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Episode 8 – Dr Hendrik Van Poppel
Talking Urology
Prof Van Poppel is the Chairman of the Department of Urology at the University Hospital Gasthuisberg, Katholieke Universiteit Leuven, Belgium. He is a Board Member of the European Association of Urology (EAU), the European Society of Surgical Oncology and the European Organization for Research and Treatment of Cancer, where he is also Study Coordinator and Treasurer of the Genito-Urinary Group. He is Chairman of the Educational Office of the EAU and Director of the European School of Urology. Proudly supported by IPSEN
TALKING UROLOGY podcast transcript
Talking Urology – Episode 8 Dr Hendrik Van Poppel
I'm Joseph Ischia
And I'm Nathan Lawrentschuk.
And we're Talking Urology where we go to the source and chat to the world opinion leaders about their landmark papers. Our goal is to empower doctors to develop a deeper understanding of the literature to ensure we apply the right evidence to the right patient.
We are all about "bringing the literature to life".
Joseph: Today we are talking about the landmark partial vs radical nephrectomy paper by Hein Van Poppel but we still have some great podcasts coming up:
Montorsi's landmark penile rehab paper following radical prostatectomy with tadalafil
Neil Fleshner discussing his REDEEM study on dutasteride in men on AS for prostate cancer.
Stephen Boorjian monitoring the SRM
Maurizio Brausi on his paper of short term vs. long term maintenance BCG for NMIBC
A prospective, randomised EORTC intergroup phase 3 study comparing the oncologic outcome of elective nephron-sparing surgery and radical nephrectomy for low-stage renal cell carcinoma'
European Urology in 2011.
And now introducing Dr Hendrik Van Poppel
Hendrik: I am Dr Hendrik Van Poppel, I am a urological surgeon. I am confined actually to do oncological urology- so bladder, kidney, prostate and testicular cancer. I started doing my first partial nephrectomy around 1980 and I had my first paper published in the BGU at that time and in 1985 – 1986.
Joseph:
Why was study done?
PN provided equal cancer control with improved renal function
Safe with a slightly higher complication rate
Retrospective data about the improved survival (decreased CVS risk)
But there were no prospective trials
Hendrik: The idea of designing the trial was actually, I was doing partial nephrectomies as I said in the very early stages, even on tumours of 12cm in my first publication; and I wanted to show that at least it was as good as a radical nephrectomy when it comes to the oncological outcome.
Aim- to assess both morbidity and cancer control RN vs PN
Primary endpoint- OS
Secondary end points
Disease-specific survival (DSS),
Surgical side-effects
Study was originally designed as a non-inferiority European multicenter study
Initially intended 310 patients
Trying to rule out a difference of 10% in 5-yr survival from 90% for RN to 80% for PN.
Solitary renal lesion ≤5 cm suspicious for RCC
Normal contralateral kidney
WHO PS of 0–2.
Accrual began in 1992, and 300 patients were entered in 5.5 yr.
Going ok but realized that 10% difference in survival was not realistic.
In 1998- redesign: 3% in 5-yr survival from 90% on RN to 87% on PN (hazard ratio [HR]: 1.3)
But now you need more patients! Now- 1300 patients and 368 deaths were now required
Also, there was a shift going on out there- PN was becoming the new normal and accrual was dropping
Hendrik: That was one of the major problems. I was the most accruing centre, and while the enthusiasm of randomising patients was very high in the beginning everybody started doing partial nephrectomy because in the other literature it was said that the partial was probably better when it comes to kidney function to cardiovascular disease and so on. And everybody believed it and did not want their patients to be randomised for a radical because we were convinced that it was worse. So I continued to randomise the patients for the sake of the study, but many of the other centres stopped. Because it went so slowly in Europe, we went across the ocean and we asked our colleagues from SWOG and we asked people from University of Southern California we even asked the Canadians with Laurie Klotz to join, but this had an implication that instead of having a non inferiority study where we needed 350 patients, we wanted to have an equal results study on partial versus radical, and we needed 1300 patients to be randomised. It took about 11/2 years before we got this off the ground and finally when they should start randomising it faded out and essentially the EORTC closed the study prematurely.
So it was opened to North Americans- SWOG and ECOG, American College of Surgeons Oncology Group, National Cancer Institute of Canada [NCIC])
But- January 2003, the study was prematurely closed – poor accrual.
In total, 541 patients were randomized
(EORTC: 527 patients; NCIC: 11 patients; USA (ECOG/SWOG): 3 patients).
Joseph: So American centres doing over 100 partial nephrectomies were not submitting patients to the trial and it all comes down to what Hein said- surgeons were just not prepared to submit patients with small renal tumours that might be randomized to RN.
Hendrik: Many centres, major ones such as Germany for example; were doing partial nephrectomies for years and then we needed to convince them that they needed to randomise the patients in the trial to finally show and evidence based basis that partial and radical were equal but they continued to do the partials and not randomising the patients.
The primary analysis was based on intention-to-treat (ITT) principle- important- crossover between groups – discuss in a minute
Tests for both non-inferiority and superiority were carried out.
541 patients from 45 institutions (17 countries) were randomized- around 270 in each arm.
4 patients- multifocality or other cancers
136 patients- were pathologically ineligible
No renal adenocarcinoma
Tumour pT3+
Tumour >5 cm,
Positive surgical margins (3)
Of the patients randomised to RN, 6% underwent NSS (in general as a result of the patient's decision).
Of the patients randomised to NSS, 15% underwent RN (in general as a result of pathologic disease characteristics).
This is one of the problems with non-blinded studies- patients or surgeons will choose their treatment.
Also, this unequal crossover has been one of the criticisms of the paper.
We asked Hein if he was disappointed or concerned about the crossover:
Hendrik: No. This can be expected in a trial like this where you have patients in major centres. I remember that one surgeon randomised a patient for a radical and then another surgeon took the patient on and he saw a small tumour and then said I'm not going to do a radical for that tumour and he did a partial. Although, he had informed consent from the patient to have a radical. Sometimes also the partial seemed to be too difficult for the guy who was doing the case and he intraoperatively decided to do a radical nephrectomy. But I think there was no other major reasons why there was this high percentage of cross over.
Another critique has been that there was a significantly higher rate of other chronic diseases in the nephron sparing group compared to the radical nephrectomy group being 13% versus 8%
It was close to significance but didn't achieve it
We asked Hein if he thought that that this affected overall survival in favour of radical nephrectomy?
Hendrik: I do not believe that this really impacts on it. I don't think that this is important. The difference is not statistically significant and I do not believe that it's impacted in favour of radical nephrectomy.
All performed by open operation
Pleural damage rate of almost 10%- you rarely see this laparoscopically.
There was a higher complication rate with NSS
Double the perioperative bleeding 30% c/w 15%
Urinary leak rate of 4% in NSS, 0 in RN.
I asked Hein if he thought there would be any differences in the modern laparoscopic era:
Hendrik: I don't think so.
Lets get to the crux of the paper- the results
Median follow-up 9.3 years
Serum creatinine better in NSS arm 1.3 mg/dl c/w 1.5 in RN-wide ranges- not statistically different
Of 541 patients- 117 deaths
67 in the NSS group
50 in the RN group.
Only 12 (i.e. 2.2%) died of renal cancer- 8 in NSS, 4 in RN- small numbers-not significant.
Cardiovascular disease- the leading cause of death (almost 40%)- i.e. it is significant cause of death to consider
25 CV deaths in the NSS group
20 in the RN group
NB When you look back and remember that this was powered assuming a 90% 5 year survival in the RN group that is about right.
The ITT analysis showed 10-yr OS rates:
76% for NSS
81% for RN.
With an estimated HR of 1.50
The statistical test for non-inferiority of OS is not significant ( p = 0.77),
While the unplanned test for superiority is significant (p=0.03
But- just look at patients who had confirmed RCC on final pathology, after excluding clinically and pathologically eligible patients: i.e.
pT3+
Multifocality
Positive surgical margins
Then the test for superiority is no longer statistically significant (p = 0.07 and p = 0.17, respectively).
Regarding the secondary end point, progression- small numbers
12 patients in the NSS group
9 patients in the RN group
Not statistically significant
So knowing all this- what does Hein think is the role of partial nephrectomy:
Hendrik: The conclusion from all the open studies, the respective studies and also the prospective ones that have been showing the so called advantage of the partial over the radical, has only to do via selection of the patients that were brought to partial nephrectomy. There's a very nice study and meta analysis done by Capitano where you look at the difference of the two curves of the partial and the radical nephrectomy patients. If you would believe that, partial is indeed better than radical, you should see this effect over time getting bigger and bigger. But if you look at the curves, at the start; they both drop immediately and then they go apart and then in the end, it's like a banana they come together again. So, I believe that simply the patients in all the open studies were subjected to partial nephrectomy were better patients. And because they were better they had a better survival, and then you look for what reason – cardiovascular or whatever disease, so they live longer than the radical nephrectomy in the open series. But then the only randomised study, this does not show. Importantly, all the patients in the EORTC trial had normal contralateral kidney. So, probably we do not need to do this complex and sometimes morbid, difficult, oncologically unsafe partial nephrectomy for the T1b tumours when the contralateral kidney is normal because it has been shown that kidney function has a small drop but then recovers, and they remain stable. In the secondary analyses of the trial by Scosyrev, Messing, Richardson, Lester and myself you see that there is no deleterious effect over time. It exactly remains the same in the partial and in the radical nephrectomy. So, I do not believe that radical is worse and I continue to believe in the randomised trial and not in the others.
Nathan: So did the trial change Hein's approach to surgery for the SRM?
Hendrik: I've done so many partial nephrectomies and I love to do the surgery, I love to do difficult partial nephrectomy even when it is not needed in the presence of normal contralateral kidney I still do partial nephrectomy. Why is that? Because in reference centre we are, you'll get cases referred with solitary kidney with tumours and you can gain experience. I've gained enormous experience by doing maybe superfluous, not really necessary partial nephrectomies in very difficult situations. And now I feel happy to do partial nephrectomy on tumours of 15cm and then reconstruct the kidneys. So that's probably the only advantage for the surgeon – doing this in elective cases is that he is going to get a quota and is going to get the experience to do this when it's really needed in the imperative cases.
Maybe that explains it- in retrospective studies- more likely to do RN in less healthy and older patients- more likely to have CVS disease rather than NSS preventing CVS disease
NB- present study was not designed to test the hypothesis of reduced CV events with NSS.
Underpowered- failed to accrue- selection bias
Significant crossover
Maybe some issue with differences in morbidities between groups
Not powered to detect difference in CKD, CVS events
Central pathology in only 49% of patients
Serum creatinine rather than eGFR for assessment of renal impairment
These study- patients from 1990. Is it still applicable in modern cohort of patients with stage migration from increased incidental detection with modern imaging?
Nathan: We asked Hein- if he did the trial again what would he do differently?
Hendrik: Firstly, I would go to the T1b and the T1a tumours and not to the 5cm cut off. Secondly, I would not include only patients with normal contralateral kidneys. Nephron sparing surgery is important in CKD2 and CKD3 patients, in CKD4 it doesn't matter. Even if you operate on a bad kidney, you take the kidney out or you do a partial; they do not so much worse they do badly already. It's the 2 and 3, that's the category where you need to do partial nephrectomies and not taking the kidney out. So we would probably stratify must stronger and say, this is a group of patients with normal kidney function, these are patients with CKD – CKD1, CKD2; and those then should be the ones for partial or for radical.
Joseph: Do you think we need another trial as you suggested to answer this question or do we have enough information?
Hendrik: I am fed up with trials. I have done 3 major trials in my life. The first trial was comparing high-risk renal cell cancer patients with no post-operative treatment or adjuvant treatment with interleukins, interferons and five FU. It turned out to be a negative trial. The second trial was the Bolart trial. After radical prostatectomy and high-risk positive surgical margins T3a and b, to give immediate post operative radiotherapy or not give it. There is a biochemical progression free survival benefit. There is no overall survival benefit, so it's actually a negative trial. And now we know today that early salvage is probably as good as immediate adjuvant. And to show that partial nephrectomy is as good as radical nephrectomy, everybody does it. The only evidence that says that actually it's not needed, but everybody does it so it didn't help. And another randomised trial is not going to change that. We are not going to do randomised trials for radiofrequency ablation; we do not do randomised trials for robot surgery. This is not the way in which surgery makes progress. Surgery makes progress because there's experts that do a different thing in a different way that everybody accepts is good to do.
Nathan: So what is Hein's take home message?
Hendrik: In the beginning I could not believe it because I designed the trial to show that partial was at least as good as probably better than radical which I couldn't. In the beginning I didn't believe it and I presented the trial the first time to the Academic Association of? Surgeons, and in the end I got the question – so what do you do now? I said, I continue to do partials. That's very strange because the evidence points towards another politic. I will continue to say that all the advantages shown by open studies is a selection of patients. If you have normal contralateral kidneys and you have an easy tumour on the left side, why would we as urologists take the kidney out? You do a proper partial nephrectomy – no
complications, not too much pain, no open surgery. And the patient will do well. If you have a complicated tumour, that's different. If it's a complex tumour invasion of the pelvic calyceal system, maybe invasion of segmental veins; sometimes you can do it. Because in imperative cases you do the same. But I think they are the normal urologists who is not doing high volumes of partial nephrectomies. He should just do a simple laparoscopic radical nephrectomy, which is not morbid at all, and the patient will not suffer chronic kidney disease. Unless at the beginning he was CKD2 or 3. So with a normal contralateral kidney, my advice would be – do the safe thing. Take the kidney out.
There you have it. When you are sitting in your next MDM looking at a SRM in a kidney, quote the guidelines- do a partial.
And if its too hard, and they have normal renal function and a normal contralateral kidney, quote the literature- do a radical. Simple.
Thank you to Hein Van Poppel for his comments
And any feedback to talkingurology@gmail.com
Remember, there are lots of great podcasts on our website Talkingurology.com.au. You can also follow us on Twitter @talking_urology, Apple podcasts or SoundCloud for the latest podcast releases. We would love you to rate us and spread the word.
Tags: Cancer, Nephrectomy, Prostate
Episode 7 – Dr Stacy Loeb
Dr Peter Black


The Deposition, considered one of Caravaggio's greatest masterpieces, was commissioned by Girolamo Vittrice for his family chapel in S. Maria in Vallicella (Chiesa Nuova) in Rome. In 1797 it was included in the group of works transferred to Paris in execution of the Treaty of Tolentino. After its return in 1817 it became part of Pius VII's Pinacoteca.
Caravaggio did not really portray the Burial or the Deposition in the traditional way, inasmuch as Christ is not shown at the moment when he is laid in the tomb, but rather when, in the presence of the holy women, he is laid by Nicodemus and John on the Anointing Stone, that is the stone with which the sepulchre will be closed. Around the body of Christ are the Virgin, Mary Magdalene, John, Nicodemus and Mary of Cleophas, who raises her arms and eyes to heaven in a gesture of high dramatic tension.
Caravaggio, who arrived in Rome in 1592, was the protagonist of a real artistic revolution as regards the way of treating subjects and the use of colour and light, and was certainly the most important personage of the "realist" trend of seventeenth century painting.


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redpajama_set_name: RedPajamaCommonCrawl


It's been over three years since the Diamondbacks shocked the baseball world by signing Zack Greinke to a massive six-year, $206.5 million deal, but the jury is still out on whether or not this was a good deal.
Greinke has been very good in his time with the D-backs, but the remaining three years and $104.5 million on his contract have left the team financially handicapped.
Because of this, ESPN's David Schoenfield listed Greinke's deal as the D-backs's worst and the 18th worst in baseball in his column ranking every major league team's worst contract.
After a less-than-stellar first season with the Diamondbacks, Greinke topped 200 innings the past two seasons with ERAs of 3.20 and 3.21 in a hitters park. His 10.3 WAR over those two seasons ranks eighth among starting pitchers, so the idea that Greinke hasn't lived up to the contract doesn't really add up. That said, if Greinke's contract was viewed as a good deal, they'd have traded him this offseason — and that hasn't happened.
As Schoenfield notes, Greinke's contract is lower on the list because he is still a very productive pitcher. The 35-year-old ranked 17th in the majors in ERA last season and 19th in strikeouts with 199.
This is a far cry from some of the names at the top of the list like Chris Davis, Albert Pujols and Jacoby Ellsbury, all of whom have seen their production nosedive during their respective big-money deals.
Greinke's deal still stands as the highest ever given out by average annual value, though, and for a team that doesn't appear to be in the playoff picture for the foreseeable future, this could be seen as a burden.
The D-backs reportedly had a desire to move Greinke this offseason, but a deal is unlikely given the fact that they have not found any takers with less than two weeks until pitchers and catchers report.


SARS has announced the dates of the 2017 Employer Annual Reconciliation filing season. This year it will run from 18 April to 31 May 2017.
Please note that this is slightly different from other years, where the filing season started on 1 April.
You will have until 31 May 2017 to submit your Annual Reconciliation Declarations (EMP501s) for the period 1 March 2016 to 28 February 2017, in respect of the Monthly Employer Declarations (EMP201s) submitted, payments made, Employee Income Tax Certificates [IRP5s / IT3(a)s] and ETI, if applicable.
Remember that we have a help page about this bi-annual filing process, as well as a guide – to take you through it step by step.
You can also refer to the SARS website for news about this.


Our second METHXX release of the year comes from US-based Adred who debuts on the label with a 6 track EP entitled 'Instant Everything'.
The lead track features the amazingly talented Robert Manos on vocals as Adred provides a complimentary backdrop in the form of 'Lazy Jungle'. Another 5 tracks complete the EP including '160 Breaks' with its charming subtleties, whilst there's a clear nod to the autonomic sound in 'Can Jam'.
Adred is already working on more music for Metalheadz, something which we're very excited about hear at HQ.


On this six day Nova Scotia kayaking trip you will experience all of the best paddling and island camping of Nova Scotia's incredible South Shore. We will travel through three distinct areas, all of which offer exceptional island hopping and camping opportunities: experience the vast white sand beaches and historic settlements of the LaHave Archipelago, the narrow channels and unique geology of Blue Rocks & Stonehurst area, and the sheltered drumlin islands protected by the Mahone Islands Conservation Association (MICA) for their ecological significance and beauty.
On this kayaking trip we have the opportunity to see a diversity of bird life including osprey, eagles, guillemots, cormorants, herons, razor bills, leach's storm petrels, and terns. Seals, porpoises, sunfish and other marine life may also be spotted on our travels. Paddle through a varied, intricate coastline that has been shaped by a fascinating history of privateers & rum-runners, shipbuilding and vibrant Nova Scotian coastal culture. Breathtaking open ocean crossings are a highlight when weather permits, for more adventurous paddlers. Some paddling experience recommended.
I took part in the 6 day expedition from the LaHave Islands to Mahone Bay in early July 2018 and it was spectacular. I had only minimal kayaking experience, but personalized instruction and practice with Robert helped me feel comfortable and confident in no time. The trip was worth the personalized instruction, gear, sights, company, or food (holy smokes, Gavin!) - alone! And as a local, I'm grateful to have gotten to know my home more intimately. Thanks to all involved. What magic!
Other dates and trip lengths are available in the LaHave Islands. Please inquire for more information, and ask about our group rates!


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redpajama_set_name: RedPajamaGithub


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Home » Land Rover Kentucky Three-Day Event Cancels 2021 Five-Star Event
Land Rover Kentucky Three-Day Event Cancels 2021 Five-Star Event
Event organizers are looking to hold other competitions at the Kentucky Horse Park without spectators instead of LRK3DE.
By Edited Press Release | February 2, 2021 | 3 minutes read
The Land Rover Kentucky Three-Day Event presented by MARS Equestrian™(LRK3DE) will not hold its famed Five Star three-day event this year, previously scheduled for April 22-25. The Kentucky CSI3* Invitational Grand Prix presented by Hagyard Equine Medical Institute and other events are being explored to be held over that weekend but without spectators.
"We have been working with US Equestrian, the Kentucky Horse Park, and state and local government on several different scenarios for April," said Mike Cooper, president of Equestrian Events, Inc. which produces the world-class event. "With so many uncertainties still remaining regarding the COVID-19 pandemic, it is premature for US Equestrian to remove its restrictions on spectators. Given the importance of the health and well-being of our spectators and competitors, we feel the only option at this time is to cancel the Five Star Event and hopefully proceed with other events that our fans can enjoy via livestream and other outlets."
Germany's Michael Jung and fischerRocana won the Kentucky Three-Day Event in 2015, 2016 and 2017. © Amy K Dragoo/AIMMEDIA
Among the other competitions being considered is a new CCI-4*-S which will likely feature many of the same horses and riders that would have been competing in the Five Star, plus the Kentucky CSI3* Invitational Grand Prix which normally takes place on Saturday afternoon.
"While disappointing that all our fans can't join us again this April," added Lee Carter, EEI executive director, "we are excited that some of those same fans can now compete in new levels we will be offering during the 'Best Weekend All Year!' April 21-25 … Save the Date! Plans are being developed and will be communicated as approved."
Spectators, patrons, vendors and sponsors who paid for the 2020 event and chose to roll their money over for 2021 will have the option of full refunds or rolling their money over again for 2022. Ticket holders can expect an email regarding their options. Sponsors may choose to be part of whatever events are held in 2021 with new agreements that fit this year's situation.
"We want to thank everyone who has been so patient throughout this difficult process," Carter added. "We remain committed to all our supporters across the country and around the world and we look forward to putting on a great event this spring and welcoming everyone back for our full-scale Land Rover Kentucky Three-Day Event Five Star, with the Kentucky CSI3* Invitational Grand Prix, in 2022!"
Known as "The Best Weekend All Year," LRK3DE is one of only seven annual Five Star three-day events in the world along with Badminton and Burghley in England; Luhmuhlen in Germany; Pau in France; Adelaide in Australia and the new Five Star event in Maryland. As the United States' premier three-day event, LRK3DE serves as the Land Rover/USEF CCI-5*-L Eventing National Championship Presented by MARS Equestrian™ for U.S. athletes. The event was scheduled to return to the Kentucky Horse Park in Lexington, KY, April 22-25.
About Equestrian Events, Inc.
Equestrian Events, Inc. (EEI) is a 501(c)(3) non-profit charitable Kentucky corporation that was established initially to produce the World Three-Day Event Championships at the Kentucky Horse Park in 1978. Following the success of those championships, EEI established an annual event that evolved into the world-renowned Kentucky Three-Day Event which draws more than 80,000 spectators to the Kentucky Horse Park each year. EEI also produces other events and supports several local and equine charities. EEI has donated more than $725,000 to various charities since 2011. Further information about EEI and the Land Rover Kentucky Three-Day Event is available at www.eq-events.com.
Posted in Competitions, NewsTagged #LRK3DE, 2021 Kentucky Three-Day Event, Coronavirus Land Rover Kentucky Three-Day Event, COVID 19 Kentucky Three-Day Event, Kentucky Three-Day Event
A Legendary Horseman: Jimmy Wofford


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Work has just begun on one of the last development sites available on London Road, the main southern arterial gateway to Wellingborough, which will deliver a new roadside retail scheme.
Wellingborough Trade Park provides for five new retail/trade-counter units on a prominent 1.1 acre site, formally developed by Gloverall in the early to mid 1960s as a state-of-the-art factory manufacturing their famous duffle coats. Having brokered the sale of the site a couple of years ago, award-winning commercial property consultancy Prop-Search, has subsequently agreed the pre-let of 90% of the scheme.
Tenants signed up to take accommodation include Formula 1 Auto Centre, which is leasing a 4,400 sq ft tyre, exhaust, MOT and servicing centre; a new concept drive-thru for Greggs; the UK's largest independent decorating chain Brewers; and plumbing, heating and electrical supplier City Plumbing.
Simon Toseland, a Director of sole letting agent Prop-Search, said: "The construction of the 14,100 sq ft scheme will see the development of a prominent brownfield site on one of the main routes in and out of the town."
"It is a shot in the arm for the local area in the early stages of the post-pandemic recovery and will undoubtedly enhance the retail opportunities available as well as generating significant new employment prospects."
"There have been many proposals for the development of this site over the last 15 years, but certain challenges have previously prevented the site coming forward. Working with specialist trade park developer, Ambit Developments and the Barkby Group plc, we have successfully brought forward this site and are delighted that construction has now commenced.
Completion of the scheme is scheduled for later this year.
Further information on the development and opportunity to acquire the last remaining unit of 1,400 sq ft can be obtained from Prop-Search on 01933 223300, st@prop-search.com or on-line at www.prop-search.com


Technology in updated cVu product family improves network visibility, deep-packet inspection and filtering, and granular real-time performance monitoring.
CPacket Networks is includes advanced features in its cVu product family that enable improved intelligence for traffic monitoring and aggregation switches. The intelligence can significantly improve the efficiency of operations teams running data centers and sophisticated networks.
The company's hardware and software technology enables the cVu family's enhanced pervasive real-time network visibility. This includes granular performance monitoring, microburst auto-detection, and filtering of network traffic based on complete packet-and-flow-inspection or pattern matching anywhere inside the packet payload.
The new cVu features facilitate this intelligent "tool hub" approach. A cVu monitoring switch can filter, balance, and forward any relevant traffic to any downstream tools as needed, provide realtime performance information, and initiate automatic alerts based on user-defined counters and triggers.
In addition to the basic aggregation functionality that would be in any product in this class, the built-in intelligence provides cPacket customers easy-to-use, efficient visibility into the behavior of their network and applications. The intelligence of the "hub" streamlines critical tasks such as troubleshooting of application and performance issues, capacity planning, and microburst and bottleneck analysis -- at the same cost as aggregation products without these capabilities.
Realtime monitoring and reporting of network performance and applications health indicators based on user-defined counters, triggers, and thresholds. cVu products also provide historical archives of all the counters to enable trend analysis and microburst measurement at user-configurable time intervals.
On-demand tunneling of specific filtered traffic to a remote location over the network This is useful for efficient troubleshooting of remote issues in a centralized location. Users can interactively snap and analyze matching packets from a standard web browser. Multiple cVu devices in a virtual stack can be managed centrally.
Coherent flow-balancing, which is increasingly important in virtualized cluster environments, with flexible dynamic and static balancing policies, and scriptable support for redundancy and automatic fail-over.
Traffic normalizations options including packet truncation, dynamic slicing and TCP-payload obfuscation, MPLS-stack stripping, and packets de-duplication, which ensure that down-stream tools receive consistent input.
More information is available at www.cpacket.com.


Outdoor entertaining doesn't have to be complicated. In fact, if you have some sort of seating area and a tree (yep, just one), you're all set. If your biggest problem is not having anyone to throw a party for (kinda like me), well just do it for your most precious guests. The kids. Remember when you were young, you loved playing dress up? Whether it was dressing up for the beach inside while snowing outside or dressing up…just because; it was all so much fun.
Here are my two little ones all dressed up for tea time…just because!
This little tea party happened while we were in Florida at my parent's backyard. I strung cherry blossom lantern lights on this fruit tree that my parents grew when we first moved into the house. The lights made it super summery and festive.
The kids enjoyed small treats including the cutest sprinkle cupcakes, mini croissants, berries, and cherries.
Teapots were used for decoration because these two munchkins were obviously not drinking tea! Plus you can't have a tea party without teacups and such.
Fresh flowers are a must for outdoor entertaining. They add vibrancy and make any setting even more beautiful.
Perfect weather, perfect place make for some happy faces!
Hope you've enjoyed this little tea party of Zoey and Axel and grabbed some outdoor entertaining ideas along the way.
Oh my goodness, this is lovely. You're children are super, super lucky to have such an awesome mum. I can't wait to do this for Molly when she's older!
I'm in awe and totally inspired!
This tea party is very lovely and interesting. I like the way you arrange the dishes of cup cakes, cherries, strawberries and croissants along with fresh flowers.
OMG! how adddorrrrable…my siss and i use to play pretend with tea sets too…nothing so fancy as this though!
This is beautiful! I would love to do this.
Gorgeous! Great ideas! This is something I'd love to do with my little ones. Thanks for sharing.
Love the smiling faces on your kids…..in the winter we used to have living room picnics…take the table away and it becomes a picnic…LOL love the lanterns….do the kids have twinkle lights in their bedrooms??? Makes bedtime a little more magical….


Polished Lift for Bodiless Hair!
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Suitable for all hair types, it contains a volumising formula that works to condition whilst boosting fine, flat, lifeless hair. Enriched with a blend of volume-boosting Filloxane and Silicone, it weightlessly detangles whilst improving body, texture & fullness. You can expect silky smooth, manageable hair with mirror-like shine!
Apply shampoo to damp hair, massage gently with fingertips into lather.


If you're going to stuff the Red Hot Chili Peppers into a car with "The Late Late Show's" James Corden for a round of Carpool Karaoke, don't be surprised when clothes get shed!
Anthony Kiedis, Flea, Chad Smith and Josh Klinghoffer were red hot and game to sing and play along, adding in some slap-bass and wrestling (they got out of the car for that one). They shared stories (Smith told one about two men fighting with their prosthetic legs at a festival in the Netherlands; it also turned out that Cher once baby-sat Kiedis).
Meanwhile, the gang ran through hits like "Give It Away" (in which they discussed the somewhat racy lyrics), "Californication," "Under the Bridge" and "Can't Stop."
Our favorite moment? When Flea launched into "Food, Glorious Food" from the 1968 musical "Oliver!"
And at some point, the shirts come off! (It's kind of obligatory, if you know the Peppers, though they don't always stop with the shirts.) And, of course, Corden also joined in. Brave man.
Watch the whole video for all the funky weirdness!


Two classic, fragrant teas come together in this exotic Vanilla Jasmine Tea blend. Aromatic and complex, our Vanilla Jasmine loose leaf tea makes a special dessert tea best served with pastries and fruits. This bestseller Vanilla Jasmine Tea is delicious prepared hot or iced.


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Browse: Home / 2020 / October / 26 / Ema: A Premonitory Performance of Fire and Dance
dtierney / October 26, 2020 / Leave a comment / Film
Link to Ema Dossier Index
by Laura Hatry*
It's not likely that Pablo Larraín could have imagined the extent to which Ema would anticipate real-world events when it was released in Venice on August 28, 2019. For his eighth feature film, he had, for the first time, explicitly set his story in contemporary Chile, and among a younger generation, as opposed to his own or to the generation that came before him. His dictatorship trilogy (Tony Manero [2008], Post Mortem [2010] and No [2012]) had focused on the Pinochet era, Neruda (2016) and Jackie (2016) on historical figures, and though El club (2015) was set in Chile, its time and place were never specifically defined. When asked during a Q&A in Toronto following a screening of Ema about this aspect of "looking almost to the future," he answered that, for him, it was more like the immediate past, given that it was already in the process of taking place. Nevertheless, the notion of looking to the future has taken on greater weight in view of Ema's premonitory relationship to the social upheaval that was to erupt in Chile subsequent to the release of the film. Indeed, two of its central motifs, namely fire and dance, turned out to be focal points of the so-called estallido social during the fall of 2019: arson was ubiquitous, and the validity of its use during the protests was hotly debated, while the performance piece "Un violador en tu camino" became an international feminist anthem.
The estallido social began with a seemingly "innocent" decision: a fare increase on the public transport system of the city of Santiago on October 6, 2019. That the increase of a mere 30 pesos during rush hour (from 800 to 830 pesos, or from around $1.13 to $1.17 at the time) would be sufficient reason to protest might strike readers outside of Chile as improbable, but the local – and the bigger – picture was quite different. This was only the most recent in a string of similar increases, and, for a working population already struggling with high public transportation costs relative to income – the average monthly cost of public transportation is 13.78% of the minimal wage – amidst society-wide dissatisfaction with the now decade-long consequences of the end of the dictatorship and inherited neoliberal policies, as well as a rising clamour against Chile's immense socioeconomic inequality, it became the straw that broke the camel's back. Following the announcement of the fare increase, hundreds of students organised evasiones masivas (mass turnstile-jumping), leading to clashes with the police, which escalated on October 18, and Sebastián Piñera's declaration of a state of emergency the following day. Notably, it was accompanied by the imposition of a curfew for the first time during the democratic era for reasons other than natural disaster. Two days later, on October 20, Piñera would give a press conference in which he declared that the country was at war. The next morning Larraín uploaded a black image to his Instagram account with the hashtag #noestamosenguerra. Four days after the start of the upheaval and fifteen deaths later, the Senate rescinded the fare increase.
However, as most protesters described it, "Chile had woken up," and the flame kept burning. Within ten days an explanatory document by Hans Stange, Antoine Faure, Claudia Lagos, Claudio Salinas, René Jara, and Alejandro Lagos, called Rabia, started making the rounds on social media, informing the world of the injustices to which citizens had been subjected during this period and exposing both human rights violations and state violence. The first image in the document (2019: 10) shows an enormous blaze that couldn't be more reminiscent of the conflagrations we see in Ema (Figure 1).
Figure 1: Chile despertó (Rabia)
Figure 2: Ema (Pablo Larraín 2019)
Ema is not an easily likeable character, and Gastón may be even less so; after all, they returned their adopted son to the orphanage after he committed horrible acts of violence, although he probably got the inspiration for his actions from Ema and her own obsession with pyromania. But that's one of the beauties of Larraín's filmmaking: he compels us to grapple with injustices experienced not only by the righteous, but by problematic characters as well. It's easy to identify and feel empathy with a "perfect" protagonist, but how do you empathize with someone like Ema? And how should we understand the physical violence committed during the estallido social – can we possibly justify burning down public property, regardless of the injustices that have led to it?[i] But under the oppression of the neoliberal ruling order, some protesters saw no other means of adequately expressing their fury and showing that these unsustainable disparities must cease. Without condoning violence, it remains imperative to try to understand the complex situation from which it arose, as opposed to simply crushing its perpetrators and ignoring the conditions that drove them to their actions – and let's not overlook the fact that a large part of the upheaval was likely fomented by police infiltrators fanning the flames so as to justify the systematic use of force against the protesters. Images reminiscent of the worst days of the dictatorship emerged in which police used firehoses to disperse protesters. In Ema as well, it's not only the stream of fire, but also of water that reflects the arbitrary and insuperable prerogatives of power. When Aníbal, a firefighter, teaches Ema how to operate a firehose, we see – we can actually feel – the power in her hands: a force that can be used to extinguish fires both literal and political.
Though they are definitely striking, these images of fire and vandalism reflect just a minor aspect of the behaviour of the predominantly peaceful protesters who took to the streets in their millions. The streets became a canvas for popular protest – and also for wisdom, as Rabia suggests (2019: 31) – filled with banners, spontaneous actions, chants, and performances. Similarly, Ema's dancing and her nocturnal arson turn into performance art through the lens of Sergio Armstrong's cinematography. The very first image in the film depicts a burning traffic light, assailing the viewer with scorching rings that might well call to mind another artist who used fire as medium; but where Yves Klein scorch-painted actual canvasses with his flamethrower (Figures 3 and 5),[ii] Ema's canvasses are the sky and public buildings, a variation on the famous graffiti-covered walls of Valparaíso, according to a comparison by Larraín in the aforementioned Q&A (Figure 4).
Figure 3: Yves Klein's fire painting process
Figure 4: Ema's pyromania turned into performance art (Ema)
Figure 5 Untitled Fire Painting (Yves Klein)
Figure 6: The traffic light, a symbol of order and rules to which Ema sets fire
If the traffic light is the perfect symbol of order and the set of rules citizens are expected to follow (Figure 6), Ema symbolically sets those rules on fire, challenging a system that, in the words of the social worker who accepted their bribe to enable them to adopt their son Polo, "está hecho para eliminar a gente como ustedes." The system insists on controlling its citizens, whether by means of the subway fare, biopolitics, organisation of the family, or dominance over the female body.
Ema's defiance of tradition or conservatism is played out on multiple levels. For one, she questions the "standard," nuclear, heteronormative family structure, and thanks to a devious plan she eventually succeeds in establishing an eccentric, patchwork sort of family more suited to her values; for another, she severs her ties to the high-brow dance troupe with which she'd been associated. The latter decision is closely connected to her feminism: while Gastón in some ways exemplifies the male gaze when he, the male presence, oversees the performance of his own choreography from the margins, within what we might call the traditional dance circuit, Ema uses dance as a direct form of liberation. First, as a school teacher, she conveys the feeling of freedom to her students by dancing with them, not just observing them as Gastón does, which Larraín underlines visually by showing her among them, kneeling so as to be on the same level.
Figure 7 Ema rejects conservatism kneeling with her students so as to be on the same level
Second, when Ema and her girlfriends quit the theatre company, they take to the streets, they dance the city, they perform what's considered low-brow reggaeton – as a minute-long mansplaining monologue by Gastón reveals his traditionalist view on the matter. While his stage performance is drenched in red and blue neon light, their spontaneous outpouring, with the port of Valparaiso as backdrop, establishes a connection in the real world with the two elements these colours represent: fire and water. And it is not just the dancing that makes them feel good on the streets, but more importantly, the female solidarity and friendship, and the fact that "social power arises only through collective action, from a we" (Han 2018: 120). Ema's girlfriends support her incendiary intentions, and the representation of the intimate moments among them while they dance is simply sublime.
This feminist awakening is inscribed in the larger context of feminist movements in Latin America that started with the famous Ni una menos in Argentina in 2015. But as a direct precedent I would like specifically to mention the 2019 spring issue of Revista Rufián, "El despliegue del fuego feminista," a title that seems to precisely incorporate the points discussed here and which includes a beautiful photo essay by Paulina Barrenechea that gives an account of the use of fire during the feminist demonstrations in the city of Concepción, Chile, over recent years. The fire that is depicted here, "ruge, activa y […] transforma. El fuego es el conector que permite que el grito colectivo haga tambalear las cortezas patriarcales, la chispa que activa la acción" (2019: 10). These sparks lead us, finally, to the performance by the collective, Lastesis, first staged on November 20, 2019, in Valparaíso, as part of the project "Fuego. Acciones en Cemento." The choreography of "Un violador en tu camino" and the women calling for rebellion against the "estado opresor," which is the "macho violador," perfectly embody Ema's spirit of burning down the patriarchy. Lastesis and Ema equally conquer the urban space to collectively denounce an oppressive neoliberal, patriarchal system through the power of dance and female solidarity, and with Ema, maybe his most daring film to date, Larraín shows that he is eager to learn from these women who represent the generation of the future.
Cádiz, Pablo. "¿El Metro más caro de Sudamérica? Esto gastan los chilenos en transporte (y qué pasa en el mundo)," T13, October 18, 2019. Available at: https://www.t13.cl/noticia/nacional/evasion-masiva-metro-valor-pasaje-chile-mundo-sueldo-minimo
Carter Jackson, Kellie. "The Double Standard of the American Riot," The Atlantic, June 1, 2020. Available at: https://www.theatlantic.com/culture/archive/2020/06/riots-are-american-way-george-floyd-protests/612466/
Han, Byung-Chul (2018). Topology of Violence. Trans. Amanda DeMarco. Cambridge, MA: MIT Press.
Reid, Nicky. "A Message Written in Fire: In Defense of Social Upheaval," Counterpunch, June 12, 2020. Available at: https://www.counterpunch.org/2020/06/12/a-message-written-in-fire-in-defense-of-social-upheaval/
Revista Rufián. Issue 9, number 29, May 2020. Available at: https://rufianrevista.org/wp-content/uploads/2019/06/Rufian-29-huelga.pdf
Stange, Hans, et al. (2019). Rabia. Miedos, abusos y desórdenes en el oasis chileno. Available at: http://www.luisemiliorecabarren.cl/files/recursos/rabia.pdf
*Laura Hatry earned her PhD from Universidad Autónoma de Madrid in Hispanic Studies. Her research focuses on cinematic adaptations of Latin American literary works, as well as other convergences (and divergences) among the arts. In addition, she holds an MA in Contemporary Art History and Visual Culture from the Reina Sofía Museum in Madrid and a postgraduate certification in Library Science. She is the editor of Refocus: the Fims of Pablo Larrain (Edinburgh University Press, 2020).
[i] Permit me to recommend this article in The Atlantic or this opinion piece on the subject written in the wake of the protests following the murder of George Floyd.
[ii] You can get a glimpse of Yves Klein's fire-painting process here.
Tags: ema, Estallido social, pablo larrain, rabia, un violador en tu camino
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Ema's Mise en Abyme: Music Video Aesthetics and Women in Reggaeton →
Falling into the Embrace of the Serpent by Deborah Shaw


One naturally assumes that our social, political and everyday worlds and attitudes are simply what we inherit, either from our genetic constitutions or socio-economic, material situations. Philosophy, on the contrary, teaches that human beings largely fashion their lives and worlds by the choices they make, the words and concepts they employ, the thoughts and perceptions they generate, and how they interact and interrelate with others. To this end, philosophy studies such important questions as: What is the nature of the self? What can one genuinely know and knot know? What can one hope for? What is to dwell in a political society? Does God exist? Do we have a unique purpose in this world?
The philosophy program at King's offers students the possibility of following a general stream of study with the possibilities of focusing on the Continental European tradition and/or the intersection between philosophy and religion. Committed to humanist and personalist model of teaching, our classes are designed to develop critical reasoning skills, sustained thinking and reading abilities, sound argumentation, and, above all, philosophical capacities for reflection and insight. The unique foundation year in philosophy for all majors and specialists not only gives students an enhanced basic training in philosophy but also helps students participate in and form unique study and philosophy communities.


LOOK WHO'S PLAYING FIRST BASE Will Mike stand up to his teammates to defend his friend? When the Checkmates need a new first baseman, Mike Hagin's new friend, Yuri, seems like a logical choice. But when Yuri starts flubbing plays and the team's star player threatens to quit as a result, Mike is not sure Yuri is such a good choice after all-for a teammate or for a friend. It appears as if Mike will have to choose between his friendship with Yuri and his loyalty to the team-or is there another solution?


At St. Joseph School your child's sense of wonder is recognized and celebrated as the foundation to discovering, investigating and building big ideas.
Our teachers recognize children to be curious, inventive and independent, competent and capable. By providing rich and intentional experiences in the environment exploration, concentration, interaction, play and collaboration are fostered. These are habits of learners engaged in a thoughtful process .
Fully accredited by NEASC, our developmentally-appropriate curriculum reflects the benchmarks of RI Early Learning and Development Standards (RIELDS) and State/National Standards. St. Joseph Early Childhood Programs celebrate and draw inspiration from the Reggio-Emilia Philosophy. This emergent-based curriculum focuses on careful observation of each child in the context of their environment, interactions and interests.
The individual spirit of your child is valued, honored and nurtured as this journey of learning takes flight.
The Early Childhood Program at St. Joseph School provides classrooms for 3 and 4 year-old pre-Kindergarten and Kindergarten. St. Joseph School continues through Grade 8. Begin this dialogue with us today. Contact St. Joseph School at 401-821-3450.


The Orchard Theatre Is Gearing up to Christmas with a Variety of Festive Shows!
Prepare yourself for a party as the legendary That'll Be The Day, will be making a visit to The Orchard Theatre on Monday 11 December. The 'Number One Award Winning' entertainment show, returns with its brand new 2017 Christmas Show! That'll Be The Day is all about nostalgia and live entertainment, reflecting the music and tone of an era that changed the course of music history and youth culture forever.
The Belvedere Concert Band are delighted to be back at The Orchard Theatre, Dartford for the sixth year running, on Monday 18th December at 7.30pm. The Magic of Christmas charity concert in aid of Parkinson's UK and the Samaritans. Get into the festive spirit and celebrate Christmas with the Belvedere Concert Band and guests as they bring you the very best of music and song from the classics, stage and big screen with plenty of Christmas favourites!
Renowned dance company, Moscow City Ballet returns to Dartford following a triumphant season with its dramatic traditional story-telling and captivating performances The enchanting and romantic story of The Sleeping Beauty inspired Tchaikovsky to write some of his most glorious music, and the ballet has captivated the imaginations of people for well over a hundred years and will be at The Orchard Theatre from Tuesday 10 and Wednesday 11 January 2018.
Direct from the USA the international smash hit show New Jersey Nights comes returns to Dartford from Tuesday 2 – Saturday 6 January 2018 as part of their world tour. The show is a spectacular celebration of the music of Frankie Valli and The Four Seasons, and takes the audience on a nostalgic musical journey through the career of one of the biggest selling groups of all time. From the back street studio in New Jersey where it all began, this vibrant production includes all of The Four Seasons greatest hits, Including Sherry, Rag Doll, Big Girls Don't Cry, Walk Like A Man and many more.
Moscow City Ballet's production of The Nutcracker will be performed in all its original splendour by some of the world's finest dancers at The Orchard Theatre from Wednesday 10 – Saturday 13 January. Artistic Director Smirnov-Golovanov's version of The Nutcracker has an innovative freshness and the orchestra, choreography, interpretation, beauty and outstanding virtuoso performances win repeatedly rave reviews.
Cilla – The Musical is the spectacular and heart-warming musical adaptation of the critically acclaimed hit ITV television series by Bafta-Award winner Jeff Pope (The Moorside, Philomena, From The Cradle To The Grave, Mrs Biggs and the acclaimed Little Boy Blue which had ITV audiences glued to their screens). It tells the extraordinary story of the ordinary girl from Liverpool whose teenage dreams of stardom lead her to becoming one of Britain's best-loved entertainers of all time. The new musical will be at The Orchard Theatre from Tuesday 16 – Saturday 20 January 2018.
Just when you thought Christmas was over, the New Year brings with it one more festive treat, this time for the adults! Hot of the heels of last year's Adult Panto – Sinbad The Seaman the Market Theatre Company return to bring to life the story of Sinbad the Sailor and his epic adventures across the seas to defeat the one-eyed monster – packing it with corny jokes, raunchy plots and blatant sexual innuendo at The Orchard Theatre on Saturday 7 January.
Jamie Wilson and Gavin Kalin are delighted to announce that Claire Sweeney will take over the role of 'Irene' in the national tour of the Watermill Theatre's acclaimed production of Crazy For You. Claire joins Tom Chambers who plays Bobby and Charlotte Wakefield who plays Polly from Tuesday 23 – Saturday 27 January 2018.
Pre-show dining is also available before all shows. The Orchard Theatre's Restaurant provides a range of delicious, unique and memorable dishes, using the freshest local produce and prepared daily by the Head Chef. Reserve your table when booking your show tickets.
For more information or to book tickets visit orchardtheatre.co.uk or call the Ticket Office on 01322 220000.


Background & objectives : It is important to understand the role of cell surface receptors in susceptibility to infectious diseases. CD155 a member of the immunoglobulin super family, serves as the poliovirus receptor (PVR). Heterozygous (Ala67Thr) polymorphism in CD155 has been suggested as a risk factor for paralytic outcome of poliovirus infection. The present study pertains to the development of a screening test to detect the single nucleotide (SNP) polymorphism in the CD155 gene.
Methods: New primers were designed for PCR, sequencing and SNP analysis of Exon2 of CD155 gene. DNAs extracted from either whole blood (n=75) or cells from oral cavity (n=75) were used for standardization and validation of the SNP assay. DNA sequencing was used as the gold standard method.
Results: A new SNP assay for detection of heterozygous Ala67Thr genotype was developed and validated by testing 150 DNA samples. Heterozygous CD155 was detected in 27.33 per cent (41/150) of DNA samples tested by both SNP detection assay and sequencing.
Interpretation & conclusions: The SNP detection assay was successfully developed for identification of Ala67Thr polymorphism in human PVR/CD155 gene. The SNP assay will be useful for large scale screening of DNA samples.
Global Polio Eradication Initiative (GPEI) was launched by the World Health Assembly at its 41 st meeting in Geneva in 1988  . Although the goal is not completely achieved as yet, significant progress has been made. Wild poliovirus transmission has been eliminated in four out of the six WHO Regions. As of 2014, Pakistan, Afghanistan and Nigeria remain the only three polio-endemic countries in the world  . Notably, last case of polio of wild poliovirus 2 was detected in November 1999 and of wild poliovirus 3 in 2012 ,[  . Thus global eradication of two of the three poliovirus serotypes has been achieved  . Though wild poliovirus is on the verge of eradication, poliovirus pathogenesis and susceptibility to the disease has not been understood completely ,[  .
Poliovirus belongs to the genus Enterovirus in family Picornaviridae . There are three distinct poliovirus serotypes, each capable of causing paralytic poliomyelitis in susceptible individuals  . Humans are the only natural host for poliovirus infection and non-human primates can be infected experimentally  . Poliovirus receptor (PVR/CD155), a type I transmembrane glycoprotein in the immunoglobulin super family is the poliovirus cell surface receptor  . CD155/PVR gene is specific to the primate lineage ,, . It is located on the chromosome 19q13.2 (http://www.ncbi.nlm.nih.gov/gene/5817). PVR has three extracellular immunoglobulin-like domains (D1-D3), a transmembrane region and a cytoplasmic tail  . Poliovirus interaction with D1 domain is the first step in the virus replication , . No other Enterovirus uses CD155/PVR as its cellular receptor  . Four transcript variants encoding different isoforms have been found for the CD155 gene  . Normal cellular function of CD155 is in the establishment of intercellular adherens junctions between epithelial cells. It may be involved in intestinal humoral immune responses  .
In recent years investigators have tried to explore interest is growing to investigate genetic basis of susceptibility to infectious diseases ,, . Saunderson et al found significantly higher frequency of heterozygous Ala67Thr change in PVR in patients with progressive muscular atrophy than in controls. Kindberg et al reported an increased risk of developing paralytic poliomyelitis in heterozygous individuals carrying the Ala67Thr mutation in PVR. Genetic predisposition to poliomyelitis due to heterozygous (Ala67Thr) has neither been supported nor refuted by case-control studies in other countries ,, .
Polio eradication efforts in India faced several challenges including poor personal hygiene and environmental sanitation and low oral polio vaccine (OPV) immunization coverage in stopping wild poliovirus transmission in Uttar Pradesh and Bihar , .Low per dose efficacy of OPV has been found especially in Uttar Pradesh  . Increasing the number of supplementary immunization campaigns and introduction of monovalent/bivalent OPV were some of the important innovations introduced to improve population immunity and break all chains of transmission of wild poliovirus , . It would be interesting to investigate whether genetic predisposition to paralytic outcome of poliovirus infections due to Ala67Thr heterozygous polymorphism played any role in delaying polio eradication in the Indian population.
DNA sequencing and PCR followed by restriction fragment length polymorphism (RFLP) have been used, so far, to detect the single nucleotide polymorphism (SNP, GCG®ACG) in CD155/PVR gene  . Both these methods are slow and require processing to obtain final results. The objective of the present study was to develop an assay suitable for large scale screening of samples for identification of heterozygous SNP in the CD155/PVR gene.
This study was conducted in the Enterovirus Research Centre, Mumbai, India, after prior approval from the institutional ethics committee. The assay involved (i) isolation of DNA from blood leukocytes and/or oral cavity cells, (ii) PCR amplification of a segment of exon2 of CD155 gene containing the nucleotide of interest, (iii) designing primers for the new SNP detection assay, and (iv) identification of the single nucleotide of interest by using the SNapShot method. DNA sequencing of the PCR amplicon was used as the gold standard method for confirmation of the nucleotide of interest.
Samples were collected from three different sources.
(1) Institutional staff members were informed about the development of the new assay and the need for DNA samples to test and validate the assay. Blood samples were collected from consenting members (n=46). Blood sample (100µl) was obtained by pricking the middle finger-tip with a sterile lancet. Blood drops were collected using a sterile micro-tip and pipette in a vial containing 200µg EDTA as anticoagulant; 2.5µl of the blood sample was used for PCR reaction.
(2) Blood samples (n=29) were drawn from a collection of samples for polio antibody serologic survey done in Bihar in 2010.
(3) Oracol sponges were used for collection of crevicular fluid for testing mucosal antibody response to poliovirus vaccines during a polio vaccine campaign conducted in Moradabad, UP, in 2011. Seventy five Oracol sponges were used for obtaining cellular DNA for this study. Briefly, for obtaining crevicular fluid, the Oracol sponge was rubbed on the molar teeth area for one min. The sponge was placed in a tube containing one ml PBS with antibiotics and 0.2 per cent Tween 20. In the laboratory, crevicular fluid was extruded from the sponge by squeezing it on the inner wall of the tube and centrifugation. Crevicular fluid (supernatant) was collected aseptically for polio antibody testing and the cell debris was used for DNA extraction.
100 µl of neutralization solution. All required reagents are supplied with the kit.
Primers: CD155 GenBank sequence NM001135770 and OligoPerfect Designer Software (http://tools.lifetechnologies.com) were used for identifying primer regions. Primers were designed for (i) PCR amplification of a 234 bp segment of Exon2 of CD155 gene, (ii) sequencing of the 234 bp amplification product, and (iii) identification of the nucleotide at the first base of the codon (GCG/ACG) for the 67 th amino acid (Ala/Thr). Details of the primers designed for this study are given in [Table 1]. Primers were self designed and got synthesized from SIGMA Chemical (USA).
1 µl each forward and reverse primers (1 µM/µl), 1 µl Phusion Blood DNA Polymerase, and 19.5 µl nuclease free water. Amplification was carried out in a 9700 PCR Cycler (Applied Biosystems, Foster City, CA) at 98 o C for 5 min (initial denaturation), followed by 40 cycles of 98 o C 30 for 30 sec (denaturation), 67 o C for 30 sec (annealing), and 72 o C for 30 sec (extension). The last cycle of extension was at 72 o C for 10 min.
Fast Tissue to PCR kit (Fermentas, Thermo Scientific, USA) was used for PCR of DNA extracted from the oral cavity cells. Briefly, each 50 µl reaction contained 5 µl neutralized tissue extract (DNA sample), 25 µl Tissue Green PCR 2× Master Mix, 1 µl each of forward and reverse primers (10 pmole/µl) and 18 µl nuclease free water. Amplification was carried out in 9700 PCR Cycler at 95 o C for 5 min followed by 40 cycles of 95 o C for 30 sec, 58 o C for 30 sec, 72 o C for 30 sec. The last cycle of extension was at 72 o C for 10 min.
PCR amplification was detected by electrophoresis in 2 per cent Agarose (Roche, Germany) gel stained with ethidium bromide. Amplification product (234 bp DNA) was purified using QIAquick Gel Extraction Kit (QIAGEN, Germany) as per the manufacturer's instructions.
SNP assay: SNapShot Multiplex reagent (Applied Biosystems, Foster City, CA) was used for single nucleotide polymorphism analysis of the 234 bp DNA amplified product. Briefly, 1 µl of the 234 bp amplification product, 1.5 µl (2.5 uM/µl) of either forward or reverse SNP primers and 2.5 µl SNaPshot Multiplex Reagent were reacted in a 200 µl PCR tube and 25 cycles of denaturation, annealing and extension were carried out at 96 o C for 10 sec, 50 o C at 5 sec, and 60 o C for 30 sec in a 9700 PCR Cycler. At the end of the 25 cycles, 0.5 µl Shrimp alkaline phosphatase and 0.5 µl buffer (Fermentas, Thermo Scientific, USA) were added and the reaction was incubated at 37 o C for 15 min. The reaction mix was heated to 75 o C for 10 min to inactivate the enzyme to stop the reaction; 0.5 µl of the reaction product was mixed with 9 µl HiDi-Formamide and 0.5 µl GeneScan 120 Liz (Applied Biosystems, Foster City, CA) for electrophoresis at 60 o C at 15KV and 5 µAmp current for 45 min in ABI 3130xl Genetic Analyzer (Applied Biosystems, Foster City, CA). Results were analyzed using GeneMapper Software v4.0 (Applied Biosystems, Foster City, CA).
8 µl sequencing reaction contained 2 µl of 234 bp PCR amplification product, 1 µl BigDye Ready Reaction v.3.1 mix (Applied Biosystems, Foster City, CA), 1 µl primer (3.2pmole), 1.5 µl 5× sequencing buffer and 2.5 µl nuclease free water. After initial denaturation at 95 o C for 3 min, 25 cycles of sequencing were performed at 95 o C for 20 sec, 57 o C for 20 sec, and 62 o C for 1 min. The last cycle of extension was at 62 o C for 7 min. Cycle sequencing product was purified using BigDye X terminator Purification Kit (Applied Biosystems, Foster City, CA). Sequences were resolved on ABI 3130xl Genetic Analyzer. Sequences were analyzed by Sequencher v.4.10.1 (Gene Codes, USA).
CD155 gene is situated on the chromosome 19q13.2 and 29332 bp (Accession No. NG_008781). Four transcript variants (mRNAs) have been identified. The first four exons are common to all the four variants. Exon1 is 1 st nt to 378nt, exon 2 is 379 to 726nt (shown in blue colour in [Figure 1], exon3 is 727 to 1023nt and exon4 is 1024 to 1141nt. Nucleotides 1 to 299 constitute the 5' non-translated region. Translation of the mRNA was initiated from the AUG codon at nucleotide 300. A nucleotide change (G®A) at position 499 led to an amino acid substitution Ala67Thr in the D1 domain of CD155/ PVR. The SNP assay was designed to target the first nucleotide coding for the 67 th amino acid (GCG/ACG) of CD155/ PVR protein. Transcript variant 4 mRNA (1643nt long; Accession no. NM_001135770) sequence was used to design the primers in this study. At the gene level this nucleotide is situated in the exon2.
Positions and sequences of the primers designed for PCR, sequencing and the SNP assay with respect to the mRNA transcript4 are presented in [Figure 1]. In this study the assays targeted the gene (DNA) and not the mRNA.
The PCR primers (CD155 exon2F and CD155 exon2R) amplified a 234 bp segment from exon2 (66-300nt) in CD155/PVR gene. PCR primers were used for sequencing with some modifications. We added 20 non-complementary bases at the 5' end of the forward PCR primer (CD155 exon2 F20) so that the nucleotide of interest was not very close to the starting point of the sequencing reaction, thus improving the quality of the sequences. PCR reverse primer was used for sequencing without any modification.
The 22nt long forward SNP primer was designed with eight non-complementary bases at the 5' end and 14nt complementary to the target sequence (484 to 497nt). The reverse SNP primer was 26nt long consisting of four non-complementary bases at 5'end and 22nt complementary to the gene sequence (499 to 520nt).
SNP detection by SNapShot: SNapShot reaction adds a single base to the primer. The single base is detected by capillary electrophoresis of the reaction. Each base is colour coded (blue:G; black:C; green:A and red:T).
SNapShot results of a DNA sample with the forward SNP primer is shown in [Figure 2]a. The blue peak indicated "nucleotide G" at the targeted position. The same DNA sample tested with the reverse SNP primer showed "nucleotide C" in the complementary strand [Figure 2]b. SNP test results of DNA sample of another person showed two peaks blue and green (G and A) at the targeted nucleotide, revealing the heterozygous nature of the sample. Reaction with the reverse SNP primer also showed two peaks, black (C) and red (T) which confirmed the heterozygous nature of the DNA sample [Figure 2]c and 2d. Results of the SNapShot reactions were unambiguous and easy to interpret.
SNP detection by sequencing: DNA sequence of the 234bp PCR amplification product of the DNA sample used for the SNP assay as shown in [Figure 2]a and 2b is given in [Figure 3]A (forward direction) and 3B (reverse direction), respectively. The codon GCG for the target (Ala67) is highlighted. Sequence of the other DNA sample showing two peaks (as shown in [Figure 2]c and 2d is presented in [Figure 3]c and 3d. Both the forward and reverse sequences confirmed the heterozygous nature of the sample.
We tested DNA samples of 150 different individuals consisting of 75 DNA from blood samples and 75 DNA samples from cells of oral cavity by the SNapShot method. The 150 samples were then sequenced in both forward and reverse directions to confirm and validate the results of the newly developed SNP assay. Results obtained by both the methods were 100 per cent concordant for all 150 samples. Heterozygous single nucleotide polymorphism (Ala67Thr) was detected in 41 of 150 (27.33%) samples [Table 2].
Cell surface molecule CD155 serves as the receptor for the three polioviruses. Poliovirus initiates infection when it recognizes and binds to CD155/PVR, the only poliovirus receptor known to date  . Humans are the only natural host of poliovirus, although chimpanzees and Old World monkeys, who express receptors closely related to human CD155, can be experimentally infected  . When poliovirus recognizes its receptor, the virus changes from a 160S to a 135S particle before releasing its genome into the cytoplasm  . The other cellular functions of CD155 are not fully understood ,[  .
Heterozygous SNPs (Ala67Thr) in CD155 gene was found to be between 6.8 to 8.5 per cent in normal healthy population. It was significantly higher in patients with polio paresis (13.3%) and progressive muscular atrophy (20%). Ala67Thr polymorphism was proposed as a genetic risk factor for susceptibility to poliomyelitis ,, . However, the hypothesis has not been tested in other studies involving large numbers of polio patients.
Presently, DNA sequencing and PCR followed by RFLP have been used to detect the snp0 s (GCGàACG) in CD155/PVR gene in the human sample  . Both these methods are slow and require processing to obtain final results. We developed and validated an SNP assay to detect the single nucleotide substitution (GCG®ACG) in CD155/PVR gene. The assay may be suitable for the large scale screening of samples for identification of heterozygous SNP in the CD155/PVR gene in human DNA samples. The SNP assay results were confirmed by DNA sequencing of all the samples.
Our aim was to develop a simple assay for the large scale screening of the SNP. It was found that the carrier rate of heterozygous (Ala67Thr) among the 150 anonymous DNA samples was about 27 per cent which was higher than that reported for normal healthy persons. Bhattacharya et al reported prevalence of heterozygous Ala67Thr genotype in normal population to be 5-7.5 per cent and 45 per cent in patients with post-polio syndrome in India. These findings also indicate that large scale screening for the heterozygous CD155/PVR may be needed amongst the Indian population. Our SNP assay would be useful for such screening. It would be interesting to investigate the prevalence of heterozygous carrier rate in India and whether it had any bearing on the success of polio eradication programme in certain populations.
P. Nalavade for processing the samples.
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Ken Gregg died in March 2008 at the young age of 57. He was one of the finest, most decent human beings I have ever met....a freethinker, a libertarian scholar, an adoring father, a superlative friend, a pacifist and an extremely kind man. I am collecting and reposting his writing on this site in order to preserve it.
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