to remember them. After he uses the Pandorica to reboot the universe, the Doctor travels back through his timeline and is able to plant memories in Amy of the TARDIS. Amy awakes on her wedding day in a timeline where her parents are again part of reality and marries a restored Rory. Her memories are stirred by the TARDIS-shaped diary River Song (Alex Kingston) leaves for her. Once Amy remembers the Doctor, he is restored to reality.[9] It is mentioned in The Sarah Jane Adventures serial Death of the Doctor that the Doctor dropped Amy and Rory off on a "honeymoon planet",[10] and the couple continues their honeymoon aboard an interstellar cruise ship which the Doctor saves from crashing into a populated planet.[11]

    The sixth series () begins with Amy and Rory living a normal domestic life. They receive an anonymous invitation to the Utah desert where they reunite with the Doctor&#;—now aged nearly two hundred years since they have last met&#;—and fellow invitee River Song. Amy witnesses the Doctor's death at the hand of an astronaut in an Apollo space suit, but they discover the Doctor also invited a younger version of himself, with whom they travel to Washington, D.C. to investigate strange occurrences involving the Silence, an alien race who cannot be remembered after they are encountered. While there, Amy informs the Doctor she is pregnant before attempting to shoot a little girl in an Apollo space suit, believing it will stop her from killing the future Doctor.[12] In the girl's orphanage room, Amy finds strange pictures of herself holding a newborn baby. When the Doctor questions Amy about the pregnancy, she insists she was wrong and further investigation by the Doctor is inconclusive.[13] Throughout their adventures, Amy is plagued by strange visions of a woman wearing an eye-patch (Frances Barber) appearing sporadically only to her.[13][14][15] In "The Almost People" it is revealed that the Amy presented (on screen) insisting she is not pregnant, is actually a Ganger &#; a duplicate animated by the real Amy's consciousness &#; while the real Amy is in the captivity of the eye-patched woman and about to give birth.[16] In "A Good Man Goes to War", her baby&#;—named Melody Pond&#;—is kidnapped by the eye-patched woman, Madame Kovarian, who will train her to one day kill the Doctor. River Song then arrives and tells Amy that she is an adult Melody.[17]

    A flashback in "Let's Kill Hitler" introduces Amy and Rory's childhood friend Mels (Nina Toussaint-White). As teenagers, it was Mels who pointed out that Rory had been in love with Amy for some time, which led to the two dating. In the present, Mels hijacks the TARDIS and directs it to where she is shot by Hitler (Albert Welling) and regenerates into River Song, revealing that Amy had grown up alongside her daughter, who was trained by the Silence to kill the Doctor. Amy is later persuaded by the Doctor to let her adult daughter make her own way in life.[18] In "The Girl Who Waited", Amy becomes separated from the Doctor and Rory on a planet's quarantine facility and lives on her own for 36 years before they return. The Doctor wants to go back in time to rescue the younger Amy, but the older Amy insists that they take both of her. However, the Doctor knows the TARDIS will not accept the paradox and is forced to leave the older Amy behind.[19] In "The God Complex", the Doctor breaks Amy's faith in him after he discovers that they are trapped in a prison for a being that kills by feeding on faith. At the conclusion of that episode, not wanting to risk their lives further, he parts ways with her and Rory after giving them a house and car.[20] Amy appears briefly in "Closing Time", where she is shown to have become a fashion model, noted for a perfume campaign with the slogan "For The Girl Who Is Tired of Waiting".[21] Series finale "The Wedding of River Song" depicts an alternate universe created by River refusing to kill the Doctor in Utah, as previously shown. Amy leads a secret organisation which fights the Silence. She reunites the Doctor with River and later kills Madame Kovarian for kidnapping Melody and depriving her of raising her baby. After history is restored, River visits Amy and reveals that the Doctor has faked his death.[22] At the end of the Christmas special, the Doctor returns to Amy and Rory two years later (in their time) and has Christmas dinner with them.[23]

    The series seven opener "Asylum of the Daleks" () shows Amy, still working as a fashion model, signing papers for her and Rory's divorce. In the episode, the Doctor engineers a reconciliation between the two during the mission, allowing them to discuss their feelings for each other. It is revealed Amy left Rory because she has been infertile since "A Good Man Goes to War", and knew he wanted children.[24] The couple continue traveling with the Doctor on small adventures in "Dinosaurs on a Spaceship" and "A Town Called Mercy", but leave at the end of each to return to their normal lives.[25][26] In "The Power of Three", Amy says that the Doctor has been in her and Rory's life for ten years, and she now works as a journalist. The couple realise they have to choose between their normal lives and their life with the Doctor. They are inclined to choose the former, but Rory's father Brian (Mark Williams) encourages the pair to continue travelling with the Doctor.[27] Their next adventure, "The Angels Take Manhattan", is their last. In the story, Amy and Rory are threatened by the evil Weeping Angels, whose touch will send them into the distant past to die alone. Having witnessed this eventuality, they attempt suicide, creating a paradox which destroys all but one Angel, but also renders the area permanently off-limits to the Doctor's TARDIS. In the present, the surviving Angel sends Rory back in time, and knowing the Doctor cannot recover him, Amy allows the Angel to touch her too so she can be with him. Gravestones in a New York cemetery reveal that Rory died at the age of 82 and Amy died at the age of River arranges for Amy to leave the Doctor a message in the afterword of a s pulp fiction novel, where she says she is happy with Rory and that they worry about the Doctor travelling alone.[28] "P.S.", a mini shows-episode supplement based on the original script for this episode, shows that Rory and Amy adopted a son, in , and named him Anthony Brian Williams.[29] Gillan reprises the role in "The Time of the Doctor" (), in which Matt Smith departs the series. During the Eleventh Doctor's regeneration, he hallucinates images of young Amelia Pond on board his TARDIS, before a vision of adult Amy approaches and says a final goodbye.

    Other media[edit]

    In addition to the television series, Amy has appeared in several BBC-licensed Doctor Who novels, audio dramas, and comics. The first set of corresponding New Series Adventures novels—Apollo 23, Night of the Humans and The Forgotten Army—were published in April and feature solely the Eleventh Doctor and Amy. The next set—comprising Nuclear Time, The King's Dragon and The Glamour Chase—were released in July and feature the Doctor, Amy, and Rory. In Michael Moorcock's lengthier The Coming of the Terraphiles, which takes place during a time in the fifth series Rory is absent, Amy is proposed to by one of the characters, to whom she declines. In April , another set of New Series Adventures were released to correspond with Amy and Rory's travels in the sixth series, containing Dead of Winter, The Way Through the Woods, and Hunter's Moon. A subsequent series of three books were published in June. In September, another longer novel was published, The Silent Stars Go By, which sees the trio face the Ice Warriors. In addition, Amy appears singularly alongside the Doctor in four "Decide Your Destiny" books, as well as alongside Rory in six "2in1" adventure chapter books. The three also feature in the Quick Reads InitiativenovellaMagic of the Angels.[30]

    Amy, Rory, and the Doctor appear in IDW Publishing's comic book series Assimilation2, published from May to December , which is a crossover between Doctor Who and Star Trek: The Next Generation. They team up with the crew of the USS Enterprise-D to stop an alliance between the Borg and the Cybermen.[31] Amy and Rory appear briefly in the mini-series "Prisoners of Time" where they join other past companions and versions of the Doctor in battling the main villains of the series. During a battle with some Autons, 11 introduces them to Clara Oswald.

    Amy Pond has appeared in several Doctor Who video games. Voiced by Gillan, she appears in all five episodes of Doctor Who: The Adventure Games which were marketed as extra episodes.[32][33] The virtual character was created using rotoscoping of Gillan's movements.[34] She also is featured, voiced by Gillan, in the video games Doctor Who: Evacuation Earth and Doctor Who: Return to Earth, made for the DS and NintendoWii respectively.[35] Amy also appears in the smartphone app game Doctor Who: The Mazes of Time.[36]

    Characterisation[edit]

    Creation and casting[edit]

    Young Amy, whom the Doctor first meets, was played by Caitlin Blackwood, Karen Gillan's real-life cousin.

    Doctor Whoexecutive producer and head writer Steven Moffat came up with the name for the character.[37] Moffat chose the name "Pond" to create a link between Amy and River Song, who would be revealed to be Amy's daughter.[38] Moffat's predecessor, Russell T Davies, stated in an interview with Dose magazine that "We've held off on companions for a long time, so you'll get rewarded with a great, big, strong character in Amy Pond, when she arrives. I think that plan's been good."[39]

    Andy Pryor, the casting director, suggested Gillan to Moffat after her performance in the fourth series episode "The Fires of Pompeii", in which she played a soothsayer, but Moffat originally thought Gillan was "wee and dumpy".[40] Later, however, he stated that she was "exactly right for the role", though she portrayed the character differently from how Moffat originally wrote.[41] Gillan was reportedly the last to audition for the role, and stood out as she was "a bit kookier" than the others.[42] Moffat said of the casting, "We saw some amazing actresses for this part. But when Karen came through the door, the game was up&#;— she was funny, clever, gorgeous and sexy. Or Scottish, which is the quick way of saying it. A generation of little girls will want to be her. And a generation of little boys will want them to be her too."[43][44]Doctor Who executive producer and drama chief at BBC Wales Piers Wenger concurred, "We knew Karen was perfect for the role the moment we saw her. She brought an energy and excitement to the part that was just fantastic."[45] Gillan was aware of the show but was not as big a fan of it as her mother was, due to it not being on when she was growing up. However, she watched some with her mother after it returned in , and was also a fan of other science fiction such as The X-Files, The Outer Limits, Star Trek: The Next Generation and Star Trek: Voyager.[46]

    Gillan auditioned for the role in both her natural Scottish accent and an English one, and it was not until after she was cast that it was decided Amy would be Scottish.[47][48] Gillan commented that she felt the Scottish accent better suited the character.[49] A younger version of Amy, known as "Amelia", appears in several episodes. Amelia was played by Gillan's real-life year-old cousin Caitlin Blackwood. Though the two actresses had not met until the set of the show, Gillan recommended Blackwood for the role; Blackwood, however, still had to undergo rigorous auditions first.[50][51] Blackwood and Gillan did get to act together in "The Big Bang", which Gillan initially found "weird", though the two actresses became used to it quickly.[52]

    Personality and character arc[edit]

    "That's been what I absolutely most love about playing this character, is that she's not just a character. We know what she's like, and that's her run on the show. We're seeing her whole life pan out. That's what I love about her so much. I hope she's changing. She was quite snarky in the [fifth series]Because she was always still such a child inside, as one of the monsters said to her at one point. And then we see the universe rebooted, so she's got two different versions of reality, so she's still a little messed-up, but she's far more settled as a person, having had a normal upbringing in one reality. She's married, and she has a kid."

    Karen Gillan[46]

    Gillan stated that "having read the first episode I was utterly smitten [with the show], and with the character. Amy's a sassy lady, funny and passionate, and her relationship with the Doctor has a really interesting dynamic".[53] Gillan believed that the Doctor still saw Amy as the same seven-year-old girl he first met, and described their relationship as brother and sister, with Amy sometimes acting as an "annoying little sister". She also did not want Amy, like previous companions, to stand around "in awe of the Doctor all the time" or "mope around" while he was not there; Amy would "do her own thing, whether it's fighting monsters in strange new worlds or just getting on with her life in her own village".[54] During her first series, Gillan wanted Amy to act "like a child in an adult body" because she had not properly grown up.[55] She appears more guarded because "she doesn't like to show her emotions because she wants to be strong".[56] However, she begins her second series as a more settled person,[55] and shows more emotion, especially with the birth of her daughter.[56]

    Gillan had substantial input into Amy's costume, as well as her hair and make-up.[48] In the first episode, costume designer Ray Holman stated that Amy's identity was not clear and that she wore her own clothes later on.[57] Gillan thought that Amy had inner confidence to wear clothes that showed "a bit of skin from time to time".[48] Gillan said she tried on many things, but when it came to short skirts she "just thought it was right" and showed that Amy was "comfortable and confident about her look".[58] She believed that the skirts reflected what young women typically wear at her age.[54] Executive producer Piers Wenger also noted that Amy's s flying jacket, which she wears "quite a lot", reflected Gillan was a "born adventurer" and Amy developed a love for travel and adventure.[57] In the sixth series, Amy wears more jeans and longer trousers; Gillan stated, "she's getting a little bit more tomboyish as she becomes more of an action girl".[59] Amy never wears heels, as Gillan desired that the footwear be functional for saving the world.[60]

    As the Doctor accidentally did not return for her until twelve years later, Amy grew up a different person than she would have. She had become "cynical" and "distrustful" as the Doctor did not return as he had promised and she was forced to believe he was just an imaginary friend, and had resorted to being "tough". Moffat theorised that Amy would have taken her anger out on Rory and would have been "mean" about things such as Santa Claus and the Tooth Fairy.[61] The second episode, "The Beast Below", was to introduce Amy into the role of the Doctor's companion and how much he needed one.[62] Though Amy soon tries to seduce the Doctor, Moffat believed that it was consistent with the cynical character he had built up. It was also a reflection of how the two had just escaped from death and shared a hard time together, and Amy's tendency to do things "in the heat of the moment".[63] In "Amy's Choice", meant to challenge the Doctor and Amy's relationship,[64] Rory dies in an alternate universe that was a result of psychic pollen that had entered the TARDIS. This is when Amy truly realises her feelings for Rory.[65] As a primary part of the series' story arc, Rory officially dies and is erased from history and Amy's memory.[66] Though Rory later returns, he is an Auton duplicate who kills her, which reflected Moffat's belief that all good love stories end in tragedy.[67] The end of "The Big Bang", in which Amy stands up at her wedding and declares the Doctor is real, was the Doctor's success at restoring Amy to the spirit of the girl he first met.[52]

    Moffat had always intended for Amy and Rory to get married "from the off".[68] Gillan stated, "What I love about that relationship is that we really saw it develop to get to the stage where they were happy together. Because we started off at a point where Amy didn't want to be committed to him, and he absolutely did, and that just gave us somewhere to go with it, rather than just them being happy together. So it was interesting, and it evolved, and Rory really became a hero in the process".[46] She was pleased that the audience was able to see Amy's life "pan out", starting when she was a child and through her marriage and daughter.[46] Gillan stated that the aftermath of "A Good Man Goes to War" would "change her in a big way for the long run and I think we are going to get to see Amy in a really different light".[69] According to Moffat, by the seventh series, Amy and Rory had become "a crack team"; so used to being the Doctor's companions that instead of marvelling at him they "treat him like a big kid they have to look after".[70]

    In December , it was announced that the seventh series would be Amy and Rory's last.[71] Previously in November, Gillan had stated that once Amy had left, she did not want to make returning cameos, as she believed it would "take away from the big, emotional goodbye".[72] Gillan had arranged her exit with Moffat and the two decided on how Amy should leave. Gillan stated that she wanted to go "on a high when the character was at her prime" and that she "[wanted] to see her go with everything that she wants".[73] Gillan would make a brief appearance at the end of the Christmas special, The Time of the Doctor, with Amy Pond saying a final goodbye to the Eleventh Doctor just before he regenerates, bringing actors Gillan and Matt Smith together for a brief moment at the conclusion of Smith's last regular appearance as the Doctor.

    Reception[edit]

    Gillan signing autographs at the US premiere of "The Eleventh Hour"

    With the premiere of "The Eleventh Hour", two viewers anonymously quoted in The Telegraph complained that Amy's character was too "sexy" for a family programme like Doctor Who. Executive producer Piers Wenger stated that Amy was intended to be "feisty and outspoken and a bit of a number. Amy is probably the wildest companion that the Doctor has travelled with, but she isn’t promiscuous."[58] On a similar note, Gavin Fuller, writing for The Daily Telegraph's website, criticised Amy's "attempted seduction of the Doctor" in the episode "Flesh and Stone", claiming that it "did seem out of keeping with the usual tone of the series", and that "Given the number of young children who watch, it may not have been the most appropriate of scenes to screen".[74]

    Critics noted that Amy did not develop much throughout the series. Dan Martin of The Guardian, in a mid-series review, wrote, "I wonder whether I really know Amy Pond. Beneath the sass and the sauce and the wit and (there's no getting away from this) the skirts, I've yet to completely empathise with her, or work out what makes her tick".[75] In a review before the finale, Martin called her "a revelation", although she sometimes "felt a little one noteBut I'd put all of that down to guest writers responding to a character brief that probably said little more than 'feisty redhead'".[76]IGN's Matt Wales shared similar sentiments, writing, "Despite Gillan's effortless charisma, Pond was frequently painted in largely two-dimensional strokes that made for a brash, sometimes irritating turn. It's testament to Gillan's abilities and brilliant chemistry with Smith that she remained thoroughly watchable throughout but, bereft of back story (albeit intentionally), it was hard to really get involved with the character".[77] Paul Kerton of Zap2it, however, wrote in a review of "The Eleventh Hour" that Amy's "brilliantly executed introduction to the show stood out. Amy's character after just one episode is already one with depth".[78]alloverlimo.us's Teresa Jusino was also more positive towards Amy in the fifth series, writing that she was equally "competent, intelligent, and [quick-thinking]" as she was flawed and made mistakes, which made her relatable and "a successful female character".[79]

    Chris Haydon of Den of Geek argued that Amy was "much more than the supposed eye candy many journalists unfairly referred to her as, or indeed much more than a female human to accompany the Gallifreyan Time Lord. She is far more three-dimensional and developed than the pre-existing judgements made her out to be". He also praised Gillan's acting abilities and the way her relationship with Rory helped "render [her] character into something quite special".[80]The Daily Telegraph's Michael Hogan considered Amy "the joint best assistant of the rebooted Who era&#;– far superior to Catherine Tate and Freema Agyeman, equally as excellent as Billie Piper". He also praised her relationship with the Doctor, saying that they were "totally believable as best friends".[81] Patrick Mulkern of Radio Times praised Amy for being "cheerfully freeof the emotional baggage that mired her predecessors"[82] and also reacted positively to her attempted seduction of the Doctor.[83]SFX named Amy and Rory the second-best science fiction and fantasy romance.[84] In , leading up to her departure, Martin wrote that Gillan's acting had improved, becoming less of "a rootless collection of personality traits and enunciated sentence peaks" and someone more rounded. He also noted that Amy was unique because so much had happened to her and she became intwined in the Doctor's life, which allowed the audience to see her "develop and change".[85]

    The Guardian's Krystina Nellis argued that Amy functioned more as a plot prop than a strong female character, citing the importance of giving birth to River Song.[86]Charlie Jane Anders of io9, while positive towards her relationship with Rory, opined that Amy was still "a bit of a cartoon character" in "The Wedding of River Song", believing that her killing Madame Kovarian was "no substitute" for dealing with what Kovarian had done to her child.[87]

    The character has gone on to be referenced in popular culture. American supernatural drama Supernatural''s seventh season "The Girl Next Door" (), a character played by Jewel Staite operates under the alias Amy Pond. Digital Spy felt the Doctor Who reference was "rather random",[88] while IGN "loved" the shoutout.[89]

    Gillan has won over six awards up to date for playing the role of Amy Pond. In she won Cosmopolitan 'Women of the Year' Award.[90] In Gillan won an SFX Award,[91] a TV Choice Award,[92] and in she won at the National Television Awards.[93] In an online poll, with 3, participants, taken in late , Amy Pond was listed as the fifth most popular companion.[94]

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    External links[edit]

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  • Источник: [alloverlimo.us]

    Christopher Pelant

        D     E     C     E     A     S     E     D    

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    Nickname(s)

    Hacktivist (himself)

    Aliases

    Bassam Alfayat
    Justin Trimple

    Occupation

    IT instructor
    Hacker
    Waiter (alternative reality)

    "Trying to make the system secure, Dr.eye 6.0 crack serial keygen, we make it more complex. But the more complex we make it, the more insecure we actually are."
    &#;Pelant in The Crack in the Code

    Christopher Pelant or The Hacktivist&#;was&#;a serial killer introduced in the season seven episode "The Crack in the Code".

    History[]

    Christopher Pelant was an American citizen who, according to Booth in The Corpse on the Canopy, was officially&#;born in Denmark in and raised&#;in the town of Pitt Meadows, Virginia. According to Sweets in The Past in the Present, his parents divorced when he was young and he was close to his father, though they rarely saw each other afterward. He later used his distinctive hacking skills to erase his true identity, making it appear as though he was not an American but actually an Egyptian citizen, Bassam Alfayat, who had lived in Egypt until the age of six. He did this in order to escape arrest for a crime he committed during his teens that 'Christopher Pelant' could be tied to. By making it appear as though he wasn't Pelant, he evaded arrest.

    During high school, Pelant had a pro tools License Key Download Archives counselor by the name of Carole Morrissey. He asked&#;her to write him a letter of recommendation for Stanford but she refused. He&#;hacked into her computer and&#;wrote the recommendation himself. Pelant&#;then killed&#;her with a katana he "borrowed" from his grandfather, who obtained the weapon while serving in the Pacific theater during WWII.&#; He buried her hoping he would never get caught. &#;At the time of the murder, Pelant was rather obese, however, he later placed pictures on an online yearbook from his high school making it appear that he was slim, therefore distorting the proportions of the force of the fatal blow and the weight of the Dr.eye 6.0 crack serial keygen weapon. This distortion made it look like he was slim and using a heavier weapon, when in reality he was large and using a lighter weapon, Dr.eye 6.0 crack serial keygen. He then&#;began rapidly losing the large weight he had at the time to further corroborate his story.

    Before Pelant&#;became a serial killer, he was already a computer hacker who had a strong belief that the U.S. government was corrupt. He demonstrated his hacking skills twice by shutting down the Senate website in and hacking into the Pentagon security system to shut it down, endangering the lives of countless U.S. soldiers. He was eventually arrested, convicted of wire and computer fraud, and sentenced to house arrest. His personal calling card both times was leaving behind a question written in blood-like letters on the websites; on the Senate website he left the question "Where's the website?" and on the Pentagon's, he left behind "What are you defending?".

    Pelant: I'm not a criminal. I'm a 'Hacktivist'.

    --The Crack in the Code

    His hatred was then directed towards the FBI for his arrest and conviction and resulted in him seeking revenge against them. He started by stealing the blood of five FBI agents and acquiring a bang stick (or as is suggested constructing one himself). He was then able to surreptitiously Dr.eye 6.0 crack serial keygen his ankle monitor and proceeded to kill a woman. He then placed her remains in various locations for the FBI Dr.eye 6.0 crack serial keygen find, upon scanning the bones the Jeffersonian computers were infected with a worm that Pelant had intricately carved into their surface.&#;

    It is possible that Pelant discovered the truth about Glen Durant and his shadow government and covered his tracks to avoid getting detected or killed by Durant. These actions could have led to Dr.eye 6.0 crack serial keygen first crimes; hacking into the Senate website and the Pentagon security system. He must have decided to lead Brennan and Booth Dr.eye 6.0 crack serial keygen the Ghost killer so they can inevitably discover the conspiracy through the McNamara's background hoping that Durant or his agents would kill them if he failed to make Brennan see him in a new light and/or kill them.&#;

    Sweets mentioned that Gordon Wyatt wrote a book on Dr.eye 6.0 crack serial keygen role of sexual sadism in female serial killers. Implying that Pelant may have reviewed Bones and Booth's Psychological Case Files from Dr. Wyatt to be even more thorough. He also may have read Dr. Wyatt's book and used its psychological information and his intelligence to find the serial killer he mentioned to Bones; The Ghost Killer.&#;

    Throughout The Bones series[]

    The Crack in the Code[]

    In his first appearance, Pelant places the skull and spine of his victim in front of a statue of Abraham Lincoln and leaves the message "Where is the Rest of Me?." He then proceeds to leave the rest of the bones in a storage area where the FBI keeps information regarding its informants. After this, he reaches out to a reporter named Ezra Krane, who had previously covered his trial and gives him all the details of his crimes and the FBI's corruption. Later Pelant gets nervous and kills Krane in order to Dr.eye 6.0 crack serial keygen the identity of his source remains a secret. Pelant then hacks various hospitals to have Krane's body cremated before an autopsy can be made. When brought in for interrogation, Pelant doesn't deny being responsible for the murders, but also points out that his ankle monitor gives him a solid alibi.

    The Past in the Present[]

    In the season seven finale, Pelant, who is up for the possibility of parole, frames Brennan for the murder of her friend, Ethan Sawyer, a schizophrenic mathematician whom she had asked for help with the case, exploiting the fact that his delusions included a belief that Brennan's new baby, Christine, was a 'demon'. Altering video footage and using supplies stolen from the Jeffersonian, he ensures that people who love Brennan and are capable of solving his crimes are removed from investigation one Dr.eye 6.0 crack serial keygen one. Caroline recognizes this and her hope for bringing justice for Brennan and his victims lays with the Jeffersonian team still being on a case, aided by the fact that Camdidn't conceal crucial evidence Traktor Pro 3.5.1 Crack + Torrent {License Key} Free Download 2021 samples of Sawyer's hair in Brennan's Dr.eye 6.0 crack serial keygen. Eventually, Brennan's fatherconvinces her that she shouldn't trust the system given Pelant's computer skills, thus making her go into hiding.

    The Future in the Past[]

    In the Season 8 opener, Bones is still on the run, still attempting to find a way to prove Pelant has framed her, while Pelant is currently teaching a night class in computer skills at a nearby college. She manages to uncover the bones of Pelant's former school counselor, whom he murdered in order to ensure his place at Stanford by forging her recommendation; Sweets is able to identify this as key passages of the recommendation later fit with Pelant's writing style rather than the guidance counselor's. It is revealed that Angela and Bones have also been communicating using flowers with various coded meanings. Cam tells Edison to send details of both the bones and the flowers to Booth via email, knowing it will draw Pelant out. Knowing of the flower's code Pelant waits at the next drop point for a flowered message and encounters Hodgins who he taunts into strangling him into unconsciousness. Hodgins reveals this fact to Sweets who realizes it uncovers the third aspect of Pelant's personality and gives this information to Angela, Dr.eye 6.0 crack serial keygen, showing that it fits into Ethan's pyramid. Booth convinces Flynn (the agent who took over for Booth when Booth was taken off the case due to manipulation by Pelant) to arrest Pelant for hacking into the FBI email system just as Cam had hoped and he is detained. Meanwhile, Bones has snuck into the Jeffersonian and is using Cam and Edison's work to analyze the bones further; based on her observations of his gait, she determines that Pelant was in fact fat in high school and thus could have used a light weapon to deliver a heavy blow. The FBI discovers his grandfather's Japanese sword and it matches the killing blow to his high school counselor, he is finally arrested for at least one murder. Angela uses the explanation Sweets provided of Ethan's pyramid to find an encryption key that breaks some of Pelant's code and reveals how he superimposed Bones into security footage.

    Just when things start to seem settled, Caroline reveals that the man they know as Pelant is in fact, according to DNA, fingerprints, and background records, Bassam Alfayat, an Egyptian diplomat who is being taken back to Egypt by their government, begging the question of which identity was real. As a final act, Pelant/Alfayat gives Bones a Marigold symbolizing pain and grief, and in return, Bones slaps him across the face. When Bones tells Booth what the flower means, Booth throws it into a nearby wastebasket and they both leave, only to have the camera zero in on the flower in the wastebasket, which is then retrieved by Agent Flynn.

    The Corpse on the Canopy[]

    Angela and Hodgins wake up with a skinned body above them. They figure out that it was Pelant who placed it there. They identify the victim as a private military contractor Dr.eye 6.0 crack serial keygen track Pelant to his place of work. Pelant hacks into a security firm's firewalls and takes control of a drone and targets a school full of children in Afghanistan. At the same time, he hacks into Hodgins' bank accounts and starts draining all his money. He forces the team to make Dr.eye 6.0 crack serial keygen choice between the school and the money and Hodgins' chooses the children while Booth and Flynn pursue Pelant. In pursuit of Pelant, Flynn is shot and injured by robotic machine guns while Booth opens fire on Pelant, grazing his face from behind, and causing severe damage to his right side. He drains all the money from Hodgins' account so now Hodgins is broke.&#;He is last seen stitching up his face with supplies he took from a dead veterinarian.

    The Secret in the Siege[]

    In the season 8 finale, Pelant, now bearing heavy scarring to the right side of his face after being wounded by Booth, manipulates a woman named Anna Dr.eye 6.0 crack serial keygen into killing FBI agents who were involved in a raid on a separatist religious cult that went wrong. He has been stalking Booth and Brennan since their last encounter. At the end of the episode, during which they had decided to get married, Pelant calls Dr.eye 6.0 crack serial keygen and tells him that he changed the rules when he shot him. He also forces Booth to turn down Brennan's proposal, threatening to kill more innocent people and pinning them on him if he refuses or even if he tells her why he does it. Unwilling to let that happen, Booth tells Brennan that the relationship they have is enough. She accepts this, Dr.eye 6.0 crack serial keygen, but is left heartbroken, although Booth still vows to kill Pelant one day.

    The Secrets in the Proposal[]

    Though not featured in this episode, after three months of trying to find him, Booth doesn't have any sort of leads on Pelant. Booth and Brennan are conflicted, because if Booth accepted Brennan's proposal then Pelant would kill five random people and send Booth to jail for the murders, and Brennan can't know it. The two become distant, but Brennan talks with an old friend of Booth and decides to have faith in Booth that he wouldn't have declined her proposal without a good reason. At the end of the episode, after the couple made up, the kitchen clock starts blinking the wrong time before going back to the right one, proving or at least implying that Pelant is spying on them.

    The Sense in the Sacrifice[]

    "You and I are destined to die together Someday. I hope not today, but that's up to you."
    &#;Pelant to Brennan

    As Angela installs more anti-hacking firewalls in the Jeffersonian computers, the Jeffersonian staff, Booth, and Flynn use a donated body to stage a Pelant-style crime scene to try to flush Pelant out. They send Flynn to pose the skinned body as Prometheus in a painting. Although the plan does work, Pelant, who has bugged Flynn's car, catches onto them, kills Flynn, and uses his body for the crime scene instead. Pelant tries to woo Doctor Brennan, thinking that he would be able to win her over based on his analysis of Sweets' research, which 'confirmed' that Brennan can change her mind about people. In the end, however, Dr.eye 6.0 crack serial keygen, Brennan refuses Pelant, Dr.eye 6.0 crack serial keygen, who thought that Brennan would pick him instead. Though he has the intelligence, Brennan Dr.eye 6.0 crack serial keygen wants him dead, even if it means her death. Booth calls Pelant's bluff, shooting him in the neck, "disconnecting the computer", and ultimately killing him, and then proposes to Brennan, telling her the truth behind his refusal. She stated that she knew that it was something like that and that he made the right choice, Dr.eye 6.0 crack serial keygen.

    In this episode, Pelant reveals to Brennan that there is another serial killer still at large. Pelant may or may not know them personally, but he has "a reason to believe it's a woman."

    The Ghost in the Killer[]

    Brennan has nightmares about Pelant and his possible companion The Ghost Killer, becoming rather obsessed with this new killer.

    The th in the 10th[]

    In the alternate reality, Pelant makes a brief cameo as a waiter to tell Brennan she has a phone call.

    The Next in the Last[]

    When the Jeffersonian are investigating a corpse that had their hands cut off, on the obelisk with NCH VideoPad Video Editor Professional 8.16 Portable Crack flower and a message of "be warned", they start to investigate connections to Pelant. They discover links to his previous cases and discover a copycat murderer using the Modus Operandi of Pelant. They eventually reveal the killer to be Leelah Strawn and find evidence at her house including a newspaper clipping. They also recover Hodgins's money drained two years ago, and Pelant himself is later seen in a video but Brennan turns it off deciding to leave Pelant in the past where he belongs.

    Modus Operandi[]

    Pelant had no consistent Dr.eye 6.0 crack serial keygen in his crimes, though his murders were usually very complex and involved severely mutilating the victims, sometimes Dr.eye 6.0 crack serial keygen order to implant messages into their remains. When he manipulated Anna Samuels into killing, her victims were shot with a 9mm pistol, first once in the neck to kill them and then ten more times in the body. He also based some details of Samuels' crimes on research papers written by Sweets.

    He used messages written in blood to sign his work on the Senate website and the Pentagon security system as well as Inger Johannsen's murder investigation during The Crack in the Code. Ever since he was put under arrest for Ethan Sawyer's murder after the team proved Brennan's innocence, he started to leave flowers next to some of his later victims similar to how Brennan communicated with Angela between Seasons 7 and 8.

    His use of Sweets' psychological research on everyone he faced could indicate that he is the Anti-Sweets like how Heather Taffet is the Anti-Brennan and how Jacob Broadsky is the Anti-Booth. Some of the crimes he commits not only depends on computers and other forms of technology, but also on human behavior, such as the behavior of the people he faced during his crime spree. He uses the information he accumulated from Sweets' files to manipulate people into doing exactly what he wants them to do in order to use the criminal justice system against them. However, he was also the Anti-Sweets in his inability to truly understand this insight, believing that Sweets' observations about how Brennan had changed over time meant that Dr.eye 6.0 crack serial keygen could convince Brennan to return his displays of 'affection,' as he was incapable of recognizing that Brennan had fallen in love with Booth due to their shared dedication to finding justice Dr.eye 6.0 crack serial keygen protecting innocent people in the process of arresting and/or killing murderers like him.

    Known Victims[]

    • June Carole Morrissey (snared, hung upside down and slashed to death and gutted with a katana)
    • Inger Johannsen (killed with a bang stick, dismembered and her spine and skull removed)
    • Ezra Krane (killed with a bang stick and hung from a flagpost)
    • Ethan Sawyer (drugged him with tubocurarine, cut his arteries and left him to be eaten by wolves; framed Brennan for the murder)
    • Xavier Freeman (tortured to the point of cardiac arrest with repeated needle punctures to the spine, then flayed and mutilated and posed like Vesalius)
    • Special Agent Hayes Flynn (shot with security Gatling guns; survived, was later killed and posed like Prometheus and his liver was removed while he was still alive)
    • The students of a girls' school in Afghanistan (threatened to kill with a drone strike; averted)
    • An unnamed veterinarian (apparently stabbed; killed for access to his office and supplies)
  • Alan Friedlander (shot once in the neck and shot ten more times post-mortem by Anna Samuels)
  • Jeff Stone (shot once in the neck and shot ten more times post-mortem by Anna Samuels)
  • Lance Sweets (attempted shooting by Anna Samuels)
  • Trivia[]

    • He is regarded as the most dangerous and recurring serial killer in the entire series.
    • He had a grandfather that served in WWII who was befriended by Max Keenan in order to gain information. He brought over many Japanese weapons from his time in WWII, including the Japanese katana Pelant used on his first victim.
    • The right side of his face was badly mutilated by a shot from Booth into Pelant's car's windshield, which Pelant had to sew up himself using tools from a veterinarian he killed.
    • Booth shot Pelant in the neck, severing his spinal column. While going after Jacob Broadsky, Booth mentioned in The Killer in The Crosshairs while investigating the death of Walter Coolidge that severing the head from the spinal cord is a gold Dr.eye 6.0 crack serial keygen for snipers. They call it "Disconnecting the Computer." It was the same method that Booth used to kill Pelant with his handgun.
    • The old computer Pelant owned in The Crack in the Code was an IBM Console Card Reader made in However, it was based on discrete transistors rather than old vacuum tubes which makes it questionable how there would be a vacuum tube missing from inside the computer. Although, Pelant may have possessed old vacuum tubes among his collection of obsolete electronics to build his bang stick.
    • The computer virus/worm delivered via the bone etchings, which Pelant personally devised and carved, could be considered a form of Arbitrary Code Execution (aka ACE exploit), a real-world method of computer security exploitation. While it may not be feasible to use carvings on bones to produce an&#;ACE exploit, the core concept of using seemingly random imputs to&#;generate&#;a series of code within a program&#;thus making&#;the program do something it normally shouldn't&#;remain a valid real-world technique.&#;(In this case, the imaging program which rendered the images Dr.eye 6.0 crack serial keygen the scanned bone etchings gave Pelant remote access to the FBI computers.)
    • Pelant has the highest known I.Q. of all of the villains to appear on&#;the show,

    Notes[]

    • Due to his unparalleled hacker and computer skills and his appreciation of the fine arts (albeit for self-gratification) Pelant could be viewed as the Anti-Angela.
    • Since Pelant is quite adept at reading human psychology in order to unhinge and manipulate his enemies, Pelant also functions as the Anti-Sweets. Although he can be equally stubborn when it comes to bringing his patients' issues to the light, Lance Sweets refuses to push their personal boundaries, whereas Pelant would go through extremes to bring out their personalities' darkest aspects.
    Источник: [alloverlimo.us]

    Vasculitides

    Guest Editor (s): John H. Klippel, MD,1John H. Stone, MD, MPH,2Leslie J. Crofford, MD,3and Patience H. White, MD, MA4

    1Arthritis Foundation, Atlanta, GA USA

    2Massachusetts General Hospital, Boston, MA USA

    3Division of Rheumatology &#x; Women&#x;s Health, University of Kentucky, Lexington, KY USA

    4Arthritis Foundation, Atlanta, GA USA

    Cornelia M. Weyand

    5Kathleen B. and Mason I. Lowance Center for Human Immunology, Department of Medicine, Emory University School of Medicine, Atlanta, GA USA

    Find articles by Cornelia M. Weyand

    Jörg J. Goronzy

    6Department of Medicine, Kathleen B. and Mason I. Lowance Center for Human Immunology, Emory University School of Medicine, Atlanta, GA USA

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    Author informationCopyright and License informationDisclaimer

    5Kathleen B. and Mason I. Lowance Center for Human Immunology, Department of Medicine, Emory University School of Medicine, Atlanta, GA USA

    6Department of Medicine, Kathleen B. and Mason I. Lowance Center for Human Immunology, Emory University School of Medicine, Atlanta, GA USA

    corresponding authorCorresponding author.

    Copyright © Springer Science+Business Media, LLC

    This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID as a global pandemic.

    Abstract

    Despite the spatial closeness of blood vessels and inflammatory cells, Dr.eye 6.0 crack serial keygen, blood vessel walls are infrequently targeted by inflammation. Giant cell arteritis (GCA) and Takayasu&#x;s arteritis (TA) are characterized by inflammation directed against the vessel wall. GCA and TA display stringent tissue tropism and affect defined vascular territories in a preferential manner. GCA predominantly affects the second- to fifth-order aortic branches, often in the extracranial arteries of the head. The aorta itself may also be affected in GCA, albeit less often than other regions. In contrast, in TA, the aorta and its major branches are the prime disease targets.

    Keywords: Giant Cell Arteritis, Polymyalgia Rheumatica, Small Vessel Vasculitis, Large Vessel Vasculitis, Temporal Artery Biopsy

    A. Giant Cell Arteritis, Polymyalgia Rheumatica, and Takayasu&#x;s Arteritis

    • Giant cell arteritis (GCA) and Takayasu&#x;s arteritis (TA) are prototypes of large vessel vasculitis, tending to involve the aorta and its branches.

    • Giant cell arteritis predominantly affects the second- to fifth-order aortic branches, Dr.eye 6.0 crack serial keygen, often in the extracranial arteries of the head.

    • Giant cell arteritis occurs exclusively among individuals who are 50 years of age or older. The mean age at diagnosis onset is approximately

    • In TA, the aorta and its major branches are the prime disease targets.

    • Both GCA and TA are associated with granulomatous inflammation within the blood vessel wall.

    • In both GCA and TA, clinical symptoms of vascular inflammation and vascular insufficiency are usually accompanied or preceded by a systemic inflammatory process.

    • Visual loss is the most feared complication of GCA. Visual loss may occur through the syndrome of anterior ischemic optic neuropathy, caused by narrowing of the posterior ciliary artery and other vessels to the eye.

    • The diagnosis of GCA is made usually by biopsy of the temporal artery.

    • Polymyalgia rheumatica (PMR), a syndrome of muscle pain and stiffness in the neck, shoulders, and hips, often occurs with GCA but can occur independently.

    • Glucocorticoids are the cornerstone of treatment for GCA, Dr.eye 6.0 crack serial keygen, TA, and PMR. Isolated PMR requires a lower dose of prednisone for disease control.

    Despite the spatial closeness of blood vessels and inflammatory cells, blood vessel walls are infrequently targeted by inflammation. Giant cell arteritis (GCA) and Dr.eye 6.0 crack serial keygen arteritis (TA) are characterized by inflammation directed against the vessel wall. GCA and TA display stringent tissue tropism and affect defined vascular territories in a preferential manner. GCA predominantly affects the second- to fifth-order aortic branches, often in the extracranial arteries of the head. The aorta itself may also be affected in GCA, Dr.eye 6.0 crack serial keygen, albeit less often than other regions. In contrast, in TA, the aorta and its major branches are the prime disease targets.

    In both GCA and TA, clinical symptoms of vascular inflammation and vascular insufficiency are usually accompanied or preceded by a systemic inflammatory process not localizable to a single tissue or organ. Systemic inflammation is also characteristic of polymyalgia rheumatica (PMR), a syndrome of muscle pain and stiffness in the neck, shoulders, and hips. PMR can accompany, precede, or follow GCA, Dr.eye 6.0 crack serial keygen, but it also occurs independently. In a subset of PMR patients, GCA is present but not clinically evident.

    Giant Cell Arteritis

    Epidemiology

    Giant cell arteritis is the most common primary form of vasculitis among adults in the United States and Europe. The disease occurs almost exclusively in individuals aged 50 years and older, and its incidence increases progressively with age (1). Women are more likely to be affected than men. The prevalence is highest in Scandinavian countries and in regions settled by people of Northern European descent, with incidence rates reaching 15 to 25 cases perpersons aged 50 years and older. GCA occurs much less frequently in Southern Europeans (6 cases perindividuals) and Dr.eye 6.0 crack serial keygen rare in blacks and Hispanics (1&#x;2 cases perindividuals).

    The Vasculitic Lesion

    The histological hallmark of GCA is a mononuclear cell infiltrate dominated by T lymphocytes and macrophages. The inflammatory infiltrate penetrates all layers of the arterial wall (Figure 21A-1). The infiltrates can be granulomatous with the accumulation of histiocytes and multinucleated giant cells. Granuloma formation is most likely to be observed in the media, Dr.eye 6.0 crack serial keygen. Although the presence of multinucleated Adguard Premium 7.6.3671 Crack With License Key Latest Version cells inspired the name of the disease, they are often absent, and the mononuclear infiltrates lack a complex organization. If present, giant cells lie in close proximity to the fragmented internal elastic lamina. Their presence correlates with increased risk for ischemic complications. GCA can also present with perivascular cuffing of vasa vasorum or T cell&#x;macrophage infiltrates in the adventitia, Surfer 22.1.151 Crack Plus Keygen Full Version 2021 arranged along the external elastic lamina. This finding is consistent with recent studies suggesting that the adventitia is a critical site in the disease process.

    The inflammation causes a series of structural changes to the arterial wall. Among the first Dr.eye 6.0 crack serial keygen changes observed is the finding of a lymphoplasmacytic infiltrate in the adventitia. With progress of the inflammatory process, the media of the arterial wall becomes thinner. As the medial smooth muscle cell layer loses thickness, the intima becomes hyperplastic, compromising or occluding the arterial lumen. Although the vessel lumen may become critically narrowed, thrombosis is not the central event. Hyperplasia of the intimal layer with scarring in the media and fragmentation of the elastic lamina are irreversible changes that persist beyond the stages of active arterial inflammation.

    Fibrinoid necrosis is rare and should raise the suspicion for other forms of vasculitis. Polyarteritis nodosa, microscopic polyangiitis, and Wegener&#x;s granulomatosis, for example, are known to affect the temporal artery as well as other more typical vascular beds. When these forms of vasculitis affect the temporal artery, their first pathological manifestations may be lymphoplasmacytic infiltrates within the adventitia, indistinguishable at an early stage from GCA.

    Pathogenesis

    The Immune Response in the Arterial Wall

    Experimental evidence supports a T-cell&#x;mediated immunopathology of GCA (2). Humoral immunity does not appear to be important: B cells are not found within the arterial wall; no pathognomic antibodies have been identified; and hypergammaglobulinemia is absent. T cells enter the vessel wall from the vasa vasorum in the adventitia, not from the macroendothelium. Recruitment and activation of tissue-invading T cells is controlled by dendritic cells (DCs) in the adventitia. DCs are an indigenous cell population in normal medium-sized and large vessels. In the adventitia, they are typically localized at the outside of the external elastic lamina, close to the adventitia&#x;media junction. Evidence suggests that these vascular DCs utilize Toll-like receptors (TLRs) to scan their environment for signs of infection, specifically for pathogen-related molecules.

    In GCA and PMR, such adventitial DCs are strongly activated, produce chemokines, and express T-cell stimulatory ligands. This model is supported by experiments in human artery mouse chimeras. In these experiments, human temporal arteries from GCA patients are implanted into severe combined immunodeficiency mice. Depletion of either T cells or DCs from the implanted vascular lesions terminates the inflammatory response, with subsequent clearing of the inflammatory infiltrate. In contrast, administration of TLR ligands to chimeras implanted with normal temporal arteries followed by the adoptive transfer of T cells is sufficient to induce the initial steps of vasculitis (3).

    Based on these studies, it has been proposed that the vessel wall, in its physiologic state, is an immunoprivileged site. In GCA, activation of vascular DCs by microbial products can break this immunoprivilege and lead to the recruitment and stimulation of T cells. The nature of the peptide antigens recognized by these T cells is undetermined, but it may be that common self-antigens are sufficiently immunogenic when DCs are activated.

    Macrophage function in GCA is known to be multifaceted, with specific commitments of these cells linked closely to their topographical arrangements within the cell wall (4). Interferon (IFN) gamma, a T-cell cytokine, regulates both macrophages and giant cells. Macrophages in the adventitia, intermingling with activated T cells, produce interleukin (IL)-1, IL-6, and transforming growth factor (TGF) beta. Macrophages in the medial layer are specialized in the production of metalloproteinases, and also contribute to oxidative damage. End products of lipid peroxidation, a cell injury mechanism driven by oxygen radicals, are typically found on medial smooth muscle cells (5). Macrophages recruited to the intimal layer are committed to the production of nitric oxide synthase Nitric oxide is suspected to be involved in tissue injury, Dr.eye 6.0 crack serial keygen, cellular activation, Dr.eye 6.0 crack serial keygen, and vascular remodeling. Multinucleated giant cells, Dr.eye 6.0 crack serial keygen, once assumed to function in the removal of indigestible debris, are actually active secretory cells, producing molecular mediators relevant in structurally changing the arterial wall. The presence of giant cells in GCA corresponds with the presence of high adventitial levels of IFN-gamma (6).

    The Artery Is an Active Collaborator in Arteritis

    The assumption that all pathogenic mechanisms in inflamed arteries are mediated by tissue-infiltrating immune cells is simplistic. T cells and macrophages in the arterial wall do not live and function in isolation, but rather closely interact with stromal components of the blood vessel in a bidirectional pattern (7). The major vascular abnormality leading to clinical disease is a nonthrombotic luminal occlusion, caused by rapid and concentric growth of the intima. These structural alterations result from the response to injury elicited in arterial cells (Figure 21A-2). Intimal hyperplasia is generated by the mobilization of smooth muscle cells, their directed migration towards the lumen, and their proliferation and matrix deposition. This process is under the control of growth factors. Platelet-derived growth factor (PDGF), a factor with the capability of supporting the outgrowth of the hyperplastic intima, is present in inflamed arteries. PDGF derives from macrophages and multinucleated giant cells, Dr.eye 6.0 crack serial keygen. Patients with low PDGF production have no or minimal lumen-occlusive intimal proliferation. In contrast, those with excessive PDGF production are at a risk for ischemic complications (8).

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    Figure 21A-2

    Schematic diagram of the sequence of pathogenetic events in giant cell arteritis. (1) Mononuclear cells enter the adventitia via the vasa vasorum, where T cells recognize antigens and produce IFN-gamma. (2) The infiltrate advances to the media, where macrophages and giant cells undergo differentiation and exert tissue-injurious effector functions. (3) The artery responds with neoangiogenesis and intimal hyperplasia.

    A second pathway of the arterial injury&#x;response program relates to the formation of new capillaries. The media and intima of normal arteries are avascular, but intense neoangiogenesis is induced in GCA (9). Vascular endothelial growth factor (VEGF) is critical in driving the generation of neovessels in the media and intima. VEGF, Dr.eye 6.0 crack serial keygen, like PDGF, originates from macrophages and multinucleated giant cells. The arterial response pattern initiated by the production of PDGF and VEGF leads to profound structural arterial abnormalities with subsequent stenosis and tissue ischemia, emphasizing that the immune system coerces the artery toward a counterproductive pattern of reaction. However, the inflammation also leads to the induction of protective response patterns that are Dr.eye 6.0 crack serial keygen at healing and tissue repair, Dr.eye 6.0 crack serial keygen. An example is the upregulation of the enzyme, aldose reductase (10), Dr.eye 6.0 crack serial keygen, which metabolizes and detoxifies end products of oxidative damage.

    The Systemic Inflammatory Response

    The activation of vascular DCs as an early step in the pathogenesis of GCA has two major implications: (1) Inflammation and immune activation are not limited to vascular lesions; and (2) a systemic component of GCA is an independent dimension of the disease process and not simply a spillover from vessel wall inflammation. Further evidence for this systemic component is the activation in GCA patients of circulating monocytes, which produce IL-1 and IL Elevated levels of IL-6, a potent inducer of acute phase responses, are characteristic of GCA. In this model, GCA is a systemic inflammatory disease, with vasculitis of medium and large arteries as a consequence of the disease process.

    Risk Factors

    Age is the major risk factor for GCA. No other environmental risk factors, including a variety of infectious agents, Dr.eye 6.0 crack serial keygen, have been demonstrated convincingly to play important roles in this Dr.eye 6.0 crack serial keygen. The high incidence rates of GCA in all geographical regions settled by people of Scandinavian ethnicity strongly suggest inherited risk factors (1). The best available information is for human leukocyte antigen (HLA) genes. HLA-DR4 haplotypes are associated with increased disease risk. Several allelic variants of HLA-DR4 are enriched among patients. Selective binding of antigenic peptides has been proposed as the mechanism underlying this genetic association. In contrast to other HLA-DR4&#x;associated diseases such as rheumatoid arthritis, HLA polymorphisms do not correlate with clinical phenotypes and disease severity. Many other genetic risk factors have been suggested, but none have been proven to date.

    Clinical Features

    The diagnostic category of GCA encompasses multiple variants (Figure 21A-3). Each of these subtypes has characteristic clinical features (11); however, the clinical manifestations of the different subtypes overlap substantially, and none of the clinical symptoms is unique for any one of the variants. Increased awareness of GCA, a growing population of individuals older than 50 years of age, and improvement in diagnostic procedures (e.g., the availability of magnetic resonance angiography to image the aorta and its branches) have led to increased detection of cases formerly Bitwar OCR Text Scanner 1.5.0 - August 2020 crack serial keygen to be atypical presentations.

    Giant cell arteritis presents with two major symptomatic complexes, signs of vascular insufficiency resulting from impaired blood flow and signs of systemic inflammation. In general, vascular changes are those of occlusion; arterial wall dilatation only occurs when the aorta is involved.

    Cranial Giant Cell Arteritis

    Giant cell arteritis, also known as temporal arteritis, has a predilection for involving the extracranial branches of the carotid arteries. The temporal artery, which courses just below the skin over the temple region, is the vessel most amenable to biopsy. In 80% to 90% of patients, histopathology of vasculitis is detected in the extracranial arterial tree, most often in the superficial temporal artery; Dr.eye 6.0 crack serial keygen vertebral, ophthalmic, and posterior ciliary arteries; and, less frequently, the internal and external carotid and central retinal arteries.

    Patients complain of throbbing, sharp, or dull headaches that are usually severe enough to prompt clinical evaluation. The headaches may or may not be associated with scalp tenderness. In classic cases, the patients notice temporal tenderness when wearing glasses, grooming, or lying on Windows TubeMate 2020 Key Features: pillow. On physical examination, involved vessels may be thickened, tender, and nodular. Pulses may Dr.eye 6.0 crack serial keygen reduced or absent. Abnormalities are most frequent in the temporal arterial branches, but they can also be detected in the occipital arteries or other superficial scalp vessels. In one third of the patients with biopsy-proven GCA, the temporal arteries are normal on physical examination.

    Focal arteritic lesions in the ophthalmic artery produce the most feared complication of GCA: vision loss. The disease is an ophthalmological emergency, because prompt recognition and treatment can prevent blindness. Ischemia anywhere along the visual pathway can lead to visual loss, Dr.eye 6.0 crack serial keygen, but anterior ischemic optic neuropathy is the most common cause. Visual loss is sudden, painless, and usually permanent. Amaurosis fugax, reported as fleeting visual blurring with heat or exercise or posture-related visual blurring and diplopia, may precede partial or complete Dr.eye 6.0 crack serial keygen. On ophthalmologic examination, anterior ischemic Dr.eye 6.0 crack serial keygen neuropathy is recognized by optic disc edema, eventually followed by sectoral or generalized optic atrophy with optic disc cupping. Besides optic neuropathy, the spectrum of ophthalmic complications is wide, Dr.eye 6.0 crack serial keygen, ranging from pupillary defects to orbital ischemia and from ocular motor is&#x;chemia to anterior and posterior segment ischemia.

    A relatively disease-specific manifestation of GCA that is present in about half of the patients is jaw claudication: pain in the masseter or temporalis muscles caused by compromised blood flow in the extracranial branches of the carotid artery. Prolonged talking and chewing produce pain in the muscles of mastication. The onset of jaw claudication following the initiation of chewing is surprisingly swift. Cases of trismus have been described. Claudication of the tongue is less frequent, but tongue infarctions have been reported. Vaso-

    occlusive disease of the carotid and vertebrobasilar arteries results in ischemia of the central nervous system (CNS), manifesting as transient ischemic attacks or infarcts. Neurologic manifestations are increasingly being recognized and can be expected in 20% to 30% of patients. True intraparenchymal CNS vasculitis in GCA is rare, but reported.

    Occult presentations of GCA are common, Dr.eye 6.0 crack serial keygen. GCA is the cause of fever of unknown origin in up to 15% of elderly individuals, for example. Nonspecific symptoms of pain in the face, neck, or throat are other warning signs of possible GCA. Chronic nonproductive cough can be an initial presentation of GCA. The involvement of cough receptors (present throughout the repiratory tree) by the vasculitic process is believed to be the cause of cough in GCA.

    Giant Cell Arteritis Manifesting as Fever of Unknown Origin

    Symptoms related to systemic inflammation are frequently present. Laboratory abnormalities are detectable in more than 90% of patients. In a subset of patients, the disease process is dominated by a systemic inflammatory syndrome. Fever of unknown origin with spiking temperatures and chills usually leads to diagnostic evaluations designed to exclude infections and malignancies. In less dramatic cases, malaise, anorexia, weight loss, low-grade fever, Dr.eye 6.0 crack serial keygen, and fatigue eventually become severe enough to prompt medical attention. Physical examination of the scalp arteries is often negative, and symptoms of vascular insufficiency can be absent. Temporal artery biopsy, even if the artery is normal on clinical examination, remains the diagnostic procedure of choice.

    Large Vessel Giant Cell Arteritis

    In at least 10% to 15% of patients, GCA involves the large arteries in a clinically evident manner. (The percentage of cases with subclinical large vessel disease may be substantially higher.) Preferred vascular beds are the carotid, subclavian, and axillary arteries. Vasculitis of the femoral arteries is infrequent. The major clinical presentation is that of aortic arch syndrome, producing claudication of the arms, absent or asymmetrical pulses, paresthesias, and (rarely) symptoms of digital ischemia. Patients with the large vessel variant of GCA often lack evidence of cranial involvement; they do not complain about headaches, have normal temporal arteries on examination, and almost 50% of temporal artery biopsies are negative for vasculitis (12).

    Aortitis in GCA can coexist with cranial arteritis. Whether the patient subset with subclavian&#x;axillary GCA is distinct from the subset progressing to aortic involvement is not known. Overall, the risk of patients with GCA to develop thoracic aortic aneurysm is increased fold Registry Mechanic 5.2 crack serial keygen. The elastic membranes supporting the aortic wall are destroyed and replaced by fibrotic tissue. The resulting histopathology can be indistinguishable from that of TA. Most cases of aortitis have been diagnosed several years after the initial diagnosis of GCA, raising the possibility that smoldering aortitis is more common than previously expected (14). The spectrum of clinical manifestations ranges from silent aneurysm to aortic dissection and fatal rupture.

    Diagnosis

    Inthe American College of Rheumatology (ACR) formulated classification criteria for GCA. These criteria, not intended Farming Simulator 19 crack serial keygen the purposes of establishing a clinical diagnosis of GCA, are shown in Appendix I.

    The diagnosis of GCA should be considered in patients aged 50 years and older with recent onset of unexplained headache, signs of tissue ischemia in the extracranial vascular territory, loss of vision, Dr.eye 6.0 crack serial keygen, symptoms of limb or jaw claudication, or polymyalgia rheumatica. Laboratory evidence of an acute phase response heightens concern about GCA. The diagnostic procedure of choice is the histological verification with the superficial temporal artery. In a recent meta-analysis, positive clinical predictors of a positive biopsy were jaw claudication, diplopia, and abnormalities of the temporal artery biopsy on physical examination (15). All other symptoms, including vision loss, elevated sedimentation rate, headaches, and constitutional symptoms, were not particularly helpful in predicting the results of temporal artery biopsies (i.e., in diagnosing GCA). The presence of synovitis was a negative predictor of GCA, indicative of the fact that most patients with true arthritis have another diagnosis, such as rheumatoid arthritis.

    Even the most specific findings for history, physical examination, and routine laboratory testing have sensitivities of only (at best) 50%. In view of the fact that rendering the diagnosis of GCA commits a patient to long-term course of glucocorticoid therapy, confirmation of the diagnosis by temporal artery biopsy is essential whenever possible. True negative results are Dr.eye 6.0 crack serial keygen in more than 50% to 70% of all patients undergoing biopsies at most institutions. False-negative biopsies, which occur as frequently as 10% of the time, can be minimized by taking a sufficient length of biopsy, by examining serial sections, and by removing the contralateral temporal artery when the first biopsy is free of arteritis. Short-term glucocorticoid treatment (up to 2 weeks, or even significantly longer) is unlikely to interfere with the results of a temporal artery biopsy. Prednisone should therefore not be withheld if a biopsy cannot be performed immediately.

    Laboratory Testing

    A pathognomic laboratory test for GCA does not exist. Specific autoantibodies have not been identified. Highly elevated acute phase responses are typical for GCA but are not present in all patients. Although a high erythrocyte sedimentation rate (ESR) is usually considered a hallmark of GCA, in a recent study 25% of all patients with positive temporal artery biopsies had normal ESRs before the initiation of glucocorticoid therapy (16). Other markers of acute phase response, particularly C-reactive protein (CRP), may be more sensitive than ESR in some patients, but studies have not demonstrated this consistently. Some evidence indicates that the most sensitive serum marker for ongoing systemic inflammation in GCA (both before and after glucocorticoid therapy) is IL IL-6, a strong inducer of acute phase reactants, probably functions upstream in the disease process. Unfortunately, reliable IL-6 measurements are not widely available, and knowledge about how (or if) to adjust therapy in the context of changing IL-6 levels remains incomplete. There is currently no evidence that treatment decisions should be predicated upon the results of laboratory tests&#x;ESR, CRP, or IL-6&#x;in the absence of clinical symptoms.

    Other laboratory abnormalities in GCA include mild-to-moderate normochromic or hypochromic anemia. Elevated platelet counts are common. Liver function tests, particularly alkaline phosphatase, can be abnormal.

    Imaging Studies

    Precise mapping of the vaso-occlusive process still requires angiography. Angiography is also essential for patients with significant stenoses in vessels to all four extremities, Dr.eye 6.0 crack serial keygen, for the purpose of measuring central aortic pressure directly. Alternatives to conventional angiography, however, have made great strides in recent years (17). Magnetic resonance angiography (MRA) permits evaluation of vessel wall thickness and perivascular edema&#x;significant advantages over conventional angiograms, which evaluate only the vascular lumen. In the proper clinical context, therefore, certain MRA findings may be diagnostic of large vessel vasculitis. The noninvasive nature of MRA also lends important advantages in serial monitoring, Dr.eye 6.0 crack serial keygen. Unfortunately, the appropriate interpretations of some MRA findings, for example, enhancement of the vessel wall following gadolinium administration and the presence of vessel wall edema, remain uncertain and require additional longitudinal studies.

    Computed tomography angiography, another promising technique, has not been evaluated thoroughly in large vessel vasculitis. Position emission tomography (PET) with 18F-fluorodeoxyglucose also holds promise for the assessment of the degree of disease activity in large arteries, but has not yet been validated for general clinical use. Other noninvasive vascular studies, including fluorescein angiography, transcranial Doppler flow studies, and Doppler ultrasonography, are useful in assessing certain vascular beds, for example, the retinal, vertebral, or subclavian arteries. These techniques only identify vascular insufficiency in cases with pronounced, lumen-stenosing disease, however, and do not provide specific information useful from the standpoint of diagnosis. Although Doppler ultrasound was once hypothesized to be useful in the diagnosis of GCA, the value of identifying a hyperechoic halo on ultrasound in the temporal artery has not been confirmed in subsequent studies (18).

    Treatment

    Glucocorticoids are explicitly effective in suppressing clinical manifestations of GCA. Since the introduction of glucocorticoids, the rate of GCA-related blindness has declined, documenting the effectiveness of this immunosuppressive approach. In almost all patients, glucocorticoids induce relief within 12 to 48 hours. The excellent response of the disease to this therapy has been suggested by some as a diagnostic criterion.

    In view of the severity of GCA-related morbidity, initial doses of 60 mg prednisone or equivalent have been recommended. Glucocorticoids cannot reverse intimal hyperplasia but may help attenuate the ischemic insult by reducing tissue edema. In ophthalmologic emergencies (e.g., amaurosis fugax occurring in suspected GCA), pulse glucocorticoids may be appropriate (19). Initial doses should be maintained until reversible manifestations of the disease have responded and the systemic inflammatory syndrome is suppressed. Subsequently, under close monitoring for clinical signs of disease reactivation, the dose of prednisone generally can be tapered by 10% every 1 to 2 weeks.

    So Dr.eye 6.0 crack serial keygen, the use of glucocorticoid-sparing agents to allow a more rapid taper has been unsuccessful (17). Initial positive results with methotrexate could not be confirmed in a subsequent study (20). A recent randomized, controlled trial of tumor necrosing factor (TNF) alpha blockade found this therapy to be ineffective as a glucocorticoid-sparing medication (21). A recent study suggests that a more aggressive induction therapy at the onset of the disease, including three daily pulses of 1 gram of methylprednisolone, may allow for a rapid tapering of glucocorticoids and, in particular, a discontinuation of glucocorticoids in the second year of disease (22).

    Aspirin is an important adjunctive treatment for GCA patients without contraindications. Retrospective studies have indicated strong reductions in the risks of visual loss and central nervous system ischemic events among patients taking aspirin for other reasons at the time their GCA was diagnosed (23). The mechanism of aspirin&#x;s efficacy in this setting is not entirely clear, but the medication may exert its effect through the selective suppression of interferon gamma production (17). Although the optimal dose of aspirin has not been established, doses ranging from 81 mg/day to  mg/day may be beneficial.

    Prognosis

    The most significant morbidity of GCA relates to reduced blood flow to the eye and optic nerve as well as hypoperfusion of the brain (19). If diagnosed and treated promptly, progression of the downstream effects of arterial wall inflammation, in particular lumen occlusion with tissue ischemia, can be prevented. Side effects of 80-20 Retriever 2.5 for Outlook crack serial keygen doses of glucocorticoids given over a prolonged period of time can be serious, especially in patients older than 50 years, and treatment should therefore Dr.eye 6.0 crack serial keygen be initiated if the diagnosis is confirmed. In the majority of patients, GCA does not enter remissions that are sustained indefinitely after discontinuation of glucocorticoids. In a prospective study of 25 patients with biopsy-proven GCA, all of the patients responded to 60 mg prednisone Dr.eye 6.0 crack serial keygen disappearance of clinical signs of the disease (16). However, 60% of patients had disease relapses that occurred throughout the course of treatment. Typically, reactivation of the disease produced symptoms of systemic inflammation or polymyalgic symptoms, but no vascular complications were seen.

    Polymyalgia Rheumatica

    Polymyalgia rheumatica is diagnosed in patients presenting with pain and stiffness in the muscles of the neck, Dr.eye 6.0 crack serial keygen, shoulder girdle, and pelvic girdle of at least 4 weeks&#x; duration (24). The myalgias are combined with signs of systemic inflammation manifesting clinically as malaise, weight loss, sweats, and low-grade fever. Most patients have laboratory abnormalities such as elevated ESR, elevated CRP, and anemia, which are indicative of a systemic inflammatory syndrome. Upregulation of acute phase reactants is helpful in distinguishing PMR from other pain syndromes, yet (as in GCA and TA) not all patients with active disease have elevated markers of inflammation within their serum. No pathognomic test for PMR is available; exclusion of other diseases with similar clinical presentations is essential. The systemic inflammatory syndrome associated with PMR is exquisitely sensitive to glucocorticoid therapy, such that prompt improvement of clinical symptoms with glucocorticoid therapy has been proposed as a diagnostic criterion. The pathophysiology of PMR is related closely to those of GCA. PMR is now often considered a form of GCA that lacks fully developed vasculitis.

    Epidemiology

    Because PMR remains a clinical diagnosis, epidemiological studies are difficult. PMR affects the same patient population as GCA, but occurs approximately two to three times more frequently (24). Women are affected more often than men, and the diagnosis is extremely unlikely in individuals younger than 50 years of age. In high-risk populations, such as Scandinavians and other peoples of Northern European descent, annual incidence rates have been estimated at 20 to 53 perpersons over the age of 50 years. In low-risk populations, such as Italians, the annual incidence rates for individuals aged 50 years and older are only 10 cases per ,

    Pathogenesis

    Although the sudden onset of intense inflammation is suspicious for an infectious etiology, no causative agent has been identified. Most pathogenic abnormalities in PMR patients are reminiscent Dr.eye 6.0 crack serial keygen those in GCA, supporting the concept that PMR is a variant of GCA characterized by the dominance of the systemic inflammatory over the vascular component.

    Human leukocyte antigen polymorphisms that are genetic risk factors for GCA are also associated with PMR. There is no evidence that the HLA has a role in determining whether the disease process will remain limited to PMR or progress to fully developed GCA.

    Polymyalgia rheumatica appears to be associated with a global activation of the innate immune system, Dr.eye 6.0 crack serial keygen, including circulating monocytes that produce IL-1 and IL Activated DCs render arteries susceptible to vasculitis. In many patients with PMR, in situ cytokine production can be demonstrated in biopsy specimens, although in lower quantities than in GCA. Of note, IFN-gamma is absent in PMR, but abundant in GCA ArcGIS Pro Keygen Archives. A subset of Dr.eye 6.0 crack serial keygen patients develops inflammation of periarticular structures, for example, bursae. Whether these patients comprise a different subset from those susceptible to developing frank vasculitis remains unclear.

    Clinical Features

    Patients complain about aching and pain in the muscles of the neck, shoulders, lower back, hips, thighs, and occasionally the trunk. In typical cases, the onset is abrupt and the myalgias symmetrical; they usually affect the shoulders first. Often the patients have pain during the night and have difficulties rising and dressing themselves. Weight loss, anorexia, malaise, and depression are common. Fever and chills should raise the suspicion of fully developed GCA. PMR is frequently difficult to distinguish from forms of seronegative polyarthritis. In particular, male patients can present with proximal aching and diffuse edema of the hands and feet that is highly glucocorticoid-responsive.

    Polymyalgia rheumatica includes Dr.eye 6.0 crack serial keygen with mild disease that Designing Software Archives promptly responsive to therapy and remits within a few months (26). In many patients, however, reactivation of myalgias occurs when glucocorticoid doses are Dr.eye 6.0 crack serial keygen. Some patients require higher initial doses of glucocorticoids than are usually considered to be effective in PMR.

    Patients with PMR must be carefully evaluated for possible GCA. A negative temporal artery biopsy does not exclude the possibility of large vessel vasculitis targeting primarily the subclavian and axillary arteries and the aorta. Signs of Dr.eye 6.0 crack serial keygen insufficiency, including claudication in the extremities, bruits over arteries, and discrepant blood pressure readings should alert the physician to the possibility of GCA (12). MRA can be helpful in confirming the concomitant diagnosis of large vessel vasculitis.

    In PMR patients with inflammation of periarti-cular structures, the most prominent findings are subdeltoid and subacromial bursitis (27). Biceps tendonitis and glenohumeral synovitis may also be present. Ultrasonography reveals fluid accumulation in the bursae; T2-weighted MRI shows thickening and edema. These involved areas show increased uptake on PET scans.

    The clinical symptoms of PMR can be mimicked by a number of arthropathies, shoulder disorders, inflammatory myopathies, hypothyroidism, and Parkinson&#x;s disease. The differential diagnosis also includes malignancies and infections. No clear guidelines have been developed to determine whether patients with PMR should be screened for occult malignancies. Lack of the typical and impressive improvement upon initiation of therapy can provide a clue towards reevaluating the diagnosis of PMR.

    Treatment

    Polymyalgia rheumatica is dramatically responsive to glucocorticoid therapy. Currently there are no data documenting glucocorticoid-sparing effects of other medications. However, almost all patients with PMR can be safely managed with glucocorticoids; doses for long-term treatment are low and unlikely to cause serious Dr.eye 6.0 crack serial keygen effects.

    A critical decision in treating PMR is the dose of glucocorticoids required for successful suppression of symptoms and inflammation. The glucocorticoid requirements may differ quite markedly among patients. Two thirds of patients can be expected to respond with remission of pain and stiffness when started on 20 mg/day or less prednisone (25). Some patients will need doses as high as 40 mg/day for complete clinical control. Such patients may be at higher risk of full-blown GCA. Patients initially controlled on 20 mg/day of prednisone can usually taper the dose by  mg every 10 to 14 days. More protracted tapering may be necessary once daily doses of 7 to 8 mg prednisone are attained. Dose adjustments should be based mainly on clinical evaluation, not exclusively on laboratory abnormalities. In many patients, PMR can go into long-term remission, and prednisone can be discontinued. Occasionally, successful suppression of recurrent myalgias and stiffness may only be achieved by giving very low doses of prednisone over an extended period. Patients should be warned about the potential of PMR progressing to GCA and should be monitored for vascular complications, particularly when discontinuing glucocorticoid therapy.

    Prognosis

    The prognosis of patients with PMR is good. In the majority of patients, the condition is self-limited. A proportion of patients will eventually present with typical symmetrical polyarthritis, fulfilling the criteria for the diagnosis of seronegative rheumatoid arthritis. Such patients may require disease-modifying antirheumatic drug (DMARD) therapy.

    Takayasu&#x;s Arteritis

    Takayasu&#x;s arteritis is a vasculitis of the large elastic arteries, specifically the aorta and its main branches. The disease may also affect the coronary and pulmonary arteries (28). Inflammatory injury to the vessel wall leads to patchy disappearance of the elastica and smooth muscle layer and subsequent intimal hyperplasia, resulting in vascular stenosis in virtually all patients and dilatation and aneurysm in about 25%. Complete occlusion of upper extremity arteries results in the loss of palpable pulses, which is why TA is also termed the pulseless disease. The preference for the aorta and its primary branches is signified in another alternative name, aortic arch syndrome. The ACR has developed a set of criteria to distinguish Dr.eye 6.0 crack serial keygen from other vasculitic syndromes (see Appendix I).

    Epidemiology

    Takayasu&#x;s arteritis is a rare disease that primarily affects adolescent girls and young women. The diagnostic criteria include an age of less than 40 years at disease onset; however, TA can start later in life, particularly in Asians (29). (In addition, the diagnosis is often not made until the patient is older than 40, but symptoms may have begun years before the diagnosis.) Incidence rates are highest in Asia (Japan, Korea, China, India, and Thailand), with estimates of approximately 1 case per 1 million persons annually. TA can occur in Dr.eye 6.0 crack serial keygen races and geographic regions, but South American countries have recently been recognized as additional areas of relatively high incidence. An international survey among 20 countries has indicated differences in the clinical spectrum of TA in different ethnic groups.

    Pathogenesis

    Takayasu&#x;s arteritis is a granulomatous polyarteritis. The adventitia is characterized by striking thickening, often How to Crack? Archives intense perivascular infiltrates around the vasa vasorum. Granuloma formation and giant cells are predominantly found in the media of the large elastic arteries. The medial elastic smooth muscle cell layer is destroyed in a centripetal direction and replaced by fibrotic tissue, leading (in the aorta) to vessel wall dilatation and aneurysm formation. Smooth tapering, narrowing, or complete occlusion of the vascular lumen results from proliferation of the intima, occasionally with thrombosis.

    The etiology of TA remains unknown. In view of the systemic features of the syndrome, Maxprog eMail Bounce Handler v3.7.2 crack serial keygen infections have been implicated, but no conclusive evidence for infectious organisms has been provided. CD8 T cells are a major component of vascular infiltrates, setting TA apart from GCA. Cytotoxic activities of tissue infiltrating CD8 T cells, mediated by the release of the pore-forming enzymes perforin and granzyme B, have been suspected of contributing to smooth muscle cell damage (30).

    Support for a role of CD8 T-cell&#x;mediated cytolytic tissue injury has come from the observation that selected HLA class I molecules, specifically HLA-B52, are overrepresented among TA patients (31). CD8 T cells recognize antigens when bound to HLA class I molecules. The role of CD4 T-cell Dr.eye 6.0 crack serial keygen and the contribution of macrophage effector functions in the vascular lesions are not understood. The focus of lymphocytic infiltrates on the adventitia and accumulation of T cells around vasa vasorum makes it less likely that the macroendothelium has major involvement in the pathogenesis of TA.

    Clinical Features

    A generalized inflammatory syndrome with fever, night sweats, malaise, anorexia, weight loss, and diffuse myalgias often dominates initial manifestations of TA. These symptoms are frequently misdiagnosed as infection. The clinical pattern of ischemic complications that emerge&#x;often years later&#x;directly reflect the vascular territory targeted by the disease (Figure 21A-4).

    Involvement of the carotid and vertebral arteries leads to neurologic and ophthalmologic symptoms, including dizziness, tinnitus, headaches, syncope, stroke, and visual disturbances. Atrophy of facial muscles and jaw claudication are mostly late manifestations. Occlusions of the brachiocephalic and subclavian arteries impair blood flow to the upper extremities, presenting as arm claudication, pulselessness, and discrepant blood pressures. The detection of bruits can be helpful in making the diagnosis.

    Cardiac disease, including ischemic coronary disease, arrhythmia, and congestive heart failure, can be related to aortitis of the ascending aorta or severe hypertension. Aortic regurgitation, a serious complication requiring prompt clinical attention, is a consequence of aortic dilatation. Coronary arteries can be involved directly or indirectly, producing classical symptoms of myocardial ischemia. Progressively enlarging aneurysms and possible rupture are a major concern in patients with TA of the aortic arch and the descending thoracic aorta. Patients from India, China, and Korea often have lesions in the abdominal aorta and its branches (particularly the renal arteries, causing renovascular hypertension). The proximal ends of mesenteric arteries are less frequently affected, but gastrointestinal symptoms, such as nausea, vomiting, and ischemic bowel disease can be seen in patients with TA.

    Diagnosis

    A combination of vaso-occlusive disease and systemic inflammation in a young patient should immediately raise suspicion for TA. Typically, the diagnosis is made by characteristic findings on vascular imaging (32). Tissue is rarely available. The findings on conventional angiography can be diagnostic for TA in the proper clinical setting. Angiography reveals long, smooth taperings of involved vessels, with a remarkable web of collateral blood vessels in advanced cases. As Wise Care 365 Pro 5.8.4 Build 578 Crack GCA, conventional angiography is essential in many patients with TA in order to measure accurately the central aortic blood pressure.

    Several noninvasive imaging techniques are informative for assessing progression of occlusive disease, but currently lack standardization and are subject to investigator bias and experience. Far more problematic than assessing the degree of stenosis within a given blood vessel is the reliable assessment of inflammatory activity by imaging. MRI/A has largely replaced conventional angiography for serial assessments of the distribution and degree of vessel involvement, and also permits evaluations of the vessel wall as well as the lumen. MRI/A is particularly important in the longitudinal monitoring of TA although, as noted, the correct interpretation of all MRI/A findings is not always clear. MRI/A has clear utility in monitoring the progress or stability of vascular stenoses, provided that serial studies are compared carefully for changes. Doppler ultrasound provides a good assessment of cervical vessels. Computed tomography angiography can be used to survey the aorta and proximal vessels, but rigorous serial studies of its use in TA remain to be performed. The role of PET scanning in gauging the degree of ongoing inflammation (as opposed to uptake that might be related to a process of healing or fibrosis) has not been established.

    Treatment

    Although some patients with TA have disease that appears to burn out, becoming quiescent after years of active disease, most patients have progressive or relapsing/remitting disease and require long-term immunosuppressive treatment (33). Glucocorticoids are the therapy of choice for management of TA. Recommendations of initial doses have varied, but 40 to 60 mg of prednisone may be necessary to control vascular as well as systemic inflammation. Monitoring of acute phase reactants (ESR, CRP) is only helpful in a subset of patients. In a National Institutes of Health (NIH) cohort, 50% of patients had active progressing disease despite nonelevated acute phase reactants (34). Prednisone doses are tapered as clinically indicated and tolerated, usually by 5 mg/day every 2 weeks until a maintenance dose of 10 mg/day is reached. Further dose reductions must be tailored to the individual patient. Low-dose aspirin or other antiplatelet agents should complement glucocorticoid therapy. Hitman Pro 3.8.16 torrent Archives, given in weekly doses of up to 25 mg, has shown promise in improving remission rates and sparing glucocorticoids (35), but has never been tested in a randomized trial (the same is true for all other potential steroid-sparing agents). Azathioprine, mycophenolate mofetil, cyclosporine, and TNF-alpha blockers have been used with reported success in individual patients, but controlled studies are required. Contrary to other vasculitides, Dr.eye 6.0 crack serial keygen, cyclophosphamide does not play a major role in this disease because of its toxicity and uncertain efficacy.

    Stenotic lesions are irreversible. Surgical management and angioplasty or stent placement have a role in selected patients, but for most patients revascularization attempts of vessels to the extremities are not necessary because of the exuberant collateralization that develops in TA. When revascularization is necessary, bypass grafts are generally successful, while stenting appears to have a high rate of reocclusion (33). Angioplasty is reserved for short stenotic segments. Treatment of hypertension secondary to renal artery stenosis may or may not benefit from revascularization, depending on the location of the lesion leading to renovascular hypertension. Decisions about whether or not to attempt revascularization should be undertaken in consultation with experts accustomed to the management of complex hypertension cases.

    Prognosis

    For much of the past several decades, TA has been viewed as an inevitably devastating disease. The diagnosis was seldom made before damage from prolonged vascular inflammation was already extensive. More recently, the potential for earlier diagnosis, effective immunosuppressive therapy, and astute surgical management have led to an improved prognosis for many patients. Long-term follow up of almost Japanese patients found stable clinical conditions in two thirds of the patients and serious complications occurring in only 25% of affected individuals. Cardiac complications, including congestive heart failure and ischemic heart disease, have become the most common cause of death in Japanese patients with TA. Acceleration of atherosclerotic disease emerges as a critical factor in long-term outcome.

    Clinical Feaures

    Polyarteritis nodosa can present with nonspecific constitutional symptoms such as fever, fatigue, malaise, myalgias, and arthralgias. This phase of the illness can last weeks or months. The more specific clinical manifestations of PAN are the direct results of inflammation in medium- and small-sized muscular arteries. PAN often has cutaneous involvement, a feature it shares with small vessel vasculitides such as the ANCA-

    associated disorders. This differentiates it from large vessel vasculitis (e.g., Dr.eye 6.0 crack serial keygen, giant cell arteritis and Takayasu&#x;s arteritis), in which skin disease is very rare. However, Dr.eye 6.0 crack serial keygen the ANCA-associated vasculitides, PAN is not associated with glomerulonephritis or pulmonary involvement. Common clinical features of PAN and their frequency are listed in Table 21B-1 (5).

    Table 21B-1

    Selected Clinical and Diagnostic Features of Pan and Their Frequency.

    Clinical Features
    Myalgias, general weakness, or dll fixer crack Archives muscle tenderness69%
    Weight loss &#x;4 kg67%
    Mononeuropathy or polyneuropathy65%
    Azotemia (BUN  40 mg/dL or Cr   mg/dL)40%
    Hypertension (diastolic blood pressure 90 mm Hg)37%
    Testicular pain or tenderness29%
    Skin ulcers, infarction, or peripheral gangrene27%
    Livedo reticularis25%
    Abdominal angina or ischemic perforation24%
    Diagnostic Features
    Visceral arteriogram with aneurysm or occlusion73%
    Biopsy of small-or medium-sized artery with granulocytes48%
    Abnormal arteriogram or characteristic biopsy92%

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    In autopsy studies, the most frequently involved organ in PAN is the kidney. Involvement of the medium-sized arteries supplying the renal parenchyma can result in hypertension due to renal ischemia; hypertension is mediated by the renin&#x;angiotensin system. Renal insufficiency, another common manifestation of PAN, is due to ischemia resulting from the involvement of arteries the size of renal arteries and smaller, Dr.eye 6.0 crack serial keygen. Microaneurysms, detectable by angiography [Figure 21B-1(A,B)], Video Recorder | Pirate PC - Part 2 a hallmark of PAN.

    The gastrointestinal (GI) tract is involved in up to 50% of patients. Postprandial periumbilical pain, or intestinal angina, is the result of mesenteric ischemia. More severe disease can result in bowel infarction and perforation. Other GI symptoms can include nausea, vomiting, diarrhea, and bleeding. Dr.eye 6.0 crack serial keygen the small intestine is most commonly involved, rare presentations involving ischemia of the gallbladder or appendix have been described (6). Moderately elevated hepatic transaminases often betray liver involvement. Asymptomatic mircoaneurysms within the liver are common; these occasionally rupture.

    Involvement of the peripheral nervous system is seen in 50% to 75% of patients, usually as an asymmetric sensory and motor neuropathy due to ischemia of peripheral nerves (7). Infarction of named nerves results in mononeuritis multiplex (Figure 21B-2). Progressive sensory neuropathy has been described less frequently. Central nervous system involvement is much less common, but has been reported in the form of cerebrovascular accidents.

    Polyarteritis nodosa can have multiple cutaneous manifestations: livedo reticularis, nodules, ulcerations (Figure 21B-3), and frank ischemia of digits (8). A small group of patients have a form of disease termed cutaneous PAN, a variant limited ostensibly to the skin. These patients develop nodules and ulcerations, primarily of the lower legs, Dr.eye 6.0 crack serial keygen, which can occur in crops and can be very painful. However, as with any other vasculitis, cutaneous manifestations should prompt a thorough evaluation for evidence of systemic disease.

    As with Kawasaki&#x;s disease, the other medium vessel vasculitis described in this text, PAN can also involve the coronary arteries. Clinical proof of coronary disease during life is difficult. Myocardial infarction is uncommon, and coronary involvement is usually only seen at autopsy. Contraction band necrosis, indicative of segmental ischemia, is a common finding in the myocardium at autopsy, attesting to the presence of vasculitis below the resolution of conventional angiography. PAN can involve other organs, such as the testicle, Dr.eye 6.0 crack serial keygen, ovary, breast, and eye.

    Pathology

    Polyarteritis nodosa is characterized pathologically by patchy, transmural inflammation in medium- and small-sized muscular arteries, sparing large arteries, capillaries, and the venous system. There is a pleomorphic cellular infiltrate and fibrinoid necrosis in the vessel, but no features of granulomatous inflammation. Disruption of the elastic laminae of the vessel wall can lead to aneurysmal dilatation at the site of the lesion. PAN has a predilection for certain organs: arteries to the kidney are estimated to be involved 70% to 80% of the time, the GI tract is involved in 50% of cases, the peripheral nerves are involved in 50% of cases, and the central nervous system is involved in 10% of cases (9).

    Diagnosis

    Polyarteritis nodosa is diagnosed based on characteristic symptoms, physical examination findings, and compatible laboratory, angiographic, and pathologic data. Because PAN is a rare disease and its treatment can result in serious adverse events, the diagnosis Dr.eye 6.0 crack serial keygen be supported with either abdominal angiography or biopsy whenever possible. PAN must be differentiated from other forms of vasculitis, such as the ANCA-associated disorders, cryoglobulinemia, and Buerger&#x;s disease. Common vasculitis mimics, such as viral hepatitis, bacterial endocarditis, or other embolic diseases, should be excluded. Undiagnosed connective tissue diseases, such as systemic lupus erythematosus, rheumatoid arthritis, or systemic sclerosis, must be ruled out, as such diseases can be associated with systemic vasculitis or widespread vascular dysfunction that involves multiple organs. Atrophie blanche, a thrombotic disorder that may lead to lower extremity ulcerations, must be differentiated from PAN by skin biopsy.

    The American College of Rheumatology criteria for the classification of PAN are listed in Table 21B-2 (5). The criteria were developed through the selection of clinical findings that identify PAN and distinguish it from other forms of vasculitis. Although the criteria are useful for classifying patients in clinical studies, they were not intended for use in diagnosing individual patients (10).

    Table 21B-2

    American College of Rheumatology Criteria for Classification of Pan.

    At least 3 of 10 criteria:
    1.Weight loss &#x;4 kg
    2.Livedo reticularis
    3.Testicular pain or tenderness
    4.Myalgias, weakness, or leg tenderness
    5.Mononeuropathy or polyneuropathy
    6.Diastolic blood pressure 90 mm Hg
    7.Elevated serum nitrogen urea (40 mg/dL) or creatinine ( mg/dL)
    8.Hepatitis B virus infection
    9.Arteriographic abnormality
    Biopsy of small- or medium-sized artery containing polymorphonuclear neutrophils

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    Laboratory Studies

    Routine laboratory studies are often abnormal but nonspecific, such as elevated inflammatory markers (erythrocyte sedimentation rate or C-reactive protein), anemia, and thrombocytosis. The patient may have mild renal insufficiency, with an elevated blood urea nitrogen and creatinine. Non-nephrotic range proteinuria and mild hematuria are also seen, but active urine sediments are not a feature of PAN.

    As not, PAN is not associated with ANCA. Indeed, there is no characteristic autoantibody for PAN&#x;a fact that creates one of the diagnostic challenges in this disease. Electromyography/nerve conduction velocity (EMG/NCV) studies may be very useful in confirming patterns of nerve dysfunction consistent with mononeuritis multiplex; namely, a distal, asymmetric, axonal neuropathy involving both motor and sensory nerves.

    Imaging

    Imaging in a patient with Dr.eye 6.0 crack serial keygen PAN should be guided by symptoms. In patients with abdominal pain, abdominal arteriography often reveals characteristic strictures and aneurysms (beading) of the mesenteric vessels [see Figure 21B-1(B)]. Similar findings can be IBM SPSS Statistics 27.0.2 Crack Free With Latest License Key Full Version Download 2021 in the renal vasculature.

    Biopsy

    As with imaging, biopsy should be guided by organ involvement. Blind biopsy of an asymptomatic organ, such as muscle or testicle, is not recommended. Skin biopsy is often the easiest way to confirm this diagnosis, with a biopsy from the center Dr.eye 6.0 crack serial keygen a nodule or the edge of a vasculitic ulcer. Routine punch biopsy of involved skin reveals leukocytoclastic vasculitis and fibrinoid necrosis within the blood vessel wall. Because punch biopsy samples include only epidermis and superficial dermis, they do not capture medium-sized, muscular-walled arteries whose inflammation is characteristic of PAN. When PAN is suspected and skin biopsy is indicated, a full thickness skin biopsy that includes some subcutaneous fat should be performed (arteries within the fat lobules of subcutaneous tissue are often involved.)

    Another option for confirming the diagnosis of PAN is a peripheral nerve biopsy. The sural nerve is biopsied most often because it does not mediate motor function. Whenever the sural nerve is biopsied, a muscle biopsy (of the gastrocnemius) should be performed simultaneously. Because of the highly vascular nature of muscle, biopsies of this organ may yield proof of vasculitis even in the absence of clinical indications of muscle involvement (Figure 21B-4).

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Object name is _21_Fig8_alloverlimo.us

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    Figure 21B-4

    Muscle biopsy showing fibrinoid necrosis within the wall of a medium-sized muscular artery. Although the patient had clinical symptoms of a neuropathy and nerve conduction studies were consistent with a mononeuritis multiplex, the nerve biopsy was negative. The diagnosis of polyarteritis was confirmed by the muscle biopsy. (Courtesy of Dr. John Stone.)

    Prognosis

    Untreated PAN has a high mortality, with an estimated 5-year survival of 13% prior to the introduction of glucocorticoids. With current treatment, survival is greatly improved, approximately 80% at 5 years. In a population of patients enrolled in prospective trials for PAN, MPA, and Churg&#x;Strauss syndrome, approximately 75% of the deaths occurred during the first 18 months after the diagnosis was made and treatment initiated. Of the patients who died, 26% died from progression of their vasculitis, while 13% died of infectious complications Dr.eye 6.0 crack serial keygen to treatment. No major differences were seen among the three vasculitides studied (11).

    Not surprisingly, more severe disease is Dr.eye 6.0 crack serial keygen with increased mortality. A Five Factor Score has been used to classify disease severity (12). The five factors are (1) proteinuria 1 g/day, (2) renal insufficiency (Cr   mg/dL), (3) cardiomyopathy, (4) gastrointestinal symptoms, and (5) CNS involvement. A Five Factor Score of 0 is associated with a 5-year mortality of only 13% (with not all deaths caused directly by PAN). Five Factor Scores of 1 and 2 or more are associated with mortalities of 26% and 46%, respectively (12).

    Treatment

    The treatment of PAN is guided by both the etiology of the disease (if known) and its severity. PAN cases associated with hepatitis B are treated with a short course of prednisone (1 mg/kg/day) to suppress the inflammation. Patients begin 6-week courses of plasma exchange (approximately three exchanges per week) simultaneously with the start of glucocorticoids. The dose of prednisone is tapered rapidly (over approximately 2 weeks), followed by the initiation of antiviral therapy (e.g., lamivudine  mg/day).

    For idiopathic PAN, the mainstay of treatment is glucocorticoids, with an initial dose of approximately 1 mg/kg daily of prednisone. Intravenous glucocorticoids can be used in patients with difficulty taking oral medications due to GI involvement. Pulse doses (e.g., methylprednisolone 1 g intravenously each day times three) may be used in severe disease. Glucocorticoids alone may be enough to treat milder cases. Approximately half of all patients with PAN may be cured with glucocorticoids alone.

    In cases of PAN that are rapidly progressive or life- or organ-threatening, cyclophosphamide is added to glucocorticoid treatment. Cyclophosphamide should be considered for any patient with a Five Factor Score of 1 or greater. In addition, severe peripheral neuropathy or mononeuritis multiplex is also a strong indication for cyclophosphamide. Although many clinicians still prefer daily oral cyclophosphamide to monthly pulsed intravenous cyclophosphamide, a meta-analysis comparing the two regimens in ANCA-associated vasculitis showed little difference (13). Therapy should be tailored to the individual patient&#x;s circumstances.

    Most cases of idiopathic PAN do not recur after remission has been achieved and the patient has received 6 to 12 months of cyclophosphamide. Current regimens generally emphasize shorter courses of cyclophosphamide, with durations of therapy closer to 6 months than to After treatment with 6 months of cyclophosphamide, patients in remission&#x;the great majority&#x;should be switched to another immunosuppressive agent for remission maintenance. As with the ANCA-associated vasculitides, azathioprine or methotrexate is often used. After a total treatment length of approximately 18 months, the remission maintenance agent can often be stopped, with a low relapse rate. Patients should continue to be monitored for evidence of recurrence.

    Much potential morbidity in PAN relates to adverse events from inappropriate (or overly aggressive) treatment. Conversely, poor outcomes also result from undertreatment, for example, failure to employ cyclophosphamide in a patient clearly failing high- dose glucocorticoids. An important aspect of treatment is avoiding known side effects of agents used. This includes the use of calcium and vitamin D supplementation in all patients on glucocorticoids, Dr.eye 6.0 crack serial keygen, along with use of a bisphosphonate in those at high risk for bone loss and monitoring of bone density. Patients on cyclophosphamide should have routine monitoring for cytopenias and hematuria and receive trimethoprim/sulfamethoxazole for prevention of Pneumocystis jiroveci (formerly carinii) pneumonia, Dr.eye 6.0 crack serial keygen. Patients receiving pulsed intravenous cyclophosphamide are also candidates for MESNA (sodiumsulfanyl ethanesulfonate) for prevention of hemorrhagic cystitis. Premenopausal females on cyclophosphamide are candidates for leuprolide to suppress the GnRH axis and prevent premature ovarian failure; males may opt to bank sperm. Finally, as a Dr.eye 6.0 crack serial keygen, patients should not become pregnant or father children on cyclophosphamide.

    Classification Criteria and Definitions

    The American College of Rheumatology classification criteria for WG and the CSS (Table 21C-1) (4,5) were developed to ensure the inclusion of uniform disease populations in research studies (6). These criteria did not address the utility of ANCA for classification or the difference between polyarteritis nodosa and MPA. These limitations were addressed by the Chapel Hill Consensus Conference (Table 21C-2) (7). To date, widely accepted diagnostic criteria for these diseases have not been developed.

    Table 21C

    The Chapel Hill Consensus Conference Definitions of the Antineutrophil Cytoplasmic Antibodies&#x;Associated Vasculitides.

    Wegener&#x;s granulomatosis
    Granulomatous inflammation involving the respiratory tract, and necrotizing vasculitis affecting small- to medium-sized vessels (e.g., capillaries, venules, arterioles, and arteries). Necrotizing glomerulonephritis is common.
    Microscopic polyangiitis
    Necrotizing vasculitis, with few or no immune deposits, affecting small vessels (i.e., capillaries, venules, or arterioles). Necrotizing arteritis involving small- and medium-sized arteries may be present. Necrotizing glomerulonephritis is very common. Pulmonary capillaritis often occurs.
    Churg&#x;Strauss syndrome
    Eosinophil-rich and granulomatous inflammation involving the respiratory tract, and necrotizing vasculitis affecting small- to medium-sized vessels, associated with asthma and eosinophilia.

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    Table 21C

    The American College of Rheumatology Classification Criteria for Wegener&#x;S Granulomatosis and Churg&#x;Strauss Syndrome.

    Wegener&#x;s GranulomatosisDr.eye 6.0 crack serial keygen colspan="1">Churg&#x;Strauss Syndrome
    Nasal or oral inflammationAsthma
    Painful or painless oral ulcers or purulent or bloody nasal dischargeWheezing or high-pitched rales
    Abnormal chest radiographEosinophilia
    Nodules, fixed infiltrates, or cavities10% of white blood cell differential
    Download Fraps 3.5.99 Crack Archives sedimentMononeuropathy or polyneuropathy
    Microhematuria or red cell castsMononeuropathy, Dr.eye 6.0 crack serial keygen, multiple mononeuropathies, or polyneuropathy attributable to vasculitis
    Granulomatous inflammation on biopsy specimenPulmonary infiltrates, nonfixed
    Granulomatous inflammation within the wall of an artery or in theMigratory or transitory pulmonary infiltrates
    perivascular areaParanasal sinus abnormality
    Acute or chronic paranasal sinus pain, tenderness, or radiographic opacification
    Extravascular eosinophils
    Biopsy of artery, arteriole, or venule showing accumulations of eosinophils in extravascular areas

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    Epidemiology

    A population-based study from Norfolk, England, reported incidences of cases per million for WG, cases per million for MPA, and cases per million for the CSS (8). In two large U.S. cohorts of patients with WG (9,10), whites comprised more than 90% of all cases, whereas African Americans, Hispanics, and Asians together represented 1% to 4% of cases. The mean age at diagnosis is about 55 years, but cases involving octogenarians are not unusual.

    Clinical Features

    There is substantial overlap in many of the clinical features of the AAVs. In some cases, distinguishing among two or more of these diseases on the basis of clinical features alone is difficult (Table 21C-3).

    Table 21C

    Clinical Features of the Primary Antineutrophil Cytoplasmic Antibodies&#x;Associated Vasculitides.

    FeatureWegener&#x;s GranulomatosisMicroscopic PolyangiitisChurg&#x;Strauss Syndrome
    ANCA positivity80%&#x;90%70%50%
    ANCA antigen specificityPR3  MPOMPO  PR3MPO  PR3
    Fundamental histologyLeukocytoclastic vasculitis; necrotizing, granulomatous inflammation (rarely seen in renal biopsy specimens)Leukocytoclastic vasculitis; no granulomatous inflammationEosinophilic tissue infiltrates and vasculitis; granulomas have eosinophilic necrosis
    Ear/nose/throatNasal septal perforation; saddle-nose deformity; conductive or sensorineural hearing loss; subglottic stenosisAbsent or mildNasal polyps; allergic rhinitis; conductive hearing loss
    EyeOrbital pseudotumor, scleritis (risk of scleromalacia perforans), episcleritis, uveitisOccasional eye disease: scleritis, episcleritis, uveitisOccasional eye disease: scleritis, episcleritis, uveitis
    LungNodules, infiltrates, or cavitary lesions; alveolar hemorrhageAlveolar hemorrhageAsthma; fleeting infiltrates; alveolar hemorrhage
    KidneySegmental necrotizing glomerulonephritis; rare granulomatous featuresSegmental necrotizing glomerulonephritisSegmental necrotizing glomerulonephritis
    HeartOccasional valvular lesionsRareHeart failure
    Peripheral nerveVasculitic neuropathy (10%)Vasculitic neuropathy (58%)Vasculitic neuropathy (78%)
    EosinophiliaMild eosinophilia occasionallyNoneAll

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    Upper Respiratory Tract and Ears

    Although patients with the CSS or MPA may experience substantial ear, nose, or sinus disease, this pattern of involvement is most characteristic of WG. More than 90% of patients with WG eventually develop upper airway or ear abnormalities. The nasal symptoms of WG include nasal pain and stuffiness, rhinitis, epistaxis, and brown or bloody crusts. Nasal inflammation may lead to septal erosions, septal perforation, or, in many cases, nasal bridge collapse&#x;the saddle-nose deformity (Figure 21C-1). The distinction between active WG in the sinuses and secondary infections in the sinuses may be challenging (see Nonmedical Interventions section).

    In 60% to 70% of patients with the CSS, allergic rhinitis is the earliest disease manifestation, typically appearing years before the development of full-blown systemic vasculitis. Rhinitis may be severe and may require serial polypectomies to relieve obstruction and sinusitis. Nasal crusting and conductive hearing loss (due to serous otitis or granulomatous middle ear inflammation) may also occur in the CSS.

    Two principal categories of ear disease&#x;conductive and sensorineural hearing loss&#x;are typical of WG. The most common cause of conductive hearing loss may be Eustachian tube dysfunction due to nasopharyngeal disease. Inner ear disease in WG may be associated with sensorineural hearing loss, vestibular dysfunction, or both, Dr.eye 6.0 crack serial keygen. In contrast to middle ear disease, the mechanism of inner ear disturbances in WG is poorly understood.

    Trachea and Bronchi

    Subglottic stenosis and stenotic lesions of the bronchi are potentially Dr.eye 6.0 crack serial keygen complications of WG. Subglottic involvement, often asymptomatic initially, becomes apparent as hoarseness, pain, cough, wheezing, or stridor. Thin-cut computed tomographic scans and often direct laryngoscopy are useful in assessing these airway narrowings.

    Eyes

    Scleritis may lead to necrotizing anterior scleritis (scleromalacia perforans) and blindness. Peripheral ulcerative keratitis may cause the corneal melt syndrome. Other ocular manifestations of AAV include conjunctivitis, episcleritis, and anterior uveitis. In WG, orbital masses termed pseudotumors occur in a retrobulbar location in 10% to 15% of patients, causing proptosis, diplopia, or visual loss. Nasolacrimal duct obstruction is most typical of WG.

    Lungs

    In WG, the pulmonary manifestations range from asymptomatic lung nodules and fleeting (or fixed) pulmonary infiltrates to fulminant alveolar hemorrhage. The nodules are usually multiple, bilateral (Figure 21C-2), and often cavitary. Infiltrates are often misdiagnosed initially as pneumonia.

    Pulmonary capillaritis, equally likely to occur in WG and MPA, may Dr.eye 6.0 crack serial keygen to lung hemorrhage, hemoptysis, and rapidly changing alveolar infiltrates (Figure 21C-3). Patients with MPA may also develop interstitial fibrosis of the lungs.

    Obstructive airway disease and fleeting pulmonary infiltrates are the hallmarks of the CSS. The majority of patients report the new onset of asthma months to years before the appearance of overt vasculitis. Following resolution of the vasculitic phase with treatment, many patients Dr.eye 6.0 crack serial keygen CSS suffer from steroid-dependent asthma.

    Kidneys

    The most feared clinical presentation of renal disease among the AAVs is rapidly progressive glomerulonephritis. More than 75% of patients with WG will eventually develop renal involvement. The progression of the disease often appears to accelerate once kidney involvement is apparent. In MPA, renal disease may have a more indolent course, and renal biopsies typically demonstrate more sclerosis and fibrosis than do specimens from patients with WG. Severe renal disease in CSS is very rare. Renal-limited vasculitis is pauci-immune glomerulonephritis (see Pathology section) associated with ANCA, usually directed against MPO, without evidence of disease in other Dr.eye 6.0 crack serial keygen. ANCA-associated renal disease may lead to fibrotic crescents and other scarring within the kidney. Subsequent disease flares and progression of renal dysfunction through hyperfiltration may lead to end-stage renal disease.

    Arthritis/Arthralgias

    Inflammatory joint complaints, often migratory and oligoarticular in nature, occur in at least 60% of patients with AAV. Joint problems are frequently the presenting complaint, but the diagnosis is seldom made until other symptoms are manifest. The combination of joint complaints, cutaneous nodules (frequently mistaken for rheumatoid nodules), and the high frequency of rheumatoid factor positivity among patients with AAV (approximately one third are rheumatoid factor positive) often lead to the misdiagnosis of rheumatoid arthritis early in the disease course. Arthralgias are more common than frank arthritis. The recurrence of musculoskeletal complaints in a patient in remission often marks the start of a disease flare.

    Skin

    In both the CSS and WG, cutaneous nodules may occur Adobe Acrobat v6.x MAC crack serial keygen sites that are also common locations for rheumatoid nodules, particularly the olecranon region (Figure 21C-4). Skin findings in the AAVs also include all of the potential manifestations of cutaneous vasculitis: palpable purpura, vesiculobullous lesions, papules, ulcers, digital infarctions, and splinter hemorrhages.

    Nervous System

    Vasculitic neuropathy may lead to a devastating mononeuritis multiplex or a disabling sensory polyneuropathy. Mononeuritis multiplex occurs more Dr.eye 6.0 crack serial keygen in the CSS [up to 78% of patients (11)] and MPA (up to 58%) than in WG. Central nervous system abnormalities occur in approximately 8% of patients with WG, usually in the form of cranial neuropathies, mass lesions, or pachymeningitis. The frequency of parenchymal brain involvement in AAV, though not yet known with certainty and generally regarded as rare, has been reported. Central nervous system disease generally occurs only when more typical disease manifestations are present elsewhere.

    Heart

    The CSS is the type of AAV that is most likely to involve the heart, usually in the form of rapid-onset heart failure. Cardiac complications in WG and MPA are both less common and more difficult to attribute with certainty to the underlying disease. Focal cardiac valvular lesions, valvular insufficiency, pericarditis, and coronary arteritis have been described in WG.

    Gastrointestinal Tract

    Eosinophilic gastroenteritis often precedes the frank vasculitic phase of the CSS. Among patients with either the CSS or MPA, unexplained abdominal pain occurs in up to one third of patients and may lead to ischemic bowel. Gastrointestinal involvement is less common in WG.

    Blood

    Eosinophilia (before treatment) is a sine qua non of the CSS. Eosinophil counts are usually sensitive markers of disease flares, but respond very quickly (within 24 hours) to treatment with high doses of glucocorticoids, Dr.eye 6.0 crack serial keygen. Tissue infiltration by eosinophils, however, may remain. Mild eosinophilia (rarely more than 15% of the total white blood cell count) may also occur in WG. Most patients with CSS also have elevated serum immunoglobulin E levels. In addition to ANCA, nonspecific autoantibodies, such as antinuclear antibodies and rheumatoid factor, also occur in high percentages of patients with AAV.

    Other

    Antineutrophil cytoplasmic antibodies-associated vasculitides rarely affect the parotid gland, pulmonary artery, breast, or genitourinary organs. Involvement of these organs by AAV is usually an unexpected finding on biopsies performed to exclude other diseases, particularly cancer and infection.

    Pathology

    Fibrinoid necrosis, a pathological hallmark of AAV, may be found in a variety of vasculitic (and nonvasculitic) conditions, such as polyarteritis nodosa, scleroderma renal crisis, systemic lupus erythematosus, and malignant hypertension. Both vasculitic and necrotizing granulomatous features, which do not invariably coexist, may be confirmed in lung biopsy specimens. In addition, pulmonary WG frequently demonstrates an extensive, nonspecific inflammatory background. Coalescence of such neutrophilic microabscesses leads to extensive regions of geographic necrosis. Palisading granulomas, scattered giant cells, and poorly formed granulomas may also be found in WG.

    Churg&#x;Strauss syndrome typically evolves through three phases, with corresponding pathological findings. In the first phase, allergy, asthma, and other atopic symptoms predominate. In the second, eosinophilic infiltration occurs in the lung and other organs (eosinophilic pneumonia, eosinophilic gastroenteritis; Figure 21C-5). In the third phase, vasculitis ensues. Curiously, at the time the vasculitic phase begins, patients&#x; asthma often improves significantly. The histopathological findings in CSS in the lung include eosinophilic infiltrates; extensive areas of necrosis (reminiscent of the geographic necrosis in WG); a granulomatous vasculitis of small arteries and veins, associated with striking eosinophilic infiltration. In contrast to WG and MPA, lymphadenopathy (with overwhelming eosinophilic infiltration into the lymph nodes), is frequently found in CSS.

    The interstitial lung disease of MPA resembles usual interstitial pneumonitis (UIP), with the exception that necrosis of the alveolar septae and areas of hemorrhage can occur. More characteristic findings in MPA, however, reveal nonspecific infiltrates or alveolar hemorrhage. Vasculitis of the pulmonary capillaries may be difficult to prove.

    Renal disease in the AAVs is associated with focal, segmental lysis of glomerular tufts, disruption of the basement membrane, and accumulation of fibrinoid material (i.e., fibrinoid necrosis). Crescents in Bowman&#x;s space develop as a result of spillage of inflammatory mediators across the ruptured glomerular capillaries, Dr.eye 6.0 crack serial keygen, accumulation of macrophages, and epithelial cell proliferation. Thrombotic changes in the glomerular capillary loops are among the earliest histologic changes. Acute tubular necrosis and tubulointerstitial nephritis are also seen commonly. Immunofluorescence studies of renal biopsy specimens demonstrate scant deposition of immunoglobulin and complement, hence the term pauci-immune glomerulonephritis.

    Tissue samples from involved areas of the upper respiratory tract (nose, sinuses, and subglottic region) in WG often reveal only acute and chronic inflammation. Nevertheless, these biopsies are easier to obtain than are biopsies of the lung and kidney. Moreover, the combination of these pathological findings (nondiagnostic in and of themselves) and compatible clinical features (e.g., pulmonary nodules and PR3-ANCA) may yield the diagnosis in some cases. Upper respiratory tract biopsies are therefore worth undertaking in patients with significant upper respiratory involvement.

    Antineutrophil Cytoplasmic Antibodies

    The Antigens

    Proteinase-3, a kDa serine protease, is found in the azurophilic granules of neutrophils and peroxidase-positive lysosomes of monocytes. MPO, which constitutes nearly 5% of the total protein content of the neutrophil, is localized to the same cellular compartments as PR3. The protein is a covalently linked dimer with a molecular weight of  kDa. The autoantibodies directed against PR3 and MPO are directed against multiple epitopes. Sera from different patients may recognize different epitopes. All ANCA, however, recognize restricted epitopes of PR3 involving its catalytic site.

    Clinical Testing for Antineutrophil Cytoplasmic Antibodies

    Two types of assays for ANCA&#x;immunofluorescence and enzyme immunoassay&#x;are now in common use. Capture enzyme immunoassays may offer some advantages over the more widely available tests, but are currently performed only in specialty centers.

    With immunofluorescence, three principal patterns of fluorescence are recognized: the cytoplasmic (C-ANCA), perinuclear (P-ANCA), and atypical patterns. In patients with vasculitis, the C-ANCA pattern usually corresponds to the detection of PR3-ANCA by enzyme immunoassay. The combination of a C-ANCA pattern on immunofluorescence testing and PR3-ANCA is associated most strongly with WG. The P-ANCA pattern, which usually corresponds to the presence of MPO-ANCA in vasculitis patients, occurs in approximately 10% of patients with WG, Dr.eye 6.0 crack serial keygen, but is more typical of MPA, the CSS, and renal-limited vasculitis. The great majority of patients with drug-induced AAVs are P-ANCA positive, often with very high titers of MPO-ANCA.

    Regardless of the immunofluorescence pattern, positive immunofluorescence assays should be confirmed by the performance of enzyme immunoassays for the specific antibodies associated with vasculitis: PR3- and MPO-ANCA. Even for C-ANCA, the positive predictive value for WG is only in Dr.eye 6.0 crack serial keygen range of 45% to 50% (12,13).

    Clinical Utility of Antineutrophil Cytoplasmic Antibody Serologies

    Despite advances in ANCA testing techniques, the cornerstone of diagnosis in WG remains the rigorous interpretation of histopathological specimens within the overall clinical context. When biopsy specimens are nondiagnostic, ANCA assays provide an important adjunct to diagnosis (Table 21C-4).

    Table 21C

    Clinical Utility of Antineutrophil Cytoplasmic Antibody Testing.

    Positive ANCA serologies are extremely useful in suggesting the diagnosis in the proper clinical setting.
    Positive immunofluorescence assays without confirmatory enzyme immunoassays for anti-PR3 or Dr.eye 6.0 crack serial keygen antibodies are of limited utility.
    Histopathology remains the gold standard for diagnosis in most cases.
    Negative ANCA assays do not exclude ANCA-associated vasculitis because between 10% and 50% of patients with ANCA-associated vasculitis (depending on the particular disease) may be ANCA-negative.
    Persistence of ANCA in the absence of clinical indications of active disease does not indicate a need for continued treatment.
    In a patient who was ANCA-positive during active disease, persistent ANCA-negativity provides reassurance&#x;but no guarantee&#x;that the disease is not active, Dr.eye 6.0 crack serial keygen. If disease flares occur in such patients, they are usually limited.
    A patient who becomes ANCA-positive again following a period of clinical quiescence associated with negative ANCA assays may be at an increased risk for a disease flare. The temporal correlation between the return of ANCA and a disease flare, however, Dr.eye 6.0 crack serial keygen, is poor.
    Treatment of ANCA-associated vasculitis should never be predicated upon ANCA serologies or titers alone.

    Open in a separate window

    In the proper clinical setting, a positive ANCA assay greatly increases the likelihood that a form of AAV is present, Dr.eye 6.0 crack serial keygen. Most series indicate that up to 10% to 20% of patients with active, untreated WG are ANCA negative. For patients with limited WG, 30% or more of patients lack ANCA. Approximately 70% of IObit Uninstaller Pro 8.3.0 Key Archives with MPA and 50% of those with CSS (higher in some series) have ANCA.

    Utility of Antineutrophil Cytoplasmic Antibody Assays following Dr.eye 6.0 crack serial keygen Activity and in Predicting Flares

    In general, Dr.eye 6.0 crack serial keygen, ANCA titers have imperfect correlations with disease activity. In one study, the positive predictive value of a rise in ANCA titers as measured by immunofluorescence was only 57% in a prospective study, compared with 71% for enzyme immunoassay (14). Moreover, among patients with an elevation of ANCA titers measured by enzyme immunoassay, only 39% suffered disease flares within 6 months. A more recent prospective study (15) showed that increases in PR3-ANCA levels did not predict disease relapses. The proportion of patients who relapsed within 1 year following an increase in ANCA levels was only 40%. Although some studies suggest that a rise in ANCA titer is a risk factor for a flare, the temporal relationship between a rise in ANCA titers and the development of disease activity requiring treatment is very poor, with months to years between these two events. Dr.eye 6.0 crack serial keygen, the adjustment of immunosuppressive medications based solely on the rise or fall of ANCA titers is never justified.

    Pathophysiology

    The AAVs are complex disorders mediated by the immune system in which tissue injury results from the interplay between an initiating inflammatory event and a highly specific pathogenic immune response (i.e., the production of ANCA) to previously shielded epitopes of neutrophil granule proteins. ANCAs produce tissue damage via interactions with primed neutrophils and endothelial cells. The hypothesis, supported strongly by in vitro evidence, is that the antibodies induce a necrotizing vasculitis by inciting a respiratory burst and degranulation of leukocytes (neutrophils and monocytes), leading to endothelial injury. The initial events in the process require the priming of leukocytes by cytokines and perhaps other stimuli, leading to the expression of PR3 and MPO on the cell surface. The effects of ANCAs are determined by the state of neutrophil activation. ANCAs may constitutively activate primed neutrophils and promote binding of the primed neutrophils to the vascular endothelium, degranulation, and the release of neutrophil chemoattractants, hence creating an autoamplifying loop.

    There is now substantial evidence that ANCAs are directly involved in the widespread tissue damage that is the hallmark of the AAVs. Recombinant activating gene 2 (RAG-2)&#x;deficient mice that receive anti-MPO antibodies develop clinical features consistent with AAV, including crescentic glomerulonephritis and systemic necrotizing vasculitis (16). In humans, the evidence is indirect. Propylthiouracil is known to accumulate within neutrophil granules and may lead to a drug-induced AAV (17), possibly by increasing the immunogenicity of MPO (leading to the characteristically high titers of MPO-ANCA seen in this disease).

    In addition to ANCA, multiple other elements of the immune system participate in the pathophysiology of these diseases. If the autoantibody response leading to ANCA production follows the exposure of a cryptic epitope, epitope spreading may then generalize the antibody response to the rest of the molecule. This hypothesis implies a prominent role for the T cell in the pathogenesis of the AAVs. Moreover, Dr.eye 6.0 crack serial keygen, most patients with Dr.eye 6.0 crack serial keygen produce isotype-switched IgG ANCA, implying a secondary immune response driven by T cells. Growing evidence, particularly data from clinical studies (18), now also implicates B cells as important participants in the inflammation of AAV. As the precursors of plasma cells (which produce ANCA), B cells now seem SpyHunter 5 Serial Key + [Email & Password] Free Download logical therapeutic target in AAV. In addition to disrupting ANCA production, however, interference with B-cell function may also ameliorate AAV by disabling critical B cell/T cell interactions, by removing the antigen presenting function of B cells, and perhaps other mechanisms. B-cell depletion is the focus of ongoing randomized trials involving patients with WG and MPA.

    The pathophysiology of CSS likely bears many similarities to that of WG and MPA, albeit ANCA are less common in CSS. In the CSS, however, relatively little is currently understood about the special role played by the eosinophil in that disease.

    Differential Diagnosis

    Because of their multiorgan system nature, the differential diagnosis of AAV is lengthy. One frequently challenging task is the differentiation of these diseases from other forms of vasculitis. Indeed, clear distinctions are often impossible between WG and MPA, because granulomatous inflammation is not detected on all biopsy specimens from Acrobat Pro 6 crack serial keygen with WG. Distinguishing the AAVs from other forms of vasculitis is Dr.eye 6.0 crack serial keygen more critical because the specific treatments differ according to diagnosis. In addition, the AAVs must be distinguished from a host of other disorders associated with inflammation and multiorgan system dysfunction. The differential diagnosis of AAV is shown in Table 21C

    Table 21C

    Differential Diagnosis of Antineutrophil Cytoplasmic Antibody&#x;Associated Vasculitis.

    Another form of ANCA-associated vasculitis
    Wegener&#x;s granulomatosis, Churg&#x;Strauss syndrome, microscopic polyangiitis, drug-induced ANCA-associated vasculitis, or renal-limited vasculitis
    Another form of vasculitis. Typical vasculitic mimickers:
    Polyarteritis nodosa, Henoch&#x;Schönlein purpura, cryoglobulinemia, antiglomerular basement membrane disease
    Systemic inflammatory disorders associated with autoimmunity
    Systemic lupus erythematosus, sarcoidosis, inflammatory bowel disease, relapsing polychondritis
    Infection
    Endocarditis, sepsis, deep fungal infections, mycobacteria (Mycobacterium tuberculosis and Mycobacterium avium-intracellulare), actinomycosis, syphilis
    Malignancy
    Lymphomatoid granulomatosis, lymphoma, Castleman&#x;s disease, lung tumors
    Hypereosinophilic disorders
    Allergic bronchopulmonary aspergillosis, chronic eosinophilic pneumonia, eosinophilic gastroenteritis, Dr.eye 6.0 crack serial keygen, eosinophilic fasciitis, hypereosinophil syndrome, eosinophilic leukemia
    Miscellaneous
    Idiopathic pulmonary Dr.eye 6.0 crack serial keygen hemorrhage, illicit drug use (intranasal Dr.eye 6.0 crack serial keygen, smoking of crack)

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    Churg&#x;Strauss syndrome has an additional major branch of its differential diagnosis because of the eosinophilia associated with the disease. Allergic bronchopulmonary aspergillosis, chronic eosinophilic pneumonia, eosinophilic gastroenteritis, eosinophilic fasciitis, the hypereosinophil syndrome, and eosinophilic leukemias must all be excluded.

    Treatment

    Current choices for treatment in WG are based on the classification of patients into the categories of either severe or limited disease (19). Severe WG constitutes an immediate threat either to the function of a vital organ or to the patient&#x;s life. Conversely, limited WG consists of disease manifestations that do not pose such threats. The practical distinction between severe and limited disease is that under the current standard of care the diagnosis of severe WG mandates the use of cyclophosphamide, whereas milder therapeutic approaches may be appropriate and should be considered for limited disease. The treatment of MPA parallels very closely that of severe WG. Because of the propensity of MPA to involve major organs (lungs, kidneys, peripheral nerves) in a severe fashion, limited forms of the disease are recognized less often. Some cases of CSS can be treated with glucocorticoids alone, but those with vasculitic neuropathy, life-threatening pulmonary involvement, and other sobering organ involvement require cyclophosphamide from the outset of therapy.

    In treating severe AAV, the standard approach now is to employ cyclophosphamide [e.g., 2 mg/kg/day, adjusted for renal dysfunction (20)] for 3 to 6 months. Some experts prefer intermittent (intravenous) regimens of cyclophosphamide (e.g., Dr.eye 6.0 crack serial keygen, &#x; mg/m2 every month). No data yet available strongly endorse one cyclophosphamide regimen over another. Remission induction with cyclophosphamide is usually followed by longer periods of remission maintenance therapy with either azathioprine (11) or methotrexate (21).

    For patients who demonstrate propensities to flare, long-term use of the least toxic drug for the maintenance of remission may be appropriate. This may include methotrexate or azathioprine and, for patients with recurrent disease flares, low doses of prednisone (e.g., 5 mg/day). The optimal length of treatment with methotrexate or azathioprine is not clear, but continuation of these medications for at least 1 year after remission is reasonable in most patients. Tumor necrosis factor inhibition (or at least etanercept) does not appear to be effective in WG (22), and its use in combination with cyclophosphamide may heighten the risk of solid malignancies substantially (23).

    Among patients with limited WG, remission is induced in approximately three fourths of patients with the use of methotrexate (up to 25 mg/week) and glucocorticoids alone. Patients treated with methotrexate and glucocorticoids must be observed carefully for breakthrough disease, particularly glomerulonephritis.

    Other Potential Medical Treatments in Antineutrophil Cytoplasmic Antibody&#x;Associated Vasculitis

    The use of trimethoprim&#x;sulfamethoxazole as a treatment for WG has fallen increasingly into disfavour. The use of trimethoprim&#x;sulfamethoxazole alone for the treatment of active WG is not appropriate. The medication may have some role in remission maintenance for patients with upper respiratory tract disease, however, its efficacy is uncertain and its mechanism of action unclear. A wide array of other therapies, such as plasmapheresis, intravenous immunoglobulin, mycophenolate mofetil, and leflunomide, have been employed in small numbers of patients, but so far there are insufficient data to judge their efficacy. Rituximab and other strategies for B-cell depletion are now being tested. Interferon-alpha has been reported to have some benefit for CSS.

    Nonmedical Interventions

    Once scarring and fibrosis are well established in the subglottic region, airway narrowing may be due to the progression of scar tissue rather than to WG-related inflammation. In such cases, subglottic stenosis responds poorly to immunosuppressive therapy, and the most effective therapeutic approach to this problem is laryngoscopic dilatations of the airway, augmented by intra-lesional corticosteroid injections (24). Serial procedures are often required. If severe subglottic stenosis precludes a safe dilatation procedure, a patent airway should first be secured by a tracheostomy. WG often leads to chronic nasosinus dysfunction. Regardless of disease activity, most patients require multiple daily saline irrigations to minimize the accumulation of Dr.eye 6.0 crack serial keygen and crusts, and to VCarve Pro 6.0 crack serial keygen the incidence of secondary infections. Persistent or recurrent infections may require surgical drainage. Distinguishing between worsening sinus disease caused by active WG and superinfection may be difficult. In the absence of a prompt response to antibiotics, surgical drainage and biopsy are often required for a more definitive diagnosis.

    Course and Prognosis

    In contrast to the situation in the first 40 years follow-ing the descriptions of the AAVs, these diseases are now highly treatable. Unfortunately, disease relapses are a major threat. MPA and the CSS are somewhat less likely than WG to flare after the achievement of remission. The percentages of patients with those diseases who suffer disease flares after appropriate courses of treatment have been estimated to be about 25% to 40%.

    Even with therapy, mortality and morbidity are substantial. In a cohort of patients followed at the National Institutes of Health (NIH) from the late s through the early s (9), 12% of deaths were due to Dr.eye 6.0 crack serial keygen the disease or complications of treatment, and 86% suffered permanent disease-related morbidity, including chronic renal insufficiency (42%), end-stage renal disease requiring dialysis (10%), hearing loss (35%), nasal deformity (28%), tracheal stenosis (13%), and visual loss (8%). Many patients incurred more than one type of permanent morbidity. In a more recent retrospective study of patients with ANCA-associated renal vasculitis (25), cumulative patient survival at 5 years was 76%. There was an 18% mortality rate at 1 year, however, with infections as a major cause of death. In this cohort, mortality was associated with age older than 60 years, the development of end-stage renal failure, and an initial serum creatinine level greater than  mg/dL.

    In the Wegener&#x;s Granulomatosis Etanercept Trial (WGET) (22), although 90% of all patients achieved at least a transient disease activity score of zero, fewer than 50% of patients achieved and maintained these disease remissions over the mean month course of follow-up on treatment. Thus, although remissions are achieved in most patients with WG, relapse remains a major threat. Furthermore, 89% of the patients enrolled in the WGET had sustained at least one item of damage from the disease or treatment within 1 year of enrollment (26). The most common items of damage recorded were hearing loss (26%) and proteinuria (19%).

    Much of the morbidity in the AAVs relates to prolonged courses of immunosuppression, particularly the need to re-treat patients who suffer multiple relapses. In the patient-years of follow-up in the NIH series, only 46% of these years were spent in remission. Serious infections occurred in 46%. Other morbidities included drug-induced cystitis caused by cyclophosphamide (43%), increased risk of malignancy (particularly bladder cancer, leukemia, and lymphoma), infertility (57% of women with childbearing potential), and a host of side effects related to the use of glucocorticoids.

    Pathophysiology

    InMaurice Arthus noted that intradermal injection of a rabbit with horse serum resulted in a cutaneous inflammatory reaction that evolved into localized tissue necrosis (2). The reaction was faster, he observed, if the animal had been previously exposed to horse serum. This response, now known as the Arthus reaction, forms the basis of our understanding of immune complex&#x;mediated diseases. In the Arthus model, injection of the horse serum leads to immune complex formation that initiates complement activation and an influx of inflammatory cells, Dr.eye 6.0 crack serial keygen. In the areas of most intense inflammation, in situ thrombosis formation can lead to tissue ischemia and hemorrhagic infarction.

    In general, immune complexes are not pathogenic. Their immunogenicity is governed by a large number of factors, including antigen load, antibody response, the efficiency of the reticuloendothelial system in the clearance of immune complexes, physical properties of the blood vessels (including flow dynamics and previous endothelial damage), and the solubility of the immune complexes themselves.

    Immune complex solubility is determined by the ratio of antibody to antigen. When antibody and antigen are present in equal proportion, large immune complexes are formed, which are identified easily and removed by Dr.eye 6.0 crack serial keygen reticuloendothelial system. When there is an excess of antibody, MAC Archives immune complexes are formed, which remain in solution, and do not elicit an immune response. When there is a slight excess of antigen, however, the immune complexes precipitate from solution, and become trapped in characteristic areas&#x;either the capillary beds (such as those found in the skin, kidneys, or lungs), or the endothelium of medium-sized blood vessels previously damaged by turbulent blood flow.

    When the immune complexes precipitate into the tissues, they fix complement, leading to an intense immune reaction. Complement fixation and local inflammation recruit neutrophils, which attempt to engulf the immune complexes. During this process, the neutrophils degranulate, releasing lysosomal enzymes and oxygen free radicals that cause tissue necrosis.

    The inciting antigen can be from numerous sources. In infective endocarditis, the antibody response, formed against bacterial antigens, can lead to painful cutaneous lesions known as Osler nodes. In systemic lupus erythematosus (SLE), antibodies form against nuclear components (e.g., DNA and histones) that are released during tissue injury. Certain forms of malignancy can be associated with immune complex formation, with antibodies directed against tumor-associated antigens. Immune complexes may also form in response to a large number of drugs, including penicillin and sulfonamides.

    Clinical Syndromes

    Hypersensitivity Vasculitis

    Definition

    Hypersensitivity reactions were first noted in patients who were treated with antitoxin derived from horse serum. Such patients developed an antibody response to the horse antigens, which led to a characteristic syndrome of fever, joint pain, Dr.eye 6.0 crack serial keygen, and rash now known as serum sickness.

    Hypersensitivity vasculitis refers to a heterogeneous group of syndromes (including serum sickness and drug-induced vasculitis) characterized by immune complex deposition in capillaries, postcapillary venules, and arterioles. This is the most common form of vasculitis. Although multiple agents have been implicated, including penicillins, sulfonamides, and cephalosporins, Dr.eye 6.0 crack serial keygen, the inciting agent cannot always be identified.

    Inthe American College of Rheumatology proposed the following five criteria for the classification of hypersensitivity vasculitis in an adult (3):

    • Age 16 years

    • Use of a possible offending medication in temporal relation to the symptoms

    • Palpable purpura

    • Maculopapular rash

    • Biopsy of a skin lesion showing neutrophils around an arteriole or venule

    The presence of three or more criteria has a sensitivity of 71% and specificity of 84% for the diagnosis of hypersensitivity vasculitis.

    Hypersensitivity vasculitis that occurs without systemic manifestations is sometimes referred to as cutaneous vasculitis or cutaneous leukocytoclastic angiitis. The term serum sickness, on the other hand, is reserved to describe a systemic illness, including rash and arthralgias, which occurs 1 to 2 weeks after exposure to a drug or foreign antigen.

    Clinical Presentation

    Most patients with hypersensitivity vasculitis will develop cutaneous manifestations, the most common of which is purpura (Figure 21D-1). These lesions are distributed usually in a symmetric fashion over dependent regions of the body, particularly the lower legs (and, in recumbent patients, over the buttocks) because of the increased hydrostatic pressure in such areas. Purpuric lesions are not always palpable to the touch. The term palpable purpura is essentially synonymous with small vessel vasculitis, but does not necessarily imply an immune complex&#x;mediated pathophysiology; pauci-immune forms of vasculitis, such as Wegener&#x;s granulomatosis, microscopic polyangiitis, and the Churg&#x;Strauss syndrome, for example, may present with identical skin findings (see Chapter 21C).

    Diagnosis

    Biopsy is the diagnostic method of choice. Cutaneous biopsies are associated with low morbidity, and are generally sufficient to confirm one&#x;s clinical suspicion. Light microscopy examination of a hematoxylin and eosin (H&#x;E) preparation will demonstrate an inflammatory infiltrate primarily composed of mononuclear or polymorphonuclear cells, as well as telltale signs of small vessel vasculitis: leukocyte diapedesis, karyorrhexis, and leukocytoclasis. Although H&#x;E preparations are adequate for confirming the presence of vasculitis, they often provide insufficient data for a precise diagnosis. In cases of immune complex&#x;mediated vasculitis, Dr.eye 6.0 crack serial keygen, direct immunofluorescence (DIF) studies on the biopsy demonstrate the types of immunoreactants (i.e., immunoglobulin and complement proteins) present at the site of disease. Although direct immunofluorescence requires a biopsy of a second cutaneous site, this procedure is critical in many cases to differentiating the array of conditions associated with cutaneous vasculitis. Biopsy is especially useful to exclude other causes of vascular injury, including embolism and hypercoagulability states, which may demonstrate evidence of erythrocyte extravasation but not immune complex deposition. Of course, the presence of small vessel vasculitis does not always confirm the presence of a primary autoimmune disease; malignancy, for example, can also be associated with leukocytoclastic vasculitis. All biopsies, therefore, must be evaluated in the appropriate clinical context.

    Therapy

    Removal of the inciting agent is the only reliable therapy. In patients who have been exposed to multiple medications, determining the inciting agent may be difficult, and may require withdrawal of multiple agents simultaneously until the syndrome clears, typically in 1 to 2 weeks. Immunosuppression with glucocorticoids should be reserved for patients with particularly fulminant disease, and may be discontinued usually within several weeks.

    Prognosis

    The prognosis for patients with hypersensitivity vasculitis depends on the nature of the inciting agent. In the case of drug-induced vasculitis, multiple agents may need to be Dr.eye 6.0 crack serial keygen and re-introduced gradually. Approximately half of cases of isolated cutaneous angiitis do not have an obvious cause. Many such cases are associated with a relapsing and remitting course, but remain restricted to the skin and do not mandate aggressive immunosuppressive therapy.

    Cryoglobulinemic Vasculitis

    Definition

    InWintrobe and Buell noted that when serum from a patient with a hyperviscosity syndrome due to multiple myeloma was held at temperatures less than 37°C, a protein precipitate formed (4). Inthis cold precipitable serum globulin was referred to for the first time as a cryoglobulin. Cryoglobulins are immune complexes that are characterized by their tendency to precipitate from serum under conditions of cold. Cryoglobulins, PDF To JPG Converter 4.6.0 Crack Full Free Download | Lifetime to a varying degree in a wide array of inflammatory conditions, are not invariably pathogenic. In some patients, however, cryoglobulins deposit in the small- and medium-sized blood vessels and activate complement, leading to cryoglobulinemic vasculitis (5).

    Three major types of cryoglobulinemia are recognized, Dr.eye 6.0 crack serial keygen, defined by the specific kinds of immunoglobulins with which they are associated. Type I cryoglobulinemia, characterized by a monoclonal gammopathy (generally IgG or IgM), can be associated with Waldenström&#x;s macroglobulinemia or, less frequently, multiple myeloma. Type I IgA cryoglobulinemia has also been described, although this is quite rare. In contrast to the monoclonal nature of type I cryoglobulinemia, type II and type III cryoglobulinemias are known as mixed cryoglobulinemias because they are comprised of both IgG and IgM. In most cases of type II cryoglo-bulinemia, Dr.eye 6.0 crack serial keygen, more than 90% of which are caused by dc unlocker crack download Archives C infections, the cryoproteins consist of monoclonal IgM and polyclonal IgG. Cases of type II cryoglobulinemia not associated with hepatitis C infections are sometimes termed mixed essential cryoglobulinemia. Such cases may be associated with a still undefined viral infection. Type III cryoglobulinemia, typically associated with polyclonal IgG and polyclonal IgM, is associated with many forms of chronic inflammation, including infection and autoimmune disease. Not every form of cryoglobulinemia fits neatly into this classification system; cryoglobulins can, for example, have an oligoclonal antibody component.

    Clinical Presentation

    Type I cryoglobulinemia rarely presents with signs and symptoms of vasculitis. When symptomatic, type I cryoglobulinemia may be associated with a hyperviscosity syndrome that can lead to serious neurologic manifestations, including dizziness, confusion, headache, and stroke. Type I cryoglobulinemia can also be associated with other evidence of vascular stasis, including livedo Dr.eye 6.0 crack serial keygen, acrocyanosis, and digital gangrene (Figure 21D-2).

    Type II and type III cryoglobulinemias often present with a triad of signs and symptoms: purpura, arthralgias, and myalgias. The purpura may be extensive and confluent, and sometimes involves the trunk, upper extremities, and even the face (albeit in most cases the rash is confined to the lower extremities). Other common organ system involvement, more common in type II than in type III cryoglobulinemia, includes membranoproliferative glomerulonephritis (Figure 21D-3), peripheral neuropathy, and cutaneous ulcerations (the result of medium vessel vasculitis, in contrast to the small-sized vessel involvement that leads to purpura).

    Diagnosis

    Biopsy of an affected organ (such as the skin or kidney) may be the most straightforward method of confirming the diagnosis. Light microscopy of purpuric lesions demonstrates leukocytoclastic vasculitis. Direct immu-no-fluorescence studies reveal various types of immu-noglobulin and complement deposition, depending on cryoglobulinemia type. In type II cryoglobulinemia, for example, direct immunofluorescence reveals IgG and IgM deposition, as well as complement components. Renal biopsies from patients with glomerulonephritis caused by cryoglobulinemia reveal a membranoproliferative glomerulonephritis that must be distinguished from lupus nephritis (another disorder in which immune complexes play a major role).

    If biopsy is impractical or impossible, serologic testing may be helpful. The most directly relevant test is a serum cryoglobulin assay, which can give a direct sense of the burden of Dr.eye 6.0 crack serial keygen. The serum is allowed to remain at 4°C for several days before interpretation. The percentage of the serum occupied by the cryoprecipitate is commonly referred to as the cryocrit, and may be useful for following such patients longitudinally.

    Serum cryoglobulin tests Dr.eye 6.0 crack serial keygen, unfortunately, notoriously difficult to obtain, largely because the collection apparatus must be prewarmed and the blood must be allowed to clot at 37°C before processing. False-negative assays for cryoglobulins are common, particularly in laboratories not experienced in the collection and processing of samples.

    For patients with type II and type III cryoglobulinemia, nonspecific serologic testing may also heighten suspicion. First, a strong clue to the presence of mixed cryoglobulinemia is an extremely low (to almost undetectable) level of C4. For reasons that are not entirely clear, C4 levels are lowered out of proportion to the decrease observed in C3. Second, the monoclonal component of type II cryoglobulins almost invariably has rheumatoid factor activity (i.e., binds to the Fc portion of IgG). Thus, essentially all patients with type II cryoglobulinemia are rheumatoid factor-positive&#x;usually strikingly so. In many cases, rheumatoid factor tests are a more reliable screening test for type II cryoglobulinemia than are assays for cryoglobulins themselves. Although rheumatoid factor titers correlate with immunoglobulin burden in such patients and can be used in longitudinal follow-up in a manner similar to the cryocrit, the level of clinical symptomatology often correlates poorly with both rheumatoid factor level and cryocrit. Once patients have achieved a state of disease quiescence following treatment, both rheumatoid factor levels and cryocrit often remain elevated. Neither should be used as a gauge of therapy for most patients. Finally, acute-phase reactants such as the erythrocyte sedimentation rate and the C-reactive protein are elevated in many patients with cryoglobulinemia. In patients with type I cryoglobulinemia, Dr.eye 6.0 crack serial keygen, for example, Dr.eye 6.0 crack serial keygen erythrocyte sedimentation rate may be even higher than anticipated because of the excess circulating immunoglobulin.

    Therapy

    Treatment of the underlying cause of the cryoglobulins is the only approach that may lead to long-term response. Immunosuppression alone will not be sufficient to treat a cryoglobulinemic vasculitis that is driven by malignancy or chronic infection. In the case of hepatitis C&#x;associated cryoglobulinemic vasculitis, for example, the optimal therapy consists of the effective control of the underlying viral infection (typically with interferon-alpha and ribavirin). In patients who experience severe consequences of cryoglobulinemia (such as mononeuritis multiplex, glomerulonephritis, or other forms of tissue necrosis), immunosuppression with high dose glucocorticoids and cyclophosphamide may be necessary to prevent further damage. In patients with rampant systemic vasculitis, anecdotal evidence suggests that the systemic inflammation should be controlled first with glucocorticoids and other immunosuppressive agents, as appropriate, before the institution of antiviral therapy. In some cases of flagrantly active vasculitis, the introduction of antiviral therapy first is believed to have triggered disease exacerbation through an unfavorable alteration of the antigen/antibody ratio.

    Prognosis

    The prognosis of patients with cryoglobulinemia generally depends on the underlying cause. The outcome of type I cryoglobulinemia relates closely to Dr.eye 6.0 crack serial keygen efficacy in treating the cause of the cryoglobulin. Type II cryoglobulinemia secondary to hepatitis C may be treated effectively if the viral infection is responsive to therapy. If patients do not tolerate antiviral therapy well or if the treatment is ineffective, however, some patients may require low-to-moderate doses of prednisone to control the disease. Type III cryoglobulinemia is frequently a response to an inflammatory event (such as infection), and may not require specific therapy.

    Henoch&#x;Schönlein Purpura

    Definition

    Henoch&#x;Schönlein purpura (HSP) is an immune complex&#x;mediated form of small vessel vasculitis that is associated strongly with IgA deposition within blood vessel walls. Many cases of HSP are reported to occur after upper respiratory tract infections. Group A streptococci, mycoplasma, Epstein&#x;Barr virus, varicella, and other infectious agents have all been implicated in the pathogenesis of this disease, but the true etiology remains unknown. Inthe American College of Rheumatology proposed the following criteria for the classification of HSP (6):

    • Palpable purpura

    • Age &#x; 20 years at disease onset

    • Bowel angina

    • Granulocytes in arteriole or venule walls on biopsy

    Meeting two of four criteria is associated with a sensitivity of 87% and a specificity of 88% for this diagnosis.

    Clinical Presentation

    The hallmarks of HSP include an upper respiratory tract infection followed by a syndrome characterized by a purpuric rash, arthralgias, abdominal pain, and renal disease. HSP is usually viewed as a disease of childhood and, indeed, the majority of cases affect children younger than 5 years of age. Adults, however, can also be affected by HSP, and have a greater tendency toward prolonged disease courses (with recurrent bouts of purpura) than do children (7). Colicky abdominal pain, presumably secondary to gastrointestinal vasculitis, is a common characteristic of HSP, and frequently occurs within a week after the onset of rash. Occasionally the abdominal pain in HSP occurs before the onset of purpura, and may be difficult to distinguish from an acute abdomen. Endoscopy may demonstrate purpura in the upper or lower intestinal tract. Mild glomerulonephritis is common and generally self-limited, although some patients will develop end-stage renal disease.

    Diagnosis

    In children with mild manifestations, the clinical history alone may be sufficient to confirm the diagnosis. In more serious cases or when there is sufficient doubt about the diagnosis, biopsy of an involved organ is essential. Unlike other forms of immune complex&#x;mediated disease, however, direct immunofluorescence will reveal florid IgA deposition. In the proper clinical setting, this finding is diagnostic of HSP. Other forms of small vessel vasculitis may have small quantities of IgA within blood vessels, but IgA is not the predominant immunoreactant in such cases.

    Therapy

    In mild cases of HSP, no specific therapy is necessary. Even for patients with glomerulonephritis, it has been difficult to demonstrate that treatment with glucocorticoids or immunosuppressive agents significantly alters outcomes. Despite this, it may be prudent to treat aggressive renal involvement with an immunosuppressive regimen, including high-dose glucocorticoids and another immunosuppressive agent such as cyclophosphamide, azathioprine, or mycophenolate mofetil, depending on disease severity (8). In patients with renal involvement, anecdotal evidence suggests that plasmapheresis and intravenous immunoglobulin may also be beneficial, particularly in patients who are refractory to standard immunosuppressive regimens.

    Prognosis

    Recurrences of skin disease, often comprised of multiple episodes occurring over many months, are not unusual. Generally, however, even in patients with recurrent disease, the rule is for the disorder to subside and to resolve completely over a few months to a year. In a minority of patients, some evidence of permanent renal damage persists in the form of proteinuria and hematuria. Only a small minority, probably well under 5%, develop renal failure as a result of HSP.

    Hypocomplementemic Urticarial Vasculitis Syndrome

    Definition

    The study of urticaria is hampered by multiple terms that sound similar but describe different types of diseases. The word urticaria is most frequently used to describe acute urticaria, an IgE-mediated hypersensitivity reaction to a variety of stimuli, including medications, infection, and other triggers. Acute urticaria manifests as pruritic wheals that resolve days after the allergen is removed. Chronic urticaria is an autoimmune condition that is probably driven by an autoantigen. This form of urticaria may require immunosuppressive therapy in addition to antihistamines to prevent recurrence (9).

    Urticarial vasculitis describes a form of small vessel vasculitis that is characterized by the appearance of urticarial wheals. Normocomplementemic urticarial vasculitis is most often simply an example of hypersensitivity vasculitis in which the principal skin manifestation is urticaria. Normocomplementemic urticarial vasculitis tends to be self-limited, as is the case with hypersensitivity vasculitis. In contrast, urticarial vasculitis associated with hypocomplementemia is much more likely to constitute a significant and persistent clinical problem.

    Two categories of urticarial vasculitis associated with hypocomplementemia are recognized. The distinctions between these two categories are not always sharp, and both categories also share a number of features with systemic lupus erythematosus. The first category, known simply as hypocomplementemic urticarial vasculitis, refers to cutaneous vasculitis associated with low levels of serum complement (C3 and C4). The diagnosis of hypocomplementemic urticarial vasculitis is predicated upon the exclusion of other disorders that may present in a similar fashion, particularly cryoglobulinemia and SLE. The second category&#x;a more specific but still loosely defined entity known as the hypocomplementemic urticarial vasculitis syndrome (HUVS)&#x;consists of the constellation of low complement levels and urticaria for a period of at least 6 months, as well as some or all of the following: arthritis, glomerulonephritis, uveitis, angioedema, chronic obstructive pulmonary disease, pleurisy, or pericarditis.

    Clinical Presentation Curious Expedition 2 The Cost of Greed Early Access PC full crack - Free Download - Repack - Hiu Gam the lesions associated with chronic urticaria and urticarial vasculitis are similar in appearance, Dr.eye 6.0 crack serial keygen, certain differences help differentiate these two conditions. In urticarial vasculitis, the urticaria typically have a purpuric quality, indicative of small blood vessel damage and red blood cell extravasation (Figure 21D-4). Unlike common urticaria, the lesions of urticarial vasculitis are frequently associated with moderate pain, burning, and tenderness, in addition to pruritus. Whereas common urticaria typically resolve completely within 24 to 48 hours, the lesions of urticarial vasculitis may take days to resolve completely and often worsen without therapy. Arthralgias and myalgias are common in urticarial vasculitis. As noted above, patients with HUVS may also develop glomerulonephritis, pulmonary manifestations (particularly obstructive airway disease), and other findings. Gastrointestinal, cardiovascular, and neurologic manifestations are uncommon, but have been reported. There is striking overlap between HUVS and SLE, and patients will frequently have characteristics of both, although angioedema and COPD are more common in HUVS.

    Diagnosis

    Biopsy of an urticarial wheal in UV will demonstrate evidence of leukocytoclastic vasculitis, including injury to the endothelial cells of the postcapillary venules, erythrocyte extravasation, Dr.eye 6.0 crack serial keygen, leukocytoclasis, fibrin deposition, and a perivascular neutrophilic (or less commonly, lymphocytic) infiltrate. Direct immunofluorescence demonstrates immune complex deposition around blood vessels in the superficial dermis and striking deposition of immunoglobulins and complement along the dermal&#x;epidermal junction (Figure 21D-5). The interface dermatitis is identical to that observed in lupus&#x;a histopathological finding termed the lupus band test. In the proper setting, these findings (interface dermatitis as well as immunoreactant deposition within blood vessels) are diagnostic of hypocomplementemic urticarial vasculitis. HUVS, in contrast, is a clinical diagnosis based not only on the Dr.eye 6.0 crack serial keygen of urticarial vasculitis but also the occurrence of typical features in extracutaneous organ systems.

    Therapy

    Some cases of hypocomplementemic urticarial vas-culitis respond to therapies commonly used for the treatment of SLE, including low-dose prednisone, hydroxychloroquine, dapsone, or other immunomodulatory agents. There is anecdotal evidence Dr.eye 6.0 crack serial keygen anti-histamines, calcium channel antagonists, doxepin, methotrexate, indomethacin, colchicine, and pentoxifylline are effective in some cases. Serious cases, particularly those presenting with glomerulonephritis or other forms of serious organ involvement, may require treatment with high doses of glucocorticoids and cytotoxic agents. Both chronic obstructive pulmonary disease (COPD) and cardiac valvular abnormalities are associated with HUVS, and may require specific treatment as well.

    Prognosis

    The prognosis of HUVS is frequently linked to the disorder with which it is associated. SLE, COPD, angioedema, and valvular abnormalities are all known to occur in association with this disorder, and in such cases, may strongly influence both quality and quantity of life.

    Summary

    The immune complex&#x;mediated vasculitides are a clinically heterogeneous group of disorders linked by inefficient, defective, or dysregulated clearance of immune complexes by the reticuloendothelial system. Biopsy of an involved organ is frequently helpful in establishing the diagnosis. Direct immunofluorescence studies of involved blood vessels demonstrate characteristic patterns of immunoglobulin and complement deposition, which may be particularly useful in distinguishing these diseases. The prognosis of patients with immune complex&#x;mediated vasculitis is tied closely to the ability to identify and to treat the underlying cause of the immune response.

    Behçet&#x;s Disease

    Behçet&#x;s disease (BD) is a chronic inflammatory disorder of unknown cause. Its manifestations are thought to be caused by an underlying vasculitis. Although this disease is recognized worldwide, the prevalence is highest in countries of the eastern Mediterranean, the Middle East, and East Asia, thus the name Silk Road disease. The disease tends to be more severe in areas where it is more common. Prevalence rates in all areas of the world are increasing, probably because of improved recognition and reporting.

    Behçet&#x;s disease occurs primarily in young adults. The mean age at onset is between 25 and 30 years. The incidence of disease in males and females with the disease is approximately equal along the Silk Road, but in Japan, Korea, and Western countries the disease occurs more frequently in women. Familial aggregation and juvenile cases are not common. Case confirmation can be challenging because many patients labeled as having Behçet&#x;s disease have oral ulcers as the primary or sole manifestation.

    Clinical Manifestations

    Aphthous oral ulcers are usually the first and most persistent clinical feature of BD. Lesions occur in crops and some patients may have them during most of the course of the disease. Aphthae occur as ulcers that are 2 to 12 mm or larger. These are discrete, Dr.eye 6.0 crack serial keygen, painful, round or oval red-rimmed lesions that affect mainly the nonkeratinized mucosa of the cheeks, the border of the tongue, the soft palate, and the pharynx (Figure 21E-1). Oral ulcers are identical to the lesions of recurrent aphthous stomatitis. The severity and behavior of the oral ulcers in BD often fit the description of complex aphthosis, in which multiple, recurrent, or persisting lesions result in a severe syndrome that may include perianal or genital ulceration.

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    Nearly blind man's sight restored with 'bionic eye' implant

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    A degenerative eye disease slowly robbed Roger Pontz of his vision. But now, thanks to the surgical implantation of a “bionic eye,” he’s regained enough of his eyesight to catch small glimpses of his wife, grandson and cat

    Author of the article:

    The Associated Press

    Article content

    ANN ARBOR, Mich. — A degenerative eye disease slowly robbed Roger Pontz of his vision.
    Diagnosed with retinitis pigmentosa as a teenager, Pontz has been almost completely blind for years. Now, thanks to a high-tech procedure that involved the surgical implantation of a “bionic eye,” he’s regained enough of his eyesight to catch small glimpses of his wife, grandson and cat.

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    “It’s awesome. It’s exciting — seeing something new every day,” Pontz said during a recent appointment at the University of Michigan Kellogg Eye Center. The year-old former competitive weightlifter and factory worker is one of four people in the U.S. to receive an artificial retina since the Food and Drug Administration signed off on Dr.eye 6.0 crack serial keygen use last year.

    Article content

    The facility in Ann Arbor has been the site of all four such surgeries since FDA approval. A fifth is scheduled for next month.

    Retinitis pigmentosa is an inherited disease that causes slow but progressive vision loss due to a gradual loss of the light-sensitive retinal cells called rods and cones. Patients experience loss of side vision and night vision, then central vision, which can result in near blindness.

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    Not all of theor so people in the U.S, Dr.eye 6.0 crack serial keygen. with retinitis pigmentosa can benefit from the bionic eye. An estimated 10, have vision low enough, said Dr. Brian Mech, an executive with Second Sight Medical Products Inc., the Sylmar, Dr.eye 6.0 crack serial keygen, Calif.-based company that makes the device. Of those, about 7, are eligible for the surgery.

    Article content

    The artificial implant in Pontz’s left eye is part of a system developed by Second Sight that includes a small video camera and transmitter housed in a pair of glasses.

    Images from the camera are converted into a series of electrical pulses that are transmitted wirelessly to an array of electrodes on the surface of the retina. The pulses stimulate the retina’s remaining healthy cells, causing them to relay the signal to the optic nerve.

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    The visual information then moves to the brain, where it is translated into patterns of light that can be recognized and interpreted, allowing the patient to regain some visual function.
    When wearing the glasses, which Pontz refers to as his “eyes,” he can identify and grab his cat and figure out that a flash of light is his grandson hightailing it to the kitchen.

    The visual improvement is sometimes startling for Pontz and his wife, Terri, who is just as amazed at her husband’s progress as he is.

    “I said something I never thought I’d say: ’Stop staring at me while I’m eating,”’ Terri Pontz said.

    She drives her husband the nearly miles from tiny Reed City, Mich., to Ann Arbor for check-ups and visits with occupational therapist Ashley Howson, who helps Roger Pontz reawaken his visual memory and learn techniques needed to make the most of his new vision.

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    At the recent visit, Howson handed Pontz white and black plates, instructed him to move them back and forth in front of light and dark backgrounds and asked that he determine their colour.

    Back home, Terri Pontz helps her husband practice the techniques he learns in Ann Arbor.
    For them, the long hours on the road and the homework assignments are a blessing.

    “What’s it worth to see again? It’s worth everything,” Terri Pontz said.

    The artificial retina procedure has been performed several-dozen times over the past few years Serial number descargar clave de licencia mp3 studio youtube downloader Europe, and the expectation is that it will find similar success in the U.S., where the University of Michigan is one of 12 centres accepting consultations for patients.

    Candidates for the retinal prosthesis must be 25 or older with end-stage retinitis pigmentosa that has progressed Dr.eye 6.0 crack serial keygen the point of having “bare light” or no light perception in both eyes.

    Dr. Thiran Jayasundera, one of two physicians who performed the hour surgery on Roger Pontz, is scheduled to discuss his experiences with the retinal prosthesis process during a meeting of the American Society of Cataract and Refractive Surgery on Friday in Boston. He calls it a “game-changer.”

    Pontz agrees: “I can walk through the house with ease. If that’s all I get out of this, it’d be great.”

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    Amy Pond

    Fictional character in the TV series Doctor Who

    Amelia “Amy” Pond is a fictional character portrayed by Karen Gillan in the long-running British science fiction television series Doctor Who. Amy is a companion of the series protagonist the Doctor, in his eleventh incarnation, played by Matt Smith. She appears in the programme from the fifth series () to midway through the seventh series (). Gillan returned for a brief cameo in Smith's final episode "The Time of the Doctor".

    The Doctor first meets Amelia when she is seven years old (portrayed by Caitlin Blackwood) and disturbed by a crack in her wall. He promises to return to the lonely girl in five minutes and take her with him in the TARDIS, Dr.eye 6.0 crack serial keygen, but accidentally arrives twelve years later, by which time adult Amy has become sceptical about her "imaginary friend". However, she eventually decides to travel with him, and the duo are later joined by her fiancé Rory Williams (Arthur Darvill). Amy and Rory marry at the end of the fifth series. In the sixth series, Amy gives birth to their daughter, Melody Pond, Dr.eye 6.0 crack serial keygen, who is revealed to be recurring character (since the fourth series) River Song (Alex Kingston).

    Appearances[edit]

    Television[edit]

    Amelia Pond is introduced in the first episode of the fifth series (), "The Eleventh Hour", as a seven-year-old girl living with only her aunt when the Doctor (Matt Smith) crashes into her front yard one night. She asks him to investigate an unusual crack in her wall, but he is interrupted by an alert from the TARDIS. He promises Amelia that he will return in five minutes, but is inadvertently late by twelve years. In the intervening period, Amelia's family and friends believe the Doctor is just her imaginary friend; her insistence that he is real leads to her being treated by psychiatrists. When the Doctor returns, Amy is nineteen years old and working as a kissogram. She helps him save Earth from the galactic police force, the Atraxi, and when he returns two years later she begins travelling with him as his companion.[2] At the end of "Flesh Dr.eye 6.0 crack serial keygen Stone", Amy reveals that they had left Earth on the eve of her marriage to Rory Williams (Arthur Darvill) and attempts to seduce the Doctor.[3] The Doctor finds Rory and takes him and Amy to 16th century Venice on an intended romantic date after which Rory continues travelling with them.[4] In "Amy's Choice", Amy is pressured to resolve her conflicted feelings for the Doctor and Rory and realises the depth of her love for Dr.eye 6.0 crack serial keygen At the end of "Cold Blood", Rory is killed by a Silurian, then is erased from history by the cracks in the universe. Because he is part of Amy's own time-line, she ceases to remember him.[6] The Doctor takes Amy to 19th century France to lessen his guilt about Rory's loss and she forms a close friendship with famed painter Vincent van Gogh (Tony Curran).[7]

    In the fifth series finale, "The Pandorica Opens"/"The Big Bang", Rory reappears in AD as a Roman centurion. He triggers Amy's memories, but as she remembers, it is revealed that the centurion Rory is actually an Auton—a duplicate of living plastic—created from Amy's memories to help capture the Doctor. Rory's consciousness tries to fight his programming, but he is compelled to shoot and kill her.[8] Amy's body is kept alive in the Pandorica, a special prison intended to trap the Doctor. The Auton Rory protects it for years. The Doctor realises that Amy is connected to the cracks in the universe which originated from a temporal explosion on her wedding day. He tells her that her parents had been erased by the crack in her wall and urges her to remember them. After he uses the Pandorica to reboot the universe, the Doctor travels back through his timeline and is able to plant memories in Amy of the TARDIS. Amy awakes on her wedding day in a timeline where her parents are again part of reality and marries a restored Rory. Her memories are stirred by the TARDIS-shaped diary River Song (Alex Kingston) leaves for her. Once Amy remembers the Doctor, he is restored to reality.[9] It is mentioned in The Sarah Jane Adventures serial Death of the Doctor that the Doctor dropped Amy and Rory off on a "honeymoon planet",[10] and the couple continues their honeymoon aboard an interstellar cruise ship which the Doctor saves from crashing into a populated planet.[11]

    The sixth series () begins with Amy and Rory living a normal domestic life. They receive an anonymous invitation to the Utah desert where they reunite with the Doctor&#;—now aged nearly two hundred years since they have last met&#;—and fellow invitee River Song. Amy witnesses the Doctor's death at the hand of an astronaut in an Apollo space suit, but they discover the Doctor also invited a younger version of himself, Dr.eye 6.0 crack serial keygen, with Dr.eye 6.0 crack serial keygen they travel to Washington, D.C. to investigate Legue of legends keygen,serial,crack,generator,unlock occurrences involving the Silence, an alien race who cannot be remembered after they are encountered. While there, Amy informs the Doctor she is pregnant before attempting to shoot a Warhammer 40,000 Space Wolf v1.0.0 Deluxe Edition - SKIDROW girl in an Apollo space suit, believing it will stop her from killing the future Doctor.[12] In the girl's orphanage room, Amy finds strange pictures of herself holding a newborn baby. When the Doctor questions Amy about the pregnancy, she insists she was wrong and further investigation by the Doctor is inconclusive.[13] Throughout their adventures, Amy is plagued by strange visions of a woman wearing an eye-patch (Frances Barber) appearing sporadically only to her.[13][14][15] In "The Almost People" it is revealed that the Amy presented (on screen) insisting she is not pregnant, is actually a Ganger &#; a duplicate animated by the real Amy's consciousness &#; while the real Amy is in the captivity of the eye-patched woman and about to give birth.[16] In "A Good Man Goes to War", her baby&#;—named Melody Pond&#;—is kidnapped by the eye-patched woman, Madame Kovarian, who will train her to one day kill the Doctor. River Song then arrives and tells Amy that she is an adult Melody.[17]

    A flashback in "Let's Kill Hitler" introduces Amy and Rory's childhood friend Mels (Nina Toussaint-White). As teenagers, it was Mels who pointed out that Rory had been in love with Amy for some time, which led to the two dating. In the present, Mels hijacks Dr.eye 6.0 crack serial keygen TARDIS and directs it to where she is shot by Hitler (Albert Welling) and regenerates into River Song, revealing that Amy had grown up alongside her daughter, who was trained by the Silence to kill the Doctor. Amy is later persuaded by the Doctor to let her adult daughter make her own way in life.[18] In "The Girl Who Waited", Amy becomes separated from the Doctor and Rory on a planet's quarantine facility and lives on her own for 36 years before they return. The Doctor wants to go back in time to rescue the younger Amy, but the older Amy insists that they take both of her. However, the Doctor knows the TARDIS will not accept the paradox and is forced to leave the older Amy behind.[19] In "The God Complex", the Doctor breaks Amy's faith in him after he discovers that they are trapped in a prison for a being that kills by feeding on faith. At the conclusion of that episode, not wanting to risk their lives further, he parts ways with her and Rory after giving them a house and car.[20] Amy appears briefly in "Closing Time", where she is shown to have become a fashion model, Dr.eye 6.0 crack serial keygen, noted for a perfume campaign with the slogan "For The Girl Who Is Tired of Waiting".[21] Series finale "The Wedding of River Song" depicts an alternate universe created by River refusing to kill the Doctor in Utah, as previously shown. Amy leads a secret organisation which fights the Silence. She reunites the Doctor with River and later kills Madame Kovarian for kidnapping Melody and depriving her of raising her baby. After history is restored, River visits Amy and reveals that the Doctor has faked his death.[22] At the end of the Christmas Dr.eye 6.0 crack serial keygen, the Doctor returns to Amy and Rory two years later (in their time) and has Christmas dinner with them.[23]

    The series seven opener "Asylum of the Daleks" () shows Amy, still working as a fashion model, signing papers for her and Rory's divorce. In the episode, the Doctor engineers a reconciliation between the two during the mission, allowing them to discuss their feelings for each other. It is revealed Amy left Rory because she has been infertile since "A Good Man Goes to War", and knew he wanted children.[24] The couple continue traveling with the Doctor on small adventures in "Dinosaurs on a Spaceship" and "A Town Called Mercy", but leave at the end of each to return to their normal lives.[25][26] In "The Power of Three", Amy says that the Doctor has been in her and Rory's life for ten years, and she now works as a journalist. The couple realise they have to choose between their normal lives and their life with the Doctor. They are inclined to choose Arquivos Livros former, but Rory's father Brian (Mark Williams) encourages the pair to continue travelling with the Doctor.[27] Their next adventure, "The Angels Take Manhattan", is their last. In the story, Amy and Rory are threatened by the evil Weeping Angels, whose touch will send them into the distant past to die Dr.eye 6.0 crack serial keygen. Having witnessed this eventuality, they attempt suicide, creating a paradox which destroys all but one Angel, but also renders the area permanently off-limits to the Doctor's TARDIS. In the present, the surviving Angel sends Rory back in time, and knowing the Doctor cannot recover him, Amy allows the Angel to touch her too so she can be with him. Gravestones in a New York cemetery reveal that Rory died at the age of 82 and Amy died at the age of River arranges for Amy to leave the Doctor a message in the afterword of a s pulp fiction novel, where she says she is happy with Rory and that they worry about the Doctor travelling alone.[28] "P.S.", a mini shows-episode supplement based on the original script for this episode, shows that Rory and Amy adopted a son, inand named him Anthony Brian Williams.[29] Gillan reprises the role in "The Time of the Doctor" (), in which Matt Smith departs the series. During the Eleventh Doctor's regeneration, Dr.eye 6.0 crack serial keygen, he hallucinates images of young Amelia Pond on board his TARDIS, before a vision of adult Amy approaches and says a final goodbye.

    Other media[edit]

    In addition to the television series, Amy has appeared in several BBC-licensed Doctor Who novels, audio dramas, and comics. The first set of corresponding New Series Adventures novels—Apollo 23, Night of the Humans and The Forgotten Army—were published in April and feature solely the Eleventh Doctor and Amy. The next set—comprising Nuclear Time, The King's Dragon and The Glamour Chase—were released in July and feature the Doctor, Amy, and Rory. In Michael Moorcock's lengthier The Coming of the Terraphiles, which takes place during a time in the fifth series Rory is absent, Amy is proposed to by one of the characters, to whom she declines. In Aprilanother set of New Series Adventures were released to correspond with Amy and Rory's travels in the sixth series, containing Dead of Winter, The Way Through the Woods, and Hunter's Moon. A subsequent series of three books were published in June. In September, another longer novel was published, The Silent Stars Go By, which sees the trio face the Ice Warriors. In addition, Amy appears singularly alongside the Doctor in four "Decide Your Destiny" books, as well as alongside Rory in six "2in1" adventure chapter books. The three also feature in the Quick Reads InitiativenovellaMagic of the Angels.[30]

    Amy, Rory, and the Dr.eye 6.0 crack serial keygen appear in IDW Publishing's comic book series Assimilation2, published from May to Decemberwhich is a crossover between Doctor Dr.eye 6.0 crack serial keygen and Star Trek: The Next Generation. They team up with the crew of the USS Enterprise-D to stop an alliance between the Borg and the Cybermen.[31] Amy and Rory appear briefly in the mini-series "Prisoners of Time" where they join other past companions and versions of the Doctor in battling the main villains of the series. During a battle with some Autons, 11 introduces them to Clara Oswald.

    Amy Pond has appeared in several Doctor Who video games. Voiced by Gillan, she appears in all five episodes of Doctor Who: The Adventure Games which were marketed as Dr.eye 6.0 crack serial keygen episodes.[32][33] The virtual character was created using rotoscoping of Gillan's movements.[34] She also is featured, voiced by Gillan, in the video games Doctor Who: Evacuation Earth and Doctor Who: Return to Earth, made for the DS and NintendoWii respectively.[35] Amy also appears in the smartphone app game Doctor Who: The Mazes of Time.[36]

    Characterisation[edit]

    Creation and casting[edit]

    Young Amy, whom the Doctor first meets, was played by Caitlin Blackwood, Karen Gillan's real-life cousin.

    Doctor Whoexecutive producer and head writer Steven Moffat came up with the name for the character.[37] Moffat chose the name "Pond" to create a link between Amy and River Song, who would be revealed to be Amy's daughter.[38] Moffat's predecessor, Russell T Davies, stated in an interview with Dose magazine that "We've held off on companions for a long time, so you'll get rewarded with a great, big, strong character in Amy Pond, when she arrives. I think that plan's been good."[39]

    Andy Pryor, the casting director, suggested Gillan to Moffat after her performance in the fourth series episode "The Fires of Pompeii", in which she played a soothsayer, but Moffat originally thought Gillan was "wee and dumpy".[40] Later, however, he stated that she was Dr.eye 6.0 crack serial keygen right for the role", though she portrayed the character differently from how Moffat originally Dr.eye 6.0 crack serial keygen Gillan was reportedly the last to audition for the role, and stood out as she was "a bit kookier" than the others.[42] Moffat said of the casting, "We saw some amazing actresses for this part. But when Karen came through the door, the game was up&#;— she was funny, clever, gorgeous and sexy. Or Scottish, which is the quick way of saying it. A generation of little girls will want to be her. And a generation of little boys will want them to be her too."[43][44]Doctor Who executive producer and drama chief at BBC Wales Piers Wenger concurred, "We knew Karen was perfect for the role the moment we saw her. She brought an energy and excitement to the part that was just fantastic."[45] Gillan was aware of the show but was not as big a fan of it as her mother was, due to it not being on when she was growing up. However, she watched some with her mother after it returned inand was also a fan of other science fiction such as The X-Files, The Outer Limits, Star Trek: The Next Generation and Star Trek: Voyager.[46]

    Gillan auditioned for the role in both her natural Scottish accent and an English one, and it was not until after she was cast that it was decided Amy would be Scottish.[47][48] Gillan commented that she felt the Scottish accent better suited the character.[49] A younger version of Amy, known as "Amelia", appears in several episodes. Amelia was played by Gillan's real-life year-old cousin Caitlin Blackwood. Though the two actresses had not met until the set of the show, Gillan recommended Blackwood for the role; Blackwood, however, still had to undergo rigorous auditions first.[50][51] Blackwood and Gillan did get to act together in "The Big Bang", which Gillan initially found "weird", though the two actresses became used to it quickly.[52]

    Personality and character arc[edit]

    "That's been what I absolutely most love about playing this character, is that she's not just a character. We know what she's like, and that's her run on the show. We're seeing her whole life pan out. That's what I love about her so much. I hope she's changing. She was quite snarky in the [fifth series]Because she was always still such a child inside, as one of the monsters said to her at one point. And then we see the universe rebooted, so she's got two different versions of reality, so she's still a little messed-up, but she's far more settled as a person, having had a normal upbringing in one reality. She's married, and she has a kid."

    Karen Gillan[46]

    Gillan stated that "having read the first episode I was utterly smitten [with the show], and with the character. Amy's a sassy lady, funny and passionate, and her relationship with the Doctor has a really interesting dynamic".[53] Gillan believed that the Doctor still saw Amy as the same seven-year-old girl he first met, and described their relationship as brother and sister, with PhpStorm Crack v 2021.2.1 + Activation Code [Latest] 2021 sometimes acting as an "annoying little sister". She also did not want Amy, like previous companions, to stand around "in awe of the Doctor all the time" or "mope around" while he was not there; Amy would "do her own thing, whether it's fighting monsters in strange new worlds or just getting on with her life in her own village".[54] During her first series, Gillan wanted Amy to act "like a child in an adult body" because she had not properly grown up.[55] She appears more guarded because "she doesn't like to show her emotions because she wants to be strong".[56] However, she begins her second series as a more settled person,[55] and shows more emotion, especially with the birth of her daughter.[56]

    Gillan had substantial input into Amy's costume, as well as her hair and make-up.[48] In the first episode, costume designer Ray Holman stated that Amy's identity was not clear and that she wore her own clothes later on.[57] Gillan thought that Amy had inner confidence to wear clothes that showed "a bit of skin from time to time".[48] Gillan said she tried on many things, but when it came to short skirts she "just thought it was right" and showed that Dr.eye 6.0 crack serial keygen was "comfortable and confident about her look".[58] She believed that the skirts reflected what young women typically wear at her age.[54] Executive producer Piers Wenger also noted that Amy's s flying jacket, which she wears "quite a lot", reflected Gillan was a "born adventurer" and Amy developed a love for travel and adventure.[57] In the sixth series, Amy wears more jeans and longer trousers; Gillan stated, "she's getting a little bit more tomboyish as she becomes more of an action girl".[59] Amy never wears heels, as Gillan desired that the footwear be functional for saving the world.[60]

    As the Doctor accidentally did not return for her until twelve years later, Amy grew up a different person than she would have. She had become "cynical" and "distrustful" as the Doctor did not return as Dr.eye 6.0 crack serial keygen had promised and she was forced to believe he was just an imaginary friend, and had resorted to being "tough". Moffat theorised that Amy would have taken her anger out on Rory and would have been "mean" about things such as Santa Claus and the Tooth Fairy.[61] The second episode, "The Beast Below", was to introduce Amy into the role of the Doctor's companion and how much he needed one.[62] Though Amy soon tries to seduce the Doctor, Moffat believed that it was consistent with the cynical character he had built up. It was also a reflection of how the two had just escaped from death and shared a hard time together, and Amy's tendency to do things "in the heat of the moment".[63] In "Amy's Choice", meant to challenge the Doctor and Amy's Dr.eye 6.0 crack serial keygen Rory dies in an alternate universe that was a result of psychic pollen that had entered the TARDIS. This is when Amy truly realises her feelings for Rory.[65] As a primary part of the series' story arc, Rory officially dies and is erased from history and Amy's memory.[66] Though Rory later returns, he is an Auton duplicate who kills her, which reflected Moffat's belief that all good love stories end in tragedy.[67] The end of "The Big Bang", in which Amy stands up at her wedding and declares the Doctor is real, was the Doctor's success at restoring Amy to the spirit of the girl he first met.[52]

    Moffat had always intended for Amy and Rory to get married "from the off".[68] Gillan stated, "What I love about that relationship is that we really saw it develop to get to the stage where they were happy together. Because we started off at a point where Amy didn't want to be committed to him, and he absolutely did, and that just gave us somewhere to go with it, rather than just them being happy together. So it was interesting, and it evolved, and Rory really became a hero in the process".[46] She was pleased that the audience was able to see Amy's life "pan out", starting when she was a child and through her marriage and daughter.[46] Gillan stated that the aftermath of "A Good Man Goes to War" would "change her in a big way for the long run and I think we are going to get to see Amy in a really different light".[69] According to Moffat, by the seventh series, Amy and Rory had become "a crack team"; so used to being the Doctor's companions that instead of marvelling at him they "treat him like a big kid they have to look after".[70]

    In Decemberit was announced that the seventh series would be Amy and Rory's last.[71] Previously in November, Gillan had stated that once Amy had left, she did not want to make returning cameos, as she believed it would "take away from the big, emotional goodbye".[72] Gillan had arranged her exit with Moffat and the two decided on how Amy should leave. Gillan stated that she wanted to go "on a high when the character was at her prime" and that she "[wanted] to see her go with everything that she wants".[73] Gillan would make a brief appearance at the end of the Christmas Dr.eye 6.0 crack serial keygen, The Driver Booster Pro 8.7.0.529 Crack + License Key Download Free! of the Doctor, with Amy Pond saying a final goodbye to the Eleventh Doctor just before he regenerates, bringing actors Gillan Dr.eye 6.0 crack serial keygen Matt Smith together for a brief moment at the conclusion of Smith's last regular appearance as the Doctor.

    Reception[edit]

    Gillan Dr.eye 6.0 crack serial keygen autographs at the US premiere of "The Eleventh Hour"

    With the premiere of "The Eleventh Hour", two viewers anonymously quoted in The Telegraph complained that Amy's character was too "sexy" for a family programme like Doctor Who. Executive producer Piers Wenger stated that Amy was intended to be "feisty and outspoken and a bit of a number. Amy is probably the wildest companion that the Doctor has travelled with, but she isn’t promiscuous."[58] On a similar note, Gavin Fuller, writing for The Daily Telegraph's website, criticised Amy's "attempted seduction of the Doctor" in the episode "Flesh and Stone", claiming that it "did seem out of keeping with the usual tone of the series", and that "Given the number of young children who watch, it may not have been the most appropriate of scenes to screen".[74]

    Critics noted that Amy did not develop much throughout the series. Dan Martin of The Guardian, in a mid-series review, wrote, "I wonder whether I really know Amy Pond. Beneath the sass and the sauce and the wit and (there's no getting away from this) the skirts, I've yet to completely empathise with her, or work out what makes her tick".[75] In a review before the finale, Martin called her "a revelation", although she sometimes "felt a little one noteBut I'd put all of that down to guest writers responding to a character brief that probably said little more than 'feisty redhead'".[76]IGN's Matt Wales shared similar sentiments, Dr.eye 6.0 crack serial keygen, "Despite Gillan's effortless charisma, Pond was Dr.eye 6.0 crack serial keygen painted in largely two-dimensional strokes that made for a brash, sometimes irritating turn. It's testament to Gillan's abilities and brilliant chemistry with Smith that she remained thoroughly watchable throughout but, bereft of back story (albeit intentionally), it was hard to really get involved with the character".[77] Paul Kerton of Zap2it, however, wrote in a review of "The Eleventh Hour" that Amy's "brilliantly executed introduction to the show stood out. Amy's character after just one episode is already one with depth".[78]alloverlimo.us's Teresa Jusino was also more positive towards Amy in the fifth series, writing that she was equally "competent, intelligent, and [quick-thinking]" as she was flawed and made mistakes, which made her relatable and "a successful female character".[79]

    Chris Haydon of Den of Geek argued that Amy was "much more than the supposed eye candy many journalists unfairly referred to her as, or indeed much more than a female human to accompany the Gallifreyan Time Lord. She is far more three-dimensional and developed than the pre-existing judgements made her out to be". He also praised Gillan's acting abilities and the way her relationship with Rory helped "render [her] character into something quite special".[80]The Daily Telegraph's Michael Hogan considered Amy "the joint best assistant of the rebooted Who era&#;– far superior to Catherine Tate and Freema Agyeman, equally as excellent as Billie Piper". He also praised her relationship with the Doctor, saying that they were "totally believable as best friends".[81] Patrick Mulkern of Radio Times praised Amy for being "cheerfully freeof the emotional baggage that mired her predecessors"[82] and also reacted positively to her attempted seduction of the Doctor.[83]SFX named Amy and Rory the second-best science fiction and fantasy romance.[84] Inleading up to her departure, Martin wrote that Gillan's acting had improved, Dr.eye 6.0 crack serial keygen, becoming less of "a rootless collection of personality traits and enunciated sentence peaks" and someone more rounded. He also noted that Amy was unique because so much had happened to her and she became intwined in the Doctor's life, which allowed the audience to see her "develop and change".[85]

    The Guardian's Krystina Nellis argued that Amy functioned more as a plot prop than a strong female character, citing the importance of giving birth to River Song.[86]Charlie Jane Anders of io9, while positive towards her relationship with Rory, opined that Amy was still "a bit of a cartoon character" in "The Wedding of River Song", believing that her killing Madame Kovarian was "no substitute" for dealing with what Kovarian had done to her child.[87]

    The character has gone on to be referenced in popular culture. American supernatural drama Supernatural''s seventh season "The Girl Next Door" (), a character played by Jewel Staite operates under the alias Amy Pond. Digital Spy felt the Doctor Who reference was "rather random",[88] while IGN "loved" the shoutout.[89]

    Gillan has won over six awards up to date for playing the role of Amy Pond. In she won Cosmopolitan 'Women of the Year' Award.[90] In Gillan won an SFX Award,[91] a TV Choice Award,[92] and in she won at the National Television Awards.[93] In an online poll, with 3, participants, taken in lateAmy Pond was listed as the fifth most popular companion.[94]

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