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Steering the straits of transplant testing
June 2006
Cover Story
Karen Titus
Having a casual conversation about cardiac allograft rejection is next to impossible. Anyone broaching the topic soon becomes absorbed in knotty details, each of which seems to hinge on an "if."
Ditto for any discourse about a test to monitor rejection, especially when gene expression microarrays are involved. Genes are plentiful. Study populations are small. Blood is tricky. And the heart is, well, the heart.
So the researchers and physicians who are helping to develop and test-drive a new gene expression test called AlloMap (XDx Inc., South San Francisco, Calif.) have plenty to say about the subject, guided by large doses of critical thinking as well as a look-and-hope optimism.
In their latest effort, they explored the test's ability to predict acute
cardiac allograft rejection, presenting data at the annual meeting and scientific
sessions of the International Society for Heart & Lung Transplantation, held
in Spain in April. In an earlier study, known as CARGO, physicians and researchers
looked at whether AlloMap could detect the absence of moderate/severe cellular
rejection in stable cardiac allograft recipients, possibly reducing the need
for endomyocardial biopsies.
They found some answers, certainly, but mostly they remain surrounded by questions, the first being, How can the AlloMap test be used in clinical practice right now?
When the CARGO (Cardiac Allograft Rejection Gene Expression Observational) study was complete, a sigh of relief must have been uttered by those involved: The test appears to detect absence of moderate/severe cellular rejection. This, in turn, might reduce the need for biopsies in certain clinical settings, particularly at institutions whose protocols call for frequent biopsying. Though every center varies, it's not atypical for heart transplant patients to undergo a biopsy weekly for the first three months, then monthly, until the end of the first year or two. Some centers, such as UCLA, stop biopsying after one year; others after two or three; yet others follow patients for a lifetime.
The study, published in the American
Journal of Transplantation (Deng MC, et al. 2006;6:150–160), looked at gene expression profiling of peripheral blood mononuclear cells to discriminate ISHLT Grade 0 rejection (quiescence) from moderate/severe rejection (ISHLT e 3A/2R1). The paper describes the gene discovery and diagnostic development phases of the study as well as its validation. The researchers identified 252 candidate genes using known alloimmune pathways and leukocyte microarrays, then developed real-time PCR assays for each gene. Eventually they created an 11-gene RT-PCR test from a training set, validating it from an independent set.
Mandeep Mehra, MD, one of the authors of the study, calls the CARGO paper complex because he and his colleagues tried to address methodology as well as clinical relevance. "I don't think we appealed to either contingent adequately," says Dr. Mehra, the Herbert Berger Professor and head of cardiology, University of Maryland School of Medicine, Baltimore, and chief of cardiology, University of Maryland Medical Center.
The eight-center study collected samples from patients who were undergoing heart transplantation and followed by EMB and hemodynamics and/or echocardiography, among other clinical data. Those parameters are important, says Mario Deng, MD, the lead author on the CARGO study, because the test, in its current form, needs to be used with clinical examination and noninvasive graft function monitoring—for example echocardiograhy— if it is to be used effectively.
Based on published and post-publication data, Dr. Deng says, the test is useful for patients six months or more after transplantation who are undergoing routine biopsies. If these patients are clinically stable with no signs or symptoms of rejection (that is, if they have no shortness of breath and no weight gain secondary to fluid overload); if they have normal graft function by echocardiography; and if they have an AlloMap test score below threshold, then the presence of a Grade 2 revised rejection (formerly Grade 3A or higher— the ISHLT recently revised its guidelines) is approximately one percent. "Therefore, in that situation, a routine biopsy need not be done," says Dr. Deng, director of Cardiac Transplantation Research, Department of Medicine, Division of Cardiology, Columbia University, New York. "These situations should be between 75 and 80 percent of all encounters, according to the CARGO database, which included more than 600 patients involved in more than 5,000 encounters."
E. Rene Rodriguez, MD, director of cardiovascular pathology and director of the autopsy service at Cleveland Clinic, simplifies matters when he explains, "As a surveillance tool for somebody who's not rejecting, it's easy: It's a good test to prove that there's quiescence."
But, he says, that's not necessarily the obvious conclusion of the paper. "The paper may overemphasize a little the value [of the test] for rejection. And in reality, what we know now is that the test is terrific to detect no rejection."
The value of that application rests on several premises, one being that it would be good to do fewer endomyocardial biopsies.
Cardiologists like this idea. First, they don't want to do any invasive test
if it can be avoided. While EMBs are generally not seen as dangerous, and risk
of infection is low, a biopsy is a biopsy. It involves time, money,2 and a
very sharp needle. It's uncomfortable for patients, and, in pediatric heart
transplant cases, the youngest recipients require sedation.
EMB, like any biopsy, is not perfect, though it is the current gold standard
for detecting cardiac allograft rejection. Whether physicians are aware of
its limitations is debatable. In a separately published study (Marboe CC, et
al. J
Heart Lung Transplant. 2005;24: [suppl] S219–S226), CARGO researchers
identified a subset of 827 biopsies, from 273 patients, that included all biopsies
graded by local pathologists as Grade 1B or higher under the old ISHLT classification
system as well as randomly chosen Grade 0 and 1A biopsies. Three study pathologists
reviewed each case (without clinical data) and assigned their own ISHLT grades.
The greatest variability between the local and the study pathologists was in the diagnosis of ISHLT Grade 2 (17 percent agreement), with the latter group significantly less likely to make a diagnosis of Grade 2 rejection, the authors report. The study pathologists were significantly more likely to diagnose grades 0, 1A, and 3B rejection and significantly less likely to diagnose grades 1B and 3A rejection as well as Grade 2. Quilty lesions were a major contributing factor in the discrepancies. They were noted in 3.3 percent of local Grade 0 cases and in 31 percent and 37 percent of local Grade 2 and 3A cases, respectively. At best, says Dr. Rodriguez, who was not part of this study or the CARGO study, pathologists will disagree 30 percent of the time on the Quilty lesions versus rejection issue.
What does this have to do with the AlloMap test? It's difficult to say right now, given that its current use is to rule out rejection. But researchers are an itchy lot, and many in the CARGO clan are looking eagerly at other applications that would bring the higher grade biopsies into sharper focus.
The new ISHLT guidelines may or may not help matters. Dr. Rodriguez says the classification was changed with great pressure from cardiologists, who found the old categories of 1A, 1B, and 2 useless. In their view, he says, all such cases represented mild rejection. Under the revised classifications, Grade 0 revised is the same as the former Grade 0. Grade 1R incorporates the former grades of 1A, 1B, and 2. Grade 2R is the former 3A, and 3R encompasses the old grades 3B and 4.
The relationship of these new grades to AlloMap scores "is a question for down the road," Dr. Rodriguez says.
For now the focus is on the far ends of the spectrum—AlloMap scores in the low 30s or lower, and Grade 0 and Grade 3R biopsies.
It's fairly easy to sort out the meaning of a low AlloMap score and a Grade 0 biopsy; slightly more difficult is figuring out the implications of a high AlloMap score and a higher grade biopsy. More difficult still are cases where the AlloMap score is high and the biopsy grade low.
A high threshold molecular score returned alongside a quiescent biopsy may occur early after transplantation, specifically within the first six months, says Dr. Deng, and it may indicate a developing rejection. If it occurs several years post-transplant, the numbers could reflect a state of quiescence on low-dose immunosuppression.
The other situation—a below-threshold molecular score paired with a nonquiescent biopsy—may be less common, according to Dr. Deng, who notes it occurred in only eight patients in the CARGO study and was probably related to EMB variability. On Grade 3A biopsies, the three central readers had a maximum concordance of 77 percent; they downgraded local reads of moderate or severe rejection by up to 50 percent. Thus, one explanation for the discrepancy between positive biopsy and negative score may be overreading locally. Or, if a 3A appearance is subendocardially located, a Quilty lesion might be overlooked if the pathologist does not do serial sections. Finally, says Dr. Deng, some Grade 3A rejections "are in a sense benign—they disappear without augmentation of immunosuppression."
Physicians point to biopsy discrepancies as a reason to continue hunting for a better test. "The current gold standard at best detects 70 percent of rejection," says Dr. Rodriguez.
Jon Kobashigawa, MD, one of the CARGO researchers, sees another reason to keep pressing. "One could argue that a test that truly is picking up a fingerprint of upregulation of the immune system for rejection may be the true gold standard for the rejection process," says Dr. Kobashigawa, clinical professor of medicine at the David Geffen School of Medicine at UCLA and medical director of its heart transplant program.
But that's the future. For now, even those most familiar with AlloMap are working out what the scores mean at their own centers.
"On a practical level at Columbia, we're still in the early period of implementation," Dr. Deng says. The institution began using AlloMap clinically this January, in conjunction with biopsy, and will slowly transition to doing fewer biopsies on patients who are six months post-transplant and clinically stable.
AlloMap scoring is time dependent. In the first six to 12 months post-transplantation, the quiescent threshold is lower than it is one year or later. The reason? Some of the parameters within the score are steroid-responsive. As steroid doses are tapered down in the first year, the quiescence threshold appears to change. "If a patient less than one year has a score between, say, 31 and 34, it potentially indicates an elevated risk of rejection. If a patient more than one year has the same score, it has much more likelihood of being in the quiescent range," Dr. Deng says. Rising scores in long-term stable, quiescent, nonrejecting patients are "a research question right now. There may be inter-individual differences in gene expression profiles longitudinally."
It's too early to tell if discrepancies between AlloMap scores and biopsies will cause problems clinically. Says Dr. Mehra, "As with everything we've done in the field of heart transplantation for the last 30 years, we're going to have to spend time to learn about this. The biggest mistake would be to sell this as a perfect tool. It isn't."
Adds Dr. Deng: "The largest misunderstanding that can happen with this test is to take it as a dichotomous score, that either tells you, Yes, there is relevant rejection, or No, there is not."
The opposite, he says, is true. "I am afraid to say, this increases the requirement for intelligent interpretation of the test by the white coat taking care of the patient.
"You have to understand the concept of negative predictive value, and not everyone does," he continues, before repeating the limiting mantra: patients six months after transplantation, without signs and symptoms of rejection, with normal graft function and a below-threshold AlloMap test. "In this combination, the patient at that time does not have rejection that requires augmentation of immunosuppression. All the other situations you have to be cautious and do the classical workup. Therefore, you really have to think this through. The test needs a competent interpretation that exactly voices this with every single test."
Researchers are also trying to answer a very different question—can the AlloMap test predict future rejection?
"Initially the test was devised as a biopsy minimization procedure," says Dr. Mehra. "However, the time point of greatest vulnerability for rejection is in the first six months after transplantation. So the biggest bang for the buck for a test like this may potentially lie at the time when we are performing the most rigorous surveillance for rejection, in the first six months."
The frequency of cellular rejection in the first year is between 25 to 35 percent, Dr. Mehra says. Those rates are per patient rejection rates, not per biopsy rejection rates, in a given year, he adds. "If you look at the frequency of biopsies that are performed, then the frequency of rejection being picked up on a biopsy reduces down dramatically, to three or four percent."
The problem, he continues, "is of significant magnitude. If about one in three patients after a transplant is going to suffer at least one episode of rejection, and you have absolutely no idea when that episode is going to occur, you're left with no option but to apply the same rules to everyone—that is, biopsy everyone in the same way. There is absolutely no opportunity for personalized adjustment of surveillance. That's essentially the value that AlloMap potentially adds."
One primary finding of the study presented at the recent ISHLT meeting, Dr. Mehra reports, is the gene expression score discriminated those patients who went on to reject compared to those who did not. The negative predictive value of a gene expression score of less than 20 was 99.6 percent. The test was most robust in the first 180 days, he says, "exactly the time point when we would want it to be the most statistically strong."
Of the 11 informative genes included in the AlloMap score, three showed very strong signals, indicating they might be the prime movers and shakers during this 180-day period. Two of them are known to be corticosteroid responsive. "What we found from this study is probably the first time that two such genes could help differentiate the patients who reject from those who don't," Dr. Mehra says. While controlling for steroid dose longitudinally, he and his colleagues showed that patients who rejected had fundamentally different steroid-responsive gene expression scores than those who did not. "We may have for the first time hit upon a way of measuring adequacy of steroid dosing in heart transplantation."
Based on this data, Dr. Mehra suggests several clinical possibilities. One, a patient with a Grade 0 biopsy and an AlloMap score of less than 20 one month after transplant appears to have virtually no chance of rejection in the next three months; for these patients, additional biopsies during this time period may be unnecessary. For patients with a Grade 0 biopsy and an AlloMap score above 30, some 58 percent will reject in the next 12 weeks. Moreover, for patients with no chance of rejecting in the next three months, their current dose of steroids appears to be stable and adequate. On the other hand, clinicians may need to be cautious about moderating steroid doses in patients who are not rejecting but who have high AlloMap scores, "because they are potentially showing evidence that the dose of steroids is not adequate."
Dr. Mehra looks even further ahead, professing he's most excited by the new information on the individual genes. "Perhaps we will be able to dissect out two or three steroid-responsive genes and develop a steroid metric score, something that would be applicable not just to heart transplantation, but also to any other disease state in which corticosteroids are used."
Pediatric heart transplantation patients may also eventually benefit from the AlloMap test, although Dr. Deng urges caution. "Although we assume it has a very similar effect, we cannot at this time recommend AlloMap testing for a patient population under age 15," says Dr. Deng. He and others have investigated its use in patients under age 15, but the data are not ready "for a full peer-review publication, which I consider the minimum to start with a first statement on clinical implementation."
For someone so heavily involved in AlloMap's development, Dr. Deng is a refreshingly unadventurous proponent of the test. "Clinically implementing such a new molecular test requires responsible behavior. If there is no peer-reviewed publication, there is no scientific evidence. Abstracts don't count. And if we implement clinical recommendations, they also must be based exactly on this evidence, and not go beyond. And specifically, we must not succumb to commercial interests."
Published data are hardly the final word, however, as an emerging debate
regarding gene expression studies makes clear. An editorial accompanied the
CARGO study, sporting the somewhat inflammatory title of "Lies, Damn Lies,
and Statistics: The Perils of the P Value" (Halloran PF, et al. Am
J Transplant.
2006;6:10–11). Listening to discussion between the editorial's authors and
the CARGO researchers is a bit like following the conversational quadrille
in a Jane Austen novel. The characters disagree, but with such unimpeachably
good manners, it's hard to know for sure.
"We admire the energy and commitment and resources that went into the CARGO study," says Phil Halloran, MD, PhD, editor of the Journal and professor, Department of Medicine, University of Alberta, Edmonton. "Blood is a very vexing medium to work with. So it's courageous to try to establish a successful blood test based on gene transcripts. And if this test is confirmed, and their findings are validated by independent groups, then it's really quite a success story. Above all, we don't want to disparage what they have done."
But, he argues, the possibility of chance associations between transcripts and clinical phenotypes is frighteningly high. "Before you start using something to make a clinical decision, you should be watching the literature to see that an association of complex data with a clinical phenotype is hypothesis-based and that it's been independently validated by a completely different group, in a completely different set of patients."
Citing a Lancet article and editorial published last year (Michiels S, et al. 2005;365:488–492; Ioannidis JP. 2005;365:1686), he notes that of the seven largest microarray cancer studies, five produced results that occurred by chance. Bioinformatics techniques based on training sets and test sets "are generating a literature that can't be reproduced," Dr. Halloran says.
"This causes editors all sorts of worry," he says. Readers need to realize that determining associations between data-intensive microarray readouts and clinical phenotypes is a mind-boggling proposition. Microarray studies should be looked at with the same intensity and skepticism that physicians have brought to other complex problems, such as the association of HLA alleles with disease phenotypes. "Or cluster designation antigens," he offers. "It turns out there were hundreds of proteins on lymphocytes that you could pick up with monoclonal antibodies. That was another example of a large-scale collaborative effort, which didn't result in contaminating the literature with tens of thousands of papers contradicting one another, but which actually reached an answer. Some types of very complex questions simply need to be asked on a larger scale, where there's internal cross-validation between groups."
Dr. Mehra is equally courteous in answering the criticisms presented by Dr. Halloran and his co-authors. "I personally support that editorial. We tend to glamorize genomics research, and that editorial raised the bar."
In the end, the Journal did publish the study, of course. Drs. Deng and Mehra and Howard Eisen, MD, chief of cardiology at Drexel University and co-principal investigator on the original CARGO publication, responded with a letter to the editor (2006;6:1086– 1087), about which Dr. Halloran politely says, "We don't agree that they fully addressed our concerns. But the dialogue goes on, and people in good faith reach different points of view. We all want there to be a successful test, and if this is the successful test, time will tell."
In its current form, AlloMap is a send-out test—for which laboratories should probably be grateful. When Judy Wilber, PhD, vice president of technical operations at XDx, explains all the steps her laboratory takes to process samples, one is left with the feeling, "Who would want to do this test in-house?" "It's very complicated," she says, describing the RT-PCR procedures, each done in triplicate, for 20 different genes. It takes about 7.5 hours of hands-on work to run a sample. Not surprisingly, there are no plans right now to develop a kit format. Moreover, clinicians aren't convinced they need one. They report receiving results between 48 and 72 hours after samples are sent out, which is adequate for the test's current, non-acute use. "I would have expected turnaround time to be an issue, but it's the least of our problems," says Dr. Deng.
Dr. Mehra agrees. "If the idea is of prediction in a stable population, it would not bother me if the test result came back after even five days," he says.
What users would like to see from AlloMap, instead, is another test, or maybe several tests, each perhaps using a different complement of genes. "I joke about this with the XDx folks," says Dr. Rodriguez. "I tease them a little and say, 'Hey, when are you going to put out AlloMap version 2, or 2.5, or 3?'"
"It is a strong test, don't get me wrong," he adds. "But I don't think this is a test that walks on water. It's a good test that needs to evolve to become a terrific test."
The AlloMap, as mentioned, looks at cellular response. But that's one of only several types of rejection that can threaten a transplant. Patients may also develop antibody-mediated rejection (also known as humoral rejection), vasculopathy, chronic rejection, or graft dysfunction of another etiology.
All are shrouded in their own fogs. The new ISHLT guidelines standardized the description of antibody-mediated rejection. "So now we have two things—cellular and antibody-mediated rejection—that we can start disagreeing on," says Dr. Mehra with a laugh. Up until now, rejection trials have focused on cellular rejection, because antibody-mediated rejection is such a poorly characterized entity, he says. "And data on its frequency are not clearly available."
"I have always felt that rejection, when it does occur, is always a combination," says UCLA's Dr. Kobashigawa. "In some cases, it's more cellular than humoral; in some cases, perhaps fewer cases, it's more humoral than cellular. So I think it's important to try to delineate whether the current AlloMap test can pick up humoral rejection." UCLA is looking at just that, he says, but "the results are not complete. So I can't even hint at commenting on those findings."
At Cleveland Clinic, pathologists do EMBs using frozen sections, which allows pathologists to quickly address possible antibody-mediated rejection through special stains. By protocol, Dr. Rodriguez and his colleagues stain for AMR only on the first biopsy after transplant, to establish a baseline, unless the patient has a clinical problem. That could soon change.
"We have been discussing increasing the number of antibody-mediated rejection surveillance stains, because we have had a few surprises," he says. That reflects a shift in the heart transplant community and literature in recent years. Common wisdom held that antibody-mediated rejection is an acute event, happening within the first three months. "The truth is, it can happen late—sometimes very late. Most of the patients we are seeing, if they have antibody-mediated rejection, it's two or three years, or even a decade later" (Rodriguez ER, et al. Am
J Transplant. 2005;5:2778–2785).
An even bigger problem is cardiac allograft vasculopathy, a transplant-induced coronary artery narrowing. "The patients we lose every year, if we don't lose them to a rejection that really got out of hand, which is rare, most of the time we will lose them secondary to vasculopathy, or maybe to cancer," says Dr. Rodriguez. "Clearly we need to be able to stop allograft vasculopathy or detect it earlier, and there are no good methods of detection." The best method—intravascular ultrasound—is invasive and expensive and, for now, "very much a research tool," he says. "So it would be great to have a molecular marker."
XDx is listening, and CARGO II is already underway. Dr. Wilber reports the company is conducting an international trial to assess the current test's ability to detect vasculopathy, humoral rejection, and immunosuppressant weaning. Plenty of complex conversations lie ahead for a topic already rife with rococo detail.
The only simple advice right now comes from Dr. Deng. "This is not a no-brainer." He pauses, then drives the point home even more directly, if slightly inelegantly: "This is a brainer."


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There was a flurry of attention over the last few days when home-run hitters supreme Mark McGwire and Sammy Sosa went head to head in three games at Chicago's Wrigley Field.
Sosa (salary this year: $9 million) hit no more homers in the series, leaving his season total thus far at 61. McGwire ($8.8 mil) added one more, giving him 59. These are unfathomable numbers. It's a soaring achievement for both.
But it was only a flurry.
Why is it we are decidedly less than mesmerized with their prodigious accomplishments this year when we were riveted last year? It's because we are a nation that embraces first and historic but cools off dramatically when presented with again and repeat. Again lacks punch. Repeat tends to be even more drab. Our eyes glaze over when we read about "repeat offenders" and "repeated blunders."
Last month, a headline in the Bend (Ore.) Bulletin regarding men's slow-pitch softball read, "Bend Team Repeats as State Champs." In Atlanta, the news was, " '98 Trap Shoot Champs Repeat." Either one of those fire you up or give you goose bumps?
People who repeat things, they have told us, drive us nuts. We tune out. Another example would be in Atlanta, where the news was, " '98 Trap Shoot Champs Repeat."
The fact is, again and repetition often deserve far more respect. Let's look at McGwire and Sosa. Last season, the two dueled in a scintillating battle to determine not only who would hit the most homers but whether one, both, or neither would break the 1961 record of 61 held by Roger Maris. Turned out McGwire boomed 70, Sosa 66.
Incredible. Sports' most-honored record, which almost always stands as a towering monument with a bunch of ants scampering around at its base, suddenly underwent a two-pronged attack. It was fascinating. We heard of the latest blasts at the top of the 10 o'clock news and saw reports at the top of the newspaper page.
To go through what these two did physically and emotionally, and then do it again this year, is a searing accomplishment. Repeating in sports is difficult for many reasons, mainly because it's just hard to psych the spirit for another assault on the same mountaintop. Plus, even if an athlete fails to repeat, there is little more than a shrug: "Well, I did it once, and they can't take that away from me."
This year the same race is chopped liver.
We're trying to act worked up this time around, but it's like opening a Christmas present and discovering it's socks. We want to be more excited. We just aren't. We feel guilty. Newspapers still occasionally try to get in the spirit by putting some McGwire-Sosa exploit on the front page, but it looks silly. It's like headlining: "Halloween Scheduled Next Month; Thanksgiving to Follow."
Besides our general dislike of repetition, McGwire and Sosa trouble us on three fronts:
*They are mocking a record we think of as legendary. In our hearts, it's Babe Ruth's record (he hit 60 in 1927) and always will be. If it was such a big deal, then how come McGwire and Sosa toy with it? We like things that last. Change troubles.
*Just as nobody wants to dwell on the fact that McGwire beat the record when he was using performance-enhancing drugs banned by a number of sports, likewise nobody wants to point out that, in many respects, McGwire and Sosa are only solid, journeymen hitters. In their series this week, each managed one hit in a combined 19 at bats. Both hit around .280 in a game in which .300 minimally defines excellence. Both lead their clubs in strikeouts.
*McGwire's Cardinals and Sosa's Cubs are dreadful, two of the worst teams in baseball. There are a few left who stubbornly insist that baseball is a team game.
*Have the pitchers no pride? It's as if they are part of the circus, standing out there on the mound with the mission of making the stars look good. They are the Washington Generals to the Harlem Globetrotters. There is no reason they should keep serving up waist-high fast balls out over the plate. Come on.
Let's see McGwire and Sosa sprawled in the dirt, desperately avoiding a smoking high inside fastball. That always does something for leveling the playing field between pitcher and batter.
Or maybe we have succumbed to what familiarity breeds.
*Send comments to firstname.lastname@example.com
(c) Copyright 1999. The Christian Science Publishing Society


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This paper toy is Ron Weasley, a pure-blood wizard, the sixth son of Arthur Weasley and Molly Weasley, based on the Harry Potter fantasy novel / film, the papercraft created by zenturtle651692.
Ron Weasley was also the younger brother of Bill, Charlie, Percy, Fred and George, and the elder brother of Ginny. Ron and his brothers and sister lived in The Burrow where Harry and Hermione stayed quite often. Ron began attending Hogwarts School of Witchcraft and Wizardry in 1991 and was sorted into Gryffindor house. He soon became best friends with fellow student Harry Potter and later Hermione Granger.
Together, they faced many challenges during their adolescence, including keeping the Philosopher's Stone from Quirinus Quirrell, saving Ron's sister from the Chamber of Secrets, forming Dumbledore's Army, and fighting in numerous battles of the Second Wizarding War, including the Battle of the Department of Mysteries, the Battle of the Astronomy Tower, and the Battle of the Seven Potters. Ron also became a Gryffindor prefect and a Keeper on the Gryffindor Quidditch team during his fifth year at Hogwarts. He skipped his last year of school in order to accompany Harry and Hermione on a quest to destroy the Horcruxes of Lord Voldemort and fought in the Battle of Hogwarts in 1998, in which he lost his brother, Fred, a loss which devastated him.
After the war, Ron, along with Harry Potter and Neville Longbottom, joined the Aurors at the invitation of Minister for Magic Kingsley Shacklebolt, in order to track down Death Eaters who escaped capture. Eventually, he went to work at Weasleys' Wizard Wheezes with his brother George. He and Hermione eventually married and had two children: a daughter named Rose and a son named Hugo Weasley. Ron was also the godfather to James Sirius Potter, his sister Ginny Weasley and Harry Potter's eldest child. [Source: wikia]
You can download the papercraft toy here: Harry Potter - Ron Weasley Free Paper Toy Download


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NASA's newest delivery service pulled up at the International Space Station on Sunday after a week's delay, bringing more than a half-ton of meals and special treats to the astronauts who assisted in the high-flying feat.
With the smooth linkup, Orbital Sciences Corp. became only the second company to accomplish such a far-flung shipment.
The space station astronauts used their ship's huge robot arm to grab the Cygnus capsule, as the two vessels zoomed 260 miles above the Indian Ocean.
"Everybody is just so excited," Mission Control radioed. Ground teams described the achievement as "epic" and "superb."
(Read more: That's No Space Station! Asteroid 1998 QE2 Has a Moon)


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Toni Kroos signs contract extension with Real Madrid until 2022
Real Madrid have secured the services of one of their best midfielders in Toni Kroos. The German midfielder has signed a new contract with the Spanish giants which will keep him at the Bernabeu until 2022.
Kroos joined Real Madrid in 2014 from Bayern Munich and since then has been an important part of the Los Blancos team ever since he made his debut. Xabi Alonso went the other way joining the Bavarian giants.
Kroos has so far made 75 appearances scoring 4 goals but his role in Madrid is to be the creator and playmaker of the team along with Luka Modric. Now his presence holds even more importance because of the injury crisis the club are currently facing.
Both Casemiro and Luka Modric are out of the side and the creative and defensive burden has fallen on him. The club have taken a very important step in extending his contract and the best years of Kroos is yet to come.
This is the official statement from the club:
"Real Madrid C. F. and Toni Kroos have come to an agreement on a contract extension which will see the player linked to the club until 30 June 2022"
Bild are reporting that his current salary is at par with some of the best players in the world. Kroos new contract allows him to collect a cool 350,000 pounds every peek as part of criteria of the club's fee structure.
This makes him the highest paid German footballer ever. Quite an achievement for the player.
Kroos is only 26 years of age and still has his prime years ahead of him. The German has already won more than most footballers on the planet in his short stay with the club including the UEFA Champions League.
The German also won the World Cup in 2014 when they overcame Argentine in 120 minutes in that very famous final in Brazil. Kroos is one of Zidane's favourites at the club and has quickly endeared himself to the Bernabeu faithful.
Kroos struggled to find his feet at the beginning of his career but has now established himself as one of the best in the league and probably the world. His biggest asset is his range of passing.
He plays 40-yard passes from deep with a lot of ease and that enables Real Madrid to attack with speed and efficiency. Madrid's next game in La Liga is against Betis away. They desperately need a win after 4 consecutive draws in


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This week's Beauty Detox assignment was to create a variation of Kimberly Snyder's Warm Kale and Mushroom Beauty Salad. I made my salad over the weekend and then I used the leftovers in spring rolls for dinner last night. I didn't photograph my salad on its own, so here I'm sharing my Kale and Mushroom Spring Rolls. I enjoyed them with a bowl of miso soup and a small salad topped with sauerkraut and black sesame seeds. So my entry for this week's challenge is a salad in a spring roll, ok? Yeah, let's go with that!
I recently made spring rolls and cooked them with a quick shallow fry. They tasted great but a couple didn't hold together that well and I thought they might have soaked up a bit too much oil. This time around, I baked them in the oven and it was a lot easier that having to stand over the stove while avoiding getting burned by hot oil.
I sautéed my vegetables first since they were originally made for the salad, but another option is to coat the raw veg with a tablespoon of oil before wrapping. That might increase the bake time a bit.
Usually in a stir-fry salad like this, I would add some tamari. But since it's Sugar-Free September, I've been avoiding most sauces. To give this salad flavour, I loaded on the spices, and the flavours worked really well in my spring roll version, too.
- 6 rice paper wrappers
- 2 tbs coconut oil
- 4 cups chopped kale
- 1 cup sliced mushrooms
- 2 cloves garlic, minced
- 1" ginger root, minced
- ¼ cup thinly sliced carrot
- ¼ cup chopped zucchini
- ¼ cup chopped broccoli
- ¼ onion, chopped
- ¼ tsp crushed chili pepper flakes
- ¼ tsp chili powder
- ¼ tsp onion powder
- ½ tsp garlic powder
- ½ tsp paprika
- ½ tsp cumin
- ¼ tsp salt
- Preheat oven to 375F
- Place a wire baking rack over a parchment lined baking sheet and brush with small amount of oil
- Heat 1 tbs oil over medium heat
- Add mushrooms, kale and onion and sautee for 3 minutes
- Add remaining vegetables, garlic, ginger and spices
- Cook for an additional 5 minutes, until kale is softened and onions are translucent
- Working one at a time, prepare rice wrappers by placing in a shallow dish with warm water for 30 seconds
- Transfer to a clear surface and place ½ cup vegetables in centre
- Fold over sides and roll, placing seam side down on baking rack
- Brush each roll with remaining oil
- Bake on rack over sheet for 20-30 minutes
Make sure to check out Kimberly's warm kale and mushroom salad. And for my other Beauty Detox assignments, click here.


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text: I created hubbuddy over a year ago... and it was meant to fill a specfiic need. My thoughts in creating the site was from thinking back to what made people come back to a site - and mostly, it's loyalty... and real interest in the content provided. Hubbuddy was meant to be a personal messageboard for you and your friends... which certainly exist... but also by using "hubs" or groups of friends that were brought together into one single page. Each person is a part of many hubs... so you can see posts by those people in your hubs. The central thought is that you shouldn't be able to post to or see posts from those that aren't in one of your hubs... So if Joe and I are in a hub. And Joe and Peter and in a hub. I won't be able to post anything for Peter to see and vice-versa. See the intro. Anyway... i've been using hubbuddy with my friends, and their friends... and it's been very useful... and a good replacement for the spam-pool that is email. I never got around to opening it up to the public for various reasons... including support, limitation of downloads/uploads, possible extra serverload/bandwidth. Anyhow - thoughts/comments? arn


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Friday, 11 July 2014
A Postcard From Cornwall
There's been lots of sightseeing trips during the day and fishing in the grounds of our accommodation on an evening.
I'm not sure who's winning in the who's caught the most fish competition at the moment, suffice to say that all three of them have got a good tally.
We're all having a good time, even Archie. His favourite bit of the holiday is running through rock pools.
Another week to go yet, I'm hoping that we get a little more sunshine in our second week than we have in the first, but the weather so far hasn't put a dampner on our jollies.
26 comments:
I hope you have a great second week weather wise too Jo. I didnt think this last week had been too bad, maybe just up here in Yorkshire?ReplyDeleteReplies
We've had rain, but sunshine too, so it hasn't been too bad. It hasn't stopped us doing anything.Delete
Sounds like you are all having a fab time! Archie looks like a very happy little dog splashing through the water.ReplyDeleteReplies
Having been here three times before, it's a place we know we love. We're all enjoying our time here, especially Archie.Delete
enjoy the second half of your holidays.......looks like you are all having fun!ReplyDeleteReplies
We're having a lovely time, even on the rainy days.Delete
Sounds reasonably OK so far and the weather certainly looks better than ours. Have you ever visited Lanhydrock, Cotehele or the Eden Project? I love all 3 especially the first couples gardens. Take care and the four of you enjoy.ReplyDeleteReplies
There's plenty to do even on rainy days, so I don't mind a bit of rain, just so long as it isn't every day. We've been to the Eden Project when we've been in Cornwall previously, but not the other two. They're not places which Daniel and Eleanor would enjoy so we'll leave them until we're on our own.Delete
Hi JoReplyDelete
Glad you"'re having a good break. Hope the weather improves for you.
It's dull and drizzly today, but we've got plenty of things planned for the day. There's an indoor heated swimming pool here and a games room with a pool table and a table tennis table if we decide not to go out, though we'll probably have a drive out somewhere and then come back for a swim and a few games.Delete
Looks like you're all having a grand time, Jo - especially Archie. :o)ReplyDeleteReplies
Archie's having a whale of a time, he absolutely loves the sploshing noise he makes as he's running through the rock pools.Delete
- AnonymousSaturday, July 12, 2014
It looks and sounds like you're all having a lovely time, especially Archie.ReplyDelete
There wasn't a lot of sunshine here during the week either, although it is nice today.
Enjoy the rest of your holiday and fingers crossed that you get more sunshine. Flighty xxReplies
I rang home today and my mum said that it's been lovely there this past week. We had glorious sunshine yesterday, we've all got a bit of sunburn, but back to rain today. I'm hoping the weather improves now.Delete
Glad you are having a wonderful time, lots to chose from whatever the weather,ReplyDelete
have a great second week. xcxReplies
A holiday is what you make of it, whatever the weather, so we're sure to have a great second week.Delete
It looks like you're having a wonderful time. I hope the second week is just as good.ReplyDeleteReplies
We're having a lovely time. I'm sure the second week will be lovely too.Delete
I'm sure you'll be keeping busy not matter what the weather, being away together is what counts and I'm sure there is plenty to see and do!ReplyDelete
Lisa xReplies
I know this will be the last holiday that Daniel comes on with us so I'm making the most of us all spending time together, that's the most important thing.Delete
Have you visited Tintagel? We loved it although it was slightly heart attack inducing with three small kids on slippery rocks! Enjoy the rest of your hols :-)ReplyDeleteReplies
We went to Tintagel last week. Surprisingly, it was our first visit. It wasn't a very nice day so we didn't venture right down to the cliff edge but the village was so much bigger than I expected, a lovely place.Delete
Looks as though you are having a great time!! Archie looks as though he is really enjoying it. I hope that week 2 is just as good if not better than week 1!! xxReplyDeleteReplies
The weather has come out beautiful today, I'm hoping that the rest of the week follows suit as it's so much nicer here when the sun's shining.Delete
It looks like you are having a great time and I know the weather has been really nice this week! You picked a really good time to go! :)ReplyDeleteReplies
Some days have been good, it's currently thundering and lightening, though it's been very hot today.Delete


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A person may need a knee replacement when dealing with joint complications, such as arthritis, deformities or injury. This procedure basically deals with removal of a person's natural knee joint and replacing it with an artificial one in order to ensure proper movement or ease of pain. More than 4.5 million Americans have had knee replacement surgery, according to a report by the Los Angeles Times.
One of the main reasons why an individual may require knee replacement is to correct arthritis related complications. When a person is affected by arthritis, he or she may eventually experience severe damage to the joints. Pain and inflammation are some of the things associated with arthritis which is why doctors may recommend knee replacement surgery.
When involved in an accident or an unfortunate incident that causes extensive damage to the knee, doctors may recommend replacement. Doctors usually examine the extent of damage and prescribe a treatment most suitable. In a few cases, knee replacement may be done to correct deformities such as bow legs or knock knees.
Before carrying out a surgery involving knee replacement, most doctors explore alternatives such as exercises, weight loss, walking aids, shoe inserts and medicine. Physiotherapy may also help relieve knee pain and correct mild complications.


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Many of us still use rollerball mouses for our computers, and if you use one, you know how annoying they can get when they're dirty. They start getting less accurate, start moving jerkily, or just plain won't do what you want them to do. When this happens, the solution is a simple cleaning.
Supplies: soft cloth, cotton swabs, isopropyl alcohol
Step One: Unplug your mouse.
Step Two: Look at the bottom of your mouse. You will see a circular cover plate that holds the ball in place. Give this cover plate a slight turn to the right, and it will pop right off. Remove the ball.
Step Three: Use a swab dampened with alcohol to wipe down the ball, the cover plate, and the inside of the mouse.
Step Four: Use the cloth, slightly dampened with a bit of water, to clean the top and sides of the mouse. Let dry.
Step Five: Pop the ball back in, replace the cover plate, and plug your mouse back in.


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Hi there
Sorry for the novice question.
I just wanted to double check before I go ahead and write something…
If I want to fade down an EventCategory before I pause it,
Do I need to write a callback to make the fade manually each frame?
(Or do it in my update function of course).
I know that the Fade Down Time is used when stopping an event,
But I was wondering if there was similar in-built functionality for lerping volume changes, muting and pausing etc.
Thank you
(I am on iOS, and wanting this to work on streaming and non-streaming sounds)
- Gillies asked 7 years ago
- You must login to post comments


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- What: The Undergarden
- Where: GamersGate
- Current Price: £3.50
- The Undergarden price Comparison
GamersGate has reduced a few downloadable games to £3.50 today, and The Undergarden is one of the most noteworthy. Or least, if you don't engage with its rather aimless yet soothing puzzly gameplay. Either way, less than £4 is a great price for this surreal zen float 'em up and a 50% saving compared to Steam and XBLA.


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Toyota set to build $27m parts facility in Indonesia
Indonesia's biggest car seller, PT Toyota Astra Motor (TAM), will spend 249 billion rupiah ($27 million) to build a new auto-parts facility on Cikarang industrial estate, West Java, reported local daily the Jakarta Post.
President director Johnny Darmawan said Wednesday the facility would compliment an already built auto-parts facility in Sunter, North Jakarta, by guaranteeing supply for Toyota's domestic and international customers.
The facility, which will function primarily to distribute and supply auto parts, will be built on a 10-hectare plot.
"This center will be able to anticipate demands until 2015. Toyota car sales in Indonesia in 2015 will reach about 300,000 units, while this year we hope to reach 200,000 units," TAM marketing director Joko Trisanyoto said as reported by Antara.
TAM aims to sell 193,000 units this year, or equivalent to 34 percent of the total 570,000 units predicted to be sold in the country in the period. As of the end of July, TAM had sold 119,000 units this year.
The company also exports its products through one of its units, PT Toyota Motor Manufacturing Indonesia, to Thailand, Brunei, Malaysia, the Philippines and the Middle East.
Last year, TAM sold 152,040 cars, or 35 percent of market share. As of the end of the first semester, TAM held 33.7 percent of market share.
The latest data from the Association of Indonesian Automotive Industries shows that behind Toyota in market share were Mitsubishi and Suzuki in second and third with 14.9 and 13.4 percent shares, respectively.
TAM said earlier it would continue to gradually raise product prices until the end of the year by an average of 10 percent to compensate for increasing material costs. Among TAM's car models are the Avanza, Kijang Innova and Fortuner.
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The host defense responses are obviously triggered by chemokines and cytokines which are released by infected macrophages. Cultured IFN-γ-activated human monocytes inhibit replication of L. pneumophila and it has been shown that this effect can be reversed when the cells are supplemented with iron transferrin [51] . The killing and lysis of macrophages, monocytes and epithelial cells has been shown to occur in two phases. During the early stage of infection Legionella induces apoptosis [52] . This programmed cell death, which is mediated by the activation of caspase-3, is characterized by condensation of chromatin at the nuclear boundary and interchromosomal DNA cleavage [53] . In the post-exponential phase of growth Legionella causes necrosis of its host cell, appearingly by inducing pore formation [ 54 , 55 ].
L. pneumophila exhibits a remarkable phenotypic plasticity. The VBNC state and two distinguishable phenotypes during the infection cycle have been described [ 26 , 50 ]. Meanwhile it is generally accepted that the virulence of L. pneumophila corresponds to sequential growth phases of the bacterium. Post-exponential phase bacteria which are released from a depleted host cell are short, thick, flagellated and highly motile. In addition, this phenotype is more resistant to biocides, antibiotics and it is more invasive and virulent in different infection models [ 21 , 56 ]. Within the reprogrammed, maturation-blocked vacuole, L. pneumophila alters its physiology and converts to a replicative form (exponential growth phase). These replicative bacteria are more sodium resistant, do not express flagella and display reduced cytotoxicity [50] . Without lessening the importance of specific virulence genes, it becomes increasingly evident that the phenotypic plasticity of Legionella contributes significantly to the transmission and virulence of the pathogen. Therefore, one has to consider that it is not only the expression of specific virulence factors of L. pneumophila which are responsible for the prevalence of pneumophila species in disease, but also certain specificities in physiology and gene regulation.
Amino acid depletion and low temperature lead to the transition from the replicative to the infectious phase ( Fig. 2 ). The conversion involves a stringent response-like mechanism in which uncharged tRNAs activate RelA, a guanosine 3′,5′-bispyrophosphate synthetase [ 50 , 57 ]. The following accumulation of ppGpp then coordinates the entry of bacteria into stationary and infectious phase. By analogy to Escherichia coli it has also been speculated that the accumulation of ppGpp increases the amount of the alternative sigma factor RpoS. In support of this hypothesis it has been observed that the expression of RpoS increases during the stationary phase of Legionella and apparently coordinates the expression of virulence traits [ 50 , 58 ].
Not applicable.
The data and materials supporting the conclusions of this article are included within the article and its additional files.
adenomatous polyposis coli
antibiotic resistance gene-ANNOTation
colorectal cancer
the database for annotation, visualization and integrated discovery
database of essential genes
epithelial-mesenchymal transition
gene ontology
host-pathogen interaction database
host-pathogen protein-protein interactions
inflammatory bowel disease
kyoto encyclopedia of genes and genomes
lymphoid enhancer factor
outer membrane proteins
resistance-nodulation-cell division
The Cancer Genome Atlas
toll-like receptors
virulence factors database
Dr. R. Krishna and Amit Kumar gratefully acknowledge Council of Scientific and Industrial Research (CSIR), India for providing financial support to carry out this research work.
The Council Of Scientific And Industrial Research (CSIR), New Delhi, India (37(1610)/13/EMR-II).
Open Access
This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (
Mens 44899713403 Jeans Q/S designed by Factory Outlet For Sale Outlet Store Cheap Online SCYK7TEB
), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/ ) applies to the data made available in this article, unless otherwise stated.
The authors declare that they have no competing interests.
Daniel Paul Valencia…at Spanish River High School (Boca Raton, FL), earned three 1st-team All-Palm honors…named team MVP, 1st-team All-County, and 2nd-team All-State as a senior; Offensive Player of the Year, 1st-team All-County, and 2nd-team All-State as a junior; and team MVP and 1st-team All-Palm Beach County honors as a sophomore…Freshman of the Year by Southern Conference Sports Media Association and 2nd-team All-Southern Conference selection while at UNC-Greensboro after hitting .338 with 8 home runs, 36 RBI and 39 runs in 55 games…transferred to the University of Miami…named to the All-Regional team as a sophomore in 2005 after batting .300 with 6 home runs, 15 doubles, 63 RBI and 39 runs scored in 60 games (56 starts at 1st base and 2 starts at 3rd base)…hit .324 with 9 home runs and 61 RBI as a junior.
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text: Hey all, Waiting for UPS to deliver my 1st tablet (an EGlide 10" XL) on Thursday. 1. I can find virtually nothing on the net or here about this tablet or any of their products. Does anyone here have any experience with an eglide? Mine is the 10" model with Android 2.2 installed. 2. I have read here that the first charge up should be to 100% charged. Can it be used during that initial charge without causing problems? Thanks for any help SB


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|VA Acting Secretary Sloan Gibson - VA.gov
In a news conference on Friday at Phoenix VA, the agency's Acting Secretary, Sloan Gibson, said that at least 18 Arizona veterans died while waiting for initial appointments with a doctor. But he added that it is unclear whether any of the deaths was because of a delay in care.
However, The Reno Dispatch has learned that at least two veterans did die because of delayed care at Phoenix VA, according to two wrongful death lawsuits filed against the government that have both been settled for hundreds of thousands of dollars.
|Phoenix VA
Kitzinger's widow, Grace Kitzinger, filed the lawsuit in July 2013. Last month, just days after the story of the Phoenix VA's "secret list" of veteran patients was reported by CNN, Treasury Department records show that the government issued a payment of $800,000, according to a report in the National Law Journal.
The detailed complaint alleges there was negligence by Phoenix VA doctors. In its response to the complaint, the U.S. Attorney in Arizona said Kitzinger's injuries, damages and losses "were not proximately caused by the negligence of any employee of the United States."
A spokesman for the U.S. Attorney in Phoenix had no further comment.
Brewster Rawls, an attorney at Rawls McNelis & Mitchell who represented Kitzinger's widow in the lawsuit, told The Reno Dispatch that neither he nor Kitzinger would be commenting on the settlement because of the widow's wish for privacy. But an attorney who regularly represents veterans in lawsuits against VA and is familiar with this case said the amount of the settlement means the government did not want to take it to a trial.
"The response from the government is standard boilerplate language," said the attorney, who asked not to be named. "They will always deny any liability and admit no negligence. But there's no way they would ever pay that kind of money if they didn't think they would lose in a trial. They might pay $10,000 or $25,000, but not $800,000, not that kind of money, unless you think you're gonna lose."
While Leonard Kitzinger's attorneys have no evidence that Kitzinger was on the Phoenix VA's notorious secret waiting list, they do assert in the complaint that Kitzinger died because of a delay in care at Phoenix VA.
According to VA, more than 100,000 veterans were victims of manufactured waiting lists for medical appointments, And treatment delays have already led to deaths at VA hospitals nationwide.
As USA Today reported last month, 23 veterans died as a result of delays in endoscopy screenings for potential gastrointestinal cancer at VA hospitals in Columbia, S.C., Hampton, Va.; Augusta, Ga.; Charleston, S.C.; Miami; West Palm Beach, Fla.; Huntington, W.Va.; Cleveland; Prescott, Ariz.; Tucson; Grand Junction, Colo.; and Iowa City, Iowa.
The Phoenix complaint states that when doctors did an EKG on Kitzinger on November 18, 2011, the result was "severely abnormal," but doctors sent Kitzinger home without any anti-ischemic medications and without a referral to a cardiologists for further follow-up.
The consult request form indicated that Kitzinger would be scheduled for the next available stress test, according to the complaint. However, the complaint said, the appointment was scheduled for January 4, 2012, almost seven weeks later.
Three days later, on Nov. 21, Kitzinger had a heart attack while at work, the complaint said, and four days later Kitzinger's wife made the difficult decision to terminate life-support for her husband. He died seven minutes later.
The complaint said Kitzinger's primary care doctor and the Phoenix VA "deviated from appropriate standards of medical care."
Meanwhile, the National Law Journal also reported that in December 2012, the government agreed to pay $600,000 to the wife of a veteran at Phoenix VA who died of liver cancer.
In October 2009, veteran Alphonso Coronado was diagnosed with liver cancer, and he died nine months later, according to the Journal, which noted that the complaint in that case cited actions that "resulted in significant delay in Alphonse Coronado's care and treatment and more likely than not resulted in his death and/or the loss of a chance at an improved result."


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I cannot believe Halloween is only a few weeks away! I have been doing tons of Halloween crafts over here and it has been so much fun! Today, I'm so excited to share with you all a tutorial for making a Spider Den & Crystal Ball- a spooktacular addition to any fireplace mantel, table or counter! I got my inspiration for this project from the Halloween booklet written by the folks at FloraCraft® and I have to say that this FREE resource is full of inspirational Halloween ideas! I'll tell you more about the book soon but here is a peek at my Halloween craft! #MakeItFunCrafts
Halloween DIY: Spider Den & Crystal Ball
So, are you curious to know how I made this project? Let's get to it!
FloraCraft® Make It: Fun® Foam: 2 Balls (6″ and 5″)
FloraCraft® Make It: Fun® Foam: 4 Balls (1″)
Patching plaster compound
candlestick holder
black paint
white paint
print-out of a spooky word or numbers
matte decoupage medium
chenille stems (8 small strips per spider)
small white beads
craft knife
hot glue
1. Let's start with the spiders. Paint the small foam balls with black paint.
2. Take the chenille stems and cut 8 strips for each spider. Choose shorter strips to make a small spider and longer strips to make a large spider. Stick them into the foam balls, with 4 on each side.
3. Using hot glue, adhere two tiny white beads onto the balls for eyes. And just like that, the spiders are done! Pretty cute, right?
4. Now, let's move on to the spider den and crystal ball. First, cut a flat edge on each of the large foam balls to make the next few steps much easier.
5. For the spider den, draw the shape of the den with a black marker and then carve it away using a craft knife.
6. Use a spackle compound on both foam balls to give them a more interesting texture.
7. Paint the crystal ball white. Paint the spider den and candle stick holder black.
8. Print out a word or some numbers to be displayed on the crystal ball. I chose the word "BOO."
9. Cut out the letters carefully and use a matte decoupage medium to adhere the letters to the front of the crystal ball. Set the crystal ball on top of the candlestick, place the spiders in position and admire your work!
How fun was this?! I love how the spiders look like they're climbing into their den!
The Halloween booklet has so many other crafts from fun headbands to elegant pumpkins to scary skeletons! There are beautiful, large photographs of the crafts, along with complete tutorials (including supplies and directions) for each one! Be sure to take a peek at this FREE resource and get some amazing inspiration for all your Halloween crafting!
Now, learn more about FloraCraft® here and tell me in the Comments below: what Halloween crafts are you still planning to make?!
40 Responses to "Halloween DIY: Spider Den & Crystal Ball"
These are really cute Halloween decorations! I love the foam balls – you can be so creative with them – perfect for giant Christmas ornaments too!
Your Spider and Crystal Ball craft is wonderful. I do believe I have some of those balls with my craft supplies. Looks like a fun Halloween project.
I love the idea of these spiders!! They are super cute and easy to make for Halloween decorations.
This is super cute & creative and I know my kids would love to make versions of their own. I like how the materials for this project are simple and affordable.
Oh how cute is this? I love Halloween crafts, although I must admit I haven't made many since my daughter became a teen. But I do love these cute spiders.
That's a really cute and simple idea! I love all the cute halloween decorations, especially the ones that aren't scary.
This is a cute idea! I love the idea of using styrofoam balls. I never thought about using those to make decorations.
awww both look so cute <3 My niece would love this DIY project, will forward her your blog… this is so easy to make
This is the cutest idea. And I love that it is easy. I'm sharing this one!
Those are cute designs! I love the spiders, they are so adorable, and those foam balls can be used as well for the Christmas!
What a cute idea! My youngest would just love those spiders. I love making DIY Halloween decor.
This is brilliant, I love how simple and gorgeous they look. I may have to sneak out this weekend and pick up some supplies to do this weekend. I think my daughter will be game to help me as well. Happy Halloween.
What a cute idea! So crafty! Loving that spider. Looks so easy to make! Can't wait to try it with my daughter.
Cute! Though I wonder if a shimmery white would have looked really cool for the crystal ball? So that it looked more crystal and less matte?
First of all, let's make it known I HATE SPIDERS! Second of all my grandsons would think this is totally awesome, and my granddaughters would probably go ewwwwwwwww! I'll pass this stuff onto my daughters and let them decide. LOL
Such a cute and easy DIY project. Great way to make the house festive for Halloween!
I am LOVING these Halloween ideas! Super cute, loving your creativity! Thanks for sharing 🙂
That's really cute! I like Halloween crafts that are cute, rather than ones that are gross. I'm so not into eyeballs and blood and guts.
The Crystal Ball and Spider Den are so fun and easy. I love that the kids will have a blast with these, too. Thank you!
That is so spooky and adorable at the same time! I love that it's so simple, easy to do with kiddos around.


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Big enough to serve you, yet small enough to know you. This is what has made EOE Group Inc so successful over the past 25 years. We work hard to deliver leading edge digital imaging solutions to all of our customers who we have the privilege to serve. Our team is dedicated to providing a fast, efficient, and effective response to all sales and service needs. EOE Group Inc's goal, each and every day, is customer satisfaction.
In order to expand our product line, we recently decided to investigate the market. After researching products, serviceability, functionality and pricing, we determined that we could offer our customers additional equipment and pricing solutions by carrying the Kyocera Mita product line as well. While it had been our intention to continue to offer Konica Minolta equipment to our customers as well, the recent events mean that we will now be offering our clients Kyocera Mita equipment as our primary product line, though we continue to have the full ability to service your current Konica Minolta equipment with the same high level of support as we have in the past.
George Kormentzas
President, E.O.E. Group Inc.


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How do you change a persistent online world in a way that makes it feel like completing a quest made a difference? Blizzard's phasing was one way, where parts of the world were altered to reflect the consequences of your actions. You could see it in Northrend after Wrath of the Lich King launched and throughout post-Cataclysm Azeroth. While phasing fights the impression that you're running around a static, changeless prison, it also separates you from others if they're not as far along in the same quest. So while you may be running around in a sparkling flower garden filled with eternally grateful, glassy-eyed woodland creatures after vanquishing a threat, your friends still a few quests behind will be stuck in a charred wasteland filled only with ill-tempered demons. With Mists of Pandaria, Blizzard is hoping to avoid cutting up the social experience for the sake of story.
"I always tell my quest designers that phasing is like the story sledgehammer," said Dave Kosak, lead quest designer at Blizzard. "We want to start using it sparingly because I found the downside of phasing is it separates the players. It separates people. You've done the content, I haven't done the content, suddenly we can't adventure together. If you do too much phasing pretty soon everybody's seeing something different and they're not together. We didn't like that, so we are still doing phasing for those big, really important story moments where they have a big visual impact on the world in a very specific area, but otherwise we're trying to avoid doing a lot of phasing. It separates the players and that's less of a fun experience."
Though large-scale phasing won't be as prevalent, the team still wants to use it to convey subtler effects. "I might see flags everywhere, I might see fireworks going off, you might not see that yet because you haven't done those quests, but we're still adventuring together," said Kosak. "We did that with patch 4.2 in Cataclysm. We had a series of daily quests that had an individual progression so you and I could be in the same place. Because I've gone farther in the quest line, I would see that the [quest] hub has evolved. I would see a vendor standing there. If you're earlier the vendors aren't there yet for you. We can adventure together but still see changes in the world. We're doing a lot of that kind of thing in Pandaria so you'll definitely get a sense of a personal progression in a lot of different places."
In addition to favoring smaller-scale phasing, the quest lines will be broken up so there are fewer extended, linear stories. "In Cataclysm we had some really linear zones that you play through in order and we had a really tight story," said Kosak. "But the second or third time you play through with a different character you had to play it the same way." By breaking the quest lines up into smaller chunks and spreading them out across Pandaria's zones, Blizzard hopes to make quest progression a little more open-ended. "You'll be able to pick and choose the stories and the quests that you want to play through. They're all thematically related so they all kind of deal with the big theme of the zone but you can play them out of order. We just wanted to give players more freedom to experience the level up process differently with each character."
In past expansions Blizzard has introduced quest types where you hop on temporary mounts and are presented with a new ability set for the quest's duration. While these help break up the pace of standard questing, don't expect to see quite as many of these quest types in Mists of Pandaria. Instead, Blizzard wants to use special quest types sparingly to ensure they don't become too distracting. "I think that if, as a player, you get too many quests in a row where you don't get to play your class, it stops feeling like WoW," said Kosak. "Your Rogue stops being a Rogue because 'Oh, I'm driving in a car, now I'm driving a tank and now I'm climbing a tree.' We want you to feel like a Rogue. Those kind of special quests are nice when sprinkled about so that they become a highlight, they become something you really appreciate."
Kosak used an example of a quest in Mount Hyjal where, in the midst of a burning forest, you toss baby bears from a tree onto a trampoline to save them. "It's a one-off quest, I can't say there was much gameplay because it's very easy, it was more of a toy. You could throw the bears at other players, you could do all kinds of fun stuff with it, so that quest felt special because afterwards you went back to fighting again. If every quest you do is trying to be special then none of them are special, so we really try and mix it up."
This contributes to Blizzard's idea of World of Warcraft "flow", as Kosak called it, which determines quest structure and story delivery. "You shouldn't be more than a couple of minutes away from combat," he explained.
When you reach level 90, you'll find a different style of daily content. You'll get a series of quests to raise a Cloud Serpent mount, for instance. The process begins as you receive an egg, then continues as you essentially raise the Serpent through a series of quests until it's mature enough to ride all around Pandaria. In the Valley of the Four Winds, one of Pandaria's seven zones, you'll be able to set up a personal farm with one of the factions there. You can plant crops, set up herbalism harvesting nodes, harvest cooking ingredients and maybe, just maybe, some kind of harvestable pet.
Kosak provided another example. "There are these four temples for the August Celestials, the guardian spirits of Pandaria. Every day there's a problem at one of the temples and that's where your daily quest hub is that day. So there are different sets of dailies and at each temple there are also little randomizations as well; it won't always do the exact same thing at the temples every day. So working with that faction should be really different every day. There should be a lot of different things you can do and we really just put a lot of emphasis on that and a lot of emphasis on telling a story as you progress through the faction. We wanted factions to not be just a bar in the bottom of your screen."
Quest progress through Mists of Pandaria will also occasionally take you through dungeons, teasing eventual encounters you'll have with a five man group. Some dungeons, such as the towering Stormstout Brewery, are built fully to scale out in the open world. You can run around the entire Brewery as it's simply sitting in a field in the middle of the terraced farmlands of the Valley of the Four Winds zone. "That was a huge, huge thing for us because historically, you know, a dungeon is just a portal," said Cory Stockton, lead content designer. "Normally everything's faked, you know? Like back with Hellfire Ramparts in Outland, it was a version that was like twenty percent the size of the real version to get it to fit in the world. Then the real version was huge because it had to really work for a five man party."
In terms of what you'll find inside dungeons, Blizzard is pushing for clarity over complexity in Mists. "Looking back at Cataclysm, we had some fights that were in our eyes still too complicated for a lot of players to deal with right up front," said Stockton. "We firmly don't believe that someone should have to come into a fight and have to read this detailed journal to know how to complete the fight. If we find out stuff like that is happening, we'll go back in and try to find out ways we make the fight still super fun and engaging, but have it be clear enough that you don't have to go to Wowhead."
Within the Brewery, for instance, you'll face a giant rabbit boss called Hoptalus. After you fight your way through packs of vicious bunnies, some of which carry explosives, Hoptalus bursts from a beer keg and assaults you with a whirlwind (which Blizzard is calling a furlwind), a carrot breath attack and a hop attack. "He actually hops can land on someone," said Stockton. "When he does that he puts a giant marker on the ground so that you can see it and know where he's coming."
This is part of how Blizzard hopes to communicate boss mechanics to players so checking the dungeon journal isn't a requirement for success. "A dungeon is there to beaten," said Stockton. "A dungeon is not there to have you fail on a boss seven times because you don't know what's going on. If that's happening then we're not reaching our goals. So moving into Panadria we're not going to make things so simple that people can just walk through it, but we want things to be more clear. I think there's a big separation between clarity and something being complicated."
Through Mists of Pandaria's quests and dungeons, it seems as though existing gear will be replaced fairly quickly with the rewards offered in the expansion. How fast, exactly? "By the end of the first zone for sure," said Stockton. "We're actually looking at giving out rewards in a little bit of a different way. We're not going to actually give out rewards on every single quest. Instead we're going to give out rewards that directly correlate to your class and your spec." Stockton explained that quest rewards will be handed out more sparingly, so that you might go through seven or eight quests without getting an item reward, just gold. But then when you are finally offered an item, it'll be more useful and meaningful. "Most players throw away ninety some percent of that stuff. They just look at it, vendor, boom, gone. We just don't think that's fun. It's almost more of a chore. Why not just give the players the gold? If they're not going to get something useful, give them the gold."
Mists of Pandaria Video Preview
A new class of questing will also be made available in Mists of Pandaria. Called Scenarios, these quests will be set in instanced versions of the world, but will not be dungeon encounters that require a healer, tank and DPS group to complete. Instead, they're story-driven group encounters that present multiple tiers of objectives, and give Blizzard an opportunity to experiment more than would be possible in the open world or within dungeons. "They're a completely different type of gameplay in that they're step-based," said Stockton. "You'll come into a scenario and it'll be like 'kill fifteen of X'. You finish that step, and now the next step says defend this town from an invasion for three minutes. Step three is kill a boss."
Mists of Pandaria Video Preview
Because the Scenarios aren't within the open world of Pandaria, all players contribute to totals. If the goal is to collect thirty items, everyone in the Scenario works toward that goal cooperatively instead of collecting only for themselves, similar to public questing systems in other MMOs. The separation of Scenarios from the main game world also means specialized methods of story delivery can be used without running into the open world phasing issues Blizzard is trying to avoid.
If you really want to see all this for yourself, a recent update to Blizzard's Mists of Pandaria page states a closed beta testing period is "very close." If you signed up for WoW's Annual Pass, expect to get an invite. Otherwise you can opt-in through Battle.net, though you need to attach a Blizzard game to be eligible.
Assuming the beta test does start up sometime soon (update: it did, the beta is actually live right now), it could be a strong sign that Blizzard might ship Mists of Pandaria before the end of the year. Testing for its previous expansion, Cataclysm, started up in June of 2010, and the finished product wound up shipping in December of that same year.


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2008 BMW X5: Monster In the Box
November 07, 2008
This morning I woke up especially early for no particular reason so I decided I to just go to work. I hate time change, it's like jet lag while staying home.
I don't know if it was due to the X5's massive engine or that people weren't caffeinated just yet, but I every time I punched the gas from a traffic light I left my fellow commuters in my dust trail by massive margins.
The X5 is nice to your ego.
Scott Jacobs, Senior Photographer


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Posting ID : A1068529250
Date Posted : 2015-08-19
Category : Household Items By Owner
Bought this around a month ago for our growing puppy and he has already outgrown it. It's in very good shape, just a little scuff here and there. It says it's for pets up to 25lbs, officially "medium" size but I would say it's on the small end of medium. Please text or e-mail, don't call.


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Originally posted by JackofBlades
I remember seeing this online a couple weeks ago, and I have to say it was chilling!
They blink, you can see them move out from behind the rock and (maybe this is just me) but you can sort of make out the shape of a head and shoulders.
I don't know too much about the skinwalker legends because, honestly, they give me the shivers, but whatever it was in that cave is something that I'd have loved to see.
Regarding the attitude towards things like that in the community; I hope that it wasn't simply a case of the officer's courage being bolstered by the presence of the cameras, and that they will instead be a bit more intent on finding whatever this 'Howler' is/was and revealing it to the world!


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H.i I see that Calcate is good to help students with studying, but can you advise me which colour would help most please?
Hi D:
Thanks so much for your question about which color of Calciteis best to help students with their work.
Blue crystals are always excellent for mental activity and I especially like Blue Calcitefor studying. It opens up the Third Eye and the communication centers and helps with retaining information. I also like Optical Calcitefor clarity when students are trying to understand something that they are learning or if they are trying to express themselves in a paper or presentation.
Thank you again for your question and for your support of Healing Crytals.com. If you have more questions please feel free to write back. We would love to hear from you again.
Wishing you lots of love and light!
Crystal Blessings!
Tara Mideaker
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Please Note: Crystals are for healing and should be used as a compliment to other therapies and not as a replacement for regular medical care. Crystals are not a medical treatment and should not be used as a replacement for medical care. Please consult your healthcare specialist for your particular needs


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New 95 E320 Hd Gasket - Runs Hotter Now
View Single Post
Registered User
Join Date: Dec 2000
Location: Fairfax County, Virginia
Posts: 856
Sounds like you are down to:
1. Bad radiator (corrosion may not be evident) as most expensive I would consider it last
2. Bad viscous clutch - also a very expensive item if someone else does the work ... can trouble shoot by locking it up by bolting the fan blade to the assembly, but, if bad, it will cause overheating at slow speeds
3. Thermostat - I know you said you put in a new one, but if you have done searches on tstats you will find they are very unpredictable - very cheap to replace, especially if you are doing it yourself ... try another one from another manufacturer and source
Me? I would start with tstat and don't change anything else. If that doesn't do it, then lock up the vclutch on the far and see what happens. Radiator is last ... and, expensive ... try getting a used one and giving it a try ... R and R is not all that hard.
If these don't do it, it has to be either a pressure issue (sounds like you believe coolant system is absolutely tight and since it isn't boiling over, I don't think that is it either); or, a head gasket problem.
Try the tstat - a lot of folks have been very surprised to find their new tstats don't work.
George Stephenson
1991 350 SDL (200K and she ain't bent, yet)
former 2002 E320 4Matic Wagon - good car
former 1985 300 CD - great car
former 1981 300 TD - good car
former 1972 280 SEL - not so good car
a couple of those diesel Rabbits ...40-45 mpg
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Powered paragliding fail compilation
BASEjumperPublished: November 22, 2016Updated: November 23, 201618,568 views
Published: November 22, 2016Updated: November 23, 2016
This raw footage captured throughout the years shows us just how challenging it is to successfully pull off a powered paragliding session. From failed landings to disastrous takeoffs, these paragliding students have a lot more work to do!
1 comment
- 1 rumbleJoKidd · 1 year ago
Ouch, some of these look dangerous


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Words by Sean Moeller, Illustration by Johnnie Cluney, Recording engineered by Ian Grimble and Richard Matthews of Communion Music at 2KHz, Crouch End, London
Dan Croll does a little gazing and his day is shot. His night could go that way as well. It's hard to tell how deep he's going to get himself in when he looks into a certain pair of eyes. He will be mesmerized - he knows that. It's just that there's no way of telling when the spell will wear off and then there's a question of whether or not he'd like it to wear off. You get the sense that he doesn't, even if he's been thrown into some paralyzing, emotional stagnancy. It really could just be exactly what he was hoping for - just watching all of those minutes and hours swirl down the drain in a big, pipe-clogging lump. He wants to be there - aching in that good way. He LOVES those eyes and the person that they belong to, infuriating temptress and all.
Croll's songwriting is uplifting in its misery. His characters deal with indecisions and distance between hearts in ways that are mostly healthy, but there's nothing that leads us to believe that anyone's getting out of these quagmires anytime soon. These lovers will continue to ask the same question to the ones that they love, barely getting an utterance. They rarely know where they stand. Even when they might have a feeling, they're unwilling to put up with what they're hearing from someone who obviously doesn't know a good thing when they see one. They're just confused because, what more could they want then the promise of devotion that's being offered. It's always what makes these unrequited love songs, doesn't it? It's that impossible to digest feeling that the longer feels toward the object of his or her affection of, "What is wrong with you that makes you unable to see how true and good I will be to you if you'd just give me a chance?"
Croll writes these men who, while still being explorers, maybe casting a few nets, have determined that they can be that ONE love for someone else, but they're "just wondering if you're my special thing." They feel like they know, but they need a few more signs. They'd like some confirmation and some reciprocation, and not getting it - the looks, the touches, the words, the kisses - is traumatic. They refuse to give up though, as he sings, "I'll hold you safe til it's light/Hold you safe til the summer's right." It could be that it will take longer than that, or the summer will never be right.


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Flipping Fun Back to School Fest
Chris Cakes as seen on the Food Network is coming to
Northville to celebrate a new school year! Chris is world
famous for his wonderful pancakes and being able to flip an
average of 250 pancakes in an hour! He is the Guinness
World Record holder for 555 pancakes in one hour! Bring the
family to witness his amazing cooking skills and have fun with
age appropriate games, inflatables and giveaways while you
enjoy all you can eat pancakes with Chris Cakes!
Age: ALL
Location: Northville Community Center
Date: Saturday, September 22
Time: 10:00 - 11:30am
Fee: $8/person
Code: 100F
Deadline to register is Wednesday, September 19 at 4:30pm
Trick or Treat Trail
Get ready for a spooky, frightful, family friendly, delightful
event! Enjoy a trick or treat trail, crafts, entertainment, and a
Haunted Hallway! Advance ticket sales are sold by specific
event time. Please arrive at the event entrance a few
minutes before your scheduled time to check in. No on-site
registration will be available. We recommend everyone
wear costumes and bring a trick-or-treat bag.
Grade: Preschool - 3rd Grade
Location: Recreation Center at Hillside
Date: Saturday, October 20
Session 1: 4:00 - 5:00pm
Session 2: 5:00 - 6:00pm
Fee: $8/child, adults are free
Code: 101F/102F
Deadline to register is Friday, October 19 at 4:30pm
Tiny Pumpkins
Have a "FANG"tastic time at our not-so-spooky Halloween
Event! Enjoy a magician, pumpkin decorating, cider and donuts, and a costume contest for the tiny pumpkins! Parents
& Grandparents are welcome at no charge.
Age: 0 - 4
Location: Northville Community Center
Date: Tuesday, October 23
Time: 4:00 - 5:00pm
Fee: $8/child, adults are free
Code: 103F
Deadline to register is Monday, October 22 at 4:30pm
Dog Park Costume Contest
Attention dog park members! Dress up your dog and bring
them for a fun night out at the Cady Street Dog Park! A
costume contest will be held for the best dog/owner costume.
All K-9 participants will receive a yummy treat! We look
forward to a Howling Fun Time! Please note you must have an
active dog park membership to participate & register.
Age: ALL
Location: Cady Street Dog Park
Date: Tuesday, October 30
Time: 5:00 - 6:00pm
Fee: $5/owners and dogs
Code: 105F
Deadline to register is Monday, October 29 at 4:30pm
Mother and Son Dance
Mothers and Sons enjoy a fun and exciting way to spend
some quality time together. We are having a "Minute to
Win It" themed game night! You can still dance the night
away with our DJ, have your face painted, enjoy dinner and
snacks, and much more!
Age: 5 -13
Location: Northville Community Center
Date: Friday, November 9
Time: 6:00 - 8:00pm
Fee: $30/couple
Code: 106F
Deadline to register is Friday, November 9 at 4:30pm
Pancakes and Pajamas
Welcome Santa to town with a rise and shine pancake
breakfast. The holly, jolly event will include Pictures with
Santa, breakfast, crafts, sing-alongs and goodies. Advanced
ticket sales are sold by specific event time.
Age: ALL
Location: Northville Community Center
Date: Saturday, December 1
Session 1: 9:00 - 10:00am
Session 2: 10:00 - 11:00am
Fee: $10/person
Code: 107F/108F
Deadline to register is Monday, November 26 at 4:30pm
Holiday Funtastic Night
Tis the season to enjoy a night
of cookies, hot chocolate, and
a classic holiday movie. Kids
will also make crafts and write
letters to the North Pole. You
never know who may stop by and
visit… A guest appearance by Santa!
Age: 4 - 10
Location: Northville Community Center
Date: Friday, December 14
Time: 6:00 - 7:30pm
Fee: $8/person
Code: 109F
Deadline to register is Monday, December 10 at 4:30pm


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Potentilla Gibson's Scarlet
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Keywords: agm, autumn, botanical, botany, cinquefoil, clump-forming, colour, colours, deep-red, flower, flowering, flowers, foliage, garden, horticultural, horticulture, leaf, leaves, many, multiple, nature, perennial, plant, plants, potentilla gibson's scarlet, red, summer
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Intercity Hotel is located in Dubai. It consists of freshly renovated and spacious guest rooms which meet the guest needs. The property offers amazing facilities, amenities and services which make the customers enjoy.
The hotel is located in Deira, 17 minutes from Dubai International Airport.
Mid rise yellow colored building with balconies located on the street corner.
The hotel has a small lobby.The reception is located in the lobby as you enter the hotel.
Cancellation policies can vary seasonally or depending on the hotel or room type. You can review the specific policy for the hotel you selected during the reservation process.
Pets are not allowed
Reach us, we're available 24/7.