Here is a controversial subject that I want to air. How should we think about nudity? I see that Christian groups are protesting about a new logo for Starbucks which has a bare breasted mermaid (were mermaids ever other?).
You might think that it is a storm in a coffee cup, but I want to link it with a movie that I watched the other night "Mrs Henderson Presents" and an episode of 'House' in which the diagnosis was missed because a woman would not take off all her clothes.
"Mrs Henderson Presents" (rated 12) starred Judy Dench and Bob Hoskins and was about the Windmill Theater in London's West End, which was the first to allow nudity on stage in London. It was done purely and simply (would that better be impurely?) to bring in the punters and they got round the censorship of the Lord Chamberlain's office by presenting the nudes as 'art' in tableau. Like the nudes in paintings and sculpture, they did not move. The plea by Mrs Henderson, that when he son died in World War I she found a French postcard amongst his effects and realised that he had never seen a naked woman, so that thereafter she was determined that the young soldiers going to die in the second war should not suffer the same fate, seems like special pleading to me; an argument dreamed up after the fact when she was threatened with closure.
In the episode of 'House' the patient had refused to remove her socks so that he missed a broken toe. It happened to me once; I missed a melanoma on the sole of a foot. So as a doctor I see the necessity for taking all the clothes off and 40 years of examining naked men and women has left me rather devoid of the special frisson that some people experience at the thought of nudity.
But what is it there for? And have we lost something in our society because we have become more accustomed to stripping off? After all, naked flesh is hardly a novelty on the movie screen and it appears regularly on our televisions. We have to admit that it is a social mores. We long ago adjusted to bare breasted black women in grass skirts dancing in the shadow of Kilimanjaro. South Sea Islanders run around hardly clad. In Elizabethan times fashion decreed that the bosom was visible while under that other great Queen, Victoria, even a glimpse of an ankle provoked extremities of male emotion. Under the Taliban, only the eyes are visible.
If complete nudity is an offence to some, we get as near to it as maybe on our advertising hoardings and billboards. Three small triangles leave little to the imagination.
For those still in the dark, take the advice of a doctor: the sexual organs of plants are much more pleasant to look at.
Saturday, May 31, 2008
Private Eye
What is the first use in literature of the term 'private eye'?
I would like to put in a bid for Sherlock Holmes. Although he was never called a private eye, he is the doyen of all such. In the Valley of Fear, early in the tale one policeman writes to another "This is for your private eye." meaning 'for your eyes only.' Since he had Sherlock alongside him as he read it and he was asked to share the information with him and to bring him along on the case, it surely here has a double meaning.
I would like to put in a bid for Sherlock Holmes. Although he was never called a private eye, he is the doyen of all such. In the Valley of Fear, early in the tale one policeman writes to another "This is for your private eye." meaning 'for your eyes only.' Since he had Sherlock alongside him as he read it and he was asked to share the information with him and to bring him along on the case, it surely here has a double meaning.
Tuesday, May 27, 2008
Immunodeficiency 6
Vaccines
Patients commonly ask whether they should receive vaccinations. Their enquiries have two purposes; they want to know if vaccination is safe and if it is effective. Although vaccination may sometimes transiently raise the peripheral lymphocyte count, there is no evidence that it triggers an exacerbation of the CLL. On the other hand, patients with CLL should be regarded as immunodeficient as far as vaccination with live attenuated organisms is concerned and these should be avoided. A list of such vaccines is given in Table 1.
Table 1
Vaccines that should be avoided in CLL
BCG
MMR
Poliomyelitis (oral)
Typhoid (oral)
Vaccinia
Varicella-Zoster
Yellow fever
Vaccines that are permissible
Anthrax
Cholera (oral)
Diphtheria
Haemophilus influenzae type b
Hepatitis A
Hepatitis B
Influenza
Menningococcus
Pertussis
Poliomyelitis (injection)
Rabies
Tetanus
Tick-borne encephalitis
Typhoid (injection)
Patients with CLL respond very poorly to vaccination. Even newly diagnosed Rai stage 0 patients with normal serum immunoglobulins fail to mount a primary response against a previously unseen antigen though on repeated injection about half the patients are able to mount a secondary response at a level substantially less than in normal individuals [33]. Vaccination studies in CLL have been comprehensively reviewed by Sinisalo [34]. Over the past fifty years there have been numerous investigations of vaccination against Streptococus pneumoniae, Haemophilus influenzae type b, influenza, tetanus, diphtheria, mumps, and Salmonella typhi. In general antibody responses to vaccines have been weak. Protein vaccines have produced weak to moderate responses in up to 50% of patients, chiefly in early stage patients with normal serum immunoglobulin levels, but responses to polysaccharide vaccines have been virtually zero [34]. There have been several attempts to enhance responses.
Histamine exerts a complex influence on the immune response via receptors on dendritic cells, macrophages and T and B lymphocytes. It is involved in the regulation or helper T cell polarity and through the type 2 histamine receptor interferes with regulatory T cell function [35]. Attempts have been made to enhance antibody responses to vaccines using the H-2 antagonist, ranitidine. One such study used ranitidine 300mg twice daily for 90 days in an attempt to enhance antibody production to Haemophilus influenzae type B (Hib) conjugated to tetanus toxoid and influenza virus with vaccines given on day 0 and boosted on day 45. The study showed a significantly increased response rate of 90% compared with 43% for controls in patients receiving the ranitidine with the Hib vaccine though no significant difference could be seen for the influenza vaccine [36]. Improved responses to the tetanus toxoid conjugated Hib vaccine against both Hib and tetanus were also reported following ranitidine treatment by an independent group, but ranitidine failed to induce any responses to an unconjugated pneumococcal polysaccharide vaccine. Patients receiving ranitidine had higher levels of interleukin-18, a proinfllammatory cytokine that induces T cells to produce -interferon [37].
The problem of poor response to polysaccharide vaccines can be partially overcome by conjugation to protein antigens. In the case of Hib, conjugation to tetanus toxoid is effective [36, 37]. For pneumococcal vaccines, conjugation to diphtheria CRM197 carrier protein produces an more effective vaccine capable of elliciting antibody responses in 40% of patients with CLL, most effectively in Binet stage A patients [38]. Studies using this vaccine with ranitidine are awaited.
Patients with CLL undergoing splenectomy will almost certainly not benefit from vaccination with pneumococcal polysaccharide vaccines. Vaccination with the conjugated vaccine maight be tried, but prophylaxis with appropriate antibiotics should be considered mandatory.
References
33. Hamblin-TJ, Verrier jones J, Peacock DB. The immune response to phiX174 in man IV Primary and secondary antibody production in patients with chronic lymphocytic leukaemia. Clin Exp Immunol 1975; 21:101-8.
34. Sinisalo M. Responses to vaccine antigens in chronic lymphocytic leukaemia. Academic Dissertation. University of Tampere Medical School, Finland. 2008. Available at http://acta.uta.fi/pdf/978-951-44-7271-8.pdf
35. Jutel M, Blaser K, Akdis CA. The role of histamine in regulation of the immune response. Chem Immunol Allergy 2006; 91:174-87.
36. Jurlander J, deNully Brown P, Skov PS et al. Improved vaccination response during ranitidine treatment, and increased plasma histamine concentrations, in patients with B cell chronic lymphocytic leukaemia. Leukemia 1995; 9:1902-9.
37. Van der Velden AM, Van Velzen-Blad H, Claessen AM et al. The effect of ranitidine on antibody responses to polysaccharide vaccines in patients with B-cell chronic lymphocytic leukaemia. Eur J Haematol 2007; 79:47-52.
38. Sinisalo M, Vilpo J, Itala M, Vakevainen M, Taurio J, Aittoniemi J. Antibody response to 7-valent conjugated pneumococcal vaccine in patients with chronic lymphocytic leukaemia. Vaccine 2007; 26:82-7.
Patients commonly ask whether they should receive vaccinations. Their enquiries have two purposes; they want to know if vaccination is safe and if it is effective. Although vaccination may sometimes transiently raise the peripheral lymphocyte count, there is no evidence that it triggers an exacerbation of the CLL. On the other hand, patients with CLL should be regarded as immunodeficient as far as vaccination with live attenuated organisms is concerned and these should be avoided. A list of such vaccines is given in Table 1.
Table 1
Vaccines that should be avoided in CLL
BCG
MMR
Poliomyelitis (oral)
Typhoid (oral)
Vaccinia
Varicella-Zoster
Yellow fever
Vaccines that are permissible
Anthrax
Cholera (oral)
Diphtheria
Haemophilus influenzae type b
Hepatitis A
Hepatitis B
Influenza
Menningococcus
Pertussis
Poliomyelitis (injection)
Rabies
Tetanus
Tick-borne encephalitis
Typhoid (injection)
Patients with CLL respond very poorly to vaccination. Even newly diagnosed Rai stage 0 patients with normal serum immunoglobulins fail to mount a primary response against a previously unseen antigen though on repeated injection about half the patients are able to mount a secondary response at a level substantially less than in normal individuals [33]. Vaccination studies in CLL have been comprehensively reviewed by Sinisalo [34]. Over the past fifty years there have been numerous investigations of vaccination against Streptococus pneumoniae, Haemophilus influenzae type b, influenza, tetanus, diphtheria, mumps, and Salmonella typhi. In general antibody responses to vaccines have been weak. Protein vaccines have produced weak to moderate responses in up to 50% of patients, chiefly in early stage patients with normal serum immunoglobulin levels, but responses to polysaccharide vaccines have been virtually zero [34]. There have been several attempts to enhance responses.
Histamine exerts a complex influence on the immune response via receptors on dendritic cells, macrophages and T and B lymphocytes. It is involved in the regulation or helper T cell polarity and through the type 2 histamine receptor interferes with regulatory T cell function [35]. Attempts have been made to enhance antibody responses to vaccines using the H-2 antagonist, ranitidine. One such study used ranitidine 300mg twice daily for 90 days in an attempt to enhance antibody production to Haemophilus influenzae type B (Hib) conjugated to tetanus toxoid and influenza virus with vaccines given on day 0 and boosted on day 45. The study showed a significantly increased response rate of 90% compared with 43% for controls in patients receiving the ranitidine with the Hib vaccine though no significant difference could be seen for the influenza vaccine [36]. Improved responses to the tetanus toxoid conjugated Hib vaccine against both Hib and tetanus were also reported following ranitidine treatment by an independent group, but ranitidine failed to induce any responses to an unconjugated pneumococcal polysaccharide vaccine. Patients receiving ranitidine had higher levels of interleukin-18, a proinfllammatory cytokine that induces T cells to produce -interferon [37].
The problem of poor response to polysaccharide vaccines can be partially overcome by conjugation to protein antigens. In the case of Hib, conjugation to tetanus toxoid is effective [36, 37]. For pneumococcal vaccines, conjugation to diphtheria CRM197 carrier protein produces an more effective vaccine capable of elliciting antibody responses in 40% of patients with CLL, most effectively in Binet stage A patients [38]. Studies using this vaccine with ranitidine are awaited.
Patients with CLL undergoing splenectomy will almost certainly not benefit from vaccination with pneumococcal polysaccharide vaccines. Vaccination with the conjugated vaccine maight be tried, but prophylaxis with appropriate antibiotics should be considered mandatory.
References
33. Hamblin-TJ, Verrier jones J, Peacock DB. The immune response to phiX174 in man IV Primary and secondary antibody production in patients with chronic lymphocytic leukaemia. Clin Exp Immunol 1975; 21:101-8.
34. Sinisalo M. Responses to vaccine antigens in chronic lymphocytic leukaemia. Academic Dissertation. University of Tampere Medical School, Finland. 2008. Available at http://acta.uta.fi/pdf/978-951-44-7271-8.pdf
35. Jutel M, Blaser K, Akdis CA. The role of histamine in regulation of the immune response. Chem Immunol Allergy 2006; 91:174-87.
36. Jurlander J, deNully Brown P, Skov PS et al. Improved vaccination response during ranitidine treatment, and increased plasma histamine concentrations, in patients with B cell chronic lymphocytic leukaemia. Leukemia 1995; 9:1902-9.
37. Van der Velden AM, Van Velzen-Blad H, Claessen AM et al. The effect of ranitidine on antibody responses to polysaccharide vaccines in patients with B-cell chronic lymphocytic leukaemia. Eur J Haematol 2007; 79:47-52.
38. Sinisalo M, Vilpo J, Itala M, Vakevainen M, Taurio J, Aittoniemi J. Antibody response to 7-valent conjugated pneumococcal vaccine in patients with chronic lymphocytic leukaemia. Vaccine 2007; 26:82-7.
Saturday, May 24, 2008
Crewe Blues
Coming on top of a 20% lead in the local elections, a 20% lead in the opinion polls and the overthrow of Red Ken in London, the Tory victory in Crewe and Nantwich, which was the 165th most likely target seat for the next General Election, is a crushing blow for New Labor. If this were to be repeated in 2010 half the Cabinet would be expelled from Parliament and the Tories would have a massive majority.
How come New Labor, which hasn't lost a by-election to the Tories for 30 years and which has swept to victory in three successive elections, has come to so great a grief?
There were several factors at play. There was certainly a local dimension. The seat had been held for a very long time by Gwyneth Dunwoody. I remember the time when she was regarded as a far-Left firebrand, but of late she had morphed into the chairman of an important parliamentary committee, unafraid to confront the government over injustice and remarkably bipartisan in her pronouncements. It was her death that precipitated the by-election. Her daughter, Tamsin, had been selected as the Labor candidate to succeed her. The Tory candidate was Edward Timpson, son of multi-millionaire John Timpson. Dunwoody ran a campaign which attacked the Tory candidate as a rich, effete do-nothing, running on inherited money, educated at a posh private school, and driving around in a a gas-guzzling Bentley. (Bentleys are made at Crewe, by the way). She presented herself as a class-warrior, battling for the ordinary people against the toffs.
It was a particularly crass campaign. Edward Timpson certainly is the son of a rich man. But this was not inherited money. John Timpson started work repairing shoes and cutting keys and by dint of hard work built himself up into a national brand. His company is extremely generous to its employees and he and his wife have fostered 80 unwanted children in their home. Edward Timpson grew up with many of the most deprived children in the country as foster brothers and sisters. Labor falsely portrayed him as a top-hat-wearing waster who drove through working class settlements at 4 in the morning with his speaker system full on and trailing blue balloons from his SUV. When the voters found out that it was part of the Labor team in disguise doing this they were not best pleased.
Tamsin Dunwoody herself came across as a most unpleasant character. Aged about fifty and dressed as 30 with dyed blone hair and a skin wrinkled by too much sun and smoking she claimed to be an unmarried mother with 6 children. She was trying to identify with the locals. However, this is what her Wikipedia entry says:
Dunwoody was born in Totnes, Devon, the daughter of the late Labour MPs, Gwyneth Dunwoody, and Dr John Dunwoody. Through her mother she is the granddaughter of former Labour Party General Secretary, Morgan Phillips and Norah Phillips, Baroness Phillips. She was educated at the Grey Coat Hospital Church of England girls' school in Westminster and the University of Kent.Dunwoody was elected (under the name Tamsin Dunwoody-Kneafsey) as Assembly Member for Preseli Pembrokeshire from 2003 to 2007. In October 2005 she was appointed Deputy Minister for Environment, Planning and Countryside and Deputy Minister for Economic Development and Transport in the Welsh Assembly Government. She was defeated in the 2007 election by Conservative Party candidate Paul Davies.
Far from Timpson being heir to a dynasty, Dunwoody is daughter of two Labor MPs, granddaughter of one of the Labor grandees and a Baroness. She was educated at one of those top class schools in Westminster where Labor MPs send their children at our expense rather than pay for an improved education themselves. You don't get many children of Labor MPs at what they themselves call 'bog-standard comprehensives'.
But apart from the local effect, Labor nationally are in big trouble. Getting Tony Blair to be their leader was a masterstroke. Blair was personable, articulate, charming and remarkably self-effacing. In contrast John Major appeared old-fashioned, grey, verbose and had a strange way of pronouncing some of his vowels. Two years in to an economic recovery, the public had tired of the Tories. They remembered the end days of Mrs Thatcher rather than in her pomp and the sorry attempt to align the pound with the Euro prior to ditching our currency had been very unpopular. The young, smart, clean-cut (call me Tony) Blair seemed just what they wanted. With the economy thriving and a smart leader, Labor held power for 10 years. But Blair ran into Iraq, which was enough to unseat him.
Meanwhile, Gordon Brown had kept his head down for ten years. As Chancellor of the exchequer he had claimed the credit for a decade of economic success (though in fact the period of growth had started under Ken Clarke and had been built of China exporting deflation, allowing him to pursue public spending policies that would have been inflationary but for the Chinese factor). With Tony Blair as front man there was no need for Brown to show himself in public. indeed whenever Blair got into trouble he remembered an urgent appointment in Geneva or Davos or Bali. All the time though he coveted the top job, and when it was clear that Blair had to go - Iraq had become like the poll tax for Mrs Thatcher - it seemed natural for Labor to turn to Brown. He enjoyed a few months honeymoon period but then things started to go wrong. It is pointless to list them, but they have their genesis in decisions he took as Chancellor and what is more important is how he reacted to them. All politicians get undone by 'events' (as Harold Macmillan put it), but skillful leaders turn them to their advantage (as Margaret Thatcher did with the Falklands and the miners' strike). Brown turned out to be a ditherer. As the economy took a downward turn, he blamed the world economic factors. The public are not so stupid as to believe the good times were down to him but the bad times are somebody else's fault.
The Northern Rock fiasco was laid at his door, and the abolition of the 10p in the pound income tax band, which punished the 5.3 million poorest, was clearly his fault. His reaction to that, which was to give a tax rebate to 22 million while still hitting the million poorest demonstrated monumental incompetence in the eyes of the electorate.
There are plenty of other things to blame New Labor for - immigration, crime, MRSA, identity cards, 42 days detention without trial, food and fuel prices, mortgage famine, negative equity, car tax - and Iraq hasn't gone away.
How come New Labor, which hasn't lost a by-election to the Tories for 30 years and which has swept to victory in three successive elections, has come to so great a grief?
There were several factors at play. There was certainly a local dimension. The seat had been held for a very long time by Gwyneth Dunwoody. I remember the time when she was regarded as a far-Left firebrand, but of late she had morphed into the chairman of an important parliamentary committee, unafraid to confront the government over injustice and remarkably bipartisan in her pronouncements. It was her death that precipitated the by-election. Her daughter, Tamsin, had been selected as the Labor candidate to succeed her. The Tory candidate was Edward Timpson, son of multi-millionaire John Timpson. Dunwoody ran a campaign which attacked the Tory candidate as a rich, effete do-nothing, running on inherited money, educated at a posh private school, and driving around in a a gas-guzzling Bentley. (Bentleys are made at Crewe, by the way). She presented herself as a class-warrior, battling for the ordinary people against the toffs.
It was a particularly crass campaign. Edward Timpson certainly is the son of a rich man. But this was not inherited money. John Timpson started work repairing shoes and cutting keys and by dint of hard work built himself up into a national brand. His company is extremely generous to its employees and he and his wife have fostered 80 unwanted children in their home. Edward Timpson grew up with many of the most deprived children in the country as foster brothers and sisters. Labor falsely portrayed him as a top-hat-wearing waster who drove through working class settlements at 4 in the morning with his speaker system full on and trailing blue balloons from his SUV. When the voters found out that it was part of the Labor team in disguise doing this they were not best pleased.
Tamsin Dunwoody herself came across as a most unpleasant character. Aged about fifty and dressed as 30 with dyed blone hair and a skin wrinkled by too much sun and smoking she claimed to be an unmarried mother with 6 children. She was trying to identify with the locals. However, this is what her Wikipedia entry says:
Dunwoody was born in Totnes, Devon, the daughter of the late Labour MPs, Gwyneth Dunwoody, and Dr John Dunwoody. Through her mother she is the granddaughter of former Labour Party General Secretary, Morgan Phillips and Norah Phillips, Baroness Phillips. She was educated at the Grey Coat Hospital Church of England girls' school in Westminster and the University of Kent.Dunwoody was elected (under the name Tamsin Dunwoody-Kneafsey) as Assembly Member for Preseli Pembrokeshire from 2003 to 2007. In October 2005 she was appointed Deputy Minister for Environment, Planning and Countryside and Deputy Minister for Economic Development and Transport in the Welsh Assembly Government. She was defeated in the 2007 election by Conservative Party candidate Paul Davies.
Far from Timpson being heir to a dynasty, Dunwoody is daughter of two Labor MPs, granddaughter of one of the Labor grandees and a Baroness. She was educated at one of those top class schools in Westminster where Labor MPs send their children at our expense rather than pay for an improved education themselves. You don't get many children of Labor MPs at what they themselves call 'bog-standard comprehensives'.
But apart from the local effect, Labor nationally are in big trouble. Getting Tony Blair to be their leader was a masterstroke. Blair was personable, articulate, charming and remarkably self-effacing. In contrast John Major appeared old-fashioned, grey, verbose and had a strange way of pronouncing some of his vowels. Two years in to an economic recovery, the public had tired of the Tories. They remembered the end days of Mrs Thatcher rather than in her pomp and the sorry attempt to align the pound with the Euro prior to ditching our currency had been very unpopular. The young, smart, clean-cut (call me Tony) Blair seemed just what they wanted. With the economy thriving and a smart leader, Labor held power for 10 years. But Blair ran into Iraq, which was enough to unseat him.
Meanwhile, Gordon Brown had kept his head down for ten years. As Chancellor of the exchequer he had claimed the credit for a decade of economic success (though in fact the period of growth had started under Ken Clarke and had been built of China exporting deflation, allowing him to pursue public spending policies that would have been inflationary but for the Chinese factor). With Tony Blair as front man there was no need for Brown to show himself in public. indeed whenever Blair got into trouble he remembered an urgent appointment in Geneva or Davos or Bali. All the time though he coveted the top job, and when it was clear that Blair had to go - Iraq had become like the poll tax for Mrs Thatcher - it seemed natural for Labor to turn to Brown. He enjoyed a few months honeymoon period but then things started to go wrong. It is pointless to list them, but they have their genesis in decisions he took as Chancellor and what is more important is how he reacted to them. All politicians get undone by 'events' (as Harold Macmillan put it), but skillful leaders turn them to their advantage (as Margaret Thatcher did with the Falklands and the miners' strike). Brown turned out to be a ditherer. As the economy took a downward turn, he blamed the world economic factors. The public are not so stupid as to believe the good times were down to him but the bad times are somebody else's fault.
The Northern Rock fiasco was laid at his door, and the abolition of the 10p in the pound income tax band, which punished the 5.3 million poorest, was clearly his fault. His reaction to that, which was to give a tax rebate to 22 million while still hitting the million poorest demonstrated monumental incompetence in the eyes of the electorate.
There are plenty of other things to blame New Labor for - immigration, crime, MRSA, identity cards, 42 days detention without trial, food and fuel prices, mortgage famine, negative equity, car tax - and Iraq hasn't gone away.
Friday, May 23, 2008
Blind to their own sins
The final of the European Champions League in Moscow on Wednesday was an exciting match between Manchester United and Chelsea, which the Manchester club won 6-5 on penalties after a 1-1 draw after extra-time. Thus the two English teams who were almost inseparable in the Premier League were similarly very close in the European final.
In one sense this was a Russia versus America clash. Manchester United is owned by the Glazers; they were bought with borrowed money in one of those levered deals that the Free Market is prone to. Chelsea is owned by the fabulously wealthy Russian oligarch Abramovich who made his money from the privatization of Russian oil fields under Yeltsin.
United's coach is the veteran Sir Alex Ferguson, an abrasive Scot who has won everything before, but who has been the most successful football manager in the world for the last decade. Chelsea are coached (at least for now) by Avram Grant, a podgy middle aged and softly spoken Israeli who doesn't even hold the appropriate coaching certificate. Both teams comprise the best footballers money can buy from all over the world, and although United did manage to field six Englishmen to Chelsea's four, one of United's six was an ex-Canadian who has played most of his football in Germany.
The style of football is different between the two teams. United play a rapid passing game, plotting intricate patterns on the pitch, which is perhaps less beautiful than that of Arsenal at their best, but which more frequently produces spectacular goals. That end-product is perhaps chiefly due to the young Portuguese, Ronaldo. Tall, fast, delicately balanced and highly skilled, he has been the chief goal-scorer for United all season, often bewildering the opposition with his footwork. It was he who scored first in the final. For the first 40 minutes United dominated the game, hardly allowing Chelsea a touch. The assist came from Wes Brown, the United right back who is of mixed race and ginger haired, and who has been in dispute over his contract for most of the season. Cutting inside from the right he crossed the ball with his left foot and it was met by the head of Ronaldo who forced the ball into the net from ten yards like an old fashioned English centre forward. It could have been Tommy Lawton or Nat Lofthouse or even Tommy Taylor, the United and England centre forward killed just 50 years ago in the Munich air crash that wiped out half the United team. That's 42 goals for the season for Ronaldo, a fantastic run of form that made in footballer of the year in England and may yet give him the pan-European title.
Brilliant moves from Rooney and Tevez, youngsters from respectively England and Argentina, should have put United three goals to the good, but the finishing touch was just missing or the Chelsea goalie, Petr Cech, saved amazingly. Then just when we thought that the game was to be a one-sided romp Michael Essien, the Ghanaian makeshift right-back surged forward. One of the problems of teams like Chelsea is finding space for all their players. Essien is the most expensive player to come out of Africa, costing Chelsea nearly £25 million. But he is a mid-fielder, and Chelsea already have Lampard, Ballack and Makalele as mid-fielders. There seemed no room for Essien. The solution is to play him at right back with an mandate to attack from there at every opportunity. To counter this Sir Alex was playing Ronaldo on the left wing so that Essien had to mark him. All through the first half Ronaldo was running rings around him, exposing his inexperience as a defender. Now in injury time at the end of the first half Essien abandoned Ronaldo and carried the ball forward and unleashed a shot at goal. It wasn't much of a shot but it bounced of the two United central defenders, from the thigh of Vidic and the back of Ferdinand to fall at the feet at the in-running Frank Lampard. Lampard has had a distressing few weeks with the death of his other at a relatively early age. He now found himself with the ball at his feet and the goalkeeper out of position because of the ricochet. It is a simple matter to slot the ball home for the equalizing goal.
Scoring just on the stroke of half time gives a team a psychological advantage and in the second half Chelsea began to take control. It wasn't just psychology, there had been a change in tactics. In the first half the two mid-fielders, Carrick and Scholes had been allowed too much time on the ball so they were able to control tactics. Chelsea had had to bring back Joe Cole and Malouda leaving the giant Ivory Coast international Drogba isolated and ineffective. Now Lampard and Ballack were instructed to close down Scholes and Carrick and take the game to United. Scholes, in particular, was beginning to tire and for a long period Chelsea were in control. In this period Drogba hit the bar, but Chelsea could not score. They forced Ferguson into a tactical change, bringing Rooney back to right wing and moving the strong tackling Hargreaves into the centre of midfield. This had the effect of limiting the attacking options of both sides. So full time came with Giggs on for Scholes and the score at 1-1.
European finals quite frequently go into extra time (or overtime, if you like). They play another 30 minutes. It is an opportunity to bring on substitutes to see if fresh legs will resolve the deadlock. There were two significant near misses. Lampard hit the post and Giggs having a certain goal saved by a last minute header from the Chelsea captain John Terry. Both players had a reason desparately to want to win. The veteran Ryan Giggs was the only player who had played on the previous occasion that United had won the European Cup, and in this match he had set a new record of appearances for Manchester United, surpassing the previous record holder, Bobby Charlton, who had lifted the European Cup for United on the first occasion they had won it 39 years previously. Bobby Charlton, survivor of the Munich air crash and scorer of the most goals for the English national team was there in the stadium watching the match. John Terry had been captain of Chelsea and Captain of England, but with a new England coach he had been displaced from that post by the United captain, Rio Ferdinand. Terry had dislocated his elbow in the last match of the season and he was playing in this match in pain.
As the 30 minutes of extra time drew to its close, players everywhere were going down with cramp. Some players run more than 12 kilometers during the course of a 90 minute game, and to play an extra 30 minutes takes it out of them. A convention has arisen that if a player is injured, someone on the opposing side will kick the ball out of play so that the player can get treatment. When the game restarts it is considered sportsmanlike to return the ball to the side that was in possession before the interruption. On two occasions United had kicked the ball out, but on each occasion Chelsea had returned the ball to them, but in such a way as to put United at a disadvantage. Now the opposite happened. Chelsea kicked the ball out of play, but United returned it far back into the Chelsea half. Chelsea went wild. And here is the point of the whole article. We are blind to our own sins but angry when someone sins against us. In the melee that followed Drogba slapped Vidic round the face. Jostling is winked at. Abuse is allowed. Even a bit of kicking is passed over, but raise your hand at the other fellow and there is only one punishment - a red card. Drogba was sent off. There is only a minute to go, so it won't much affect the match except that now the last substitutions are made. On come those who are good at penalty kicks and off go those who are not.
Now we come to the penalties. You would think it a simple matter to score from 12 metres when the goal is eight metres wide. That without reckoning without the nerves. How many golfers have missed a three foot putt for the championship? How many tennis players have missed a simple smash? How many cricketers have dropped a dolly when the pressure is really on? Alex Ferguson later confessed that none of his teams had ever won a penalty shoot out.
Each team has five penalties. United went first. Each side score their first two penalties easily. Up steps the wunderkind Ronaldo. He is United's regular penalty taker and he seldom misses. His technique is well known. In his run up he has a little hesitation to trigger a move to one side from the goalkeeper so that he neatly slots it to the other side of the goal. He does his little jink, but Cech does not move. Ronaldo has hesitated too long and when it comes he does not have enough momentum to kick the ball hard enough. It is a tame penalty that Cech saves. Chelsea score with their third and fourth and United with their fourth and fifth. All Chelsea needs is to slot home their fifth penalty. This should be Drogba's job. Their best forward should be given the most nervy task. But Drogba has been sent off. None of the other forwards wants the job. Up steps the captain, taking control. Score and the Cup is theirs, miss and he will always be notorious as the man who lost the trophy. Terry steps up without nerves but his standing foot slips on the newly laid pitch and he kicks the ball wide of the goal. The scores are equal at 4-4. United score their 6th and so do Chelsea. United score their 7th and Chelsea nominate Anelka, the temperamental French forward, bought for next season when Drogba is expected to leave. It's a soft shot and Van de Saar saves. the match is over and United have won.
Despair for Chelsea. John Terry is in tears. Joy for United. Ecstasy! Paul Scholes gets his medal - he had been suspended for the game nine years previously. The United team is led up to receive the trophy by none other than Bobby Charlton, now a United director and half a century after he stepped out unscathed from the ruined plane at Munich, 39 years since he lifted the trophy himself as captain of United.
On the radio today a Liverpool supporter gives grudging praise to Ferguson. He is a good coach, perhaps a very good coach, but not a great coach. Bob Paisley, now he was a great coach. He took Liverpool to three wins.
Blind to his own sins; vigilant for those of others.
In one sense this was a Russia versus America clash. Manchester United is owned by the Glazers; they were bought with borrowed money in one of those levered deals that the Free Market is prone to. Chelsea is owned by the fabulously wealthy Russian oligarch Abramovich who made his money from the privatization of Russian oil fields under Yeltsin.
United's coach is the veteran Sir Alex Ferguson, an abrasive Scot who has won everything before, but who has been the most successful football manager in the world for the last decade. Chelsea are coached (at least for now) by Avram Grant, a podgy middle aged and softly spoken Israeli who doesn't even hold the appropriate coaching certificate. Both teams comprise the best footballers money can buy from all over the world, and although United did manage to field six Englishmen to Chelsea's four, one of United's six was an ex-Canadian who has played most of his football in Germany.
The style of football is different between the two teams. United play a rapid passing game, plotting intricate patterns on the pitch, which is perhaps less beautiful than that of Arsenal at their best, but which more frequently produces spectacular goals. That end-product is perhaps chiefly due to the young Portuguese, Ronaldo. Tall, fast, delicately balanced and highly skilled, he has been the chief goal-scorer for United all season, often bewildering the opposition with his footwork. It was he who scored first in the final. For the first 40 minutes United dominated the game, hardly allowing Chelsea a touch. The assist came from Wes Brown, the United right back who is of mixed race and ginger haired, and who has been in dispute over his contract for most of the season. Cutting inside from the right he crossed the ball with his left foot and it was met by the head of Ronaldo who forced the ball into the net from ten yards like an old fashioned English centre forward. It could have been Tommy Lawton or Nat Lofthouse or even Tommy Taylor, the United and England centre forward killed just 50 years ago in the Munich air crash that wiped out half the United team. That's 42 goals for the season for Ronaldo, a fantastic run of form that made in footballer of the year in England and may yet give him the pan-European title.
Brilliant moves from Rooney and Tevez, youngsters from respectively England and Argentina, should have put United three goals to the good, but the finishing touch was just missing or the Chelsea goalie, Petr Cech, saved amazingly. Then just when we thought that the game was to be a one-sided romp Michael Essien, the Ghanaian makeshift right-back surged forward. One of the problems of teams like Chelsea is finding space for all their players. Essien is the most expensive player to come out of Africa, costing Chelsea nearly £25 million. But he is a mid-fielder, and Chelsea already have Lampard, Ballack and Makalele as mid-fielders. There seemed no room for Essien. The solution is to play him at right back with an mandate to attack from there at every opportunity. To counter this Sir Alex was playing Ronaldo on the left wing so that Essien had to mark him. All through the first half Ronaldo was running rings around him, exposing his inexperience as a defender. Now in injury time at the end of the first half Essien abandoned Ronaldo and carried the ball forward and unleashed a shot at goal. It wasn't much of a shot but it bounced of the two United central defenders, from the thigh of Vidic and the back of Ferdinand to fall at the feet at the in-running Frank Lampard. Lampard has had a distressing few weeks with the death of his other at a relatively early age. He now found himself with the ball at his feet and the goalkeeper out of position because of the ricochet. It is a simple matter to slot the ball home for the equalizing goal.
Scoring just on the stroke of half time gives a team a psychological advantage and in the second half Chelsea began to take control. It wasn't just psychology, there had been a change in tactics. In the first half the two mid-fielders, Carrick and Scholes had been allowed too much time on the ball so they were able to control tactics. Chelsea had had to bring back Joe Cole and Malouda leaving the giant Ivory Coast international Drogba isolated and ineffective. Now Lampard and Ballack were instructed to close down Scholes and Carrick and take the game to United. Scholes, in particular, was beginning to tire and for a long period Chelsea were in control. In this period Drogba hit the bar, but Chelsea could not score. They forced Ferguson into a tactical change, bringing Rooney back to right wing and moving the strong tackling Hargreaves into the centre of midfield. This had the effect of limiting the attacking options of both sides. So full time came with Giggs on for Scholes and the score at 1-1.
European finals quite frequently go into extra time (or overtime, if you like). They play another 30 minutes. It is an opportunity to bring on substitutes to see if fresh legs will resolve the deadlock. There were two significant near misses. Lampard hit the post and Giggs having a certain goal saved by a last minute header from the Chelsea captain John Terry. Both players had a reason desparately to want to win. The veteran Ryan Giggs was the only player who had played on the previous occasion that United had won the European Cup, and in this match he had set a new record of appearances for Manchester United, surpassing the previous record holder, Bobby Charlton, who had lifted the European Cup for United on the first occasion they had won it 39 years previously. Bobby Charlton, survivor of the Munich air crash and scorer of the most goals for the English national team was there in the stadium watching the match. John Terry had been captain of Chelsea and Captain of England, but with a new England coach he had been displaced from that post by the United captain, Rio Ferdinand. Terry had dislocated his elbow in the last match of the season and he was playing in this match in pain.
As the 30 minutes of extra time drew to its close, players everywhere were going down with cramp. Some players run more than 12 kilometers during the course of a 90 minute game, and to play an extra 30 minutes takes it out of them. A convention has arisen that if a player is injured, someone on the opposing side will kick the ball out of play so that the player can get treatment. When the game restarts it is considered sportsmanlike to return the ball to the side that was in possession before the interruption. On two occasions United had kicked the ball out, but on each occasion Chelsea had returned the ball to them, but in such a way as to put United at a disadvantage. Now the opposite happened. Chelsea kicked the ball out of play, but United returned it far back into the Chelsea half. Chelsea went wild. And here is the point of the whole article. We are blind to our own sins but angry when someone sins against us. In the melee that followed Drogba slapped Vidic round the face. Jostling is winked at. Abuse is allowed. Even a bit of kicking is passed over, but raise your hand at the other fellow and there is only one punishment - a red card. Drogba was sent off. There is only a minute to go, so it won't much affect the match except that now the last substitutions are made. On come those who are good at penalty kicks and off go those who are not.
Now we come to the penalties. You would think it a simple matter to score from 12 metres when the goal is eight metres wide. That without reckoning without the nerves. How many golfers have missed a three foot putt for the championship? How many tennis players have missed a simple smash? How many cricketers have dropped a dolly when the pressure is really on? Alex Ferguson later confessed that none of his teams had ever won a penalty shoot out.
Each team has five penalties. United went first. Each side score their first two penalties easily. Up steps the wunderkind Ronaldo. He is United's regular penalty taker and he seldom misses. His technique is well known. In his run up he has a little hesitation to trigger a move to one side from the goalkeeper so that he neatly slots it to the other side of the goal. He does his little jink, but Cech does not move. Ronaldo has hesitated too long and when it comes he does not have enough momentum to kick the ball hard enough. It is a tame penalty that Cech saves. Chelsea score with their third and fourth and United with their fourth and fifth. All Chelsea needs is to slot home their fifth penalty. This should be Drogba's job. Their best forward should be given the most nervy task. But Drogba has been sent off. None of the other forwards wants the job. Up steps the captain, taking control. Score and the Cup is theirs, miss and he will always be notorious as the man who lost the trophy. Terry steps up without nerves but his standing foot slips on the newly laid pitch and he kicks the ball wide of the goal. The scores are equal at 4-4. United score their 6th and so do Chelsea. United score their 7th and Chelsea nominate Anelka, the temperamental French forward, bought for next season when Drogba is expected to leave. It's a soft shot and Van de Saar saves. the match is over and United have won.
Despair for Chelsea. John Terry is in tears. Joy for United. Ecstasy! Paul Scholes gets his medal - he had been suspended for the game nine years previously. The United team is led up to receive the trophy by none other than Bobby Charlton, now a United director and half a century after he stepped out unscathed from the ruined plane at Munich, 39 years since he lifted the trophy himself as captain of United.
On the radio today a Liverpool supporter gives grudging praise to Ferguson. He is a good coach, perhaps a very good coach, but not a great coach. Bob Paisley, now he was a great coach. He took Liverpool to three wins.
Blind to his own sins; vigilant for those of others.
Abortion debate
I was distressed to see that parliament did not take the opportunity to reduce the time limit for abortion. Simon Hughes made the point on television last night - although statistics show that since the present limit of 24 weeks was set medical science has not been able to save any more babies born at 20, 21, 22 or 23 weeks gestation, the fact remains that it can save some. Therefore a 24 week limit means that we are killing some babies who could survive.
My own view is that there should be very few grounds for 'therapeutic abortion' -chiefly when the mother's life is threatened, and then the aim is to deliver the mother, not kill the baby. However, this is not the majority view and we live in a democracy. What has changed is that we now have moving 3D pictures of the baby in the womb at an earlier gestation, and not only can we see that this is not a 'blob of jelly' as the abortionists claim, but a human being who flinches and moves away when given a painful stimulus.
I did find this quote on the Cramner blog:
They might even consider the words of a current practising abortionist, Dr Vincent Argent, who is a consultant gynaecologist and a former acting medical director of the British Pregnancy Advisory Service.
Dr Argent is not remotely content with Nadine Dorries’ 20-week amendment. In The Daily Telegraph he argues for 16, yet even this is considerably more than other European nations, where the limits are:
France 12, Germany 12, Italy 12, Belgium 12, Bulgaria 12, Denmark 12, Czech Republic 12, Greece 12, Hungary 12, Luxembourg 12, the Netherlands 13, Poland 12, Slovakia 12 and Sweden, the most ‘liberal’, 18.
Yet the UK persists with child sacrifice up to 24 weeks.
Dr Argent was brought up a Roman Catholic, but says: ‘any religious beliefs I ever had have left me’. His opinion on late abortions is not formed by ‘religious bigotry’, but by ‘more than 30 years' experience in abortion services for the NHS and private clinics’ during which time he saw what was involved, and the ‘flimsy grounds on which some women sought them’, and thereafter he ‘could not stomach the idea of providing such a "service".’
The doctor notes that people do not realise just how distressing late abortions can be: ‘The procedure remains the last taboo. While heart and brain surgery are regularly shown on television, the reality of a late abortion has never been seen on British screens’.
My own view is that there should be very few grounds for 'therapeutic abortion' -chiefly when the mother's life is threatened, and then the aim is to deliver the mother, not kill the baby. However, this is not the majority view and we live in a democracy. What has changed is that we now have moving 3D pictures of the baby in the womb at an earlier gestation, and not only can we see that this is not a 'blob of jelly' as the abortionists claim, but a human being who flinches and moves away when given a painful stimulus.
I did find this quote on the Cramner blog:
They might even consider the words of a current practising abortionist, Dr Vincent Argent, who is a consultant gynaecologist and a former acting medical director of the British Pregnancy Advisory Service.
Dr Argent is not remotely content with Nadine Dorries’ 20-week amendment. In The Daily Telegraph he argues for 16, yet even this is considerably more than other European nations, where the limits are:
France 12, Germany 12, Italy 12, Belgium 12, Bulgaria 12, Denmark 12, Czech Republic 12, Greece 12, Hungary 12, Luxembourg 12, the Netherlands 13, Poland 12, Slovakia 12 and Sweden, the most ‘liberal’, 18.
Yet the UK persists with child sacrifice up to 24 weeks.
Dr Argent was brought up a Roman Catholic, but says: ‘any religious beliefs I ever had have left me’. His opinion on late abortions is not formed by ‘religious bigotry’, but by ‘more than 30 years' experience in abortion services for the NHS and private clinics’ during which time he saw what was involved, and the ‘flimsy grounds on which some women sought them’, and thereafter he ‘could not stomach the idea of providing such a "service".’
The doctor notes that people do not realise just how distressing late abortions can be: ‘The procedure remains the last taboo. While heart and brain surgery are regularly shown on television, the reality of a late abortion has never been seen on British screens’.
Sunday, May 18, 2008
Psalm 126
Israel was taken into captivity in Babylon in 586 BC, but after the decree of Cyrus (559-530 BC) the return from exile began, though the walls of Jerusalem were not rebuilt until 445 BC. This psalm dates to a time after the exile. It is about revival. "We were like men who dreamed" it says, "Our mouths were filled with laughter and our tongues with songs of joy."
Revival is a time that delights the people of God. We find it thrilling to read about such times. If ever you are downhearted and depressed about the current state of the world, read about the Great Awakening or the Welsh Revival of 1908, or the Revival on the Isle of Lewis in 1948 or the American revival of 1858 or the revival in Korea or Kenya.
How does revival come? Not from the schemes of men. Not from methods. Not from great men. Revival is the gift of God. But how it is watered with prayer.
How should we recognise it? Read about the great revivals and you will find that there was great awareness of the presence of God and the power of God and the peace of God. Men are convicted of sin. Oh, they may know about sin, they may know about the remedy for sin, but suddenly they are convicted of their own sin. Their sin becomes a burden to them. It grips them like a vice. it pains them and will give them no peace.
Then, and only then, comes the presence of God. God washes over them and through them; cleansing, nay searing them clean. Men that hitherto had no time for Godly things are sujugated to Him. They can't get enough of Him. He is the all in all. And the world around them changes. At the time of the Welsh revival the newspapers were full of the numbers of conversions. The prisons emptied; the police were unemployed. Following the Weslyan revival, prisons were reformed, slavery ended, women and children came out of the coalmines, schools were started in every village. Convictions, conversions, changes.
The Lord has done great things for us and we are filled with joy.
We are like verse 4. We plead, "Restore our fortunes, O Lord." In our tears we must sow the word. He who goes out weeping carrying seed to sow, will return with songs of joy, carrying sheaves with him. Now there's a promise.
Revival is a time that delights the people of God. We find it thrilling to read about such times. If ever you are downhearted and depressed about the current state of the world, read about the Great Awakening or the Welsh Revival of 1908, or the Revival on the Isle of Lewis in 1948 or the American revival of 1858 or the revival in Korea or Kenya.
How does revival come? Not from the schemes of men. Not from methods. Not from great men. Revival is the gift of God. But how it is watered with prayer.
How should we recognise it? Read about the great revivals and you will find that there was great awareness of the presence of God and the power of God and the peace of God. Men are convicted of sin. Oh, they may know about sin, they may know about the remedy for sin, but suddenly they are convicted of their own sin. Their sin becomes a burden to them. It grips them like a vice. it pains them and will give them no peace.
Then, and only then, comes the presence of God. God washes over them and through them; cleansing, nay searing them clean. Men that hitherto had no time for Godly things are sujugated to Him. They can't get enough of Him. He is the all in all. And the world around them changes. At the time of the Welsh revival the newspapers were full of the numbers of conversions. The prisons emptied; the police were unemployed. Following the Weslyan revival, prisons were reformed, slavery ended, women and children came out of the coalmines, schools were started in every village. Convictions, conversions, changes.
The Lord has done great things for us and we are filled with joy.
We are like verse 4. We plead, "Restore our fortunes, O Lord." In our tears we must sow the word. He who goes out weeping carrying seed to sow, will return with songs of joy, carrying sheaves with him. Now there's a promise.
Sweetie
I finally saw the clip in which Obama called the female reporter by this term of endearment. A bit of vox populi followed. People from Leeds and Sheffield asked what the fuss was all about. "Everyone round her gets called 'Luv' or 'Chuck'" was the response. An obviously older woman pleaded, "I wish someone would call me 'Sweetie'". In our local market the stall holders call all women whatever their age 'Darling' and all men 'Mate'. In Glasgow you are likely to be called 'Jimmy' whatever your gender and I have noticed that young people tend to talk about each other as 'Guys' whether they are male or female.
Now I can see how such terms of address can be deliberately offensive. For a black man to be addressed as "Boy" is clearly a retrograde reference, and my wife would not take "Babe" even from me (I think she remember a pig of that name). Feminists were right to take umbrage at being thought of as air-heads, fit for nothing but kitchen and bedroom duties.
That being said I find nothing offensive in Obama's 'Sweetie' and bizarre that he should find it necessary to issue a public apology. If anything the reporter was rude in shouting out a question as he was touring a factory. But then America is an alien country and in alien civilizations they do things that other societies find strange. I remember a BBC documentary which portrayed men from Papua New Guinea walking around wearing nothing but enormous cones affixed to their private members.
On my first visit to the United States I was taken aside by a former mentor and reminded of Churchill's dictum "two countries divided by a common language". In a lift (elevator) he gave me a list of unmentionables. I can only remember one. He told me to say 'eraser' rather than 'rubber', which means something quite different.
However, I got into trouble in my talk by mentioning 'a young girlie of 35', and was harangued by a female in her twenties who seemed to lack both what is demanded of a host towards a guest and an appreciation of cultural differences.
Now I can see how such terms of address can be deliberately offensive. For a black man to be addressed as "Boy" is clearly a retrograde reference, and my wife would not take "Babe" even from me (I think she remember a pig of that name). Feminists were right to take umbrage at being thought of as air-heads, fit for nothing but kitchen and bedroom duties.
That being said I find nothing offensive in Obama's 'Sweetie' and bizarre that he should find it necessary to issue a public apology. If anything the reporter was rude in shouting out a question as he was touring a factory. But then America is an alien country and in alien civilizations they do things that other societies find strange. I remember a BBC documentary which portrayed men from Papua New Guinea walking around wearing nothing but enormous cones affixed to their private members.
On my first visit to the United States I was taken aside by a former mentor and reminded of Churchill's dictum "two countries divided by a common language". In a lift (elevator) he gave me a list of unmentionables. I can only remember one. He told me to say 'eraser' rather than 'rubber', which means something quite different.
However, I got into trouble in my talk by mentioning 'a young girlie of 35', and was harangued by a female in her twenties who seemed to lack both what is demanded of a host towards a guest and an appreciation of cultural differences.
Friday, May 16, 2008
Immunideficiency 5
Potential remedies for the immunodeficiency
As has already been seen just treating the CLL does not restore immunity and guidelines do not recommend immunodeficiency as a reason for beginning treatment [27].
Intravenous immunoglobulin
The chief means of improving the immune defect has been the use of intravenous immunoglobulin (ivIg) infusions. It should be remembered that immunoglobulin infusions only contain significant amounts of IgG and will not restore deficiencies of other immunoglobulin classes. The use of ivIg in CLL is controversial [27, 28]. Several clinical trials have demonstrated that it reduces the incidence of mild and moderate bacterial infections but none have shown a decrease in mortality. When the need to regularly attend hospital is taken into consideration, there may be no improvement in quality of life. One study estimated that the cost of one quality adjusted life year was $6 million [29]. IvIg only becomes cost effective if it is better targeted [3]. Our own practice is to confine treatment to patients whose serum IgG is less than 300mg/dL who have had at least two bacterial infections in a 12 month period. We recommend a dose of 250 mg/kg given every four weeks. Arrangements are available for patients to self-administer the immunoglobulin infusions at home.
Prophylactic antimicrobial agents
There are no clinical trials of prophylactic antimicrobial agents in CLL [27]. Although the use of cycling antibiotics to prevent infections is very common in patients with recurrent chest infections due to bronchiectasis, or recurrent urinary tract infections, there are no studies of the efficacy or cost effectiveness of this approach in CLL. Nevertheless, some patients with recurrent sinusitis clearly benefit from this sort of approach.
There are similarly no trials or prophylactic antimicrobials in patients with low CD4+ T cells levels following treatment with purine analogues or alemtuzumab [27, 28]. Current practice derives from what has been used in patients with AIDS. Prophylaxis against Pneumocystis jirovecii is normally with cotrimoxazole 960 mg on alternate days continued for a minimum of six months after stopping therapy. Some authorities recommend monitoring the count of CD4+ T cells and continuing the cotrimoxazole until the count is greater than 0.2 x 109/L. For patients who cannot tolerate cotrimoxazole, penatmidine 300mg by inhalation every four weeks is available. Alternatives are dapsone 100 mg daily or Atovaquone 750 mg twice daily, though this is an unlicensed indication in the UK.
In patients with a history of herpes simplex or herpes zoster prophylaxis with aciclovir should certainly be given following treatment with either fludarabine or alemtuzumab [27, 28]. The dose that should be used has not been established; between 400 mg and 1600 mg per day have been variously recommended on the basis of experience with AIDS patients or those undergoing stem cell transplantation. Again treatment usually continues for six months after treatment stops,though some would advocate monitoring the count of CD4+ T cells. In patients who receive treatment with alemtuzumab, though not in those receiving purine analogues, monitoring for CMV reactivation should be undertaken weekly. Evidence of reactivation should be treated with either ganciclovir 5 mg/kg iv twice daily or oral valganciclovir 900mg twice daily.
Antifungal prophylaxis is also indicated in patients receiving either purine analogue or alemtuzumab treatment. The choice of agent should be between itraconazole, voriconazole, posaconazole and caspofungin.
References
27. Oscier D, Fegan C, Hillmen P et al. Guidelines on the diagnosis and management of chronic lymphocytic leukemia. Br J Haematol 2004; 125:294-317
28. Morrison VA. Management of infectious complications in patients with chronic lymphocytic leukemia. Hematology Am Soc Hematol Educ Program. 2007; 2007:332-8.
29. Weeks JC, Tierney MR, Weinstein MC. Cost effectiveness of prophylactic intravenous immune globulin in chronic lymphocytic leukemia. New Engl J Med 1991; 325:81-6.
As has already been seen just treating the CLL does not restore immunity and guidelines do not recommend immunodeficiency as a reason for beginning treatment [27].
Intravenous immunoglobulin
The chief means of improving the immune defect has been the use of intravenous immunoglobulin (ivIg) infusions. It should be remembered that immunoglobulin infusions only contain significant amounts of IgG and will not restore deficiencies of other immunoglobulin classes. The use of ivIg in CLL is controversial [27, 28]. Several clinical trials have demonstrated that it reduces the incidence of mild and moderate bacterial infections but none have shown a decrease in mortality. When the need to regularly attend hospital is taken into consideration, there may be no improvement in quality of life. One study estimated that the cost of one quality adjusted life year was $6 million [29]. IvIg only becomes cost effective if it is better targeted [3]. Our own practice is to confine treatment to patients whose serum IgG is less than 300mg/dL who have had at least two bacterial infections in a 12 month period. We recommend a dose of 250 mg/kg given every four weeks. Arrangements are available for patients to self-administer the immunoglobulin infusions at home.
Prophylactic antimicrobial agents
There are no clinical trials of prophylactic antimicrobial agents in CLL [27]. Although the use of cycling antibiotics to prevent infections is very common in patients with recurrent chest infections due to bronchiectasis, or recurrent urinary tract infections, there are no studies of the efficacy or cost effectiveness of this approach in CLL. Nevertheless, some patients with recurrent sinusitis clearly benefit from this sort of approach.
There are similarly no trials or prophylactic antimicrobials in patients with low CD4+ T cells levels following treatment with purine analogues or alemtuzumab [27, 28]. Current practice derives from what has been used in patients with AIDS. Prophylaxis against Pneumocystis jirovecii is normally with cotrimoxazole 960 mg on alternate days continued for a minimum of six months after stopping therapy. Some authorities recommend monitoring the count of CD4+ T cells and continuing the cotrimoxazole until the count is greater than 0.2 x 109/L. For patients who cannot tolerate cotrimoxazole, penatmidine 300mg by inhalation every four weeks is available. Alternatives are dapsone 100 mg daily or Atovaquone 750 mg twice daily, though this is an unlicensed indication in the UK.
In patients with a history of herpes simplex or herpes zoster prophylaxis with aciclovir should certainly be given following treatment with either fludarabine or alemtuzumab [27, 28]. The dose that should be used has not been established; between 400 mg and 1600 mg per day have been variously recommended on the basis of experience with AIDS patients or those undergoing stem cell transplantation. Again treatment usually continues for six months after treatment stops,though some would advocate monitoring the count of CD4+ T cells. In patients who receive treatment with alemtuzumab, though not in those receiving purine analogues, monitoring for CMV reactivation should be undertaken weekly. Evidence of reactivation should be treated with either ganciclovir 5 mg/kg iv twice daily or oral valganciclovir 900mg twice daily.
Antifungal prophylaxis is also indicated in patients receiving either purine analogue or alemtuzumab treatment. The choice of agent should be between itraconazole, voriconazole, posaconazole and caspofungin.
References
27. Oscier D, Fegan C, Hillmen P et al. Guidelines on the diagnosis and management of chronic lymphocytic leukemia. Br J Haematol 2004; 125:294-317
28. Morrison VA. Management of infectious complications in patients with chronic lymphocytic leukemia. Hematology Am Soc Hematol Educ Program. 2007; 2007:332-8.
29. Weeks JC, Tierney MR, Weinstein MC. Cost effectiveness of prophylactic intravenous immune globulin in chronic lymphocytic leukemia. New Engl J Med 1991; 325:81-6.
Wednesday, May 14, 2008
Immunodeficiency 4
It should be noted that stimulation of the T-cell receptor without interaction between CD28 and CD80/CD86 leads to T cell anergy [4]
CTLA-4 is also present on a subpopulation of regulatory T cells that suppress antigen-specific T-cell immune responses. These naturally occurring cells play a central role in the maintenance of peripheral tolerance by suppressing autoreactive T-cell populations. Apart from CTLA-4, regulatory T cells are characterised by the expression of CD4 and CD25 together with Forkhead box P3 (FOXP3), CD62L, glucocorticoid-induced tumour necrosis factor-related protein (GITR), transforming growth factor 1 (TGF-1) and interleukin-10 (IL-10) [18].
In CLL dendritic cells may be derived from peripheral blood monocytes that are phenotypically and functionally normal [19], however the CLL cells themselves are poor APCs [4]. It seems more likely that the immunodeficiency stems from the interaction between B cells and T cells.
The peripheral lymphoid organs host the proliferative core of CLL. The chemokine stromal derived factor 1 (SDF-1) or CXCL12 recruits CLL cells towards the secondary lymphoid organs via their specific CXCR4 receptor [20]. Within the secondary lymphoid organs they form proliferation centres or pseudofollicles. These are indeed parodies of lymphoid follicles in which the CLL cells are able to subvert the normal helper function to their own use while denying it to normal B cells. T cells expressing CD154 interact with CLL B cells through their CD40 receptor activating them and upregulating CD38 and ZAP-70 [20, 21]. The effect on CLL cells of this interaction in the proliferation centre is to increase proliferation rate [22] (though it remains less than that of normal B cells in normal individuals) but also to induce cell cycle arrest and resistance to apoptosis [23].
However, the T cells do not come through the encounter unscathed. It is important to separate the effects of low grade reactivation of herpes viruses on T cells from the effects of their interaction with the tumour cells, but it seems clear that this interaction induces a state of relative T-cell anergy with poor responses in mixed lymphocyte reactions, poor delayed hypersensitivity reactions, Th2 polarisation and reduced expression of CD154. How this comes about is a matter of dispute, but CLL cells express a wide variety of cytokines including interleukins -1 alpha, -2, -4, -5, -6, -8 and -10; interferons -alpha and -gamma; G-CSF and GM-CSF; TNFalpha and TGF-beta. A good case has been made recently for interleukin-6 being responsible for many of the effects [24].
Regulatory T cells are increased in number in CLL and the increase is greatest in patients with the most advanced disease [18]. It is not clear whether this contributes to the immune deficiency, but what is most noticeable is that this population is exquisitely sensitive to treatment with fludarabine as opposed to treatment with alkylating agents. It has been suggested that this might be one of the mechanisms that favours the development of autoimmune haemolytic anaemia after treatment with fludarabine [12].
The suppression of T cells generally by fludarabine is so profound and persistent [25] that it overwhelms the immunodeficiency of the disease itself. Although there were early suggestions that achieving a complete remission might restore the integrity of the immune system and while it is certainly true that some patients have fewer infections following complete responses, the general rule is that patients continue to have a severe immunodeficiency after treatment and in many cases they also have more severe infections. The immune suppression following treatment with alemtuzumab is more severe in that reactivation of herpes viruses is more likely, but tends not to be so long lasting. The suppressive effects of corticosteroids have already been mentioned. Other treatments such as alkylating agents, while not so immunosuppressive, tend not to be so effective and do not ameliorate the disease-related immune defect. Although rituximab is a less effective agent in clearing tumour burden, it does appear to significantly increase serum immunoglobulin production [26].
References
18. Beyer M, Kochanek M, Darabi K et al. Reduced frequencies and suppressive function of CD4+ CD25hi regulatory T cells in patients with chronic lymphocytic leukemia after therapy with fludarabine. Blood 2006;106:2018-25.
19. Messmer D, Telusma G, Wasil T et al. Dendritic cells from chronic lymphocytic leukemia patients are normal regardless of Ig V gene mutations status. Mol Med 2004;10:7-12.
20. Deaglio S, Vaisitti T, Aydin S et al. CD38 and ZAP-70 are functionally linked and mark CLL cells with high migratory potential. Blood 2007; 110:4012-21.
21. Patten PEM, Buggins AGS, Richards J et al. CD38 expression in chronic lymphocytic leukemia is regulated by the tumor environment. Blood 2008; 111:5173-81.
22. Messmer BT, Messmer D, Allen SL et al. In vivo measurements document the dynamic cellular kinetics of chronic lymphocytic leukemia B cells. J Clin Invest. 2005;115:755-64.
23. Gricks CS, Zahrieh D, Zauls AJ, et al. Differential regulation of gene expression following CD40 activation of leukemic compared to healthy B cells. Blood. 2004;104:4002-9.
24. Buggins AGS, Patten PEM, Richards J, Thomas NSB, Mufti GJ, Devereux S. Tumor-derived IL-6 may contribute to the immunological defect in CLL. Leukemia 2007 online publication, 1 November; doi:10.1038/sj.leu2405015
25. Boldt DH, Van Hoff DD, Kuhn JG, Hersh M. Effect on human peripheral lymphocytes of the in vivo administration of 9--D-arabinofuranosyl-5'-monophosphate (NSC312887) a new purine antimetabolite. Cancer Res 1984; 44:4661-6.
26. Alexandrescu DT, Wiernik-PH. Serum immunoglobulins as a marker for immune restoration after treatment with high dose rituximab for chronic lymphocytic leukemia. Med Oncol 2008 E-published ahead of print.
CTLA-4 is also present on a subpopulation of regulatory T cells that suppress antigen-specific T-cell immune responses. These naturally occurring cells play a central role in the maintenance of peripheral tolerance by suppressing autoreactive T-cell populations. Apart from CTLA-4, regulatory T cells are characterised by the expression of CD4 and CD25 together with Forkhead box P3 (FOXP3), CD62L, glucocorticoid-induced tumour necrosis factor-related protein (GITR), transforming growth factor 1 (TGF-1) and interleukin-10 (IL-10) [18].
In CLL dendritic cells may be derived from peripheral blood monocytes that are phenotypically and functionally normal [19], however the CLL cells themselves are poor APCs [4]. It seems more likely that the immunodeficiency stems from the interaction between B cells and T cells.
The peripheral lymphoid organs host the proliferative core of CLL. The chemokine stromal derived factor 1 (SDF-1) or CXCL12 recruits CLL cells towards the secondary lymphoid organs via their specific CXCR4 receptor [20]. Within the secondary lymphoid organs they form proliferation centres or pseudofollicles. These are indeed parodies of lymphoid follicles in which the CLL cells are able to subvert the normal helper function to their own use while denying it to normal B cells. T cells expressing CD154 interact with CLL B cells through their CD40 receptor activating them and upregulating CD38 and ZAP-70 [20, 21]. The effect on CLL cells of this interaction in the proliferation centre is to increase proliferation rate [22] (though it remains less than that of normal B cells in normal individuals) but also to induce cell cycle arrest and resistance to apoptosis [23].
However, the T cells do not come through the encounter unscathed. It is important to separate the effects of low grade reactivation of herpes viruses on T cells from the effects of their interaction with the tumour cells, but it seems clear that this interaction induces a state of relative T-cell anergy with poor responses in mixed lymphocyte reactions, poor delayed hypersensitivity reactions, Th2 polarisation and reduced expression of CD154. How this comes about is a matter of dispute, but CLL cells express a wide variety of cytokines including interleukins -1 alpha, -2, -4, -5, -6, -8 and -10; interferons -alpha and -gamma; G-CSF and GM-CSF; TNFalpha and TGF-beta. A good case has been made recently for interleukin-6 being responsible for many of the effects [24].
Regulatory T cells are increased in number in CLL and the increase is greatest in patients with the most advanced disease [18]. It is not clear whether this contributes to the immune deficiency, but what is most noticeable is that this population is exquisitely sensitive to treatment with fludarabine as opposed to treatment with alkylating agents. It has been suggested that this might be one of the mechanisms that favours the development of autoimmune haemolytic anaemia after treatment with fludarabine [12].
The suppression of T cells generally by fludarabine is so profound and persistent [25] that it overwhelms the immunodeficiency of the disease itself. Although there were early suggestions that achieving a complete remission might restore the integrity of the immune system and while it is certainly true that some patients have fewer infections following complete responses, the general rule is that patients continue to have a severe immunodeficiency after treatment and in many cases they also have more severe infections. The immune suppression following treatment with alemtuzumab is more severe in that reactivation of herpes viruses is more likely, but tends not to be so long lasting. The suppressive effects of corticosteroids have already been mentioned. Other treatments such as alkylating agents, while not so immunosuppressive, tend not to be so effective and do not ameliorate the disease-related immune defect. Although rituximab is a less effective agent in clearing tumour burden, it does appear to significantly increase serum immunoglobulin production [26].
References
18. Beyer M, Kochanek M, Darabi K et al. Reduced frequencies and suppressive function of CD4+ CD25hi regulatory T cells in patients with chronic lymphocytic leukemia after therapy with fludarabine. Blood 2006;106:2018-25.
19. Messmer D, Telusma G, Wasil T et al. Dendritic cells from chronic lymphocytic leukemia patients are normal regardless of Ig V gene mutations status. Mol Med 2004;10:7-12.
20. Deaglio S, Vaisitti T, Aydin S et al. CD38 and ZAP-70 are functionally linked and mark CLL cells with high migratory potential. Blood 2007; 110:4012-21.
21. Patten PEM, Buggins AGS, Richards J et al. CD38 expression in chronic lymphocytic leukemia is regulated by the tumor environment. Blood 2008; 111:5173-81.
22. Messmer BT, Messmer D, Allen SL et al. In vivo measurements document the dynamic cellular kinetics of chronic lymphocytic leukemia B cells. J Clin Invest. 2005;115:755-64.
23. Gricks CS, Zahrieh D, Zauls AJ, et al. Differential regulation of gene expression following CD40 activation of leukemic compared to healthy B cells. Blood. 2004;104:4002-9.
24. Buggins AGS, Patten PEM, Richards J, Thomas NSB, Mufti GJ, Devereux S. Tumor-derived IL-6 may contribute to the immunological defect in CLL. Leukemia 2007 online publication, 1 November; doi:10.1038/sj.leu2405015
25. Boldt DH, Van Hoff DD, Kuhn JG, Hersh M. Effect on human peripheral lymphocytes of the in vivo administration of 9--D-arabinofuranosyl-5'-monophosphate (NSC312887) a new purine antimetabolite. Cancer Res 1984; 44:4661-6.
26. Alexandrescu DT, Wiernik-PH. Serum immunoglobulins as a marker for immune restoration after treatment with high dose rituximab for chronic lymphocytic leukemia. Med Oncol 2008 E-published ahead of print.
Tuesday, May 13, 2008
Immunodeficiency in CLL 3
Another prominent and important factor in the suppression of lymphocyte and monocyte function and thus the occurrence of opportunistic infections is the use of corticosteroids. Early trials showed no benefit to their use with alkylating agents, and trials of their addition to purine analogues were halted because of a higher incidence of infection, but they remain the drug of choice in treating the autoimmune complications of CLL. Corticosteroids are also used almost without the knowledge of the physician directing therapy to suppress transfusion reactions and reactions to infusions of rituximab. More recently high dose steroids have found favour in the treatment of bulky and drug resistant disease.
One further piece of evidence of immunodeficiency should be mentioned. It has long been believed that second malignancies are commoner in CLL than in the general population and this has been attributed to a defect of immune surveillance. A recent review [16] goes into painstaking detail of all reported studies. The risk is particularly great for skin cancers and virally induced cancers but less convincing for other tumours. There are difficulties in assembling accurate statistics, since CLL frequently goes unreported or undiagnosed in old people. Patients with cancer are more likely to have blood tests than normal individuals so that asymptomatic CLL is more likely to be diagnosed. Similarly, patients with CLL are more likely to be seen by doctors than individuals without it, and other cancers, especially skin cancers are thus more likely to be diagnosed. Nevertheless, there almost certainly is an increase in some cancers which might be attributed to a defect in cell mediated immunity.
The causes of the immune defect.
The immune defect in CLL is mediated by the presence of the tumour cell in the midst of the lymphoid organs and by the attempts of the physician to remove them. In the normal immune response T-cell activation is involves interactions with antigen presenting cells (APCs) – dendritic cells and B-cells. T-cells encounter antigen as APC-processed peptides requiring cell-cell contact via low affinity interaction between CD11a and CD54 (LFA-1 and ICAM-1) which facilitates antigen recognition between the T-cell receptor/CD3 complex and MHC class II and CD4. This signals the upregulation of certain surface markers and the secretion of certain cytokines. The activation of helper T-cells in an immune response may have a defined polarity depending on what cytokines are produced. Th-1 polarity with secretion of gamma-interferon favours cell mediated immunity; Th-2 polarity with secretion of IL-4 favours antibody production. In a Th-2 response the activated T cells are able to ‘help’ activate normal B cells and induce them to mature and secrete antibody. The upregulated activation marker CD28 interacts with the CD80/CD86 receptors on B cells and the increased expression of CD154 on T cells binds to its ligand CD40 on B cells. The cytokine interleukin-2 (IL-2) is produced, which facilitates proliferation and clonal expansion of T cells. Activation of the T-cell has a built in ‘off switch’. A late activation molecule on the T-cell surface is CTLA-4 (CD152) which on engaging with the CD80/CD86 complex on the B cells inactivates the T-cell response [17].
CTLA-4 is also present on a subpopulation of regulatory T cells that suppress antigen-specific T-cell immune responses. These naturally occurring cells play a central role in the maintenance of peripheral tolerance by suppressing autoreactive T-cell populations.
References
14. Wadhwa P, Morrison VA. Infectious complications of chronic lymphocytic leukemia. Semin Oncol 2006; 33:240-9.
15. Ravandi F, O’Brien S. Immune defects in patients with chronic lymphocytic leukemia. Cancer Immunol Immunother 2006; 55:197-209.
16. Dasanu CA, Alexandrescu DA. Risk of second nonlymphoid neoplasm in chronic lymphocytic leukemia. MedGenMed 2007; 9:35-48.
17. Teft WA, Kirchhof MG, Madrenas J. A molecular perspective of CTLA-4 function. Ann Rev Immunol 2006; 24:65-97.
One further piece of evidence of immunodeficiency should be mentioned. It has long been believed that second malignancies are commoner in CLL than in the general population and this has been attributed to a defect of immune surveillance. A recent review [16] goes into painstaking detail of all reported studies. The risk is particularly great for skin cancers and virally induced cancers but less convincing for other tumours. There are difficulties in assembling accurate statistics, since CLL frequently goes unreported or undiagnosed in old people. Patients with cancer are more likely to have blood tests than normal individuals so that asymptomatic CLL is more likely to be diagnosed. Similarly, patients with CLL are more likely to be seen by doctors than individuals without it, and other cancers, especially skin cancers are thus more likely to be diagnosed. Nevertheless, there almost certainly is an increase in some cancers which might be attributed to a defect in cell mediated immunity.
The causes of the immune defect.
The immune defect in CLL is mediated by the presence of the tumour cell in the midst of the lymphoid organs and by the attempts of the physician to remove them. In the normal immune response T-cell activation is involves interactions with antigen presenting cells (APCs) – dendritic cells and B-cells. T-cells encounter antigen as APC-processed peptides requiring cell-cell contact via low affinity interaction between CD11a and CD54 (LFA-1 and ICAM-1) which facilitates antigen recognition between the T-cell receptor/CD3 complex and MHC class II and CD4. This signals the upregulation of certain surface markers and the secretion of certain cytokines. The activation of helper T-cells in an immune response may have a defined polarity depending on what cytokines are produced. Th-1 polarity with secretion of gamma-interferon favours cell mediated immunity; Th-2 polarity with secretion of IL-4 favours antibody production. In a Th-2 response the activated T cells are able to ‘help’ activate normal B cells and induce them to mature and secrete antibody. The upregulated activation marker CD28 interacts with the CD80/CD86 receptors on B cells and the increased expression of CD154 on T cells binds to its ligand CD40 on B cells. The cytokine interleukin-2 (IL-2) is produced, which facilitates proliferation and clonal expansion of T cells. Activation of the T-cell has a built in ‘off switch’. A late activation molecule on the T-cell surface is CTLA-4 (CD152) which on engaging with the CD80/CD86 complex on the B cells inactivates the T-cell response [17].
CTLA-4 is also present on a subpopulation of regulatory T cells that suppress antigen-specific T-cell immune responses. These naturally occurring cells play a central role in the maintenance of peripheral tolerance by suppressing autoreactive T-cell populations.
References
14. Wadhwa P, Morrison VA. Infectious complications of chronic lymphocytic leukemia. Semin Oncol 2006; 33:240-9.
15. Ravandi F, O’Brien S. Immune defects in patients with chronic lymphocytic leukemia. Cancer Immunol Immunother 2006; 55:197-209.
16. Dasanu CA, Alexandrescu DA. Risk of second nonlymphoid neoplasm in chronic lymphocytic leukemia. MedGenMed 2007; 9:35-48.
17. Teft WA, Kirchhof MG, Madrenas J. A molecular perspective of CTLA-4 function. Ann Rev Immunol 2006; 24:65-97.
Monday, May 12, 2008
SNIPs
The prognostic factors of CLL are well established and include clinical stage, IgVH mutational status, CD38 expression, ZAP-70 expression (when it is done properly and well), and fluorescent in-situ hybridisation (FISH) for detecting deletions at 17p and 11q (recognising loss of either the TP53 or the ATM genes). Although FISH has proved a useful substitute for chromosomal metaphase analysis (which is difficult in CLL and only successful in the very best laboratories), it is limited in its ability to detect every possible chromosomal abnormality or indeed to detect malfunctions of individual genes which might contribute to inflicting a poor prognosis on the patient. To ameliorate this deficiency the Liverpool group have developed a test to examine the function of a particularly vulnerable cellular pathway, malfunction of which leads to drug resistance and poor prognosis [1]. Although variations of this test have been exported to other expert laboratories, it has not yet enjoyed widespread adoption.
Single nucleotide polymorphism (SNP) array analysis has proved to be a sensitive and highly specific method for determining sub-chromosomal copy number losses and gains, and this techniques has been employed by workers at the University of Michigan to perform a genome-wide copy number analysis in an attempt to risk-stratify CLL patients into low- and high-risk cohorts based on their degree of genomic complexity [2]. Using a cut off of three or more genomic losses they found that genomic complexity determined by this method was an independent poor prognostic risk factor both for time to first treatment and time to subsequent treatment.
The importance of this finding is that the test can be automated and will not depend on observer competence. This disadvantage is that at present SNP arrays are very expensive, and currently most patients are not even getting the very much cheaper IgVH gene mutational analysis.
1. Lin K, Sherrington PD, Dennis M, Matrai Z, Cawley JC, Pettitt AR. Relationship between p53 dysfunction, CD38 expression, and IgV(H) mutation in chronic lymphocytic leukemia. Blood. 200215;100:1404-9.
2. Lisa Kujawski, Peter Ouillette, Harry Erba, Chris Saddler, Andrzej Jakubowiak, Mark Kaminski, Kerby Shedden, and Sami N Malek. Genomic complexity identifies patients with aggressive chronic lymphocytic leukemia Blood First Edition Paper, prepublished online April 24, 2008; DOI 10.1182/blood-2007-07-099432
Single nucleotide polymorphism (SNP) array analysis has proved to be a sensitive and highly specific method for determining sub-chromosomal copy number losses and gains, and this techniques has been employed by workers at the University of Michigan to perform a genome-wide copy number analysis in an attempt to risk-stratify CLL patients into low- and high-risk cohorts based on their degree of genomic complexity [2]. Using a cut off of three or more genomic losses they found that genomic complexity determined by this method was an independent poor prognostic risk factor both for time to first treatment and time to subsequent treatment.
The importance of this finding is that the test can be automated and will not depend on observer competence. This disadvantage is that at present SNP arrays are very expensive, and currently most patients are not even getting the very much cheaper IgVH gene mutational analysis.
1. Lin K, Sherrington PD, Dennis M, Matrai Z, Cawley JC, Pettitt AR. Relationship between p53 dysfunction, CD38 expression, and IgV(H) mutation in chronic lymphocytic leukemia. Blood. 200215;100:1404-9.
2. Lisa Kujawski, Peter Ouillette, Harry Erba, Chris Saddler, Andrzej Jakubowiak, Mark Kaminski, Kerby Shedden, and Sami N Malek. Genomic complexity identifies patients with aggressive chronic lymphocytic leukemia Blood First Edition Paper, prepublished online April 24, 2008; DOI 10.1182/blood-2007-07-099432
Sunday, May 11, 2008
Psalm 125.
I saw Tony Curtis on television last week. Bald and bloated yet still flirtatious, he was a gross parody of the young man I first saw in 'Trapeze'. The story of Trapeze concerned a young man who wanted to perform a triple somersault on the Trapeze, who seeks out a 'catcher' to teach him, who was himself crippled by his own attempt at a triple. His progress is delayed by a love triangle to accomodate Gina Lollobrigida, but the triple is finally attempted and achieved in the last act, when to heighten the tension, Bouglione, the circus owner, removes the safety net.
For Christians Psalm 125 answers the question, "Is there a safety net?" or to put it another way, "Can I lose my salvation?"
Those who trust in the LORD are like Mount Zion, which cannot be shaken and endures for ever. The word translated 'shaken' in the NIV, elsewhere is translated 'totter' or 'fall'. Now my faith sometimes falters and if it depended on me to cling on to my hope of heaven I would surely fail. I might hang on a month or even a few years, but 'for ever'? No way.
But it does not depend on me. Like the mountains surrounding Jerusalem so the LORD surrounds his people. This is not the final perseverence of the saints; it is the final preservation of the saints. We are protected by God's presence (v2), his power, (v3) and God's promis (vv4-5).
For Christians Psalm 125 answers the question, "Is there a safety net?" or to put it another way, "Can I lose my salvation?"
Those who trust in the LORD are like Mount Zion, which cannot be shaken and endures for ever. The word translated 'shaken' in the NIV, elsewhere is translated 'totter' or 'fall'. Now my faith sometimes falters and if it depended on me to cling on to my hope of heaven I would surely fail. I might hang on a month or even a few years, but 'for ever'? No way.
But it does not depend on me. Like the mountains surrounding Jerusalem so the LORD surrounds his people. This is not the final perseverence of the saints; it is the final preservation of the saints. We are protected by God's presence (v2), his power, (v3) and God's promis (vv4-5).
Friday, May 09, 2008
Immunodeficiency in CLL 2
In most patients with CLL T cell numbers are increased. This increase mainly affects CD8+ cells, but CD4+ cells are also increased, though the CD4/CD8 ratio is reversed [16]. Analysis of the expanded CD8+ cell population demonstrates that they are also positive for CD45RA and CD57, and negative for CD27 [16, 17] indicating that they have a cytotoxic function. Moreover, both CD4+ and CD8+ T cells appear to have restricted clonality when examined for T-cell receptor V gene usage and length of the CDR3 [16, 18-21], and display an activated phenotype with upregulation of CD69, VD16, CD56, CD71 and HLA-DR with loss of CD62L and CD28 [22]. These finding was originally interpreted as evidence that there is an autologous T-cell response against the tumour [23], but convincing evidence of such a response is still lacking [17, 22].
A T cell lymphocytosis with a similar marker profile is seen during viral infections, and in patients latently infected with CMV, increased senescence of the immune system with age is associated not with a falling away of CMV-reactive T cells, but with a marked increase of such cells, which tend to be oligoclonal and have the same immunophenotype as those seen in CLL [24, 25]. In elderly individuals CMV-specific cytotoxic T cells may comprise more than half the CD8+ repertoire [25] and the figure is similar in CLL [17]. Indeed in patients with CLL who are seronegative for CMV there is no increase in T cell numbers and the CD4/CD8 ration is not reversed [17].
There are other changes in T cell function, many of which will be explored with the discussion of interactions between the CLL cells and the host T cells, but it seems clear that many of the changes observed in the T cells population in CLL are a consequence of the immune system having to ‘work harder’ to control latent herpes virus infections, especially CMV.
It has not escaped the notice of investigators that the anti-CMV response might be harnessed and redirected to attack the CLL itself [26].
Apart from viruses, some patients are susceptible to other opportunistic infections in the same way as other haematological patients treated with cytotoxic drugs. Infections with Listeria, Nocardia, Candida, Aspergillus, Pneumocystis, Histoplasmosis, Cryptococcus and atypical mycobacteria, seldom occur in untreated patients and in my estimation represent a failure of effector function in the immune system. Neutropenia may be a consequence of any cytotoxic therapy, though it is usually short-lived. Autoimmune neutropenia is exceedingly rare [27], but patients with stage C disease frequently have severe and prolonged neutropenia to accompany their anaemia and thrombocytopenia. Because the often very high lymphocyte counts in such patients interfere with automatic differential counting, the neutropenia is often not observed. Prolonged neutropenia also occurs sometimes after treatment with fludarabine based regimens. The reason for this is not clear, although unexpected cases of secondary myelodysplastic syndrome following treatment with purine analogue and alkylating agent combinations are being reported [28, 29].
Early papers identified defects in phagocytic function and cytotoxic activity of neutrophils, monocytes and NK cells [30, 31]. Although early authors were seeking to establish a common lineage between the CLL cells and other blood elements, just as exists for chronic myeloid leukaemia, the fact that features like deficient levels of -glucuronidase, myeloperoxidase and lysozyme in neutrophils and monocytes were corrected after treatment removed most of the CLL cells [30] from the circulation strongly suggests that the tumour cells affect effector cell function either by their secretions or cellular contact. NK cells function is similarly restored by removal of the CLL cells [32] and indeed it has been shown that treatment with fludarabine spares NK cells and may actually enhance their activity [33]. More recent papers have identified defects in the production of pro-inflammatory cytokines by CLL monocytes [34] and of chemotaxis, but not phagocytosis or intracellular killing in CLL granulocytes [35].
Early studies suggested that deficiency of the complement components C1 and C4 was a regular occurrence in CLL [36]. Although this has not always been confirmed [37] there is undoubtedly an abnormality of complement function in many patients, resulting in an inability to coat bacteria with C3b, and perhaps most frequently involving the alternative pathway {37, 38].
References
16. Serrano D, Monteiro J, Allen SL, Kolitz J, Schulman P, Lichtman SM, Buchbinder A, Vinciguerra VP, Chiorazzi N, Gregersen PK. Clonal expansion within the CD4+CD57+ and CD8+CD57+ T cell subsets in chronic lymphocytic leukemia. J Immunol. 1997;158:1482-9.
17. Mackus WJ, Frakking FN, Grummels A, Gamadia LE, De Bree GJ, Hamann D, Van Lier RA, Van Oers MH. Expansion of CMV-specific CD8+CD45RA+CD27- T cells in B-cell chronic lymphocytic leukemia. Blood. 2003;102:1057-63.
18. Goolsby CL, Kuchnio M, Finn WG, Peterson L. Expansions of clonal and oligoclonal T cells in B-cell chronic lymphocytic leukemia are primarily restricted to the CD3(+)CD8(+) T-cell population. Cytometry. 2000;42:188-95.
19. Farace F, Orlanducci F, Dietrich PY, Gaudin C, Angevin E, Courtier MH, Bayle C, Hercend T, Triebel F. T cell repertoire in patients with B chronic lymphocytic leukemia. Evidence for multiple in vivo T cell clonal expansions. J Immunol. 1994;153:4281-90.
20. Rezvany MR, Jeddi-Tehrani M, Osterborg A, Kimby E, Wigzell H, Mellstedt H. Oligoclonal TCRBV gene usage in B-cell chronic lymphocytic leukemia: major perturbations are preferentially seen within the CD4 T-cell subset. Blood. 1999;94:1063-9.
21. Wen T, Mellstedt H, Jondal M. Presence of clonal T cell populations in chronic B lymphocytic leukemia and smoldering myeloma. J Exp Med. 1990;171:659-66.
22. Van den Hove LE, Vandenberghe P, Van Gool SW, Ceuppens JL, Demuynck H, Verhoef GE, Boogaerts MA. Peripheral blood lymphocyte subset shifts in patients with untreated hematological tumors: evidence for systemic activation of the T cell compartment. Leuk Res. 1998;22:175-84.
23. Rezvany MR, Jeddi-Tehrani M, Rabbani H, Rudén U, Hammarström L, Osterborg A, Wigzell H, Mellstedt H. Autologous T lymphocytes recognize the tumour-derived immunoglobulin VH-CDR3 region in patients with B-cell chronic lymphocytic leukaemia. Br J Haematol. 2000;111:230-8.
24. Khan N, Shariff N, Cobbold M, Bruton R, Ainsworth JA, Sinclair AJ, Nayak L, Moss PA. Cytomegalovirus seropositivity drives the CD8 T cell repertoire toward greater clonality in healthy elderly individuals. J. Immunol. 2002;169:1984-1992.
25. Pourgheysari B, Khan N, Best D, Bruton R, Nayak L, Moss PA. The cytomegalovirus-specific CD4+ T-cell response expands with age and markedly alters the CD4+ T-cell repertoire. J Virol. 2007;81:7759-65.
26. Mous R, Savage P, Remmerswaal EB, van Lier RA, Eldering E, van Oers MH.Redirection of CMV-specific CTL towards B-CLL via CD20-targeted HLA/CMV complexes. Leukemia. 2006;20:1096-102.
27. Hamblin TJ. Autoimmune complications of chronic lymphocytic leukemia. Semin Oncol. 2006;33:230-9.
28. Tam CS, Seymour JF, Prince HM, Kenealy M, Wolf M, Januszewicz EH, Westerman D. Treatment-related myelodysplasia following fludarabine combination chemotherapy. Haematologica. 2006;91:1546-50.
29. Morrison VA, Rai KR, Peterson BL, Kolitz JE, Elias L, Appelbaum FR, Hines JD, Shepherd L, Larson RA, Schiffer CA. Therapy-related myeloid leukemias are observed in patients with chronic lymphocytic leukemia after treatment with fludarabine and chlorambucil: results of an intergroup study, cancer and leukemia group B 9011. J Clin Oncol. 2002;20:3878-84.
30. Zeya HI, Keku E, Richards F 2nd, Spurr CL. Monocyte and granulocyte defect in chronic lymphocytic leukemia. Am J Pathol. 1979;95:43-53.
31. Ziegler HW, Kay NE, Zarling JM. Deficiency of natural killer cell activity in patients with chronic lymphocytic leukemia. Int J Cancer. 1981;27:321-7.
32. Burton JD, Weitz CH, Kay NE. Malignant chronic lymphocytic leukemia B cells elaborate soluble factors that down-regulate T cell and NK function. Am J Hematol. 1989;30:61-7.
33. Robertson LE, Denny AW, Huh YO, Plunkett W, Keating MJ, Nelson JA. Natural killer cell activity in chronic lymphocytic leukemia patients treated with fludarabine. Cancer Chemother Pharmacol. 1996;37:445-50.
34. Anand M, Chodda SK, Parikh PM, Nadkarni JS. Dysregulated cytokine production by monocytes from chronic lymphocytic leukemia patients. Cancer Biother Radiopharm. 1998;13:43-8.
35. Itälä M, Vainio O, Remes K. Functional abnormalities in granulocytes predict susceptibility to bacterial infections in chronic lymphocytic leukaemia. Eur J Haematol. 1996;57:46-53.
36. Füst G, Czink E, Minh D, Miszlay Z, Varga L, Hollán SR. Depressed classical complement pathway activities in chronic lymphocytic leukaemia. Clin Exp Immunol. 1985;60:489-95.
37. Heath ME, Cheson BD. Defective complement activity in chronic lymphocytic leukemia. Am J Hematol. 1985;19:63-73.
38. Schlesinger M, Broman I, Lugassy G.The complement system is defective in chronic lymphatic leukemia patients and in their healthy relatives. Leukemia. 1996;10:1509-13.
A T cell lymphocytosis with a similar marker profile is seen during viral infections, and in patients latently infected with CMV, increased senescence of the immune system with age is associated not with a falling away of CMV-reactive T cells, but with a marked increase of such cells, which tend to be oligoclonal and have the same immunophenotype as those seen in CLL [24, 25]. In elderly individuals CMV-specific cytotoxic T cells may comprise more than half the CD8+ repertoire [25] and the figure is similar in CLL [17]. Indeed in patients with CLL who are seronegative for CMV there is no increase in T cell numbers and the CD4/CD8 ration is not reversed [17].
There are other changes in T cell function, many of which will be explored with the discussion of interactions between the CLL cells and the host T cells, but it seems clear that many of the changes observed in the T cells population in CLL are a consequence of the immune system having to ‘work harder’ to control latent herpes virus infections, especially CMV.
It has not escaped the notice of investigators that the anti-CMV response might be harnessed and redirected to attack the CLL itself [26].
Apart from viruses, some patients are susceptible to other opportunistic infections in the same way as other haematological patients treated with cytotoxic drugs. Infections with Listeria, Nocardia, Candida, Aspergillus, Pneumocystis, Histoplasmosis, Cryptococcus and atypical mycobacteria, seldom occur in untreated patients and in my estimation represent a failure of effector function in the immune system. Neutropenia may be a consequence of any cytotoxic therapy, though it is usually short-lived. Autoimmune neutropenia is exceedingly rare [27], but patients with stage C disease frequently have severe and prolonged neutropenia to accompany their anaemia and thrombocytopenia. Because the often very high lymphocyte counts in such patients interfere with automatic differential counting, the neutropenia is often not observed. Prolonged neutropenia also occurs sometimes after treatment with fludarabine based regimens. The reason for this is not clear, although unexpected cases of secondary myelodysplastic syndrome following treatment with purine analogue and alkylating agent combinations are being reported [28, 29].
Early papers identified defects in phagocytic function and cytotoxic activity of neutrophils, monocytes and NK cells [30, 31]. Although early authors were seeking to establish a common lineage between the CLL cells and other blood elements, just as exists for chronic myeloid leukaemia, the fact that features like deficient levels of -glucuronidase, myeloperoxidase and lysozyme in neutrophils and monocytes were corrected after treatment removed most of the CLL cells [30] from the circulation strongly suggests that the tumour cells affect effector cell function either by their secretions or cellular contact. NK cells function is similarly restored by removal of the CLL cells [32] and indeed it has been shown that treatment with fludarabine spares NK cells and may actually enhance their activity [33]. More recent papers have identified defects in the production of pro-inflammatory cytokines by CLL monocytes [34] and of chemotaxis, but not phagocytosis or intracellular killing in CLL granulocytes [35].
Early studies suggested that deficiency of the complement components C1 and C4 was a regular occurrence in CLL [36]. Although this has not always been confirmed [37] there is undoubtedly an abnormality of complement function in many patients, resulting in an inability to coat bacteria with C3b, and perhaps most frequently involving the alternative pathway {37, 38].
References
16. Serrano D, Monteiro J, Allen SL, Kolitz J, Schulman P, Lichtman SM, Buchbinder A, Vinciguerra VP, Chiorazzi N, Gregersen PK. Clonal expansion within the CD4+CD57+ and CD8+CD57+ T cell subsets in chronic lymphocytic leukemia. J Immunol. 1997;158:1482-9.
17. Mackus WJ, Frakking FN, Grummels A, Gamadia LE, De Bree GJ, Hamann D, Van Lier RA, Van Oers MH. Expansion of CMV-specific CD8+CD45RA+CD27- T cells in B-cell chronic lymphocytic leukemia. Blood. 2003;102:1057-63.
18. Goolsby CL, Kuchnio M, Finn WG, Peterson L. Expansions of clonal and oligoclonal T cells in B-cell chronic lymphocytic leukemia are primarily restricted to the CD3(+)CD8(+) T-cell population. Cytometry. 2000;42:188-95.
19. Farace F, Orlanducci F, Dietrich PY, Gaudin C, Angevin E, Courtier MH, Bayle C, Hercend T, Triebel F. T cell repertoire in patients with B chronic lymphocytic leukemia. Evidence for multiple in vivo T cell clonal expansions. J Immunol. 1994;153:4281-90.
20. Rezvany MR, Jeddi-Tehrani M, Osterborg A, Kimby E, Wigzell H, Mellstedt H. Oligoclonal TCRBV gene usage in B-cell chronic lymphocytic leukemia: major perturbations are preferentially seen within the CD4 T-cell subset. Blood. 1999;94:1063-9.
21. Wen T, Mellstedt H, Jondal M. Presence of clonal T cell populations in chronic B lymphocytic leukemia and smoldering myeloma. J Exp Med. 1990;171:659-66.
22. Van den Hove LE, Vandenberghe P, Van Gool SW, Ceuppens JL, Demuynck H, Verhoef GE, Boogaerts MA. Peripheral blood lymphocyte subset shifts in patients with untreated hematological tumors: evidence for systemic activation of the T cell compartment. Leuk Res. 1998;22:175-84.
23. Rezvany MR, Jeddi-Tehrani M, Rabbani H, Rudén U, Hammarström L, Osterborg A, Wigzell H, Mellstedt H. Autologous T lymphocytes recognize the tumour-derived immunoglobulin VH-CDR3 region in patients with B-cell chronic lymphocytic leukaemia. Br J Haematol. 2000;111:230-8.
24. Khan N, Shariff N, Cobbold M, Bruton R, Ainsworth JA, Sinclair AJ, Nayak L, Moss PA. Cytomegalovirus seropositivity drives the CD8 T cell repertoire toward greater clonality in healthy elderly individuals. J. Immunol. 2002;169:1984-1992.
25. Pourgheysari B, Khan N, Best D, Bruton R, Nayak L, Moss PA. The cytomegalovirus-specific CD4+ T-cell response expands with age and markedly alters the CD4+ T-cell repertoire. J Virol. 2007;81:7759-65.
26. Mous R, Savage P, Remmerswaal EB, van Lier RA, Eldering E, van Oers MH.Redirection of CMV-specific CTL towards B-CLL via CD20-targeted HLA/CMV complexes. Leukemia. 2006;20:1096-102.
27. Hamblin TJ. Autoimmune complications of chronic lymphocytic leukemia. Semin Oncol. 2006;33:230-9.
28. Tam CS, Seymour JF, Prince HM, Kenealy M, Wolf M, Januszewicz EH, Westerman D. Treatment-related myelodysplasia following fludarabine combination chemotherapy. Haematologica. 2006;91:1546-50.
29. Morrison VA, Rai KR, Peterson BL, Kolitz JE, Elias L, Appelbaum FR, Hines JD, Shepherd L, Larson RA, Schiffer CA. Therapy-related myeloid leukemias are observed in patients with chronic lymphocytic leukemia after treatment with fludarabine and chlorambucil: results of an intergroup study, cancer and leukemia group B 9011. J Clin Oncol. 2002;20:3878-84.
30. Zeya HI, Keku E, Richards F 2nd, Spurr CL. Monocyte and granulocyte defect in chronic lymphocytic leukemia. Am J Pathol. 1979;95:43-53.
31. Ziegler HW, Kay NE, Zarling JM. Deficiency of natural killer cell activity in patients with chronic lymphocytic leukemia. Int J Cancer. 1981;27:321-7.
32. Burton JD, Weitz CH, Kay NE. Malignant chronic lymphocytic leukemia B cells elaborate soluble factors that down-regulate T cell and NK function. Am J Hematol. 1989;30:61-7.
33. Robertson LE, Denny AW, Huh YO, Plunkett W, Keating MJ, Nelson JA. Natural killer cell activity in chronic lymphocytic leukemia patients treated with fludarabine. Cancer Chemother Pharmacol. 1996;37:445-50.
34. Anand M, Chodda SK, Parikh PM, Nadkarni JS. Dysregulated cytokine production by monocytes from chronic lymphocytic leukemia patients. Cancer Biother Radiopharm. 1998;13:43-8.
35. Itälä M, Vainio O, Remes K. Functional abnormalities in granulocytes predict susceptibility to bacterial infections in chronic lymphocytic leukaemia. Eur J Haematol. 1996;57:46-53.
36. Füst G, Czink E, Minh D, Miszlay Z, Varga L, Hollán SR. Depressed classical complement pathway activities in chronic lymphocytic leukaemia. Clin Exp Immunol. 1985;60:489-95.
37. Heath ME, Cheson BD. Defective complement activity in chronic lymphocytic leukemia. Am J Hematol. 1985;19:63-73.
38. Schlesinger M, Broman I, Lugassy G.The complement system is defective in chronic lymphatic leukemia patients and in their healthy relatives. Leukemia. 1996;10:1509-13.
Thursday, May 08, 2008
The immunodeficiency of CLL
Introduction
Patients with chronic lymphocytic leukaemia (CLL) are all to a degree immunodeficient. The most obvious and well-known abnormality is hypogammaglobulinaemia which is present in up to 85% of patients [1]. Serum immunoglobulin levels are suppressed in other lymphoid malignancies but in CLL the suppression is to a far greater degree. Profound defects of cell mediated immunity also occur though these are most obvious in patients who have been treated with purine analogues. However, even untreated patients have defects of T cell numbers and function. This review will seek to explore the extent of the immune defect in CLL, its causes, clinical significance and possible remedies.
The extent of the immune defect
Infections are the major cause of death in between a quarter and a half of patients with CLL [1]. Bacterial infection of the respiratory tract, skin or urinary tract is the commonest problem and before the use of purine analogues for treatment, the usual organisms were Streptococcus pneumoniae, Staphylococcus aureus, Streptococcus pyogenes and Escherichia coli. Protection against these organisms is provided principally by antibody, but only 15% of patients with CLL have completely normal serum immunoglobulins [1]. It is likely that the only patients with CLL who do not have hypogammaglobulinaemia are those in whom it will occur in the future.
The extent of hypogammaglobulinaemia depends on the stage and duration of the disease. Older papers described serum IgA as the first immunoglobulin to be reduced followed by IgM and IgG [2], but this is by no means invariable and most patients have depression of all classes of immunoglobulin. It should be stressed that the hypogammaglobulinaemia is not confined to patients who have been treated. In one study of an untreated patient with stage B disease without a detectable paraprotein, the hypogammaglobulinaemia was so profound that over 90% of the detectable immunoglobulin in the serum was idiotypic, and thus derived from the tumour [3].
Despite the low levels of serum immunoglobulins, most patients suffer no clinical consequences from this, and in one study 65% of bacterial infections occurred with serum IgG levels below 300 mg/dL [4]. It is recommended that patients with primary immunodeficiency begin immunoglobulin replacement therapy when the serum IgG falls below this level.
The non-malignant B-cell population in CLL is not well characterized [5]. The proportion and overall number of non-malignant B cells is often significantly reduced, and clearly their function is impaired since the normal immunoglobulins are suppressed. What is not clear is whether they are directly suppressed by the tumour or indirectly as a consequence of inhibitory effects elsewhere in the immune response.
Apart from bacterial infections, patients with CLL also suffer from the reactivation of herpes viruses. Most commonly this involves herpes zoster. In one series from before the era of treatment with purine analogue, the incidence of herpes zoster was given as 28.6%, with 3.5% having recurrent attacks [1]. Particularly important is the observation that attacks of shingles frequently precede the clinical diagnosis of CLL [1], suggesting that the underlying immune defect does not depend on either hypogammaglobulinaemia or the physical overwhelming of immune organs by infiltrating tumour cells.
Recurrent attacks of herpes simplex also occur in some untreated patients. Both HSV1 and HSV2 may be involved. The recent recognition that herpes simplex is implicated in many cases of Bell’s palsy [6] may explain the association of Bell’s palsy, including recurrent attacks, in patients with CLL [1].
Treatment greatly increases the risk of the reactivation of herpes viruses. Reactivation of cytomegalovirus (CMV) is of course particularly associated with treatment with alemtuzumab, symptomatic infections occurring in 15% of patients treated in one clinical trial and asymptomatic reactivation in more than half (7], but symptomatic reactivation may occur after treatment with fludarabine (D Oscier, personal communication) and asymptomatic reactivation even after treatment with chlorambucil [7].
The Epstein-Bar virus (EBV) has recently been associated with the increase in the incidence of Richter’s syndrome in patients who have been treated with fludarabine [8]
Human herpes virus 8 (HHV8) is the cause of Kaposi’s sarcoma in immunodeficient individuals. The first reported case in CLL occurred in an untreated patient [9] and the second in a patient treated with fludarabine [10]. An American SEER report noted 9 cases between 1973 and 1996 among 16,367 patients observed, a statistically significant hazard ration of 5.09 [11].
Human herpes virus 6 causes the childhood exanthem, roseola, but in adults has it has been suggested as an initiating agent in chronic fatigue syndrome and multiple sclerosis [12, 13]. Fatigue is a common symptom in CLL often dismissed by physicians yet much discussed on patient websites. Multiple sclerosis has been reported as occasionally coexisting with CLL [1]. HHV6 has also been associated with giant cell hepatitis in adults [14] and I have recently been consulted by a patient with CLL and obscure giant cell hepatitis.
A systematic study of herpes viral copy number in haematological diseases has been carried out using real-time quantitative polymerase chain reaction (RQ-PCR). Occasional patients with CLL had high copy numbers of EBV, CMV and HHV6A, but not HHV6b, HHV7 and HHV8 [15]. Although interesting, the use of leukaemic B cells as a source of DNA means that T-cell lymphotropic viruses would be missed, and no indication was given as to the stage of the patients or the degree of immunosuppression.
References
1. Hamblin TJ. Chronic lymphocytic leukaemia. Balliere's Clinical Haematology 1987; 1: 449 491.
2. Foa R, Catovsky D, Brozovic M, Ooyirilangkumaran T, Cherchi M, Galton DAG. Clinical staging and immunological findings in chronic lymphocytic leukaemia. Cancer 1979; 44:483-487.
3. Stevenson FK, Hamblin TJ, Stevenson GT, Tutt Al. Extracellular idiotypic immunoglobulin arising from human leukemic B lymphocytes. J Exp Med 1980; 152:1484-1496.
4. Boughton BJ, Jackson N, Lim S, Smith N. Randomized trial of intravenous immunoglobulin prophylaxis for patients with chronic lymphocytic leukaemia and secondary hypogammaglobulinaemia. Clin Lab Haematol 1995; 17:75-80.
5. Johnston PB, Kay NE. Pathogenesis of impaired cellular immune function in CLL. In Chronic Lymphocytic Leukemia: Molecular Genetics, Biology, Diagnosis and Management. Ed GB Faguet. Humana Press: Totowa, New Jersey. 2004. p 109-121.
6. Steiner I, Mattan Y, Bell's palsy and herpes viruses: to (acyclo)vir or not to (acyclo)vir? J Neurol Sci. 1999;170:19-23.
7. Hillmen P, Skotnicki AB, Robak T, Jaksic B, Dmoszynska A, Wu J, Sirard C, Mayer J. Alemtuzumab compared with chlorambucil as first-line therapy for chronic lymphocytic leukemia. J Clin Oncol. 2007;25:5616-23
8. Thornton PD, bellas C, Santon A. Shah G, Pocock C, Wotherspoon AC, matutes E, Catovsky D. Richter’s transformation of chronic lymphocytic leukemia. The possible role of fludarabine and Epstein-Barr virus in its pathogenesis. Leuk Res 2005; 29:389-95.
9. Contu L, Carcassi C, La Nasa G, Zurrida SM, Sirigu F, Del Giacco S, Cerimele D, Longinotti M, Pitzus F. A case of classical Kaposi's sarcoma in B-cell chronic lymphocytic leukemia (B-CLL). Tumori. 1986;72:365-74.
10. Wijermans PW, van Groningen K, van Royen EA, Bruijn JA.Kaposi's sarcoma in an HIV-negative CLL patient as the cause of thrombocytopenia. Ann Hematol. 1994;68:307-10.
11. Hisada M, Biggar RJ, Greene MH, Fraumeni JF Jr, Travis LB. Solid tumors after chronic lymphocytic leukemia. Blood. 2001;98:1979-81.
12. Vojdani A, Lapp CW.Interferon-induced proteins are elevated in blood samples of patients with chemically or virally induced chronic fatigue syndrome. Immunopharmacol Immunotoxicol. 1999;21:175-202.
13. Knox KK, Brewer JH, Henry JM, Harrington DJ, Carrigan DR.Human herpesvirus 6 and multiple sclerosis: systemic active infections in patients with early disease. Clin Infect Dis. 2000;31:894-903.
14. Kuntzen T, Friedrichs N, Fischer HP, Eis-Hübinger AM, Sauerbruch T, Spengler U.Postinfantile giant cell hepatitis with autoimmune features following a human herpesvirus 6-induced adverse drug reaction. Eur J Gastroenterol Hepatol. 2005;17:1131-4.
Patients with chronic lymphocytic leukaemia (CLL) are all to a degree immunodeficient. The most obvious and well-known abnormality is hypogammaglobulinaemia which is present in up to 85% of patients [1]. Serum immunoglobulin levels are suppressed in other lymphoid malignancies but in CLL the suppression is to a far greater degree. Profound defects of cell mediated immunity also occur though these are most obvious in patients who have been treated with purine analogues. However, even untreated patients have defects of T cell numbers and function. This review will seek to explore the extent of the immune defect in CLL, its causes, clinical significance and possible remedies.
The extent of the immune defect
Infections are the major cause of death in between a quarter and a half of patients with CLL [1]. Bacterial infection of the respiratory tract, skin or urinary tract is the commonest problem and before the use of purine analogues for treatment, the usual organisms were Streptococcus pneumoniae, Staphylococcus aureus, Streptococcus pyogenes and Escherichia coli. Protection against these organisms is provided principally by antibody, but only 15% of patients with CLL have completely normal serum immunoglobulins [1]. It is likely that the only patients with CLL who do not have hypogammaglobulinaemia are those in whom it will occur in the future.
The extent of hypogammaglobulinaemia depends on the stage and duration of the disease. Older papers described serum IgA as the first immunoglobulin to be reduced followed by IgM and IgG [2], but this is by no means invariable and most patients have depression of all classes of immunoglobulin. It should be stressed that the hypogammaglobulinaemia is not confined to patients who have been treated. In one study of an untreated patient with stage B disease without a detectable paraprotein, the hypogammaglobulinaemia was so profound that over 90% of the detectable immunoglobulin in the serum was idiotypic, and thus derived from the tumour [3].
Despite the low levels of serum immunoglobulins, most patients suffer no clinical consequences from this, and in one study 65% of bacterial infections occurred with serum IgG levels below 300 mg/dL [4]. It is recommended that patients with primary immunodeficiency begin immunoglobulin replacement therapy when the serum IgG falls below this level.
The non-malignant B-cell population in CLL is not well characterized [5]. The proportion and overall number of non-malignant B cells is often significantly reduced, and clearly their function is impaired since the normal immunoglobulins are suppressed. What is not clear is whether they are directly suppressed by the tumour or indirectly as a consequence of inhibitory effects elsewhere in the immune response.
Apart from bacterial infections, patients with CLL also suffer from the reactivation of herpes viruses. Most commonly this involves herpes zoster. In one series from before the era of treatment with purine analogue, the incidence of herpes zoster was given as 28.6%, with 3.5% having recurrent attacks [1]. Particularly important is the observation that attacks of shingles frequently precede the clinical diagnosis of CLL [1], suggesting that the underlying immune defect does not depend on either hypogammaglobulinaemia or the physical overwhelming of immune organs by infiltrating tumour cells.
Recurrent attacks of herpes simplex also occur in some untreated patients. Both HSV1 and HSV2 may be involved. The recent recognition that herpes simplex is implicated in many cases of Bell’s palsy [6] may explain the association of Bell’s palsy, including recurrent attacks, in patients with CLL [1].
Treatment greatly increases the risk of the reactivation of herpes viruses. Reactivation of cytomegalovirus (CMV) is of course particularly associated with treatment with alemtuzumab, symptomatic infections occurring in 15% of patients treated in one clinical trial and asymptomatic reactivation in more than half (7], but symptomatic reactivation may occur after treatment with fludarabine (D Oscier, personal communication) and asymptomatic reactivation even after treatment with chlorambucil [7].
The Epstein-Bar virus (EBV) has recently been associated with the increase in the incidence of Richter’s syndrome in patients who have been treated with fludarabine [8]
Human herpes virus 8 (HHV8) is the cause of Kaposi’s sarcoma in immunodeficient individuals. The first reported case in CLL occurred in an untreated patient [9] and the second in a patient treated with fludarabine [10]. An American SEER report noted 9 cases between 1973 and 1996 among 16,367 patients observed, a statistically significant hazard ration of 5.09 [11].
Human herpes virus 6 causes the childhood exanthem, roseola, but in adults has it has been suggested as an initiating agent in chronic fatigue syndrome and multiple sclerosis [12, 13]. Fatigue is a common symptom in CLL often dismissed by physicians yet much discussed on patient websites. Multiple sclerosis has been reported as occasionally coexisting with CLL [1]. HHV6 has also been associated with giant cell hepatitis in adults [14] and I have recently been consulted by a patient with CLL and obscure giant cell hepatitis.
A systematic study of herpes viral copy number in haematological diseases has been carried out using real-time quantitative polymerase chain reaction (RQ-PCR). Occasional patients with CLL had high copy numbers of EBV, CMV and HHV6A, but not HHV6b, HHV7 and HHV8 [15]. Although interesting, the use of leukaemic B cells as a source of DNA means that T-cell lymphotropic viruses would be missed, and no indication was given as to the stage of the patients or the degree of immunosuppression.
References
1. Hamblin TJ. Chronic lymphocytic leukaemia. Balliere's Clinical Haematology 1987; 1: 449 491.
2. Foa R, Catovsky D, Brozovic M, Ooyirilangkumaran T, Cherchi M, Galton DAG. Clinical staging and immunological findings in chronic lymphocytic leukaemia. Cancer 1979; 44:483-487.
3. Stevenson FK, Hamblin TJ, Stevenson GT, Tutt Al. Extracellular idiotypic immunoglobulin arising from human leukemic B lymphocytes. J Exp Med 1980; 152:1484-1496.
4. Boughton BJ, Jackson N, Lim S, Smith N. Randomized trial of intravenous immunoglobulin prophylaxis for patients with chronic lymphocytic leukaemia and secondary hypogammaglobulinaemia. Clin Lab Haematol 1995; 17:75-80.
5. Johnston PB, Kay NE. Pathogenesis of impaired cellular immune function in CLL. In Chronic Lymphocytic Leukemia: Molecular Genetics, Biology, Diagnosis and Management. Ed GB Faguet. Humana Press: Totowa, New Jersey. 2004. p 109-121.
6. Steiner I, Mattan Y, Bell's palsy and herpes viruses: to (acyclo)vir or not to (acyclo)vir? J Neurol Sci. 1999;170:19-23.
7. Hillmen P, Skotnicki AB, Robak T, Jaksic B, Dmoszynska A, Wu J, Sirard C, Mayer J. Alemtuzumab compared with chlorambucil as first-line therapy for chronic lymphocytic leukemia. J Clin Oncol. 2007;25:5616-23
8. Thornton PD, bellas C, Santon A. Shah G, Pocock C, Wotherspoon AC, matutes E, Catovsky D. Richter’s transformation of chronic lymphocytic leukemia. The possible role of fludarabine and Epstein-Barr virus in its pathogenesis. Leuk Res 2005; 29:389-95.
9. Contu L, Carcassi C, La Nasa G, Zurrida SM, Sirigu F, Del Giacco S, Cerimele D, Longinotti M, Pitzus F. A case of classical Kaposi's sarcoma in B-cell chronic lymphocytic leukemia (B-CLL). Tumori. 1986;72:365-74.
10. Wijermans PW, van Groningen K, van Royen EA, Bruijn JA.Kaposi's sarcoma in an HIV-negative CLL patient as the cause of thrombocytopenia. Ann Hematol. 1994;68:307-10.
11. Hisada M, Biggar RJ, Greene MH, Fraumeni JF Jr, Travis LB. Solid tumors after chronic lymphocytic leukemia. Blood. 2001;98:1979-81.
12. Vojdani A, Lapp CW.Interferon-induced proteins are elevated in blood samples of patients with chemically or virally induced chronic fatigue syndrome. Immunopharmacol Immunotoxicol. 1999;21:175-202.
13. Knox KK, Brewer JH, Henry JM, Harrington DJ, Carrigan DR.Human herpesvirus 6 and multiple sclerosis: systemic active infections in patients with early disease. Clin Infect Dis. 2000;31:894-903.
14. Kuntzen T, Friedrichs N, Fischer HP, Eis-Hübinger AM, Sauerbruch T, Spengler U.Postinfantile giant cell hepatitis with autoimmune features following a human herpesvirus 6-induced adverse drug reaction. Eur J Gastroenterol Hepatol. 2005;17:1131-4.
Tuesday, May 06, 2008
Aphorisms again
I am writing an article on the immunodeficiency of CLL so I have little time for blogging, but here is my latest collection of aphorisms:
Hanging is too good for a man who makes puns; he should be drawn and quoted. - Fred Allen
Gratifying their desires has brought misery to millions.
I believe in getting into hot water – it keeps you clean. – GK Chesterton
If we forget that the newspapers are footnotes to Scripture and not the other way round, then we will be afraid to get out of bed in the morning. – Eugene Peterson
Politicians are like baby’s diapers; they should be changed frequently; and for much the same reason.
You can fool some of the people all of the time and all of the people some of the time, and that's actually good enough. – PT Barnum
The Devil’s most dangerous weapon is not his poison but his ice-cream.
A gold medal’s a wonderful thing; but if you can’t live without one, you won’t be able to live with one.
A good question to ask your physician: Are you doing this for me, doc, or am I doing it for you?
‘With all my worldly goods I thee endow’ means that if it comes to a divorce there are no assets to divide; you have already given yours away.
Hanging is too good for a man who makes puns; he should be drawn and quoted. - Fred Allen
Gratifying their desires has brought misery to millions.
I believe in getting into hot water – it keeps you clean. – GK Chesterton
If we forget that the newspapers are footnotes to Scripture and not the other way round, then we will be afraid to get out of bed in the morning. – Eugene Peterson
Politicians are like baby’s diapers; they should be changed frequently; and for much the same reason.
You can fool some of the people all of the time and all of the people some of the time, and that's actually good enough. – PT Barnum
The Devil’s most dangerous weapon is not his poison but his ice-cream.
A gold medal’s a wonderful thing; but if you can’t live without one, you won’t be able to live with one.
A good question to ask your physician: Are you doing this for me, doc, or am I doing it for you?
‘With all my worldly goods I thee endow’ means that if it comes to a divorce there are no assets to divide; you have already given yours away.
Sunday, May 04, 2008
Your footprints were not seen
"Your footprints were not seen." The phrase stands out, reminding us of that poster we used to hang in kitchen entitles "Footprints". You know the one. How God is supposed to walk alongside us in all that we do, like two rows of footprints on the beach. And how the author complains that when things got really bad it seemed that God had deserted him as evidenced by a single line of footprints on the beach. And how God replies, My son, that was when I was carrying you.
The phrase comes from Psalm 77 v 11. The psalm was written by Asaph during the reign of King David, at a time were going badly for Israel. Asaph is having nights made sleepless with worry. He tried to pray, but comfort never came. His despair was very great. He could not pray. He began to doubt his faith. Unfailing love was failing. An omniscient God was forgetting. A merciful God was without mercy. A truthful God was breaking his promises. A God who claimed to have chosen Israel was now rejecting her. A compassionate God had become an angry one.
Don't we think like that? We contrast God's reputed attributes with what we see happening in the world. How can a God of love allow suffering like we see in Darfur, or in the camps in the Congo, or the tsunami in Thailand, or 9/11, or those poor children in Austria, or whatever the newspapers light on next. Has our God forgotten how to be compassionate? Will he never show his favor again? Has his unfailing love vanished forever? Has his promise failed for all time?
What Asaph did next was to remember the past. In particular he remembered how the Children of Israel had been shepherded across the Red Sea dry shod, while Pharaoh's army had been drowned by the returning waves. He remembered how Moses and Aaron had led them through the wilderness of Sinai. He remembered how they had been delivered to the promised land and how the promised land had been delivered to them through Joshua.
"I entered every fashionable pulpit in London and I could scarcely distinguish the Christian Gospel in one of them. I was more likely to hear a message from Confucius, Mohammad or Krishna than from Christ."
"It is generally agreed, said a Bishop, that there can be no new enquiry into Christ. The Christian Church is fit only for ridicule or for mirth."
Six student have been sent down from Oxford University. Their crime was holding a private Bible study in their rooms.
These are quotes not from the 2000s but from the 1730s.
Shortly afterwards, God raised up George Whitfield, John and Charles Wesley, Howell Harris, John Berridge, William Romaine, Daniel Rowland, Henry Venn (who also found time to play cricket for England) and in America, Jonathan Edwards. Not only was the church revived, but the course of history was changed. England was spared the terrors of the French Revolution. The great social movements of the eighteenth century were spawned. Henry Venn's son, John, became Rector of Clapham where among his congregation came William Wilberforce. Slavery was ended. Women and children left the coal mines and the ragged children were given an education in the Sunday Schools of Robert Raikes Prisons were reformed. The great missionary societies were formed and the gospel taken to China, India and Africa.
When we remember our past we have hope for the future. But we have more to remember than just the works of men. We can look back, not like Asaph to the parting of the Red Sea, but to the rending of the Temple veil. That moment when one was sacrificed for all. Jesus has demonstrated once and for all that God is love, that we are the object of his love. For God so loved the world that he gave his one and only son.
Feel abandoned by God? Remember what he has done. Can't see his footprints? He is there nevertheless.
The phrase comes from Psalm 77 v 11. The psalm was written by Asaph during the reign of King David, at a time were going badly for Israel. Asaph is having nights made sleepless with worry. He tried to pray, but comfort never came. His despair was very great. He could not pray. He began to doubt his faith. Unfailing love was failing. An omniscient God was forgetting. A merciful God was without mercy. A truthful God was breaking his promises. A God who claimed to have chosen Israel was now rejecting her. A compassionate God had become an angry one.
Don't we think like that? We contrast God's reputed attributes with what we see happening in the world. How can a God of love allow suffering like we see in Darfur, or in the camps in the Congo, or the tsunami in Thailand, or 9/11, or those poor children in Austria, or whatever the newspapers light on next. Has our God forgotten how to be compassionate? Will he never show his favor again? Has his unfailing love vanished forever? Has his promise failed for all time?
What Asaph did next was to remember the past. In particular he remembered how the Children of Israel had been shepherded across the Red Sea dry shod, while Pharaoh's army had been drowned by the returning waves. He remembered how Moses and Aaron had led them through the wilderness of Sinai. He remembered how they had been delivered to the promised land and how the promised land had been delivered to them through Joshua.
"I entered every fashionable pulpit in London and I could scarcely distinguish the Christian Gospel in one of them. I was more likely to hear a message from Confucius, Mohammad or Krishna than from Christ."
"It is generally agreed, said a Bishop, that there can be no new enquiry into Christ. The Christian Church is fit only for ridicule or for mirth."
Six student have been sent down from Oxford University. Their crime was holding a private Bible study in their rooms.
These are quotes not from the 2000s but from the 1730s.
Shortly afterwards, God raised up George Whitfield, John and Charles Wesley, Howell Harris, John Berridge, William Romaine, Daniel Rowland, Henry Venn (who also found time to play cricket for England) and in America, Jonathan Edwards. Not only was the church revived, but the course of history was changed. England was spared the terrors of the French Revolution. The great social movements of the eighteenth century were spawned. Henry Venn's son, John, became Rector of Clapham where among his congregation came William Wilberforce. Slavery was ended. Women and children left the coal mines and the ragged children were given an education in the Sunday Schools of Robert Raikes Prisons were reformed. The great missionary societies were formed and the gospel taken to China, India and Africa.
When we remember our past we have hope for the future. But we have more to remember than just the works of men. We can look back, not like Asaph to the parting of the Red Sea, but to the rending of the Temple veil. That moment when one was sacrificed for all. Jesus has demonstrated once and for all that God is love, that we are the object of his love. For God so loved the world that he gave his one and only son.
Feel abandoned by God? Remember what he has done. Can't see his footprints? He is there nevertheless.
Friday, May 02, 2008
My week
A week of little blogging, largely because I have been so busy. This is how my week went.
Monday morning: take train to London. Listen to podcasts from Radio 4 on my newly acquired iPod.
Monday lunchtime: interviewed by New Zealand TV about the Northwick Park affair. I had to mug that one up, it's a long time since it happened and already the details are indistinct. They hired a room at the National Heart Hospital in Westmoreland St for the interview.
Monday afternoon: walk across to the Holiday Inn, Regent's Park for an Advisory Board for Roche. If they decided to bomb it, they would wipe out almost every UK CLL expert. The question was what trials should be done on Rituximab while we are waiting for NICE to approve it for CLL (which they surely will after the German CLL8 trial).
Monday evening dinner. A short walk to the restaurant. I sat between Nick Chiorazzi and Danny Catovsky, so it was an interesting evening.
Tuesday morning: Executive Board of the UK CLL Forum. This was in the Royal Institute of British Architects, close by in Portman Place. 8.30 am was an unreasonable start, but the scientific meeting was in the same building at 10.30. The meeting had talks by Nick Chiorazzi and Sylvia Deaglio as well as a few domestic speakers. It was focused on the microenvironment of the CLL cell in lymph nodes and bone marrow.
Tuesday afternoon: Presented the Hamblin prize for the best British paper on CLL during 2007. It went to Andrea Buggins for her work on IL-6. I made a little controversial speech about the journal publishing it as a 'Letter' rather than as an 'article'. This is a blatant attempt to raise the impact factor of Leukemia, and it isn't the first time they have tried underhand methods. They were caught out some time ago suggesting to authors that they should cite papers previously published in Leukemia. Impact factors work by dividing the number of times papers in a particular journal are cited by the number of papers published. Citations of 'Letters' count in the nominator but 'Letters' do not count in the denominator. Therefore to call an 'Article' a 'Letter' is dishonest. Some might call it 'gaming' the system. I call it dishonest.
Tuesday evening: take train back home in time to watch Manchester United versus Barcelona in the Champions League semi-final. United win 1-0, so it will be an all English final in Moscow.
Wednesday morning: Early train to London for GTAC committee. We have five protocols to discuss and I will be leading the discussion on one about a new type of adoptive immunotherapy for adenovirus infections in stem cell transplant recipients. It's not really gene therapy and the trial design has never been seen by a statistician. However, we pass it after suggesting a major design change. The rest of the day seems to drag and I drop off during a particularly boring discussion about prostate cancer. After the meeting we have a cake in honour of Monika, our secretary who is leaving for greener fields.
Wednesday evening: train back home in time for the Liverpool v Chelsea semi-final. It is an exciting match which Chelsea win 3-2. They will meet Man Utd in Moscow. For American readers, this is as big as the Superbowl.
Thursday morning: I spend all day writing a medico-legal report on a CLL patient who to my mind got poor treatment.
Thursday evening: We go out to vote in the local elections then off to church for the mid-week prayer meeting and then home to watch ER. Afterwards, I go back to the medico-legal report, which I finish at 1-30 am.
Friday morning: I referee a paper for Blood and one for British Journal of Haematology, then edit a few papers for Leukemia Research. Then I photocopy some papers to go with the medico-legal report, then phone a couple of contacts about our search for an associate pastor.
Friday evening: Off to the gym for an hour with my personal trainer. She really puts me through it. Then back for a shower and after dinner, at last, a bit of blogging.
Monday morning: take train to London. Listen to podcasts from Radio 4 on my newly acquired iPod.
Monday lunchtime: interviewed by New Zealand TV about the Northwick Park affair. I had to mug that one up, it's a long time since it happened and already the details are indistinct. They hired a room at the National Heart Hospital in Westmoreland St for the interview.
Monday afternoon: walk across to the Holiday Inn, Regent's Park for an Advisory Board for Roche. If they decided to bomb it, they would wipe out almost every UK CLL expert. The question was what trials should be done on Rituximab while we are waiting for NICE to approve it for CLL (which they surely will after the German CLL8 trial).
Monday evening dinner. A short walk to the restaurant. I sat between Nick Chiorazzi and Danny Catovsky, so it was an interesting evening.
Tuesday morning: Executive Board of the UK CLL Forum. This was in the Royal Institute of British Architects, close by in Portman Place. 8.30 am was an unreasonable start, but the scientific meeting was in the same building at 10.30. The meeting had talks by Nick Chiorazzi and Sylvia Deaglio as well as a few domestic speakers. It was focused on the microenvironment of the CLL cell in lymph nodes and bone marrow.
Tuesday afternoon: Presented the Hamblin prize for the best British paper on CLL during 2007. It went to Andrea Buggins for her work on IL-6. I made a little controversial speech about the journal publishing it as a 'Letter' rather than as an 'article'. This is a blatant attempt to raise the impact factor of Leukemia, and it isn't the first time they have tried underhand methods. They were caught out some time ago suggesting to authors that they should cite papers previously published in Leukemia. Impact factors work by dividing the number of times papers in a particular journal are cited by the number of papers published. Citations of 'Letters' count in the nominator but 'Letters' do not count in the denominator. Therefore to call an 'Article' a 'Letter' is dishonest. Some might call it 'gaming' the system. I call it dishonest.
Tuesday evening: take train back home in time to watch Manchester United versus Barcelona in the Champions League semi-final. United win 1-0, so it will be an all English final in Moscow.
Wednesday morning: Early train to London for GTAC committee. We have five protocols to discuss and I will be leading the discussion on one about a new type of adoptive immunotherapy for adenovirus infections in stem cell transplant recipients. It's not really gene therapy and the trial design has never been seen by a statistician. However, we pass it after suggesting a major design change. The rest of the day seems to drag and I drop off during a particularly boring discussion about prostate cancer. After the meeting we have a cake in honour of Monika, our secretary who is leaving for greener fields.
Wednesday evening: train back home in time for the Liverpool v Chelsea semi-final. It is an exciting match which Chelsea win 3-2. They will meet Man Utd in Moscow. For American readers, this is as big as the Superbowl.
Thursday morning: I spend all day writing a medico-legal report on a CLL patient who to my mind got poor treatment.
Thursday evening: We go out to vote in the local elections then off to church for the mid-week prayer meeting and then home to watch ER. Afterwards, I go back to the medico-legal report, which I finish at 1-30 am.
Friday morning: I referee a paper for Blood and one for British Journal of Haematology, then edit a few papers for Leukemia Research. Then I photocopy some papers to go with the medico-legal report, then phone a couple of contacts about our search for an associate pastor.
Friday evening: Off to the gym for an hour with my personal trainer. She really puts me through it. Then back for a shower and after dinner, at last, a bit of blogging.
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