We have established that in CLL the action is in the lymph nodes where the proliferation centers allow the interchange of signals between the CLL cells and accessory cells including T cells, 'nurse' cells and stromal cells. It is mainly in the Unmutated cases that all this conversation takes place and it is also established that the BCR (B-cell receptor) is the pathway into the cell since it tends to react with antigens that are pretty commonly present like the products of apoptosis.
However, there are some cases of mutated CLL that also proliferate and we don't think the BCR is implicated in these.
Toll-like receptors (TLRs) are a class of proteins that play a key role in the innate immune system. They are single, membrane-spanning, non-catalytic receptors that recognize structurally conserved molecules derived from microbes. One such receptor is found on some CLL cells. CD180 is a molecule that I collaborated on with Peter Lydiard before I retired. It is present on CLL cells with mutated IGHV genes. An update of this work, now in collaboration with Nick Chiorazzi has just been published in the British Journal of Haematology. They have stimulated CLL cells and normal B cells with a monoclonal anti-CD180 antibody. They find that only about half the CD180+ cells respond by proliferation and failing to apoptose.. The same cells that fail to respond also fail to respond to IL-4 + CD40L stimulation, and may be thought of as anergic. Responding cells signal via ZAP70/syk, p38MAPK, ERK and Akt. Inability to activate Akt in particular seems to be a feature of anergic cells.
Thus it may be that CD180, a TLR that highjacks the normal BCR signaling mechanism may be responsible for proliferative and anti-apoptotic signals in the proliferation centers of some mutated CLLs.
Tuesday, May 31, 2011
Regulatory T cells in CLL
Regulatory T cells (TREGS) help to control the immune response. They are one factor that restrains autoimmunity and they also suppress the body's response to cancer. a paper in Leukemia Research has looked at TREGS in CLL by enumerating cells that are CD4+, CD25 bright, CD127 dim cells in the peripheral blood in 80 cases of CLL and 40 controls.
The authors found high levels of TREGS in CLL compared with controls and most increased in advanced cases (Rai 3 and 4). There was correlation with absolute B cells number and with CD38+ B cells, but not with IGHV status, ZAP-70 status or karyotype. In two patients with AIHA very low levels of TREGS were found (something I predicted 15 years ago).
Recently it has been shown that the expansion of TREGS in CLL is not due to stimulation by a tumor antigen. It may be that stimulation of the CD27-CD70 interface in proliferation centers promotes proliferation of TREGS and also decreases their sensitivity to apoptosis..
Higher frequencies of TREGS correlates with decreased T-cell responses to viral antigens, TREGS are reduced by treatment with fludarabine and Revlimid, but treatment of ITP with rituximab increases them.
The authors found high levels of TREGS in CLL compared with controls and most increased in advanced cases (Rai 3 and 4). There was correlation with absolute B cells number and with CD38+ B cells, but not with IGHV status, ZAP-70 status or karyotype. In two patients with AIHA very low levels of TREGS were found (something I predicted 15 years ago).
Recently it has been shown that the expansion of TREGS in CLL is not due to stimulation by a tumor antigen. It may be that stimulation of the CD27-CD70 interface in proliferation centers promotes proliferation of TREGS and also decreases their sensitivity to apoptosis..
Higher frequencies of TREGS correlates with decreased T-cell responses to viral antigens, TREGS are reduced by treatment with fludarabine and Revlimid, but treatment of ITP with rituximab increases them.
Does the good life stop here?
I have come to the conclusion that I have lived at a time and place that has treated me very well. I was born with no hereditary privileges; both my parents were poor. However, I was very fortunate that my father had been diagnosed as having TB as a teenager, which meant he was unfit for military service during the second world war. So in 1945 I have two living parents, which was more than many of my contemporaries could say.
When I was five years old Britain introduced a National Health Service, which meant that all my health needs were paid for by the general taxpayer; in other words, people who were richer than my family subsidized the cost of all my medical expenses.
My father had served an apprenticeship and this meant that he was never unemployed. Indeed he was able to hold down two jobs at a time of full employment, so that although my parents have never been rich, they were comfortable and in 1956, when my father was 38 and my mother 36, they were able to buy their first house and afford the mortgage. They had been married for 20 years, living in rented single rooms, small apartments, a small house and even a gypsy caravan for a time. Now they had for the first time an indoor bathroom, an indoor WC, running hot water and a garden large enough to grow vegetables and fruit. Within a few years they could own a car (albeit a pre-war vehicle). Later, in 1963, when he was 45 and she 43 they bought a brand new house with central heating, a garage, and a fitted kitchen. My mother still lives there aged 91. The mortgage is long ago paid off.
For three years (when I was aged 4-7) my parents found enough money to pay for me to go to a private school. It was not necessary, but my father was hot-headed and took a dislike to state education which would not have allowed me to start until I was 5. Education in those post-war years was a great project for HM Government. Many modern schools were built and there was selection at 11 for a minority of pupils to be educated in a quasi-public-school manner with a view to sending these children to some of the finest universities in the world. I turned out to be very good at Maths and English and was able to take advantage of this. Again this was all at the expense of richer taxpayers than we had in our family.
When I went to university for 5 years, not only were my fees paid for but my living expenses too - all by the taxpayer. Not only that, but on qualifying as a doctor I was given a job at taxpayers' expense to not only work, but also to train as a specialist. I was given a research training again in an MRC position, again at taxpayers' expense and within 6 years of qualifying I had a consultant position in a government hospital. From here I was given salary increases that left me earning over £100,000 a year by the time I retired. For my latter years part of my salary was paid by the voluntary sector from charitable sources, and I was able, because of the renown I had achieved in the public sector, to earn even more in the private sector from my writing.
By the time I was 27 I was buying my first house. I have been able to bring up four children, all educated at public expense and with most of their university fees paid by the taxpayer too. They all have well-paid jobs - two in the public sector and two in the private sector. I live on a generous pension paid for by the taxpayer in a pleasant town with all I could possibly need.
As far as I have been able I have given back all I could and I think I have made my contribution to medicine and to science and in various ways to the community, but I am conscious of just how well this land and these times have treated me.
But what of the future? Has my generation done so well at the expense of future generations? 64% of current people between the ages of 20 and 40 apparently believe that they will never own their own house. Individuals who go to university are now hampered by long term debts which may make house purchase hazardous. Although technology has changed the world, for many young people there is the prospect of many hours of commuting every day, long hours in an office job and home to a rented apartment. Larger contributions for their pension pot will be required from their salary and they will have to work until they are 68 or older before they can draw it. There are stories that even longevity might decline; that because of diabetes and hypertension and an increasing burden of cancer, the present generation of oldsters will be the last long-lived generation.
Although there have been great technical advances in medicine, NICE-like, vice-like controls will make these advances unaffordable. Perhaps the affluence of the West will be overtaken by the burgeoning economies of China, India and Brazil. Already we are seeing an underclass of people who will live their whole lives without a job, existing of state benefits and charity. I was astonished to read the feedback on an article yesterday on benefit cheats. The general attitude was that if they could get away with it, then good luck to them. MPs who cheated on their expenses were far worse. It's as though many citizens have given up on being good citizens.
I am sure that many of my correspondents will insist that the end we see now was an inevitable consequence of socialist Britain and I agree with that diagnosis. Eventually socialists run out of other peoples' money to spend, and Britain was once the wealthiest country in the world. It has taken us a long time to spend our wealth. Of course, there is more that could be spent. The UK is the largest foreign investor in America; there are assets to be sold if necessary. Taxes were once much higher than they are now. But if the government spends more they have little control over the consequences. We now live in a global economy where the power of the multinational company exceeds that of government.
Or is this just a temporary blip? During the 1970s Britain was in a parlous state. Much of industry was owned by the government and inefficiently run at a loss. Strikes were commonplace and taxes were high. The balance of payments was a problem and sterling was devalued. Striking coal-miners reduced the country to a three-day week and there were rolling electricity cuts to share out the pain. Somehow the worm turned and we came out of that. Our current problem was triggered by our banks buying into a housing bubble. That housing bubble still exists and our banks remain in delicate health. To handicap our recovery we have bought into a myth about global warming which means that we pay more for our fuel than other economies.
I see that Mrs Thatcher impersonator, Janet Brown, has died at the age of 87. I am looking for another one.
When I was five years old Britain introduced a National Health Service, which meant that all my health needs were paid for by the general taxpayer; in other words, people who were richer than my family subsidized the cost of all my medical expenses.
My father had served an apprenticeship and this meant that he was never unemployed. Indeed he was able to hold down two jobs at a time of full employment, so that although my parents have never been rich, they were comfortable and in 1956, when my father was 38 and my mother 36, they were able to buy their first house and afford the mortgage. They had been married for 20 years, living in rented single rooms, small apartments, a small house and even a gypsy caravan for a time. Now they had for the first time an indoor bathroom, an indoor WC, running hot water and a garden large enough to grow vegetables and fruit. Within a few years they could own a car (albeit a pre-war vehicle). Later, in 1963, when he was 45 and she 43 they bought a brand new house with central heating, a garage, and a fitted kitchen. My mother still lives there aged 91. The mortgage is long ago paid off.
For three years (when I was aged 4-7) my parents found enough money to pay for me to go to a private school. It was not necessary, but my father was hot-headed and took a dislike to state education which would not have allowed me to start until I was 5. Education in those post-war years was a great project for HM Government. Many modern schools were built and there was selection at 11 for a minority of pupils to be educated in a quasi-public-school manner with a view to sending these children to some of the finest universities in the world. I turned out to be very good at Maths and English and was able to take advantage of this. Again this was all at the expense of richer taxpayers than we had in our family.
When I went to university for 5 years, not only were my fees paid for but my living expenses too - all by the taxpayer. Not only that, but on qualifying as a doctor I was given a job at taxpayers' expense to not only work, but also to train as a specialist. I was given a research training again in an MRC position, again at taxpayers' expense and within 6 years of qualifying I had a consultant position in a government hospital. From here I was given salary increases that left me earning over £100,000 a year by the time I retired. For my latter years part of my salary was paid by the voluntary sector from charitable sources, and I was able, because of the renown I had achieved in the public sector, to earn even more in the private sector from my writing.
By the time I was 27 I was buying my first house. I have been able to bring up four children, all educated at public expense and with most of their university fees paid by the taxpayer too. They all have well-paid jobs - two in the public sector and two in the private sector. I live on a generous pension paid for by the taxpayer in a pleasant town with all I could possibly need.
As far as I have been able I have given back all I could and I think I have made my contribution to medicine and to science and in various ways to the community, but I am conscious of just how well this land and these times have treated me.
But what of the future? Has my generation done so well at the expense of future generations? 64% of current people between the ages of 20 and 40 apparently believe that they will never own their own house. Individuals who go to university are now hampered by long term debts which may make house purchase hazardous. Although technology has changed the world, for many young people there is the prospect of many hours of commuting every day, long hours in an office job and home to a rented apartment. Larger contributions for their pension pot will be required from their salary and they will have to work until they are 68 or older before they can draw it. There are stories that even longevity might decline; that because of diabetes and hypertension and an increasing burden of cancer, the present generation of oldsters will be the last long-lived generation.
Although there have been great technical advances in medicine, NICE-like, vice-like controls will make these advances unaffordable. Perhaps the affluence of the West will be overtaken by the burgeoning economies of China, India and Brazil. Already we are seeing an underclass of people who will live their whole lives without a job, existing of state benefits and charity. I was astonished to read the feedback on an article yesterday on benefit cheats. The general attitude was that if they could get away with it, then good luck to them. MPs who cheated on their expenses were far worse. It's as though many citizens have given up on being good citizens.
I am sure that many of my correspondents will insist that the end we see now was an inevitable consequence of socialist Britain and I agree with that diagnosis. Eventually socialists run out of other peoples' money to spend, and Britain was once the wealthiest country in the world. It has taken us a long time to spend our wealth. Of course, there is more that could be spent. The UK is the largest foreign investor in America; there are assets to be sold if necessary. Taxes were once much higher than they are now. But if the government spends more they have little control over the consequences. We now live in a global economy where the power of the multinational company exceeds that of government.
Or is this just a temporary blip? During the 1970s Britain was in a parlous state. Much of industry was owned by the government and inefficiently run at a loss. Strikes were commonplace and taxes were high. The balance of payments was a problem and sterling was devalued. Striking coal-miners reduced the country to a three-day week and there were rolling electricity cuts to share out the pain. Somehow the worm turned and we came out of that. Our current problem was triggered by our banks buying into a housing bubble. That housing bubble still exists and our banks remain in delicate health. To handicap our recovery we have bought into a myth about global warming which means that we pay more for our fuel than other economies.
I see that Mrs Thatcher impersonator, Janet Brown, has died at the age of 87. I am looking for another one.
John 4:10. Waterworld
Jesus answered her, “If you knew the gift of God and who it is that asks you for a drink, you would have asked him and he would have given you living water.”
Water, water everywhere. Remember the Kevin Costner flop, Waterworld, where our Kevin grew gills? John's gospel has become a waterworld itself. First we had water into wine - the water of purification turned into the new wine of the Spirit. Then we had the water of Baptism, washing away the old to make room for the new life of resurrection. Now we have the old water of Jacob's well replaced by the living water of the Gospel.
Water, water everywhere. Remember the Kevin Costner flop, Waterworld, where our Kevin grew gills? John's gospel has become a waterworld itself. First we had water into wine - the water of purification turned into the new wine of the Spirit. Then we had the water of Baptism, washing away the old to make room for the new life of resurrection. Now we have the old water of Jacob's well replaced by the living water of the Gospel.
Some rain-affected draw!
On yesterday's blog "Not that it matters in this match, which is heading for a rain-affected draw." How wrong could I be!
It rained again in Cardiff yesterday morning. Play couldn't start until 3 pm. Andrew Strauss sent Ian Bell out to gather the two runs he needed to become the fourth centurion in the match. It seemed that no-one was taking the result seriously. 922 spectators turned up for the cheap last-day tickets to watch their heroes.
And what heroes! With plenty of time to spare England blew away the Sri Lankans, taking all 10 wickets for only 82 runs, winning by an innings and 14 runs.
Only a few weeks ago Sri Lanka beat England on the sub-continent in the quarter finals of the World Cup. It goes to show how different the one day game is from Test Matches. Test matches require the ability to concentrate for long periods. Exemplified particularly by Jonathon Trott's double century in Cardiff.
It rained again in Cardiff yesterday morning. Play couldn't start until 3 pm. Andrew Strauss sent Ian Bell out to gather the two runs he needed to become the fourth centurion in the match. It seemed that no-one was taking the result seriously. 922 spectators turned up for the cheap last-day tickets to watch their heroes.
And what heroes! With plenty of time to spare England blew away the Sri Lankans, taking all 10 wickets for only 82 runs, winning by an innings and 14 runs.
Only a few weeks ago Sri Lanka beat England on the sub-continent in the quarter finals of the World Cup. It goes to show how different the one day game is from Test Matches. Test matches require the ability to concentrate for long periods. Exemplified particularly by Jonathon Trott's double century in Cardiff.
Monday, May 30, 2011
Should KP have been given out?
It was a sparkling weekend of sport. The headlines were made by Barcelona's victory over Manchester United in the Champions League Final at Wembley. One thinks of the great Real Madrid team or Ajax or AC Milan or even Brazil, but this Barcelona team must be the greatest football team in history. Iniesta, Xavi and above all Messi seemed to treat the ball as their personal possession and didn't allow the opposition to get near it. As a Man U supporter I have to concede that they were decidedly second best.
In golf we are beginning to see the post-Tiger generation emerging. By beating Lee Westwood at an extra hole at the PGA, Luke Donald has supplanted him as number one in the world.
World Tennis looks set in its ways with four top names, Nadal, Djokovic, Federer and Murray likely to contest the semi-finals of the French Open.
Saracens beat Leicester to win the Rugby Premiership, reversing last year's result.
Vettel won his fifth Grand Prix out of six at Monaco in a race interrupted by safety cars.
But it is the rather boring Test Match in Cardiff between Sri Lanka and England that I want to talk about. For those who find the LBW law boring, look away now.
Should Kevin Pietersen have been given out? The LBW law is a bit of a movable feast, but as currently written, to be given out leg before wicket, a batsman must prevent a ball from hitting his wicket with any part of his body except his bat, hand or forearm. In addition the ball must bounce or look as if it would bounce in line with the wicket or outside the off stump and it must hit the body part in line with the wicket unless the batsman was not playing a shot, in which case it may hit the body part outside the line of the off stump.
You may imagine that these things are quite difficult for the Umpire to work out, especially when the ball is traveling at 80+ mph. To aid the Umpire in certain matches, they have been given technical help in the form of 'Hawkeye' and 'Hotspot'. Hawkeye is a computer aided graphics package which can predict where the ball would have gone were it not interrupted in flight, and Hotspot uses infra-red to measure the heat generated when the ball hits the pad or other part or the bat. Because of the statistical uncertainty of Hawkeye, the Umpire still has the final decision. Each side has two failed appeals per innings when they can question the Umpire's decision. If Hawkeye shows the Umpire was clearly wrong then the decision is reversed, but if the technology shows uncertainty then the batsman is given the benefit of the doubt.
In the incident in Cardiff Pietersen was receiving a ball from a rather innocuous slow left-arm bowler. (This is not irrelevant. From being a batsman who just piled on the runs without effort, he has become vulnerable to not-very-good slow left-armers. He has been out 19 times to them in Test cricket.) Undoubtedly he should have played forward to this ball but he played back and only just managed to jam his bat down on the ball before it would have taken his middle stump. The bowler appealed, but Pietersen was given not-out. The Sri Lankans then appealed to the third Umpire to use the technology. Hotspot clearly showed that the ball flicked Pietersen's pad milliseconds before it hit his bat. The Umpire therefore reversed his decision and gave him out, LBW.
But I wonder if this is right. The point is that for a player to be out LBW, the batsman must interpose his leg (or other body part) so as to prevent the ball knocking over the wicket. But in no sense could the flick on the pad be said to have done this. It was the bat coming down that prevented the skittling of the wicket. In my view the Umpire's original decision should have stood.
Not that it matters in this match, which is heading for a rain-affected draw.
In golf we are beginning to see the post-Tiger generation emerging. By beating Lee Westwood at an extra hole at the PGA, Luke Donald has supplanted him as number one in the world.
World Tennis looks set in its ways with four top names, Nadal, Djokovic, Federer and Murray likely to contest the semi-finals of the French Open.
Saracens beat Leicester to win the Rugby Premiership, reversing last year's result.
Vettel won his fifth Grand Prix out of six at Monaco in a race interrupted by safety cars.
But it is the rather boring Test Match in Cardiff between Sri Lanka and England that I want to talk about. For those who find the LBW law boring, look away now.
Should Kevin Pietersen have been given out? The LBW law is a bit of a movable feast, but as currently written, to be given out leg before wicket, a batsman must prevent a ball from hitting his wicket with any part of his body except his bat, hand or forearm. In addition the ball must bounce or look as if it would bounce in line with the wicket or outside the off stump and it must hit the body part in line with the wicket unless the batsman was not playing a shot, in which case it may hit the body part outside the line of the off stump.
You may imagine that these things are quite difficult for the Umpire to work out, especially when the ball is traveling at 80+ mph. To aid the Umpire in certain matches, they have been given technical help in the form of 'Hawkeye' and 'Hotspot'. Hawkeye is a computer aided graphics package which can predict where the ball would have gone were it not interrupted in flight, and Hotspot uses infra-red to measure the heat generated when the ball hits the pad or other part or the bat. Because of the statistical uncertainty of Hawkeye, the Umpire still has the final decision. Each side has two failed appeals per innings when they can question the Umpire's decision. If Hawkeye shows the Umpire was clearly wrong then the decision is reversed, but if the technology shows uncertainty then the batsman is given the benefit of the doubt.
In the incident in Cardiff Pietersen was receiving a ball from a rather innocuous slow left-arm bowler. (This is not irrelevant. From being a batsman who just piled on the runs without effort, he has become vulnerable to not-very-good slow left-armers. He has been out 19 times to them in Test cricket.) Undoubtedly he should have played forward to this ball but he played back and only just managed to jam his bat down on the ball before it would have taken his middle stump. The bowler appealed, but Pietersen was given not-out. The Sri Lankans then appealed to the third Umpire to use the technology. Hotspot clearly showed that the ball flicked Pietersen's pad milliseconds before it hit his bat. The Umpire therefore reversed his decision and gave him out, LBW.
But I wonder if this is right. The point is that for a player to be out LBW, the batsman must interpose his leg (or other body part) so as to prevent the ball knocking over the wicket. But in no sense could the flick on the pad be said to have done this. It was the bat coming down that prevented the skittling of the wicket. In my view the Umpire's original decision should have stood.
Not that it matters in this match, which is heading for a rain-affected draw.
John 4:7-9. Pride and Prejudice
When a Samaritan woman came to draw water, Jesus said to her, “Will you give me a drink?” (His disciples had gone into the town to buy food.) The Samaritan woman said to him, “You are a Jew and I am a Samaritan woman. How can you ask me for a drink?” (For Jews do not associate with Samaritans.)
Prejudice is a terrible thing. The Samaritan woman assumed that Jesus as a Jew would have a particular attitude towards her. (Jews did not associate with Samaritans) and any other Jew would have assumed that she was typical of what they thought of Samaritan women (she had had five husbands and was living with a man who was not her husband).
Yet Jesus, totally without prejudice, just saw her as a soul to be won for the Gospel.
Are we prejudiced? A story is told of a young man with long hair and a scruffy beard who came into a Presbyterian church dressed in a flowing robe and sandals. He went to the front of the church and sat down on the floor. One of the Elders went and sat down beside him and engaged him in conversation. There was much muttering.
Afterwards the Elder was asked how he could do such a thing. He replied, "It was a no-brainer. He was the only one in the whole building who was dressed like Jesus."
Music can put us off; so can dress, the way of praying, whether people stand up or sit down, language, accent, slang, the way of eating, where people live; we are easily prejudiced. Yet Jesus told us not to judge lest we be judged. |That instruction can be taken out of context, but at the very least it means that we should not be prejudiced.
Prejudice is a terrible thing. The Samaritan woman assumed that Jesus as a Jew would have a particular attitude towards her. (Jews did not associate with Samaritans) and any other Jew would have assumed that she was typical of what they thought of Samaritan women (she had had five husbands and was living with a man who was not her husband).
Yet Jesus, totally without prejudice, just saw her as a soul to be won for the Gospel.
Are we prejudiced? A story is told of a young man with long hair and a scruffy beard who came into a Presbyterian church dressed in a flowing robe and sandals. He went to the front of the church and sat down on the floor. One of the Elders went and sat down beside him and engaged him in conversation. There was much muttering.
Afterwards the Elder was asked how he could do such a thing. He replied, "It was a no-brainer. He was the only one in the whole building who was dressed like Jesus."
Music can put us off; so can dress, the way of praying, whether people stand up or sit down, language, accent, slang, the way of eating, where people live; we are easily prejudiced. Yet Jesus told us not to judge lest we be judged. |That instruction can be taken out of context, but at the very least it means that we should not be prejudiced.
Sunday, May 29, 2011
James Joyce
One of my little quirks is to object to the way the Irish have purloined British writers like Oscar Wilde, just because they happened to live on the island of Ireland when it was British. Now I feel justified. James Joyce, that most Dublin of Dubliners was twice offered an Irish passport while he was alive, but turned them down, preferring to remain a British citizen.
John 4:4-6. Good or bad Samaritans
Now he had to go through Samaria. So he came to a town in Samaria called Sychar, near the plot of ground Jacob had given to his son Joseph. Jacob’s well was there, and Jesus, tired as he was from the journey, sat down by the well. It was about noon.
This is modern day Nablus a Palestinian town on the West Bank. Samaria, capital of the Northern Kingdom had been conquered by the Assyrians who had scattered its inhabitants throughout their empire and resettled foreigners there. When the refugees from the Southern kingdom (Judea) returned from Babylon under Nehemiah the inhabitants of Samaria were seen as a mongrel people whose religion had been contaminated. Later they had built a Temple at Sychar but the Jews had pulled it down. There was no love lost between Jews and Samaritans.
Note how John emphasizes Jesus' human characteristics as well as his divine ones. He was tired.
This is modern day Nablus a Palestinian town on the West Bank. Samaria, capital of the Northern Kingdom had been conquered by the Assyrians who had scattered its inhabitants throughout their empire and resettled foreigners there. When the refugees from the Southern kingdom (Judea) returned from Babylon under Nehemiah the inhabitants of Samaria were seen as a mongrel people whose religion had been contaminated. Later they had built a Temple at Sychar but the Jews had pulled it down. There was no love lost between Jews and Samaritans.
Note how John emphasizes Jesus' human characteristics as well as his divine ones. He was tired.
Saturday, May 28, 2011
The Sharon Shoesmith Affair
A child dies in the inner city. A hundred and fifty years ago, in Dickens' day, it's not a problem; it's commonplace. Tuberculosis is the Captain of the men of death but there are plenty of others in the ranks. Cholera, smallpox, measles all carry away the children together with malnutrition, neglect and cruelty. The remedy? You have a lot; children are easily got.
But diseases have been done away with. We have vaccines, clean water, warm and dry houses, clean air. Contraception. Children have become few and precious. Almost gods.
So, a child dies in the inner city and someone must be to blame. Baby Peter Connelly, who had been seen 60 times by social services, was found dead in 2007 with over 50 injuries. In this case the culprit is easily found. The mother is dissolute, a wastrel, a self-gratifying good-for nothing with a live-in boyfriend unconcerned for the by-blow of a former beau. And there's a pedophile-rapist brother who's no better. All three set upon baby Peter. They do not feed him, do not care, but use him as an ash tray to stub their cigarettes out on. These three ignorant young people are responsible for intolerable cruelty and they will be punished. They will go to prison.
Surely someone should have done something to stop it. Aren't there social workers whose job it is to prevent this? Don't we all remember the intrusion of health visitors poking their noses when our children were born? They should have been spending their time where they were really needed.
But social work is in a mess in the inner cities. The case load is too high and recruitment is poor. No-one wants to work in the inner cities. They recruit and train people with 'life-skills' rather than with academic qualifications. Then they find that they can't follow the instructions. They take cups of tea with the parents and are easily taken in. Bruises? He fell down the stairs. He's clumsy. It's just what any adventurous child gets. And the doctors are no better. There is pressure on the A&E; they are trying to reduce junior doctors' hours; there are plenty of excuses. Besides, the buck stops somewhere else. As for the police, despite the case being reported to the police, no case officer had been assigned four months later.
Just where does it stop? Sharon Shoesmith had a staff of more than a thousand, a budget of £100 million and an annual salary of £100,000. In the aftermath of the Baby P case she fought to keep all three and refused to resign. At a press conference following the trial of the mother and the two live-in brothers (about whom the social services knew nothing- though a parenting class did and declined to share the information with the social services on the grounds of 'confidentiality') Sharon Shoesmith made a statement that came over very poorly. She was called cold and calculating, arrogant and smug.
Ms Shoesmith, 55, from Co Antrim in Northern Ireland, spent most of her professional life in education rather than social services. She rose from being a teacher to a school inspector and worked in the school improvement division, monitoring schools with serious weaknesses and requiring special measures. When she was appointed by Capita – the private company that oversees the borough’s schools – to be the director of children's services in Haringey in 2005, she promised to lower the number of children who were taken into care by stepping in earlier with help if needed.
There has been a tension in Social Services. There has been much anger about children being taken away from their parents and put into the care of the local authority or with foster parents. Damned if you do; damned if you don't is the position.
Shoesmith stood back from the problem and took an objective view. “It has really shocked me how much of the media has missed the point that this is a horrendous tragedy and everybody obviously is horribly shocked by it, but there is so much blame, there is so much anger and hatred out there.” And indeed the popular press made it a cause celebre.
There must be some doubt as to the wisdom of conflating social work and education under one banner of "Children's Services". Did they do it to beef up the ministry that Ed Balls, late Chief Secretary of the Treasury and a Gordon Brown favorite for future Chancelor, must take while he does his spell in a 'spending ministry'? The idea was generated by the Children Act 2004, which after the Victoria Climbié inquiry recommended that education and safeguarding be combined to increase communication between the two.
But social work and education are very different beasts, and Sharon Shoesmith, with no background in social work was perhaps not a very wise appointment to head up one of the most difficult social work jobs in the UK. Nevres Kemal, a former social worker who gave warning about Haringey council’s social services failings six months before Baby P died, believes that Ms Shoesmith was misled by her managers in the case. She reports having told the director of children’s services: “I’m not going to shut up. You don’t know what is going on in social services, what is being concealed from you.”
The October, after Baby P died, Ofsted gave Haringey a three-star rating out of four, saying it provided a good service for children, but for Shoesmith the damage had been done by the press conference. On November 13 the Sun demanded sackings, and vowed not to rest until it got them. If Shoesmith wouldn't go, it said, the government had to put in a new boss. "A price must be paid for his little life, and we will not rest until that price has been paid by those responsible."
Ed Balls ordered an independent review, and Haringey council made a formal apology. Sixty-one headteachers wrote to the papers in support of Shoesmith a couple of days later, but they were swept away by a campaign notable for the ugliness it permitted in some of its readers. On 26 November the Sun delivered a petition with 1.2m signatures to Downing Street, demanding that those involved be sacked.
At 6pm on Sunday night 30th November, the independent report was delivered to Balls. It made devastating reading. It identified insufficient strategic leadership and management oversight; failure to ensure full compliance with post-Climbié recommendations; a lack of communication between social care, health and police authorities; a conflict of interest in the serious case review; failing to identify children at immediate risk of harm; inconsistent quality of frontline work; inconsistent and often poor record-keeping; too much reliance on quantitative v qualitative data.
She only realised she had been replaced when Balls announced it on the news, on 1 December. A week later the council announced that she had been dismissed with immediate effect, without compensation, or payment in lieu of notice.
Yesterday Shoesmith won her case for unfair dismissal. Judges at the Court of Appeal said then children's secretary Ed Balls and her employers, Haringey Council, had been "procedurally unfair" when they sacked her three years ago. The judges allowed Ms Shoesmith's appeal against the former children's secretary because "the secretary of state did not afford Ms Shoesmith the opportunity to put her case". In short, she was denied the elementary fairness which the law requires," they said.
They also rejected a submission that the situation had been too urgent to allow for a fairer procedure to be adopted. In the case of Haringey, the judges said: "We were unanimously of the view that Haringey's procedures were tainted by unfairness."
This case is a good example of trial by the media. The doctor concerned with missing Baby P's broken back voluntarily erased herself from the General Medical Register. There have been no disciplinary actions for the police. Sharon Showsmith will not be reinstated but she might receive a hefty financial package of compensation.
But diseases have been done away with. We have vaccines, clean water, warm and dry houses, clean air. Contraception. Children have become few and precious. Almost gods.
So, a child dies in the inner city and someone must be to blame. Baby Peter Connelly, who had been seen 60 times by social services, was found dead in 2007 with over 50 injuries. In this case the culprit is easily found. The mother is dissolute, a wastrel, a self-gratifying good-for nothing with a live-in boyfriend unconcerned for the by-blow of a former beau. And there's a pedophile-rapist brother who's no better. All three set upon baby Peter. They do not feed him, do not care, but use him as an ash tray to stub their cigarettes out on. These three ignorant young people are responsible for intolerable cruelty and they will be punished. They will go to prison.
Surely someone should have done something to stop it. Aren't there social workers whose job it is to prevent this? Don't we all remember the intrusion of health visitors poking their noses when our children were born? They should have been spending their time where they were really needed.
But social work is in a mess in the inner cities. The case load is too high and recruitment is poor. No-one wants to work in the inner cities. They recruit and train people with 'life-skills' rather than with academic qualifications. Then they find that they can't follow the instructions. They take cups of tea with the parents and are easily taken in. Bruises? He fell down the stairs. He's clumsy. It's just what any adventurous child gets. And the doctors are no better. There is pressure on the A&E; they are trying to reduce junior doctors' hours; there are plenty of excuses. Besides, the buck stops somewhere else. As for the police, despite the case being reported to the police, no case officer had been assigned four months later.
Just where does it stop? Sharon Shoesmith had a staff of more than a thousand, a budget of £100 million and an annual salary of £100,000. In the aftermath of the Baby P case she fought to keep all three and refused to resign. At a press conference following the trial of the mother and the two live-in brothers (about whom the social services knew nothing- though a parenting class did and declined to share the information with the social services on the grounds of 'confidentiality') Sharon Shoesmith made a statement that came over very poorly. She was called cold and calculating, arrogant and smug.
Ms Shoesmith, 55, from Co Antrim in Northern Ireland, spent most of her professional life in education rather than social services. She rose from being a teacher to a school inspector and worked in the school improvement division, monitoring schools with serious weaknesses and requiring special measures. When she was appointed by Capita – the private company that oversees the borough’s schools – to be the director of children's services in Haringey in 2005, she promised to lower the number of children who were taken into care by stepping in earlier with help if needed.
There has been a tension in Social Services. There has been much anger about children being taken away from their parents and put into the care of the local authority or with foster parents. Damned if you do; damned if you don't is the position.
Shoesmith stood back from the problem and took an objective view. “It has really shocked me how much of the media has missed the point that this is a horrendous tragedy and everybody obviously is horribly shocked by it, but there is so much blame, there is so much anger and hatred out there.” And indeed the popular press made it a cause celebre.
There must be some doubt as to the wisdom of conflating social work and education under one banner of "Children's Services". Did they do it to beef up the ministry that Ed Balls, late Chief Secretary of the Treasury and a Gordon Brown favorite for future Chancelor, must take while he does his spell in a 'spending ministry'? The idea was generated by the Children Act 2004, which after the Victoria Climbié inquiry recommended that education and safeguarding be combined to increase communication between the two.
But social work and education are very different beasts, and Sharon Shoesmith, with no background in social work was perhaps not a very wise appointment to head up one of the most difficult social work jobs in the UK. Nevres Kemal, a former social worker who gave warning about Haringey council’s social services failings six months before Baby P died, believes that Ms Shoesmith was misled by her managers in the case. She reports having told the director of children’s services: “I’m not going to shut up. You don’t know what is going on in social services, what is being concealed from you.”
The October, after Baby P died, Ofsted gave Haringey a three-star rating out of four, saying it provided a good service for children, but for Shoesmith the damage had been done by the press conference. On November 13 the Sun demanded sackings, and vowed not to rest until it got them. If Shoesmith wouldn't go, it said, the government had to put in a new boss. "A price must be paid for his little life, and we will not rest until that price has been paid by those responsible."
Ed Balls ordered an independent review, and Haringey council made a formal apology. Sixty-one headteachers wrote to the papers in support of Shoesmith a couple of days later, but they were swept away by a campaign notable for the ugliness it permitted in some of its readers. On 26 November the Sun delivered a petition with 1.2m signatures to Downing Street, demanding that those involved be sacked.
At 6pm on Sunday night 30th November, the independent report was delivered to Balls. It made devastating reading. It identified insufficient strategic leadership and management oversight; failure to ensure full compliance with post-Climbié recommendations; a lack of communication between social care, health and police authorities; a conflict of interest in the serious case review; failing to identify children at immediate risk of harm; inconsistent quality of frontline work; inconsistent and often poor record-keeping; too much reliance on quantitative v qualitative data.
She only realised she had been replaced when Balls announced it on the news, on 1 December. A week later the council announced that she had been dismissed with immediate effect, without compensation, or payment in lieu of notice.
Yesterday Shoesmith won her case for unfair dismissal. Judges at the Court of Appeal said then children's secretary Ed Balls and her employers, Haringey Council, had been "procedurally unfair" when they sacked her three years ago. The judges allowed Ms Shoesmith's appeal against the former children's secretary because "the secretary of state did not afford Ms Shoesmith the opportunity to put her case". In short, she was denied the elementary fairness which the law requires," they said.
They also rejected a submission that the situation had been too urgent to allow for a fairer procedure to be adopted. In the case of Haringey, the judges said: "We were unanimously of the view that Haringey's procedures were tainted by unfairness."
This case is a good example of trial by the media. The doctor concerned with missing Baby P's broken back voluntarily erased herself from the General Medical Register. There have been no disciplinary actions for the police. Sharon Showsmith will not be reinstated but she might receive a hefty financial package of compensation.
John 4:3. Good timing
When the Lord learned of this he left Judea and went back once more to Galilee.
Timing is important. A confrontation with the Pharisees was coming, but the time had to be right. The disciples needed their three years apprenticeship. I remember a missionary candidate who was impatient to be on the mission field, disregarding the advice of more experienced Christians about first receiving the appropriate training and plunging ahead. It all ended in tears.
In our Christian life we might need to be as innocent as doves, but sometimes we need to be as wise as serpents.
Timing is important. A confrontation with the Pharisees was coming, but the time had to be right. The disciples needed their three years apprenticeship. I remember a missionary candidate who was impatient to be on the mission field, disregarding the advice of more experienced Christians about first receiving the appropriate training and plunging ahead. It all ended in tears.
In our Christian life we might need to be as innocent as doves, but sometimes we need to be as wise as serpents.
Friday, May 27, 2011
Prolymphocytes; what does the nucleolus do?
Atypical CLL is characterized by the presence of prolymphocytes like this one. These cells are unusual in that they have single prominent nucleoli in their nuclei. That's the light colored circle amongst the dark marron colored middle.The nucleolus is a prominent nuclear structure best known for its central role in the manufacture of ribosomes. When a cell enters division, the nucleoli are taken apart but at the end of cell division they begin to reassemble around clusters of ribosomal RNA genes, called nucleolar organizer regions.
The nucleolus, which is not bound by a membrane, can be divided into three sub-regions: the fibrillar centre, the dense fibrillar component and the granular component. In addition to manufacturing ribosomes, other functions include control of the cell-cycle, cellular stress responses and synthesis of small RNAs and RNA-protein complexes. Over 4,500 proteins are believed to localize to the nucleolus in human cells and these proteins are estimated to represent over 80 % of the total nucleolar proteome.
The nucleolus appears to be highly conserved throughout all life forms, since approximately 90 % of human nucleolar proteins have homologues in yeast. The size and number of nucleoli in human cells vary according to the cell type and the proliferation rate of the cell. Some inherited diseases such as Diamond-Blackfan anemia, dyskeratosis ongenita and Shwachman-Diamond syndrome, all associated with increased risk of cancer, are caused by mutated nucleolar proteins. Consistent with the nucleolus having a significant influence on cell proliferation and growth, disturbances and alterations in its structure and function have been identified in a number of types of cancer but nothing is known about nucleolar function in CLL
Leaks about the NHS Bill
One of the back-bench Tory MPs who sits on the Health committee in Parliament has released this helpful e-mail about how the Tories are thinking about the NHS.
Colleagues,
As you are no doubt aware, there has been widespread media coverage during the 'pause' about the Government's NHS reforms. Coverage has suggested rather concerning change, coming not from within our own ranks but from amongst our coalition partners. I have been closely involved with the Bill at Committee stage and in public, and many colleagues have shared with me their concern that their views need to be counted.
The recent 1922 meeting demonstrated widespread support for the Bill. It is absolutely vital that Conservative backbenchers are able to input into this process, and that our views are not ignored. Thus far, critics of this Bill have made their voices the loudest, but we still have an opportunity to set out clearly Conservative backbenchers' 'red lines' on NHS reform, the principles on which we will not budge.
1. Core 'red lines'
The Conservative Party manifesto – on which we were all elected – does the job of setting out some key red lines from which we should not retreat. These are:
• We must nail the myth about so-called 'privatisation' of the NHS. Our commitment is that the NHS must continue to be free at the point of use, available to all, funded from general taxation, and based on need and not ability to pay. We have always supported this fundamental principle of the NHS and we will not yield on this principle.
• Patients should be able to be treated at any qualified provider. Patients should have every right to be treated at the best possible service, free of charge, on the NHS, if that service meets NHS standards and NHS costs. If a provider is qualified to deliver NHS standards at NHS costs – and a patient, together with their doctor, wants them to be treated there – the Government should do nothing that stands in their way.
• Patients, together with their doctors, should have a choice over where to be treated. Without such a choice, there can never be an incentive to drive up standards in the NHS. However, vested interests will fight to restrict patients' right to choose. Therefore, Monitor must be retained as a regulator to ensure that patients' choices are not being restricted and ensure that their interests are not being harmed.
• There must be no top-down bureaucracy and political micromanagement of the NHS. Making clear that responsibility lies with doctors and nurses on the frontline in itself makes clear that responsibility does not lie with the top-down NHS bureaucracy or with Whitehall. Without the clear division of responsibility, the top-down hierarchy will remain empowered and more money will continue to be spent on bureaucracy rather than on patient care. We have been clear about the date – April 2013 – when statutory responsibility must transfer from the top-down bureaucracy to GP consortia. Contrary to what is being said in public by others, this is a very reasonable period of time. Not to proceed with this division of responsibility puts at risk our aim of releasing £5 billion from NHS administration savings during this Parliament and being able to reinvest it all back into patient care.
• There must be no two-tier NHS. GPs should take charge of commissioning budgets, through consortia, everywhere in the country. To do otherwise would repeat the mistake of GP fundholding – where some areas of the country benefitted from GP commissioning but other areas fell behind. GPs must be given support where they are unable to commission the full range of services, but the network of GP commissioning consortia must be in place by April 2013. The statutory responsibility for ensuring that NHS services are delivered to patients is too important to be fudged.
2. Next Steps
I am keen that our views are heard at the top of government so that the debate is not monopolised by others and would be grateful for your feedback on the red lines and invite you also to share your views on the following if you wish:
• Are there any other red lines which have been omitted from the list?
• What could be included in the Health and Social Care Bill to make sure that future governments cannot undermine the principle of a universal, tax payer-funded NHS without consulting Parliament first?
• Do we need to strengthen mechanisms to ensure that unfair subsidies paid to providers – such as Labour's Independent Sector Treatment Centre programme – cannot be allowed?
• How can we ensure patients have the information they need to make an informed choice?
• What measures can be developed to ensure GPs are fully supported following the transfer of commissioning responsibility in April 2013?
I apologise for the length of this email, but I am determined that we reclaim the debate over the future of the National Health Service from those who seek to use the Bill as a political tool. I intend to share these views as part of the current listening exercise and I look forward to your input.
Kind regards,
Nick de Bois
Colleagues,
As you are no doubt aware, there has been widespread media coverage during the 'pause' about the Government's NHS reforms. Coverage has suggested rather concerning change, coming not from within our own ranks but from amongst our coalition partners. I have been closely involved with the Bill at Committee stage and in public, and many colleagues have shared with me their concern that their views need to be counted.
The recent 1922 meeting demonstrated widespread support for the Bill. It is absolutely vital that Conservative backbenchers are able to input into this process, and that our views are not ignored. Thus far, critics of this Bill have made their voices the loudest, but we still have an opportunity to set out clearly Conservative backbenchers' 'red lines' on NHS reform, the principles on which we will not budge.
1. Core 'red lines'
The Conservative Party manifesto – on which we were all elected – does the job of setting out some key red lines from which we should not retreat. These are:
• We must nail the myth about so-called 'privatisation' of the NHS. Our commitment is that the NHS must continue to be free at the point of use, available to all, funded from general taxation, and based on need and not ability to pay. We have always supported this fundamental principle of the NHS and we will not yield on this principle.
• Patients should be able to be treated at any qualified provider. Patients should have every right to be treated at the best possible service, free of charge, on the NHS, if that service meets NHS standards and NHS costs. If a provider is qualified to deliver NHS standards at NHS costs – and a patient, together with their doctor, wants them to be treated there – the Government should do nothing that stands in their way.
• Patients, together with their doctors, should have a choice over where to be treated. Without such a choice, there can never be an incentive to drive up standards in the NHS. However, vested interests will fight to restrict patients' right to choose. Therefore, Monitor must be retained as a regulator to ensure that patients' choices are not being restricted and ensure that their interests are not being harmed.
• There must be no top-down bureaucracy and political micromanagement of the NHS. Making clear that responsibility lies with doctors and nurses on the frontline in itself makes clear that responsibility does not lie with the top-down NHS bureaucracy or with Whitehall. Without the clear division of responsibility, the top-down hierarchy will remain empowered and more money will continue to be spent on bureaucracy rather than on patient care. We have been clear about the date – April 2013 – when statutory responsibility must transfer from the top-down bureaucracy to GP consortia. Contrary to what is being said in public by others, this is a very reasonable period of time. Not to proceed with this division of responsibility puts at risk our aim of releasing £5 billion from NHS administration savings during this Parliament and being able to reinvest it all back into patient care.
• There must be no two-tier NHS. GPs should take charge of commissioning budgets, through consortia, everywhere in the country. To do otherwise would repeat the mistake of GP fundholding – where some areas of the country benefitted from GP commissioning but other areas fell behind. GPs must be given support where they are unable to commission the full range of services, but the network of GP commissioning consortia must be in place by April 2013. The statutory responsibility for ensuring that NHS services are delivered to patients is too important to be fudged.
2. Next Steps
I am keen that our views are heard at the top of government so that the debate is not monopolised by others and would be grateful for your feedback on the red lines and invite you also to share your views on the following if you wish:
• Are there any other red lines which have been omitted from the list?
• What could be included in the Health and Social Care Bill to make sure that future governments cannot undermine the principle of a universal, tax payer-funded NHS without consulting Parliament first?
• Do we need to strengthen mechanisms to ensure that unfair subsidies paid to providers – such as Labour's Independent Sector Treatment Centre programme – cannot be allowed?
• How can we ensure patients have the information they need to make an informed choice?
• What measures can be developed to ensure GPs are fully supported following the transfer of commissioning responsibility in April 2013?
I apologise for the length of this email, but I am determined that we reclaim the debate over the future of the National Health Service from those who seek to use the Bill as a political tool. I intend to share these views as part of the current listening exercise and I look forward to your input.
Kind regards,
Nick de Bois
John 4:1-2 The invention of lying
The Pharisees heard that Jesus was gaining and baptizing more disciples than John although in fact it was not Jesus who baptized but his disciples.
So the Jews were lying when they tried to make John jealous. The Devil always was the father of lies.
Lying is almost universally condemned in Scripture. "Thou shalt not bear false witness." Yet there are circumstances when a lie is justified. We would surely not betray RAF pilots shot down over France to the Gestapo. Kant believed that it was always possible to avoid the outright lie by giving an oblique answer, but if the intention is still to deceive, where is the difference?
My own view is that some people by their actions have frittered away their right to be told the truth. Perhaps the best example in Scripture is Pharaoh who was asked by Moses to be just allowed to worship the Lord in the Desert when his real intention was to lead the Exodus from Egypt. Pharaoh by hardening his heart and stiffening his neck against the Lord's demands had sacrificed his right to the truth.
We often justify a lie by calling it a white lie when its purpose is to let someone down lightly rather than face the bleakness of the truth.
Do I look fat in this dress? There is no answer to that.
So the Jews were lying when they tried to make John jealous. The Devil always was the father of lies.
Lying is almost universally condemned in Scripture. "Thou shalt not bear false witness." Yet there are circumstances when a lie is justified. We would surely not betray RAF pilots shot down over France to the Gestapo. Kant believed that it was always possible to avoid the outright lie by giving an oblique answer, but if the intention is still to deceive, where is the difference?
My own view is that some people by their actions have frittered away their right to be told the truth. Perhaps the best example in Scripture is Pharaoh who was asked by Moses to be just allowed to worship the Lord in the Desert when his real intention was to lead the Exodus from Egypt. Pharaoh by hardening his heart and stiffening his neck against the Lord's demands had sacrificed his right to the truth.
We often justify a lie by calling it a white lie when its purpose is to let someone down lightly rather than face the bleakness of the truth.
Do I look fat in this dress? There is no answer to that.
Thursday, May 26, 2011
John 3:35-36.
The Father loves the Son and has placed everything in his hands. Whoever believes in the Son has eternal life, but whoever rejects the Son will not see life, for God’s wrath remains on them.
Here is a plain statement of the gospel. God's wrath is on his creation since Adam's sin. How can we make things better? By obeying the Law. By trying harder. By turning over a new leaf. By being good.
None of these things is at all useful. Whoever believes the Son will have everlasting life. Rejecting the Son and living a 'beautiful' life is futile.
Here is a plain statement of the gospel. God's wrath is on his creation since Adam's sin. How can we make things better? By obeying the Law. By trying harder. By turning over a new leaf. By being good.
None of these things is at all useful. Whoever believes the Son will have everlasting life. Rejecting the Son and living a 'beautiful' life is futile.
VEGF and PKC beta. Effects on BCR signals.
I am grateful to Wayne for drawing my attention to a paper I missed from last June. It is a signaling paper which fills in some of the gaps in the complicated arrangement that CLL cells have to send messages from the BCR. It has already been established that one component of the signal is protein kinase C beta (PKC beta). This molecule is up-regulated in CLL and is involved in determining the signaling strength of the receptor. It has a double effect. It sends an anti-apoptotic message from the BCR so as to keep the CLL cell alive, but also limits the signaling strength of BCR crosslinking. This is important, because a strong signal from the BCR triggers apoptosis in B cells as part of the mechanism to stop the body making antibodies against itself..
It has been shown in the TCL1 mouse model that deleting the gene for PCK beta prevents full blown CLL developing in the animal. As an aside, when we considering how ZAP-70 works in CLL we noted that it does not itself transmit the signal, that is the role of syk, but it enhances syk signaling. It appears that it does this by recruiting PCK beta into lipid rafts.
The new information concerns vascular endothelial growth factor. When I was working with Steve Devereux at Kings, we had some evidence that VEGF is concerned with the formation of proliferation centers in the lymph nodes and we actually proposed a trial of bevacizumab in CLL to the British CLL trials organization. It was turned down, which was just as well, since trials in Germany and at the Mayo have shown no benefit for this drug. The Mayo has shown that VEGF enhances survival of CLL cells in the test tube by modulating components of the apoptosis machinery and that VEGF levels correlate with response to chemoimmunotherapy.
This essay in Blood refers to a new British paper in the same issue by Abrams et al. VEGF levels are higher in patients with unmutated IGHV genes. The interaction between CLL cells and VEGF seems to occur in CD38 positive cells and there may be a role in limiting CLL cell migration away from proliferation centers. Abrams et al propose a mechanism by which VEGF optimizes the |BCR/PCK beta signal so as to prevent it triggering pro-apoptotic signals and enhance anti-apoptotic signals.
It has been shown in the TCL1 mouse model that deleting the gene for PCK beta prevents full blown CLL developing in the animal. As an aside, when we considering how ZAP-70 works in CLL we noted that it does not itself transmit the signal, that is the role of syk, but it enhances syk signaling. It appears that it does this by recruiting PCK beta into lipid rafts.
The new information concerns vascular endothelial growth factor. When I was working with Steve Devereux at Kings, we had some evidence that VEGF is concerned with the formation of proliferation centers in the lymph nodes and we actually proposed a trial of bevacizumab in CLL to the British CLL trials organization. It was turned down, which was just as well, since trials in Germany and at the Mayo have shown no benefit for this drug. The Mayo has shown that VEGF enhances survival of CLL cells in the test tube by modulating components of the apoptosis machinery and that VEGF levels correlate with response to chemoimmunotherapy.
This essay in Blood refers to a new British paper in the same issue by Abrams et al. VEGF levels are higher in patients with unmutated IGHV genes. The interaction between CLL cells and VEGF seems to occur in CD38 positive cells and there may be a role in limiting CLL cell migration away from proliferation centers. Abrams et al propose a mechanism by which VEGF optimizes the |BCR/PCK beta signal so as to prevent it triggering pro-apoptotic signals and enhance anti-apoptotic signals.
MBL versus SLL
One of the questions that I have been asked is how one distinguishes between MBL and SLL. To recap on the problem, monoclonal B cell lymphocytosis (MBL) is the appearance in the blood of monoclonal B cells with the morphological and immunophenotypic characteristics of CLL cells but at numbers lower than 5 x 10e9 per liter. SLL or small lymphocytic lymphoma is a form of CLL in which the tumor does not appear in the blood but is present in the lymph nodes.
The question to be asked is whether there is a form of SLL that is really equivalent to MBL in that the amount of disease present in the lymph nodes is so small that it should not really be called or treated as a CLL equivalent.
An attempt at an answer has come from Philadelphia and Boston and has been published on line in Haematologica
The 2008 WHO Classification definition of CLL requires ≥5 x 10e9/L peripheral blood monoclonal B-cells with a CLL-phenotype. The 2008 IWCLL paper allows the diagnosis also to be made with lower MBC counts if the patient has cytopenias or symptoms attributable to the CLL. Patients who in the past would have been diagnosed with CLL but who no longer fulfil these new criteria are now classified as MBL with a CLL phenotype. Using highly sensitive flow cytometry techniques, MBL has been identified in up to 12% of adults with normal blood counts. While the vast majority of MBL patients maintain stable counts over time, a small proportion progress to CLL at a rate of approximately 1-2% per year. This figure is very dependent on the height of the B-cell count and the progression rate is very much smaller for those whose B-cell counts can only be detected by the most sensitive flow cytometry tests. Various studies have placed the B-cell thresholds that best predict the risk of progression, treatment-free survival and overall survival at from 1.2x10e9/L to 11x10e9/L.
The IWCLL report states that in CLL lymphocytes typically comprise more than 30% of nucleated cells in the bone marrow trephine of normal celluarity. However, bone marrow examination is not recommended at the time of the diagnosis of CLL, and the guidelines do not specify a level of bone marrow involvement that would discriminate between MBL and CLL. Neither the WHO nor IWCLL provide guidelines defining the minimal level of tissue involvement that would qualify for a diagnosis of SLL.
While palpable lymphadenopathy and/or splenomegaly are considered exclusion criteria for MBL, these criteria are not part of the WHO or IWCLL definitions of SLL and the diagnosis of SLL can therefore be made without regard to the extent of nodal involvement.
The authors have studied the clinicopathologic features of 36 extramedullary tissue biopsies (34 lymph nodes and 2 extranodal sites) containing monoclonal B cells with a CLL phenotype, but with less than 5 x 10e9/L monoclonal B cells in the peripheral blood, in order to determine if a subset of these cases might represent a more indolent disorder than SLL (i.e. a tissue equivalent of MBL).
In 16 patients, the tissue was biopsied for reasons other than to evaluate palpable lymphadenopathy. These tissues included 9 lymph nodes removed during staging for carcinoma or melanoma, 4 removed during surgery for benign diseases, and 1 removed when lymphadenopathy was detected on imaging studies performed to evaluate another process, as well as 2 extranodal tissue biopsies (one nasal biopsy in a patient with nasal obstruction without a mass and one breast biopsy performed to evaluate breast calcification without a mass). After the tissue diagnosis was made the doctors went on to find palpable lymphadenopathy on physical examination in 8 of these 16 patients. Twenty other patients underwent lymph node biopsies because they had disease that could be felt. It was localized in 14 cases and more extensive in 6 cases.
On CT scanning lymph nodes enlarged to >1 cm were detected in 32/36 (90%) patients and involved 3 or more lymph node regions in 22/36 patients (61%). In comparison, only 2/10 (20%) clinical MBL patients diagnosed on peripheral blood flow cytometry had any enlarged lymph nodes detected on CT scans. Combining physical exam and CT studies, 34/36 patients (94%) had detectable lymphadenopathy. Three patients had splenomegaly, while hepatomegaly was not identified in any patients. Bone marrow involvement was identified in 10/10 patients who underwent a bone marrow biopsy. The extent of bone marrow involvement varied from less than 5% to over 50% (median 30%) of the biopsy cellularity.
Among the 28 patients with palpable lymphadenopathy, 23 were Rai Stage I, 2 were Stage II, and 3 were Stage III (5 patients were anemic with hemoglobin <11 gm/dL, but in two cases the anemia was attributable to causes other than CLL/SLL). Twenty-five patients were Binet stage A and 3 patients Binet stage B. Rai and Binet staging was not applicable in the 8 patients lacking palpable lymphadenopathy. Among these 8 (22%) patients, all 4 examined by PB flow cytometry would have been classified as clinical MBL according to IWCLL (because lymphadenopathy or splenomegaly were absent or only detectable on imaging studies), while flow cytometry was not performed in the other 4 patients.
Thus the patients studied would mainly have been diagnosed as SLL rather than MBL, though a fifth would probably have been called MBL.
Five patients were treated for CLL/SLL. These included 2 patients treated within one month of diagnosis due to symptomatic disease (progressive myopathy attributed to CLL cell infiltration in one patient and bulky lymphadenopathy in the other) and 3 patients treated for disease progression at 5, 19, and 19 months following diagnosis. After a median follow up time of 26 months, an additional 7 patients developed progression (new or increasing lymphadenopathy on physical exam and/or CT studies) but were not treated during the follow-up period. The median time to lymph node progression in these 7 patients and the 3 patients treated for progression was 22 months (range 4 – 53 months). At last follow-up, 24 patients had no evidence of progressive lymphadenopathy and remained untreated. No patients died due to CLL/SLL.
Over the follow-up period, the peripheral blood ALC remained <5.0x109/L in 25/36 patients (69%), all of whom had CBC results available at the latest follow up. Eight of the remaining 11 patients at least doubled their ALC at a median of 27 months after diagnosis (range 3-104 months).
The following indicators showed no association with progression/treatment: age; sex; Rai or Binet stage; number of involved lymph node sites; palpable lymphadenopathy on physical exam; splenomegaly; or IPI score. There was no association between any hematologic measurements, including ALC and absolute monoclonal B cell count at diagnosis, and progression/treatment. There were no statistically significant differences in the size of the biopsied lymph node, nor were maximal lymph node diameters of greater than 1 cm, 1.5 cm, or 3 cm associated with progression or treatment. However, detection of any lymph node ≥ 1.5 cm in diameter on CT staging studies was associated with progression/treatment and the largest lymph node size measured on CT at diagnosis was greater in patients who subsequently experienced progression or were treated. The degree of histological or flow cytometric involvement of the biopsied tissue by CLL/SLL was not associated with progression/treatment.
The only histological parameter that was associated with rogression/treatment was the presence of proliferation centers, which were found in all 12 patients who progressed or required therapy but in only 9/18 (50%) of patients who did not progress. There was no significant difference in CD38 or ZAP-70 expression between those who did or did not progress or require therapy.
So, what they are saying is that there is less likely to be progression in SLL if there is no lymphadenopathy on CT scanning and there are no proliferation centers in the lymph node biopsy. Though, of course, CT scanning is not recommended. One recent study found that CT-detected abdominal lymphadenopathy in Rai Stage 0 CLL predicted
progression and earlier treatment requirement, so perhaps this question will have to be revisited in the future. Exactly who should have an abdominal CT scan. The authors suggest that CT staging of patients with CLL/SLL cells identified
in tissue biopsies may help in identifying patients more likely to progress. Rossi and colleagues identified 19 patients (15%) with clinical MBL who progressed to SLL after a median of 42.7 months (Br J Haematol. 2009;146:64-75).
The question to be asked is whether there is a form of SLL that is really equivalent to MBL in that the amount of disease present in the lymph nodes is so small that it should not really be called or treated as a CLL equivalent.
An attempt at an answer has come from Philadelphia and Boston and has been published on line in Haematologica
The 2008 WHO Classification definition of CLL requires ≥5 x 10e9/L peripheral blood monoclonal B-cells with a CLL-phenotype. The 2008 IWCLL paper allows the diagnosis also to be made with lower MBC counts if the patient has cytopenias or symptoms attributable to the CLL. Patients who in the past would have been diagnosed with CLL but who no longer fulfil these new criteria are now classified as MBL with a CLL phenotype. Using highly sensitive flow cytometry techniques, MBL has been identified in up to 12% of adults with normal blood counts. While the vast majority of MBL patients maintain stable counts over time, a small proportion progress to CLL at a rate of approximately 1-2% per year. This figure is very dependent on the height of the B-cell count and the progression rate is very much smaller for those whose B-cell counts can only be detected by the most sensitive flow cytometry tests. Various studies have placed the B-cell thresholds that best predict the risk of progression, treatment-free survival and overall survival at from 1.2x10e9/L to 11x10e9/L.
The IWCLL report states that in CLL lymphocytes typically comprise more than 30% of nucleated cells in the bone marrow trephine of normal celluarity. However, bone marrow examination is not recommended at the time of the diagnosis of CLL, and the guidelines do not specify a level of bone marrow involvement that would discriminate between MBL and CLL. Neither the WHO nor IWCLL provide guidelines defining the minimal level of tissue involvement that would qualify for a diagnosis of SLL.
While palpable lymphadenopathy and/or splenomegaly are considered exclusion criteria for MBL, these criteria are not part of the WHO or IWCLL definitions of SLL and the diagnosis of SLL can therefore be made without regard to the extent of nodal involvement.
The authors have studied the clinicopathologic features of 36 extramedullary tissue biopsies (34 lymph nodes and 2 extranodal sites) containing monoclonal B cells with a CLL phenotype, but with less than 5 x 10e9/L monoclonal B cells in the peripheral blood, in order to determine if a subset of these cases might represent a more indolent disorder than SLL (i.e. a tissue equivalent of MBL).
In 16 patients, the tissue was biopsied for reasons other than to evaluate palpable lymphadenopathy. These tissues included 9 lymph nodes removed during staging for carcinoma or melanoma, 4 removed during surgery for benign diseases, and 1 removed when lymphadenopathy was detected on imaging studies performed to evaluate another process, as well as 2 extranodal tissue biopsies (one nasal biopsy in a patient with nasal obstruction without a mass and one breast biopsy performed to evaluate breast calcification without a mass). After the tissue diagnosis was made the doctors went on to find palpable lymphadenopathy on physical examination in 8 of these 16 patients. Twenty other patients underwent lymph node biopsies because they had disease that could be felt. It was localized in 14 cases and more extensive in 6 cases.
On CT scanning lymph nodes enlarged to >1 cm were detected in 32/36 (90%) patients and involved 3 or more lymph node regions in 22/36 patients (61%). In comparison, only 2/10 (20%) clinical MBL patients diagnosed on peripheral blood flow cytometry had any enlarged lymph nodes detected on CT scans. Combining physical exam and CT studies, 34/36 patients (94%) had detectable lymphadenopathy. Three patients had splenomegaly, while hepatomegaly was not identified in any patients. Bone marrow involvement was identified in 10/10 patients who underwent a bone marrow biopsy. The extent of bone marrow involvement varied from less than 5% to over 50% (median 30%) of the biopsy cellularity.
Among the 28 patients with palpable lymphadenopathy, 23 were Rai Stage I, 2 were Stage II, and 3 were Stage III (5 patients were anemic with hemoglobin <11 gm/dL, but in two cases the anemia was attributable to causes other than CLL/SLL). Twenty-five patients were Binet stage A and 3 patients Binet stage B. Rai and Binet staging was not applicable in the 8 patients lacking palpable lymphadenopathy. Among these 8 (22%) patients, all 4 examined by PB flow cytometry would have been classified as clinical MBL according to IWCLL (because lymphadenopathy or splenomegaly were absent or only detectable on imaging studies), while flow cytometry was not performed in the other 4 patients.
Thus the patients studied would mainly have been diagnosed as SLL rather than MBL, though a fifth would probably have been called MBL.
Five patients were treated for CLL/SLL. These included 2 patients treated within one month of diagnosis due to symptomatic disease (progressive myopathy attributed to CLL cell infiltration in one patient and bulky lymphadenopathy in the other) and 3 patients treated for disease progression at 5, 19, and 19 months following diagnosis. After a median follow up time of 26 months, an additional 7 patients developed progression (new or increasing lymphadenopathy on physical exam and/or CT studies) but were not treated during the follow-up period. The median time to lymph node progression in these 7 patients and the 3 patients treated for progression was 22 months (range 4 – 53 months). At last follow-up, 24 patients had no evidence of progressive lymphadenopathy and remained untreated. No patients died due to CLL/SLL.
Over the follow-up period, the peripheral blood ALC remained <5.0x109/L in 25/36 patients (69%), all of whom had CBC results available at the latest follow up. Eight of the remaining 11 patients at least doubled their ALC at a median of 27 months after diagnosis (range 3-104 months).
The following indicators showed no association with progression/treatment: age; sex; Rai or Binet stage; number of involved lymph node sites; palpable lymphadenopathy on physical exam; splenomegaly; or IPI score. There was no association between any hematologic measurements, including ALC and absolute monoclonal B cell count at diagnosis, and progression/treatment. There were no statistically significant differences in the size of the biopsied lymph node, nor were maximal lymph node diameters of greater than 1 cm, 1.5 cm, or 3 cm associated with progression or treatment. However, detection of any lymph node ≥ 1.5 cm in diameter on CT staging studies was associated with progression/treatment and the largest lymph node size measured on CT at diagnosis was greater in patients who subsequently experienced progression or were treated. The degree of histological or flow cytometric involvement of the biopsied tissue by CLL/SLL was not associated with progression/treatment.
The only histological parameter that was associated with rogression/treatment was the presence of proliferation centers, which were found in all 12 patients who progressed or required therapy but in only 9/18 (50%) of patients who did not progress. There was no significant difference in CD38 or ZAP-70 expression between those who did or did not progress or require therapy.
So, what they are saying is that there is less likely to be progression in SLL if there is no lymphadenopathy on CT scanning and there are no proliferation centers in the lymph node biopsy. Though, of course, CT scanning is not recommended. One recent study found that CT-detected abdominal lymphadenopathy in Rai Stage 0 CLL predicted
progression and earlier treatment requirement, so perhaps this question will have to be revisited in the future. Exactly who should have an abdominal CT scan. The authors suggest that CT staging of patients with CLL/SLL cells identified
in tissue biopsies may help in identifying patients more likely to progress. Rossi and colleagues identified 19 patients (15%) with clinical MBL who progressed to SLL after a median of 42.7 months (Br J Haematol. 2009;146:64-75).
Wednesday, May 25, 2011
Country retreats
We had an all time record for page views on Monday with 779. I was not here to see it, though, as I visited my younger son, the Formula 1 engineer, at his home on the Warwickshire, Northamptonshire, Oxfordshire border. This was the first time I had been there and I was very impressed by his house which was started in the 18th Century, added to in the 19the Century and completed in the 21st Century. He has a beautiful garden full of herbaceous borders and the surrounding countryside is delightful.
He seems fully integrated into village life, playing for the village cricket team and even mowing the country churchyard once a week. He has met the Lord of the Manor who is one of the Cecil family. They were running things at the time of the first Queen Elizabeth.
I spent 5 hours driving and managed it very well. Clearly my health is improving. We also went for a 45 minute walk with the dog. Several of the roads in this part of the country are unmetalled and difficult to distinguish from farmers' fields. The weather kept well for the most part although he actually had some rain, which has been a rare event this spring.
He had some news on the job front. He is not going to be traveling so much next year. He has had three years of attending most of the Grand Prix around the world, but it looks as though Brazil we be his last. Next year he is will be promoted to the Board of the Company at double the salary. Hasn't he done well! He will be just 31.
He seems fully integrated into village life, playing for the village cricket team and even mowing the country churchyard once a week. He has met the Lord of the Manor who is one of the Cecil family. They were running things at the time of the first Queen Elizabeth.
I spent 5 hours driving and managed it very well. Clearly my health is improving. We also went for a 45 minute walk with the dog. Several of the roads in this part of the country are unmetalled and difficult to distinguish from farmers' fields. The weather kept well for the most part although he actually had some rain, which has been a rare event this spring.
He had some news on the job front. He is not going to be traveling so much next year. He has had three years of attending most of the Grand Prix around the world, but it looks as though Brazil we be his last. Next year he is will be promoted to the Board of the Company at double the salary. Hasn't he done well! He will be just 31.
John 3: 31-34
The one who comes from above is above all; the one who is from the earth belongs to the earth, and speaks as one from the earth. The one who comes from heaven is above all. He testifies to what he has seen and heard, but no one accepts his testimony. Whoever has accepted it has certified that God is truthful. For the one whom God has sent speaks the words of God, for God gives the Spirit without limit.
John's testimony about Jesus is this: His life did not begin at conception; he had a former life in heaven. His origin is higher than ours (don't get hung up over heaven being equated with the sky; accept 'heaven' as a ranking metaphor). Being from a 'higher' medium, Jesus has greater knowledge than us who speak only of what we know from experience on earth. More than simply knowing more than us, Jesus doesn't keep silent about what he knows; he speaks the word of God. We who are atheists, do not accept this truth, but some do and to those who accept the words of God receive the Holy Spirit without limit. What we know about the Holy Spirit is that he points to Jesus and sustains our faith in him.
John's testimony about Jesus is this: His life did not begin at conception; he had a former life in heaven. His origin is higher than ours (don't get hung up over heaven being equated with the sky; accept 'heaven' as a ranking metaphor). Being from a 'higher' medium, Jesus has greater knowledge than us who speak only of what we know from experience on earth. More than simply knowing more than us, Jesus doesn't keep silent about what he knows; he speaks the word of God. We who are atheists, do not accept this truth, but some do and to those who accept the words of God receive the Holy Spirit without limit. What we know about the Holy Spirit is that he points to Jesus and sustains our faith in him.
The insecure platform of science
In today's New Scientist are a series of remarkable articles on things that scientists have got wrong. I have quoted verbatim from the one about genes, but there are eight others taking in the periodic table, the classification of vertebrates, nuclear fission, hydrogen bonds, the limits of microscope optics, the number of separate species in the world, magnetism, and Einsteinian physics.
What defines life's building blocks? It depends who you ask, says Michael Le Page
As Gregor Mendel showed in painstaking experiments on peas in the 19th century, many traits of living things are all or nothing. Seeds are either green or yellow, round or wrinkled, and so on. This led to the idea that an organism's characteristics are determined by discrete “particles” passed from one generation to the next: genes.
But what is a gene? This question seemed to be settled with the discovery of the function of DNA in the 1950s. A gene, biologists agreed, was a DNA sequence that encoded the instructions for making a protein, the molecules that do all the work in living things.
Half a century on, such harmony has vanished. We now know that single “gene” can consist of dozens of distinct DNA segments that can be combined to make thousands of different proteins; that overlapping DNA sequences can encode quite distinct proteins; and that a few proteins are encoded by combining pieces of what were regarded as separate genes.
Even more confusingly, we are discovering ever more DNA sequences that are not blueprints for making proteins, but instead code for RNA molecules that carry out various functions directly. “If you open the door to RNA, it gets much more complicated,” says Mark Gerstein, a bioinformatics researcher at Yale University.
Reverting to an updated version of the original idea, and defining a gene simply as a DNA segment that affects the characteristics of offspring – by whatever means – doesn't help. That's because it would mean the inclusion not just of protein or RNA-encoding DNA segments, but also a myriad of regulatory DNA sequences that switch those segments' activity on or off.
These days, then, what a gene is depends on who you ask. Gerstein has suggested it be defined, in simplified terms, as a union of sequences that encodes one or more “functional products”. But he readily admits this is a fudge. “What is function?” he asks. “What does it mean?” A gene that is important for survival in one species may have become redundant in a closely related strain, for instance, even though the sequence is identical. Does that make it a gene in one species and not in the other?
It seems that unless you are an expert in a particular field you are operating in science with an enormous fudge factor. Science is fluid. There is no truth, just a succession of theories. When the facts change I change my mind, said Maynard Keynes. It seems he wasn't the only one.
What defines life's building blocks? It depends who you ask, says Michael Le Page
As Gregor Mendel showed in painstaking experiments on peas in the 19th century, many traits of living things are all or nothing. Seeds are either green or yellow, round or wrinkled, and so on. This led to the idea that an organism's characteristics are determined by discrete “particles” passed from one generation to the next: genes.
But what is a gene? This question seemed to be settled with the discovery of the function of DNA in the 1950s. A gene, biologists agreed, was a DNA sequence that encoded the instructions for making a protein, the molecules that do all the work in living things.
Half a century on, such harmony has vanished. We now know that single “gene” can consist of dozens of distinct DNA segments that can be combined to make thousands of different proteins; that overlapping DNA sequences can encode quite distinct proteins; and that a few proteins are encoded by combining pieces of what were regarded as separate genes.
Even more confusingly, we are discovering ever more DNA sequences that are not blueprints for making proteins, but instead code for RNA molecules that carry out various functions directly. “If you open the door to RNA, it gets much more complicated,” says Mark Gerstein, a bioinformatics researcher at Yale University.
Reverting to an updated version of the original idea, and defining a gene simply as a DNA segment that affects the characteristics of offspring – by whatever means – doesn't help. That's because it would mean the inclusion not just of protein or RNA-encoding DNA segments, but also a myriad of regulatory DNA sequences that switch those segments' activity on or off.
These days, then, what a gene is depends on who you ask. Gerstein has suggested it be defined, in simplified terms, as a union of sequences that encodes one or more “functional products”. But he readily admits this is a fudge. “What is function?” he asks. “What does it mean?” A gene that is important for survival in one species may have become redundant in a closely related strain, for instance, even though the sequence is identical. Does that make it a gene in one species and not in the other?
It seems that unless you are an expert in a particular field you are operating in science with an enormous fudge factor. Science is fluid. There is no truth, just a succession of theories. When the facts change I change my mind, said Maynard Keynes. It seems he wasn't the only one.
Tuesday, May 24, 2011
The Mighty are fallen.
Surpassing even the visit of President Obama, the news has been dominated by injunctions obtained by the rich and famous to stop newspapers publishing gossip about their sexual indiscretions. In France, as we have seen, private things are kept private. In the UK libel has always had a public interest defence. The newspapers are confused by what it is in the interest of the public to know, usually 'them' misusing our money, and what the public would be interested to know, namely scandal and gossip. It is this that sells newspapers.
Of course, injunctions issued by English courts have no power over different countries and once the news is out somewhere else it soon spreads to England. In the latest case Ryan Giggs, a Manchester United footballer of high reputation and a married man with children, is alleged to have had an affair with a former Miss Wales. Coincidentally he has been the best footballer for Wales for many years.
I suppose most people would be more concerned over whether Ryan Giggs plays well in the Champion's League Final against Barcelona next Saturday at Wembley and this publicity may well unsettle him. I guess if Manchester United win, all will be forgiven; if they lose he may well be blamed despite his 12 Premier League titles.
I wonder how Lance Armstrong feels at the moment?
Of course, injunctions issued by English courts have no power over different countries and once the news is out somewhere else it soon spreads to England. In the latest case Ryan Giggs, a Manchester United footballer of high reputation and a married man with children, is alleged to have had an affair with a former Miss Wales. Coincidentally he has been the best footballer for Wales for many years.
I suppose most people would be more concerned over whether Ryan Giggs plays well in the Champion's League Final against Barcelona next Saturday at Wembley and this publicity may well unsettle him. I guess if Manchester United win, all will be forgiven; if they lose he may well be blamed despite his 12 Premier League titles.
I wonder how Lance Armstrong feels at the moment?
How does GA101 work?
My old colleagues Tim Illidge, Mark Cragg and Martin Glennie have published their recent work on the new anti-CD20 monoclonal antibody, GA101, in a recent edition of Blood. http://bloodjournal.hematologylibrary.org/content/117/17/4519.abstract
GA101 is a fully humanized, type II, properly glycosolated monoclonal, which has been enginered to produce better killing than rituximab.
Anti-CD20 monoclonals invoke a wide range of killing methods, chief among them being antibody dependent cellular cytotoxicity (ADCC), but also phagocytosis mediated by macrophages and/or NK cells through the Fc gamma receptor link, complement dependent cytotoxicity (CDC) and sometimes direct induction of programmed cell death (PCD). PCD certainly does not play a significant part in rituximab killing, but is it important for other anti-CD20 monoclonals?
They have compared GA101 with rituximab against a panel of B-lymphoma cell lines. This shows that GA101 is much better at PCD than rituximab, even when the Fc part of teh molecule is removed. PCD seems to require what they call homotypic adhesion, which simply means that the lymphoma cells aggregate together when exposed to the antibody. The aggregation of the lymphoma cells causes alterations to the actin cytoskeleton of the cells. The actin molecules move to the points of cell to cell contact and if this is chemically inhibited then PCD is deiminished.
Next they showed that the actin-dependent death was independent of apoptosis, and could still work in apoptosis-resistent cells. Lysosymes are involved in PCD. It appears that GA101 induces lysosomal membrane permeabilization and cathepsin-mediated cell death. Cathepsin B is a classic lysosomal protease.
So how does GA101 fit into the pantheon of monoclonal anti-CD20s? It binds to a very sinilar site on the larger loop of the CD20 molecule (in contrast to ofatumumab which binds to the smaller loop). However, recent crystallographic evidence shows that it binds with a completely different orientation to rituximab. How exactly the aggregation of lymphoma cells in response to antibody coating occurs is not clear. It certainly requires bivalency, but the FC portion of the antibody is not required.
Another unexplained phenomnon is the fact that not all cells are killed by PCD, yet when the surviving cells are washed and retested they are killed in the same proportion; they have not acquired resistance.
GA101 is not the only monoclonal capable of triggering such severe actin relocalization; again it is not clear why it does so.
Lysosome function as cellular recycling and waste didposal units by degrading organelles and macromolecules delivered to the lysosomal compartment by autophagy, endocytosis and phagocytosis. They carry over 50 different degradation enzymes. If they leak they destroy the cell that conatins them in a non-apoptotic way. Again the link between actin repositioning and lysosomal permeabilization is missing.
All this work should not detract from the fact that GA101 has been glycoengineered to produce enhanced ADCC, but it does appear that it has a second string to its bow; one that should overcome the need for a TP53 pathway and therefore GA101 may prove to be effective in drug resistant CLL.
GA101 is a fully humanized, type II, properly glycosolated monoclonal, which has been enginered to produce better killing than rituximab.
Anti-CD20 monoclonals invoke a wide range of killing methods, chief among them being antibody dependent cellular cytotoxicity (ADCC), but also phagocytosis mediated by macrophages and/or NK cells through the Fc gamma receptor link, complement dependent cytotoxicity (CDC) and sometimes direct induction of programmed cell death (PCD). PCD certainly does not play a significant part in rituximab killing, but is it important for other anti-CD20 monoclonals?
They have compared GA101 with rituximab against a panel of B-lymphoma cell lines. This shows that GA101 is much better at PCD than rituximab, even when the Fc part of teh molecule is removed. PCD seems to require what they call homotypic adhesion, which simply means that the lymphoma cells aggregate together when exposed to the antibody. The aggregation of the lymphoma cells causes alterations to the actin cytoskeleton of the cells. The actin molecules move to the points of cell to cell contact and if this is chemically inhibited then PCD is deiminished.
Next they showed that the actin-dependent death was independent of apoptosis, and could still work in apoptosis-resistent cells. Lysosymes are involved in PCD. It appears that GA101 induces lysosomal membrane permeabilization and cathepsin-mediated cell death. Cathepsin B is a classic lysosomal protease.
So how does GA101 fit into the pantheon of monoclonal anti-CD20s? It binds to a very sinilar site on the larger loop of the CD20 molecule (in contrast to ofatumumab which binds to the smaller loop). However, recent crystallographic evidence shows that it binds with a completely different orientation to rituximab. How exactly the aggregation of lymphoma cells in response to antibody coating occurs is not clear. It certainly requires bivalency, but the FC portion of the antibody is not required.
Another unexplained phenomnon is the fact that not all cells are killed by PCD, yet when the surviving cells are washed and retested they are killed in the same proportion; they have not acquired resistance.
GA101 is not the only monoclonal capable of triggering such severe actin relocalization; again it is not clear why it does so.
Lysosome function as cellular recycling and waste didposal units by degrading organelles and macromolecules delivered to the lysosomal compartment by autophagy, endocytosis and phagocytosis. They carry over 50 different degradation enzymes. If they leak they destroy the cell that conatins them in a non-apoptotic way. Again the link between actin repositioning and lysosomal permeabilization is missing.
All this work should not detract from the fact that GA101 has been glycoengineered to produce enhanced ADCC, but it does appear that it has a second string to its bow; one that should overcome the need for a TP53 pathway and therefore GA101 may prove to be effective in drug resistant CLL.
John 3:27-30
To this John replied, “A person can receive only what is given them from heaven. You yourselves can testify that I said, ‘I am not the Messiah but am sent ahead of him.’ The bride belongs to the bridegroom. The friend who attends the bridegroom waits and listens for him, and is full of joy when he hears the bridegroom’s voice. That joy is mine, and it is now complete. He must become greater; I must become less.”
What a remedy for pride! John was the greatest of all the prophets according to Jesus, but he knew that the role that he had been given by God was to point the way to Jesus. To be a signpost is a great privilege. He was best man at the wedding - his role was to facilitate the marriage, not run off with the bride.
John's moment in history was a passing one. Many of us will bask in the sun for a while; we should not cling to it. Our role at its very best is to point to Jesus. We should rejoice to have served.
What a remedy for pride! John was the greatest of all the prophets according to Jesus, but he knew that the role that he had been given by God was to point the way to Jesus. To be a signpost is a great privilege. He was best man at the wedding - his role was to facilitate the marriage, not run off with the bride.
John's moment in history was a passing one. Many of us will bask in the sun for a while; we should not cling to it. Our role at its very best is to point to Jesus. We should rejoice to have served.
Monday, May 23, 2011
The Queen in Ireland
Grudges and revenges are sterile things.
I pick this phrase from Libbey Purves article in the Times today commenting on the Queen's visit to Ireland last week. Her majesty's relatives, Lord Louis Mountbatten, Baroness Brabourne, aged 83, and Nicholas Knatchbull, who was 14, and the local 15-year-old boat boy Paul Maxwell were murdered by the IRA at Mullaghmore in 1979. Nicholas’s identical twin Timothy, in a remarkable memoir of grief and reconciliation, has recently spoken of his return to Mullaghmore and meetings there.
It is perhaps easier for the young to forgive; they have a life ahead of them, but the Queen in 86, the same age as Margaret Thatcher and Marilyn Monroe, and the Prince is within weeks of his 90th birthday; it would be easier for them to sink into the old age of bitterness. That they should have behaved so remarkably well is an example to us all.
The Irish Times struck the right note when it commended the Queen on her lack of condescension. They meant that she had no sense of superiority either because she was British or because she was a sovereign. She behaved like an ordinary person, polite, without airs and graces. She went down well in Ireland and set a final seal on the troubles.
I pick this phrase from Libbey Purves article in the Times today commenting on the Queen's visit to Ireland last week. Her majesty's relatives, Lord Louis Mountbatten, Baroness Brabourne, aged 83, and Nicholas Knatchbull, who was 14, and the local 15-year-old boat boy Paul Maxwell were murdered by the IRA at Mullaghmore in 1979. Nicholas’s identical twin Timothy, in a remarkable memoir of grief and reconciliation, has recently spoken of his return to Mullaghmore and meetings there.
It is perhaps easier for the young to forgive; they have a life ahead of them, but the Queen in 86, the same age as Margaret Thatcher and Marilyn Monroe, and the Prince is within weeks of his 90th birthday; it would be easier for them to sink into the old age of bitterness. That they should have behaved so remarkably well is an example to us all.
The Irish Times struck the right note when it commended the Queen on her lack of condescension. They meant that she had no sense of superiority either because she was British or because she was a sovereign. She behaved like an ordinary person, polite, without airs and graces. She went down well in Ireland and set a final seal on the troubles.
John 3:26
They came to John and said to him, “Rabbi, that man who was with you on the other side of the Jordan – the one you testified about – well, he is baptizing, and everyone is going to him.
Jealousy is a terrible thing in the Christian church. These Jews were hoping to foment jealousy between John and Jesus. We see it all the time. People who want their work in arranging the flowers, or playing the guitar, or leading the service to be noticed and appreciated more than someone else’s service.
We should remember that all our righteousness is as dirty rags and that that no-one can compete with or repay Jesus.
Jealousy is a terrible thing in the Christian church. These Jews were hoping to foment jealousy between John and Jesus. We see it all the time. People who want their work in arranging the flowers, or playing the guitar, or leading the service to be noticed and appreciated more than someone else’s service.
We should remember that all our righteousness is as dirty rags and that that no-one can compete with or repay Jesus.
Sunday, May 22, 2011
Where now for the NHS?
When the NHS began it used to give away free hot water bottles. Things have changed. As people live longer they make more demands on health care. As technology improves health care becomes more expensive. This would not matter if growth of GDP was buoyant, but growth is sluggish. The NHS is being asked to make do within its existing budget, but to take account of demographic changes and health-specific inflation it has to make major savings elsewhere.
The last government threw huge amounts of money at the NHS, but productivity reduced. This means that doctors and nurses each saw relatively fewer patients. Part of this was the result of the European Working Time Directive which stopped junior doctors from working more than 48 hours a week, but more than that was a change from a professional contract, whereby doctors and nurses stayed working until the work was done, to a sessional contract whereby they engaged in a certain number of 3.5 hour sessions a week. Since their sessions included periods for administration, continued professional development, research and perhaps other non-clinical time, less time was spent at the coal face. The consequence was more doctors and nurses had to be employed to complete the work.
The option of throwing yet more money at the problem is not available. The new government has agreed to ring-fence the NHS budget, sparing it from the austerity package, but even with a standstill budget it has to make savings. Are there things that it is doing that it could stop doing?
One way of reducing the work in the NHS would be to encourage private practice. After all in many countries patients find that when people pay for services directly they get better results. There is no way that the NHS with its intrinsic rationing will be able to pay for the hotel services and promptness that middle class people are going to demand. These are not medical but social standards and there is no reason that they should not be paid for. Some ways that this could be done would be to give tax breaks for private health insurance, and to allow waiting lists for elective surgery on the NHS to drift. far from diminishing the NHS this would allow the national service to do what it is best at.
There are undoubtedly some health services that are best provided by the community. Even the United States recognizes this. No-one would suggest that the CDC was run as a private firm. Or the Walter Reed. There is no call to privatize the VA. I am content to let the British Public Health Service be run by the NHS. The epidemiology is best done by someone with statutory access to the data. In the UK family doctors are all independent contractors. They work for the NHS and are paid for out of general taxation, but they are effectively small businessmen. Not so the hospitals which are owned and paid for by the government and all employ thousands of health workers. But even here they have been separated into independent Trusts and are no longer one great monolith.
Still, I would have the NHS doing less. What I would concentrate on are the things that people cannot do for themselves. Lots of medical time is taken up with the trivial that does not need expensive time spent on it. Most virus infections cannot be treated (herpes is the exception) so there is no point going to the doctors with colds and flu. Many medical interventions are of unproven value. I see no reason why patients should not be allowed to purchase these as long as they don't use my money to do so. I am thinking of homeopathy especially, but there are many other 'treatments'.
A few years ago it was estimated that ten times as much money was paid by the NHS on indigestion remedies than on the whole of cancer chemotherapy. Surely this cannot be the correct priority. It is expensive treatments like cancer chemotherapy and cardiac surgery that we need help to pay for, not the provision of statins in the hope that they may prolong life. I think that NICE has things the wrong way round. Rather than setting a threshold for treatments yielding less than 1 QALY per £30,000, they should be seeking out the cheap treatments and recommending that people pay for them themselves.
The other area I find odd is to use the NHS budget for social engineering. Many illnesses are self inflicted. They are caused by smoking, drinking, eating unsuitable foods, not taking exercise, taking class A and class B drugs. Much mental illness is so engendered and much is simply unhappiness. To cram this degree of social problem into a medical model seems to me to be unwarranted. The remedy for many of these ills is not a medical one. Better housing, schooling, conditions of employment and environment may all have a part to play. Antidepressants are not the answer.
What is mainly wrong about the NHS is not poor quality medicine but its being used to answer questions it wasn’t designed to answer.
The last government threw huge amounts of money at the NHS, but productivity reduced. This means that doctors and nurses each saw relatively fewer patients. Part of this was the result of the European Working Time Directive which stopped junior doctors from working more than 48 hours a week, but more than that was a change from a professional contract, whereby doctors and nurses stayed working until the work was done, to a sessional contract whereby they engaged in a certain number of 3.5 hour sessions a week. Since their sessions included periods for administration, continued professional development, research and perhaps other non-clinical time, less time was spent at the coal face. The consequence was more doctors and nurses had to be employed to complete the work.
The option of throwing yet more money at the problem is not available. The new government has agreed to ring-fence the NHS budget, sparing it from the austerity package, but even with a standstill budget it has to make savings. Are there things that it is doing that it could stop doing?
One way of reducing the work in the NHS would be to encourage private practice. After all in many countries patients find that when people pay for services directly they get better results. There is no way that the NHS with its intrinsic rationing will be able to pay for the hotel services and promptness that middle class people are going to demand. These are not medical but social standards and there is no reason that they should not be paid for. Some ways that this could be done would be to give tax breaks for private health insurance, and to allow waiting lists for elective surgery on the NHS to drift. far from diminishing the NHS this would allow the national service to do what it is best at.
There are undoubtedly some health services that are best provided by the community. Even the United States recognizes this. No-one would suggest that the CDC was run as a private firm. Or the Walter Reed. There is no call to privatize the VA. I am content to let the British Public Health Service be run by the NHS. The epidemiology is best done by someone with statutory access to the data. In the UK family doctors are all independent contractors. They work for the NHS and are paid for out of general taxation, but they are effectively small businessmen. Not so the hospitals which are owned and paid for by the government and all employ thousands of health workers. But even here they have been separated into independent Trusts and are no longer one great monolith.
Still, I would have the NHS doing less. What I would concentrate on are the things that people cannot do for themselves. Lots of medical time is taken up with the trivial that does not need expensive time spent on it. Most virus infections cannot be treated (herpes is the exception) so there is no point going to the doctors with colds and flu. Many medical interventions are of unproven value. I see no reason why patients should not be allowed to purchase these as long as they don't use my money to do so. I am thinking of homeopathy especially, but there are many other 'treatments'.
A few years ago it was estimated that ten times as much money was paid by the NHS on indigestion remedies than on the whole of cancer chemotherapy. Surely this cannot be the correct priority. It is expensive treatments like cancer chemotherapy and cardiac surgery that we need help to pay for, not the provision of statins in the hope that they may prolong life. I think that NICE has things the wrong way round. Rather than setting a threshold for treatments yielding less than 1 QALY per £30,000, they should be seeking out the cheap treatments and recommending that people pay for them themselves.
The other area I find odd is to use the NHS budget for social engineering. Many illnesses are self inflicted. They are caused by smoking, drinking, eating unsuitable foods, not taking exercise, taking class A and class B drugs. Much mental illness is so engendered and much is simply unhappiness. To cram this degree of social problem into a medical model seems to me to be unwarranted. The remedy for many of these ills is not a medical one. Better housing, schooling, conditions of employment and environment may all have a part to play. Antidepressants are not the answer.
What is mainly wrong about the NHS is not poor quality medicine but its being used to answer questions it wasn’t designed to answer.
John 3:25
An argument developed between some of John's disciples and a certain Jew over the matter of ceremonial washing
Why do Christians engage in petty arguments? Infact or adult baptism? Pre- or post-millennium? Transubstantiation? Does the Spirit come from the Father or from the Father and the Son? Creation v evolution? and many other disputes.
In his old age John had one commandment for Christians, "Love one another." Yet through the years thousands of Christians have had their blood shed over what are in the end irresolvable disputes. CS Lewis was of the opinion that many of the disputes among Christians were semantic ones that when the time of resolving came (in heaven) both opinions will be seen as approximations to teh truth that was not expressable in human terms.
I have my views on many of the disputes but I'm not going to war on any of them. If I can gain some benefit from someone else's view, all well and good; if I cannot then I shall keep quiet for the sake of peace.
Why do Christians engage in petty arguments? Infact or adult baptism? Pre- or post-millennium? Transubstantiation? Does the Spirit come from the Father or from the Father and the Son? Creation v evolution? and many other disputes.
In his old age John had one commandment for Christians, "Love one another." Yet through the years thousands of Christians have had their blood shed over what are in the end irresolvable disputes. CS Lewis was of the opinion that many of the disputes among Christians were semantic ones that when the time of resolving came (in heaven) both opinions will be seen as approximations to teh truth that was not expressable in human terms.
I have my views on many of the disputes but I'm not going to war on any of them. If I can gain some benefit from someone else's view, all well and good; if I cannot then I shall keep quiet for the sake of peace.
Update on recovery
A sunny Sunday morning here in Bournemouth; it is good to be alive. Our new gardener seems to have settled in and after a month with the lawns unmown the garden is neat and tidy again and pleasant to sit in. The blue geraniums are out and already we are thinking of having to water every evening. One feature of our neighborhood is that wild Valerian is everywhere. Our nesting box has been colonized by a family of blue tits faithfully feeding the fledgelings.
We have been able to manage some car trips. Last Thursday we did the 150 mile round trip to see my mum. The traffic was terrible, but we managed it. It was good to see her. At 91 she has slowed down a bit but she now has someone to do her garden and some of her household chores. She likes to do her own cooking. Unfortunately, my diet has to be so regulated now that we were unable to have a meal with her but I did scoff a nice piece of lemon cake.
Yesterday we did another 150 miles along the coast to Hayling Island to see my oldest daughter and youngest grandchild. Aby is now 15 months old, running everywhere and saying words like 'shoe' and 'chair'. Karen's garden seems further advanced than ours, even. I think they benefit by being in the shelter of the Isle of Wight. We went for a little walk which I managed without too much trouble.
Tomorrow we plan to visit my younger son up in Warwickshire. This will be a round trip of 250 miles and I shall get the Jaguar out for it. It will be my longest trip since the chemotherapy ended and I trust I will be strong enough. We are taking the opportunity to take him a load of wood from out garage loft for his wood-burning stove. At the moment he is in Barcelona working at the Spanish Grand Prix, but he will have returned by tonight.
I am making plans to go to EHA in London next month. It is close enough for me to travel up each day without the need to stay away and the CLL sessions are spaced enough for me to fit in the traveling. I had intended to go to the MDS meeting in Edinburgh, but it came a little too soon for me.
Generally, my health is good. I have been left with some residual symptoms that I ascribe to the surgery and chemotherapy, but I have to learn to live with them. My energy levels are getting better every day and I am not daunted by every task as I was a month ago. I am even planning on writing an article for publication again.
We have been able to manage some car trips. Last Thursday we did the 150 mile round trip to see my mum. The traffic was terrible, but we managed it. It was good to see her. At 91 she has slowed down a bit but she now has someone to do her garden and some of her household chores. She likes to do her own cooking. Unfortunately, my diet has to be so regulated now that we were unable to have a meal with her but I did scoff a nice piece of lemon cake.
Yesterday we did another 150 miles along the coast to Hayling Island to see my oldest daughter and youngest grandchild. Aby is now 15 months old, running everywhere and saying words like 'shoe' and 'chair'. Karen's garden seems further advanced than ours, even. I think they benefit by being in the shelter of the Isle of Wight. We went for a little walk which I managed without too much trouble.
Tomorrow we plan to visit my younger son up in Warwickshire. This will be a round trip of 250 miles and I shall get the Jaguar out for it. It will be my longest trip since the chemotherapy ended and I trust I will be strong enough. We are taking the opportunity to take him a load of wood from out garage loft for his wood-burning stove. At the moment he is in Barcelona working at the Spanish Grand Prix, but he will have returned by tonight.
I am making plans to go to EHA in London next month. It is close enough for me to travel up each day without the need to stay away and the CLL sessions are spaced enough for me to fit in the traveling. I had intended to go to the MDS meeting in Edinburgh, but it came a little too soon for me.
Generally, my health is good. I have been left with some residual symptoms that I ascribe to the surgery and chemotherapy, but I have to learn to live with them. My energy levels are getting better every day and I am not daunted by every task as I was a month ago. I am even planning on writing an article for publication again.
Saturday, May 21, 2011
An honest opinion. Can you get one?
How do you get an independent opinion? The European Parliament has refused to ratify the accounts of the European Medicines Agency on the grounds that they haven't been reassured that those that advise the body on the licensing of drugs are free of potentially corrupting influence from those who stand to benefit from the award of a license - in other words the pharmaceutical companies.
Where are the experts who might do this review who have not received the largess of the pharmaceutical companies? Despite strenuous efforts by national governments to restrict payouts by Big Pharma to individual doctors, most experts have received some money from the pharmaceutical industry, but was it corrupting? Funding for research and CME often comes from the industry and certainly, in the past, this has been lavish. I can remember a trip to Monte Carlo that I spoke at where there was a massive influx of European hematologists flown in by Roche to listen to me (among many others).
I must say that I was not impressed by the entertainment that was laid on (an excerpt from the musical Chess) which I walked out on and I would certainly rather have been at home (Monte Carlo is very seedy and not a patch on Bournemouth). Generally, I have done any teaching because I enjoyed teaching rather than for any financial reward from the pharmaceutical industry. However, I have received the cost of going to educational meetings from the Industry. But don't you think that this should have been provided by my employer? After all, surely the University expects its professors to keep up to date and this is much more easily done by attendance of meetings like ASH, IWCLL and EHA.
The truth is that national governments have skimped their funding of research and secondary education, expecting industry to make a contribution. All well and good, so they should, but funds need to be transferred in a non-corrupting way.
I have on three occasions given evidence to a NICE committee. On one occasion one of the assessors accused one of the doctors giving evidence of being in the pay of the pharmaceutical company. The doctor reacted abruptly, "Either withdraw that accusation or I will sue you for slander. I have witnesses." The accusation was withdrawn with poor-grace. It does show that the adjudicators are extremely skeptical of medical evidence. I have also given evidence in Medico-legal cases on behalf of the plaintiff. I am paid for my work, but I give an honest opinion for the court. My responsibility is to the court not the plaintiff.
On the other hand the criticism is a bit rich coming from members of the European Parliament. A more corrupt body it would be hard to envisage.
In another news item a parliamentary committee has criticized the peer-review system. Peer-review has been called slow, expensive, biased, open to abuse, innovation-stifling and bad at detecting fraud. It may be all of these things as well as open to corruption, but no peer-review is worse. Most peer reviewing is honest though it is usually not paid for and often resented as a chore. However, authors accept that if they want their work published it has to be peer-reviewed and accept that their reviewing other people's work is a tit-for-tat for having their own work refereed.
Where are the experts who might do this review who have not received the largess of the pharmaceutical companies? Despite strenuous efforts by national governments to restrict payouts by Big Pharma to individual doctors, most experts have received some money from the pharmaceutical industry, but was it corrupting? Funding for research and CME often comes from the industry and certainly, in the past, this has been lavish. I can remember a trip to Monte Carlo that I spoke at where there was a massive influx of European hematologists flown in by Roche to listen to me (among many others).
I must say that I was not impressed by the entertainment that was laid on (an excerpt from the musical Chess) which I walked out on and I would certainly rather have been at home (Monte Carlo is very seedy and not a patch on Bournemouth). Generally, I have done any teaching because I enjoyed teaching rather than for any financial reward from the pharmaceutical industry. However, I have received the cost of going to educational meetings from the Industry. But don't you think that this should have been provided by my employer? After all, surely the University expects its professors to keep up to date and this is much more easily done by attendance of meetings like ASH, IWCLL and EHA.
The truth is that national governments have skimped their funding of research and secondary education, expecting industry to make a contribution. All well and good, so they should, but funds need to be transferred in a non-corrupting way.
I have on three occasions given evidence to a NICE committee. On one occasion one of the assessors accused one of the doctors giving evidence of being in the pay of the pharmaceutical company. The doctor reacted abruptly, "Either withdraw that accusation or I will sue you for slander. I have witnesses." The accusation was withdrawn with poor-grace. It does show that the adjudicators are extremely skeptical of medical evidence. I have also given evidence in Medico-legal cases on behalf of the plaintiff. I am paid for my work, but I give an honest opinion for the court. My responsibility is to the court not the plaintiff.
On the other hand the criticism is a bit rich coming from members of the European Parliament. A more corrupt body it would be hard to envisage.
In another news item a parliamentary committee has criticized the peer-review system. Peer-review has been called slow, expensive, biased, open to abuse, innovation-stifling and bad at detecting fraud. It may be all of these things as well as open to corruption, but no peer-review is worse. Most peer reviewing is honest though it is usually not paid for and often resented as a chore. However, authors accept that if they want their work published it has to be peer-reviewed and accept that their reviewing other people's work is a tit-for-tat for having their own work refereed.
1967 borders? Unlikely!
The suggestion by Barrack Obama that peace in the middle east can only be on the basis of the pre-1967 borders shows that he has no historical perspective and reveals him as an opportunist seeking to make capital of the so-called 'Arab Spring'.
The Six Day war did not arise from a blank canvas. It began with a piece of Soviet perfidy that provoked Colonel Nasser into an aggressive and warlike attitude. In May 1967, Nasser received false reports from the Soviet Union that Israel was massing on the Syrian border. In response he began assembling his troops in the Sinai Peninsula on Israel's border, expelled the UNEF force from Gaza and Sinai (it had been placed there by the UN after Suez) and took up UNEF positions at Sharm el-Sheikh, overlooking the Straits of Tiran. Israel reiterated declarations made in 1957 that any closure of the Straits would be considered an act of war, or justification for war. Nasser declared the Straits closed to Israeli shipping on May 22–23 and a week later signed a defence pact with Jordan. The following day, at Jordan's invitation, the Iraqi army began deploying troops and armored units in Jordan. They were later reinforced by an Egyptian contingent. In view of these clear preparations for an Arab strike on Israel on June 6th Israel launched Operation Focus, a large-scale surprise air strike that was the opening of the Six-Day War.
Times have changed but the same problem for Israel still exists: the 1967 borders leave Israel vulnerable to attack from her Arab neighbors and while Hamas and Hezbollah continue to insist that Israel must be wiped from the face of the map, no prospect for peace exists whatever borders are chosen as a starting point.
That being so, the development of settlements within the occupied West Bank does not make peace more likely and eventually they must be protected by major force or abandoned.
The Six Day war did not arise from a blank canvas. It began with a piece of Soviet perfidy that provoked Colonel Nasser into an aggressive and warlike attitude. In May 1967, Nasser received false reports from the Soviet Union that Israel was massing on the Syrian border. In response he began assembling his troops in the Sinai Peninsula on Israel's border, expelled the UNEF force from Gaza and Sinai (it had been placed there by the UN after Suez) and took up UNEF positions at Sharm el-Sheikh, overlooking the Straits of Tiran. Israel reiterated declarations made in 1957 that any closure of the Straits would be considered an act of war, or justification for war. Nasser declared the Straits closed to Israeli shipping on May 22–23 and a week later signed a defence pact with Jordan. The following day, at Jordan's invitation, the Iraqi army began deploying troops and armored units in Jordan. They were later reinforced by an Egyptian contingent. In view of these clear preparations for an Arab strike on Israel on June 6th Israel launched Operation Focus, a large-scale surprise air strike that was the opening of the Six-Day War.
Times have changed but the same problem for Israel still exists: the 1967 borders leave Israel vulnerable to attack from her Arab neighbors and while Hamas and Hezbollah continue to insist that Israel must be wiped from the face of the map, no prospect for peace exists whatever borders are chosen as a starting point.
That being so, the development of settlements within the occupied West Bank does not make peace more likely and eventually they must be protected by major force or abandoned.
John 3:24
This was before John was put in prison
Imprisoned for their faith:
Biplob Marandi sentenced to one year in prison in Bangladesh for selling Christian books. Released on March 29th when charges thrown out. Praise the Lord!
Three leaders of the Shouwang church in Beijing are still held in custody after meeting in the open air to worship following the closing of their church building by the Chinese authorities.
Pastor Omar Gude Perez granted conditional release from his six and a half year prison sentence in Cuba. He was originally arrested on false charges of 'human trafficking and then convicted on trumped up charges of falsification of documents.
Irene Wiens, a Geman mother of four, has been jailed in Germany for keeping her children out of mandatory sex education classes.
Two new Christian believers were conditionally released from prison in Iran after their arrest for alleged national security crimes.
Qamar David was found dead in his prison cell in Pakistan. He had been imprisoned in 2002 following a charge of 'blasphemy' against Muhammed. His appeal was due to be heard.
This is a small snapshot of people who are or have been in prison for their faith around the world. Readers can get up-to-date information from here or here.
Imprisoned for their faith:
Biplob Marandi sentenced to one year in prison in Bangladesh for selling Christian books. Released on March 29th when charges thrown out. Praise the Lord!
Three leaders of the Shouwang church in Beijing are still held in custody after meeting in the open air to worship following the closing of their church building by the Chinese authorities.
Pastor Omar Gude Perez granted conditional release from his six and a half year prison sentence in Cuba. He was originally arrested on false charges of 'human trafficking and then convicted on trumped up charges of falsification of documents.
Irene Wiens, a Geman mother of four, has been jailed in Germany for keeping her children out of mandatory sex education classes.
Two new Christian believers were conditionally released from prison in Iran after their arrest for alleged national security crimes.
Qamar David was found dead in his prison cell in Pakistan. He had been imprisoned in 2002 following a charge of 'blasphemy' against Muhammed. His appeal was due to be heard.
This is a small snapshot of people who are or have been in prison for their faith around the world. Readers can get up-to-date information from here or here.
Friday, May 20, 2011
Freedom of religion
I gather Barry O'Bama is about to visit Ireland. I wonder how his visit will compare with that of the Queen who completes a four day visit today? It's a hundred years since a British monarch has visited and by all accounts the visit was a great success.
Of course we have had nearly a century of troubles between the two largest islands of the British Isles, troubles of a largely religious nature. Although many of the early Irish nationalists were protestants what kept the two nations apart was the aggressive Roman Catholicism of Eamon Devalera. Ireland was a severely priest-ridden country which oppressed its people in an unacceptable way. No wonder the North wanted to have nothing to do with it. The pedophilia scandals that have since come out proves that they were right.
Freedom of religion is something we should all aspire to. No country that favors one particular religion over another is behaving honorably. I would favor the disestablishment of the Church of England. Disestablishment of the Anglican church in Wales certainly has not harmed the Christian church there. As for the so called Islamic states that forbid people from changing their religion, what are they afraid of? If Islam is so great who would want to depart from it?
Of course we have had nearly a century of troubles between the two largest islands of the British Isles, troubles of a largely religious nature. Although many of the early Irish nationalists were protestants what kept the two nations apart was the aggressive Roman Catholicism of Eamon Devalera. Ireland was a severely priest-ridden country which oppressed its people in an unacceptable way. No wonder the North wanted to have nothing to do with it. The pedophilia scandals that have since come out proves that they were right.
Freedom of religion is something we should all aspire to. No country that favors one particular religion over another is behaving honorably. I would favor the disestablishment of the Church of England. Disestablishment of the Anglican church in Wales certainly has not harmed the Christian church there. As for the so called Islamic states that forbid people from changing their religion, what are they afraid of? If Islam is so great who would want to depart from it?
John 3:23
Now John also was baptizing at Aenon near Salim, because there was plenty of water, and people were constantly coming to be baptized.
This is a proof text for Baptists. The point about there being plenty of water demonstrates that baptism was about immersion. When discussions were being held by King James with the Bishops and the Puritans about the 1611 translation of the Bible, one of the stipulations that James made was that Baptidso should not be translated, merely transliterated. He didn't want it realized that this was a technical term of the dyeing industry. You don't just sprinkle dye on cloth; you have to dip the cloth in the dye.
just think, John the Baptist might have been called the Big Dipper.
This is a proof text for Baptists. The point about there being plenty of water demonstrates that baptism was about immersion. When discussions were being held by King James with the Bishops and the Puritans about the 1611 translation of the Bible, one of the stipulations that James made was that Baptidso should not be translated, merely transliterated. He didn't want it realized that this was a technical term of the dyeing industry. You don't just sprinkle dye on cloth; you have to dip the cloth in the dye.
just think, John the Baptist might have been called the Big Dipper.
Do we need different trials for the elderly?
One of the bugbears of clinical trials is that they are usually conducted in younger patients. This is especially relevant in CLL where the median age of presentation is 70. The question has been asked as to whether we should have specific trials for older patients and would they give different answers to the trials that we have now.
There has been an attempt to answer these questions published in today's Lancet, not in CLL but in colorectal cancer in which I have more than a passing interest.
Colorectal cancer is the most common tumour worldwide and the second leading cause of cancer death in European countries and the USA, with about 800 000 new cases yearly. Although most clinical trials have not specifically excluded older or frail patients, as long as they have been suitable for the investigated treatment, there is always a strong selection process for patients who will be entered into clinical trials, especially if more toxic or somewhat innovative treatments are investigated. The median age at disease onset ranges between about 65–70 years and at death 72–77 years. 60% of deaths occur in patients older than 75 years and about 40% in those older than 80 years. The median age of a typical trial population for advanced disease is 60–65 years, with a maximum age mostly of 75 years. Retrospective analysis of randomised trials has shown that elderly patients have more or less the same response to chemotherapy as do younger patients.
The MRC FOCUS2 trial is the first randomised trial specifically tailored for this group of patients—elderly, frail, or both—in advanced colorectal cancer, thus representing a major part of the typical population of patients in routine practice. They compared single-agent fluorouracil with an upfront FOLFOX-type combination for overall and progression-free survival, and compared (in a factorial design) the value of the oral fluorouracil prodrug capecitabine with intravenous fluorouracil/levofolinate infusion.
The study showed that the upfront combination with oxaliplatin achieved a significantly increased response rate and made a limited, but not statistically significant, contribution to progression-free survival; overall survival was not improved. However, there was clear evidence of an overall benefit by addition of oxaliplatin defined by a composite index (overall treatment utility [OTU]) which had been developed and which was able to define the overall clinical utility depending on simple clinical variables that represent the biology of the disease and the patients' general characteristics, as well as the subjective opinion of the doctor and patient regarding the real value of the chosen treatment.
This trial supports what has been derived as “standard” from retrospective subgroup analyses of the older population of patients from previous trials, and the clinical experience which led to the definition of a treatment selection according to the treatment aim, the clinical disease characteristics, and co morbidity. Commonly, these patients are considered only for single-agent fluorouracil. FOCUS2 supports the addition of a new measure, OTU, to the selection process, and furthermore supports the use of upfront fluorouracil/oxaliplatin combination in this patient population—but in reduced doses and without capecitabine. Probably the other relevant result of FOCUS2 was that most patients do well with an a-priori dose reduction of fluorouracil or capecitabine and oxaliplatin, with a dose increase only if toxicity allowed (only 30% of the patients), indicating that an initial 20% dose reduction could be the standard of care for these patients.
As an aside I should say that after a few treatments that I found too toxic, they reduced my doses by 20%.
This trial needs confirmation. In addition, it does not represent the typical treatment scenario in most European countries. For example, in Europe many oncologists give fluorouracil/bevacizumab as first-line treatment, or at least as second-line treatment, and try at least to use oxaliplatin and irinotecan and (if the tumour is KRAS wild-type) cetuximab/panitumumab as salvage treatment, even in this population of patients with relatively poor outlook. This relative lack of use of salvage treatment, beyond the generally poorer prognosis in this elderly and frail population, might have relevantly contributed to the short overall survival of only 10–12 months in FOCUS2, rather than just the fact that the patients selected for inclusion were elderly, frail or both.
What this trial does is to emphasize that it is the biology of the disease that determines response and the robustness of the patient that determines whether he or she can survive the treatment. It is not a different disease in the elderly, but co-morbidities will affect the way the drugs are handled and regimes may need to be tailor-made for the elderly and infirm. For example we know that people with impaired renal function need a smaller dose of fludarabine for the same effect.
There has been an attempt to answer these questions published in today's Lancet, not in CLL but in colorectal cancer in which I have more than a passing interest.
Colorectal cancer is the most common tumour worldwide and the second leading cause of cancer death in European countries and the USA, with about 800 000 new cases yearly. Although most clinical trials have not specifically excluded older or frail patients, as long as they have been suitable for the investigated treatment, there is always a strong selection process for patients who will be entered into clinical trials, especially if more toxic or somewhat innovative treatments are investigated. The median age at disease onset ranges between about 65–70 years and at death 72–77 years. 60% of deaths occur in patients older than 75 years and about 40% in those older than 80 years. The median age of a typical trial population for advanced disease is 60–65 years, with a maximum age mostly of 75 years. Retrospective analysis of randomised trials has shown that elderly patients have more or less the same response to chemotherapy as do younger patients.
The MRC FOCUS2 trial is the first randomised trial specifically tailored for this group of patients—elderly, frail, or both—in advanced colorectal cancer, thus representing a major part of the typical population of patients in routine practice. They compared single-agent fluorouracil with an upfront FOLFOX-type combination for overall and progression-free survival, and compared (in a factorial design) the value of the oral fluorouracil prodrug capecitabine with intravenous fluorouracil/levofolinate infusion.
The study showed that the upfront combination with oxaliplatin achieved a significantly increased response rate and made a limited, but not statistically significant, contribution to progression-free survival; overall survival was not improved. However, there was clear evidence of an overall benefit by addition of oxaliplatin defined by a composite index (overall treatment utility [OTU]) which had been developed and which was able to define the overall clinical utility depending on simple clinical variables that represent the biology of the disease and the patients' general characteristics, as well as the subjective opinion of the doctor and patient regarding the real value of the chosen treatment.
This trial supports what has been derived as “standard” from retrospective subgroup analyses of the older population of patients from previous trials, and the clinical experience which led to the definition of a treatment selection according to the treatment aim, the clinical disease characteristics, and co morbidity. Commonly, these patients are considered only for single-agent fluorouracil. FOCUS2 supports the addition of a new measure, OTU, to the selection process, and furthermore supports the use of upfront fluorouracil/oxaliplatin combination in this patient population—but in reduced doses and without capecitabine. Probably the other relevant result of FOCUS2 was that most patients do well with an a-priori dose reduction of fluorouracil or capecitabine and oxaliplatin, with a dose increase only if toxicity allowed (only 30% of the patients), indicating that an initial 20% dose reduction could be the standard of care for these patients.
As an aside I should say that after a few treatments that I found too toxic, they reduced my doses by 20%.
This trial needs confirmation. In addition, it does not represent the typical treatment scenario in most European countries. For example, in Europe many oncologists give fluorouracil/bevacizumab as first-line treatment, or at least as second-line treatment, and try at least to use oxaliplatin and irinotecan and (if the tumour is KRAS wild-type) cetuximab/panitumumab as salvage treatment, even in this population of patients with relatively poor outlook. This relative lack of use of salvage treatment, beyond the generally poorer prognosis in this elderly and frail population, might have relevantly contributed to the short overall survival of only 10–12 months in FOCUS2, rather than just the fact that the patients selected for inclusion were elderly, frail or both.
What this trial does is to emphasize that it is the biology of the disease that determines response and the robustness of the patient that determines whether he or she can survive the treatment. It is not a different disease in the elderly, but co-morbidities will affect the way the drugs are handled and regimes may need to be tailor-made for the elderly and infirm. For example we know that people with impaired renal function need a smaller dose of fludarabine for the same effect.
Thursday, May 19, 2011
Aphorisms 14
God says, “If anyone is in Hell it will be over my dead body.” – Rico Tice
On Norman Vincent Peale Adlai Stevenson’s quipped: I find Paul appealing and Peale appalling.
“The free man owns himself. He can damage himself with either eating or drinking; he can ruin himself with gambling. If he does he is certainly a damn fool, and he might possibly be a damned soul; but if he may not, he is not a free man any more than a dog.” G. K. Chesterton
"Ninety percent of the politicians give the other ten percent a bad reputation." Henry Kissinger
Scepticism is integral to the scientific process, because most claims turn out to be false
“If today you can take a thing like xxxxxxxx and make it a crime to teach it in the public schools, tomorrow you can make it a crime to teach it in the private schools, and next year you can make it a crime to teach it in the church. At the next session you can ban books and the newspapers. Ignorance and fanaticism are ever busy… After a while it is the setting of man against man, creed against creed, until the flying banners and beating drums are marching backwards to the glorious ages of the 16th century when bigots lighted fagots to burn the man who dared to bring any intelligence and enlightenment and culture to the human mind.” - Clarence Darrow
DNA makes RNA, RNA makes protein, and proteins make us."
Francis Crick (1916-2004)
Nobody makes me; I take full responsibility.
I have always asked stupid questions and never been satisfied with easy answers. When I got to college I found this was called “Philosophy”. Keith Ward.
On Norman Vincent Peale Adlai Stevenson’s quipped: I find Paul appealing and Peale appalling.
“The free man owns himself. He can damage himself with either eating or drinking; he can ruin himself with gambling. If he does he is certainly a damn fool, and he might possibly be a damned soul; but if he may not, he is not a free man any more than a dog.” G. K. Chesterton
"Ninety percent of the politicians give the other ten percent a bad reputation." Henry Kissinger
Scepticism is integral to the scientific process, because most claims turn out to be false
“If today you can take a thing like xxxxxxxx and make it a crime to teach it in the public schools, tomorrow you can make it a crime to teach it in the private schools, and next year you can make it a crime to teach it in the church. At the next session you can ban books and the newspapers. Ignorance and fanaticism are ever busy… After a while it is the setting of man against man, creed against creed, until the flying banners and beating drums are marching backwards to the glorious ages of the 16th century when bigots lighted fagots to burn the man who dared to bring any intelligence and enlightenment and culture to the human mind.” - Clarence Darrow
DNA makes RNA, RNA makes protein, and proteins make us."
Francis Crick (1916-2004)
Nobody makes me; I take full responsibility.
I have always asked stupid questions and never been satisfied with easy answers. When I got to college I found this was called “Philosophy”. Keith Ward.
John 3:22
After this, Jesus and his disciples went out into the Judean, where he spent some time with them, and baptised.
It seems here to be clear that part of the ministry of Jesus was baptism. Was this the same baptism as John's or a different one? We Baptists hold a high view of baptism. We see it first as an act of symbolic cleansing. This is a fresh start; our old sins are washed away, but that would by itself be of no use because we would get dirty again. The Emperor Constantine only got baptized on his death bed so that he would commit no more sins afterwards. No for us Baptists there is a second symbol to do with total immersion. It is like going down into a grave and re-emerging newborn, symbolising the new birth of the Holy Spirit. With the Holy Spirit in control sin is constrained.
It seems here to be clear that part of the ministry of Jesus was baptism. Was this the same baptism as John's or a different one? We Baptists hold a high view of baptism. We see it first as an act of symbolic cleansing. This is a fresh start; our old sins are washed away, but that would by itself be of no use because we would get dirty again. The Emperor Constantine only got baptized on his death bed so that he would commit no more sins afterwards. No for us Baptists there is a second symbol to do with total immersion. It is like going down into a grave and re-emerging newborn, symbolising the new birth of the Holy Spirit. With the Holy Spirit in control sin is constrained.
Rape in the headlines.
Girl, 13, dragged into bushes and raped as she walked home from school in broad daylight
This was the headline in the Daily Mail today. On the same day the Justice Secretary was in trouble for appearing to suggest that some rapes are not as serious as others, and suggesting that some rapists might have their prison sentence halved if they pleaded guilty and so avoided the trauma of a court appearance for the victim. At the same time news comes of the resignation of the head of the IMF following his unhappy predicament in New York.
We continue to see very low conviction rates for alleged rapists and indeed prison sentences for those who falsely cry rape. There is controversy over anonymity for alleged rape victims but none for alleged rapists.
In my view sex outside marriage is wrong, but one has to admit that it goes on. Around 20% of married men admit to having had an affair. Hardly anyone would admit to being a virgin when they married these days. Sex outside marriage is not unlawful nor is adultery. The law has great difficulty in proving that sex is rape and not consensual. The circumstance being what they are it is usually one person's word against another's. Unless there is evidence of violence the case is likely to be unprovable.
This is not to diminish the offence, simply to say that is difficult to prove an allegation in a court of law. Furthermore, the gathering of evidence is distasteful and often in the past the police have not been helpful, though I believe it is better these days. Many women do not want to go through the trauma of evidence collection.
The Justice Secretary has a reputation for being forthright and no doubt he spoke out of turn. What he should have said is that we have a problem with rape. It is an offence that is difficult to prove in many cases and a crime supercharged with emotion. For a man to force himself on a woman is a very great crime which should always attract a prison sentence. Some forms of rape are even more severe than this and might be regarded as aggravated rape. For example a man who breaks into a house as a burglar and rapes or someone who attacks a young girl walking home from school are especially severe forms of rape and should attract the most severe sentences up to ad including life-imprisonment. Another, vile practice is to make the rape-victim relive the whole assault again in a court of law. Rapists who do this should expect to be treated by the judge more severely than those who plead guilty and spare the woman this sort of trauma.
Speaking for myself now and not for the Justice secretary, it is clear to me that because of its nature rape will always attract those who like to read about murky goings on, but it is also a feminist issue about centuries of oppression of women by men. From a man's point of view, I have no doubt that the greater openness about sex since the 1960s has left men in a more confused position than before and many men are really not sure how to interpret signals from women.
That being so, men must learn to live in the new circumstances. Best to save sex for marriage as God intended.
This was the headline in the Daily Mail today. On the same day the Justice Secretary was in trouble for appearing to suggest that some rapes are not as serious as others, and suggesting that some rapists might have their prison sentence halved if they pleaded guilty and so avoided the trauma of a court appearance for the victim. At the same time news comes of the resignation of the head of the IMF following his unhappy predicament in New York.
We continue to see very low conviction rates for alleged rapists and indeed prison sentences for those who falsely cry rape. There is controversy over anonymity for alleged rape victims but none for alleged rapists.
In my view sex outside marriage is wrong, but one has to admit that it goes on. Around 20% of married men admit to having had an affair. Hardly anyone would admit to being a virgin when they married these days. Sex outside marriage is not unlawful nor is adultery. The law has great difficulty in proving that sex is rape and not consensual. The circumstance being what they are it is usually one person's word against another's. Unless there is evidence of violence the case is likely to be unprovable.
This is not to diminish the offence, simply to say that is difficult to prove an allegation in a court of law. Furthermore, the gathering of evidence is distasteful and often in the past the police have not been helpful, though I believe it is better these days. Many women do not want to go through the trauma of evidence collection.
The Justice Secretary has a reputation for being forthright and no doubt he spoke out of turn. What he should have said is that we have a problem with rape. It is an offence that is difficult to prove in many cases and a crime supercharged with emotion. For a man to force himself on a woman is a very great crime which should always attract a prison sentence. Some forms of rape are even more severe than this and might be regarded as aggravated rape. For example a man who breaks into a house as a burglar and rapes or someone who attacks a young girl walking home from school are especially severe forms of rape and should attract the most severe sentences up to ad including life-imprisonment. Another, vile practice is to make the rape-victim relive the whole assault again in a court of law. Rapists who do this should expect to be treated by the judge more severely than those who plead guilty and spare the woman this sort of trauma.
Speaking for myself now and not for the Justice secretary, it is clear to me that because of its nature rape will always attract those who like to read about murky goings on, but it is also a feminist issue about centuries of oppression of women by men. From a man's point of view, I have no doubt that the greater openness about sex since the 1960s has left men in a more confused position than before and many men are really not sure how to interpret signals from women.
That being so, men must learn to live in the new circumstances. Best to save sex for marriage as God intended.
Wednesday, May 18, 2011
What is going on in the lymph nodes in CLL?
A couple of articles recently have described what is going on in the lymph nodes in CLL. I think it is pretty clear by now that the business end of CLL is in the lymph nodes and to a lesser extent the liver, spleen and bone marrow. Normally a lymph node is about the size of a split pea, so if you can feel them at all they are enormously enlarged. Most people with CLL don't have palpably enlarged lymph nodes or if they do, only one or two are enlarged. However, in some people the nodes are huge, bigger than a hen's egg, and this is generally an indication that treatment is indicated.
Lymph nodes are there to respond to infections. They are organs where B lymphocytes are brought into contact with the antigens that they have been designed for (every lymphocyte has a pre-designed pattern of immunoglobulin structure so that there is one for every antigen possible) and undergo a maturation process so that they can learn to produce the antibody that fits best to the antigen. This process is facilitated by the presence of T lymphocytes which help and control the maturation. Recognition of the driving antigen is through the BCR, a special arrangement of the lymphocyte's immunoglobulin molecule on the cell surface so that it can receive and transmit a signal through the cell's second messenger service. B lymphocytes leaving the lymph nodes are either memory cells that circulate, waiting to meet the infective agent again or turning into plasma cells which end up as antibody factories that reside mainly in the bone marrow.
In CLL this process has been circumvented. Instead of reactive follicles in the lymph nodes training the lymphocytes to make antibodies, there are what are known as pseudofollicular proliferation centers. These centers are geared up to make the B lymphocytes reproduce themselves and avoid death. Perhaps 30% of all CLL cases have a very restricted set of antibodies on their cell surfaces (so-called stereotyped BCRs) that seems to react with certain autoantigens that are exposed when cells enter apoptosis (programmed cell death). Most of these stereotyped BCRs comprise unmutated Ig and it is mainly the unmutated CLLs that produce proliferation center-laden lymph nodes.
Although the whole process of proliferation seems to be driven via the BCR it is not necessarily antigen dependent. It seems that inflammation can also be stimulatory, acting through what are known as Toll-like receptors (TLR). Stimulation of TLR by so called 'danger signals' sets in train events that keep CLL cells alive and makes them home in on lymph nodes. In any case many CLL cells express functional chemokine receptors CXCR3, CXCR4 and CXCR5. Within proliferation centers are many CD4+ T cells which express CD40L. These support the growth of CLL cells through CD40 ligation. Stromal cells and nurse-like cells interact with CLL cells to prevent apoptosis and the interaction of CD38 on the cell surface and its natural ligand CD31 also favors the twin effects of anti-apoptosis and proliferation. Cytokines such as IL-4 and chemokines like CXCL13/SDF-1 produced in proliferation centers promote the up-regulation of anti-apoptotic genes like BCL2, SURVIVIN and MCL1.
The whole effect can be summarized like this: First you need a BCR that will take messages and transmit them. This will usually,but not exclusively, be one with unmutated IgHV genes. Such CLL cells will circulate to the lymph nodes and may even be attracted there by chemokines responding to either antigenic signaling or TLR signaling. Once in the lymph node the presence of T helper cells has an effect on the CLL cell to keep it alive and cause it to divide. This effect is mediated through cell-to-cell contact and through cytokines and specific ligands. One of the effects is to up-regulate CD38. When we see CD38+ cells in the peripheral blood it is a sure sig that cell has recently visited a lymph node. Other stromal cells and nurse-like cells also participate in this dance, chuck in in their two-penneth into the cytokine soup.
So CLL cells survive and divide. and this proliferation is what is necessary for further genetic mistakes to be made, particularly ones that disable the TP53 pathway. This pathway is necessary to maintain the genetic integrity of the cell. Its function is to recognize genetic mistakes when they occur and to put the cell into stasis while a repair is made. If the cell is irreparable the TP53 is supposed to kill it off. It is a feature of cells in which the TP53 pathway is disabled that they accumulate further irreparable genetic damage and behave very wildly indeed. Clinically such disabling presages prolymphocytoid transformation or Richter's syndrome and in any case renders the cell unkillable by conventional cytotoxic drug combinations like FCR.
How can what's going on in the lymph nodes be stopped? Agents that specifically disable the CLL second messenger system, like CAL-101 and PCI32765, seem to be the best hope, but revlimid may also be useful. What the great danger is, is leaving the patient too long untreated so that TP53 pathway events occur.
Lymph nodes are there to respond to infections. They are organs where B lymphocytes are brought into contact with the antigens that they have been designed for (every lymphocyte has a pre-designed pattern of immunoglobulin structure so that there is one for every antigen possible) and undergo a maturation process so that they can learn to produce the antibody that fits best to the antigen. This process is facilitated by the presence of T lymphocytes which help and control the maturation. Recognition of the driving antigen is through the BCR, a special arrangement of the lymphocyte's immunoglobulin molecule on the cell surface so that it can receive and transmit a signal through the cell's second messenger service. B lymphocytes leaving the lymph nodes are either memory cells that circulate, waiting to meet the infective agent again or turning into plasma cells which end up as antibody factories that reside mainly in the bone marrow.
In CLL this process has been circumvented. Instead of reactive follicles in the lymph nodes training the lymphocytes to make antibodies, there are what are known as pseudofollicular proliferation centers. These centers are geared up to make the B lymphocytes reproduce themselves and avoid death. Perhaps 30% of all CLL cases have a very restricted set of antibodies on their cell surfaces (so-called stereotyped BCRs) that seems to react with certain autoantigens that are exposed when cells enter apoptosis (programmed cell death). Most of these stereotyped BCRs comprise unmutated Ig and it is mainly the unmutated CLLs that produce proliferation center-laden lymph nodes.
Although the whole process of proliferation seems to be driven via the BCR it is not necessarily antigen dependent. It seems that inflammation can also be stimulatory, acting through what are known as Toll-like receptors (TLR). Stimulation of TLR by so called 'danger signals' sets in train events that keep CLL cells alive and makes them home in on lymph nodes. In any case many CLL cells express functional chemokine receptors CXCR3, CXCR4 and CXCR5. Within proliferation centers are many CD4+ T cells which express CD40L. These support the growth of CLL cells through CD40 ligation. Stromal cells and nurse-like cells interact with CLL cells to prevent apoptosis and the interaction of CD38 on the cell surface and its natural ligand CD31 also favors the twin effects of anti-apoptosis and proliferation. Cytokines such as IL-4 and chemokines like CXCL13/SDF-1 produced in proliferation centers promote the up-regulation of anti-apoptotic genes like BCL2, SURVIVIN and MCL1.
The whole effect can be summarized like this: First you need a BCR that will take messages and transmit them. This will usually,but not exclusively, be one with unmutated IgHV genes. Such CLL cells will circulate to the lymph nodes and may even be attracted there by chemokines responding to either antigenic signaling or TLR signaling. Once in the lymph node the presence of T helper cells has an effect on the CLL cell to keep it alive and cause it to divide. This effect is mediated through cell-to-cell contact and through cytokines and specific ligands. One of the effects is to up-regulate CD38. When we see CD38+ cells in the peripheral blood it is a sure sig that cell has recently visited a lymph node. Other stromal cells and nurse-like cells also participate in this dance, chuck in in their two-penneth into the cytokine soup.
So CLL cells survive and divide. and this proliferation is what is necessary for further genetic mistakes to be made, particularly ones that disable the TP53 pathway. This pathway is necessary to maintain the genetic integrity of the cell. Its function is to recognize genetic mistakes when they occur and to put the cell into stasis while a repair is made. If the cell is irreparable the TP53 is supposed to kill it off. It is a feature of cells in which the TP53 pathway is disabled that they accumulate further irreparable genetic damage and behave very wildly indeed. Clinically such disabling presages prolymphocytoid transformation or Richter's syndrome and in any case renders the cell unkillable by conventional cytotoxic drug combinations like FCR.
How can what's going on in the lymph nodes be stopped? Agents that specifically disable the CLL second messenger system, like CAL-101 and PCI32765, seem to be the best hope, but revlimid may also be useful. What the great danger is, is leaving the patient too long untreated so that TP53 pathway events occur.
John 3:19-21
This is the verdict: Light has come into the world, but people loved darkness instead of light because their deeds were evil. Everyone who does evil hates the light, and will not come into the light for fear that their deeds will be exposed. But whoever lives by the truth comes into the light, so that it may be seen plainly that what they have done has been done in the sight of God.
There are people who believe that mankind is basically good. The evidence of our ears and eyes lays siege to such an idea. Currently in the news we read of Dominique Strauss Kahn, the leader of the IMF, who has been charged with a serious sexual assault on a chamber maid in a New York hotel. Of course, he has only been charged, but his defence appears to be that he was only fornicating not raping. His reputation precedes him. Apparently he was well known as a serial sexual predator. He is not alone. French politicians seem to have made a practice of outrageous sexual exploits and in Italy things are hardly better. Also in today's paper the former Governor of California is in sexual trouble.
In England, the problem seems to be not sex but money, with several MPs in prison and others in disgrace. There also seems to be a raft of actors and footballers in the public eye who have been going to law to save their sordid affairs from being exposed. We need not mention the preachers and bishops who have fallen from grace. I can assert that few would welcome the light being shone on their lives. Men indeed love darkness.
There are people who believe that mankind is basically good. The evidence of our ears and eyes lays siege to such an idea. Currently in the news we read of Dominique Strauss Kahn, the leader of the IMF, who has been charged with a serious sexual assault on a chamber maid in a New York hotel. Of course, he has only been charged, but his defence appears to be that he was only fornicating not raping. His reputation precedes him. Apparently he was well known as a serial sexual predator. He is not alone. French politicians seem to have made a practice of outrageous sexual exploits and in Italy things are hardly better. Also in today's paper the former Governor of California is in sexual trouble.
In England, the problem seems to be not sex but money, with several MPs in prison and others in disgrace. There also seems to be a raft of actors and footballers in the public eye who have been going to law to save their sordid affairs from being exposed. We need not mention the preachers and bishops who have fallen from grace. I can assert that few would welcome the light being shone on their lives. Men indeed love darkness.
Tuesday, May 17, 2011
Statistics
Google have added a statistics package to Blogger which means I can see whether anybody reads this blog. I am pleased to be able to tell you that most days I get over 500 page views and the maximum is 744. The most popular article is the one on how rituximab works.
John 3:18
Whoever believes in him is not condemned, but whoever does not believe stands condemned already because he has not believed in the name of God's one and only Son.
It could hardly be put more plainly. All have sinned and fallen short of the required standard. All are therefore condemned. There is one way out take it and you are free; fail to take it and you will perish. That way is belief in the Lord Jesus Christ. Those who rejecthim will surely perish.
Today Stephen Hawking said that heaven is for those who are afraid of the dark. He's right. There are those who are too stupid or willful to be afraid of the dark. The Bible tells of the outer darkness where there is wailing and gnashing of teeth. Be afraid; be very afraid.
It could hardly be put more plainly. All have sinned and fallen short of the required standard. All are therefore condemned. There is one way out take it and you are free; fail to take it and you will perish. That way is belief in the Lord Jesus Christ. Those who rejecthim will surely perish.
Today Stephen Hawking said that heaven is for those who are afraid of the dark. He's right. There are those who are too stupid or willful to be afraid of the dark. The Bible tells of the outer darkness where there is wailing and gnashing of teeth. Be afraid; be very afraid.
Telling stories.
We like stories. We like a beginning, a middle and an end. It's the way we're made. The greatest Teacher ever used stories to teach. Listen, a farmer went out to sow his seed... A man was going down from Jerusalem to Jericho when he fell among thieves... There was a man who had two sons...
As patients we like a narrative. Rather than have a series of blood tests we want to put together a story about our condition. Sometimes it is a wrong story, but it is more satisfying than the truth. I remember a young 35-year old man who worked on the railway. He had an accident and broke his leg. X-rays showed that it was a pathological fracture. He had been developing myeloma at the site and this had weakened the bone at the point where it had fractured. For him and his Union representative the story was that the industrial accident had caused the myeloma. This story was so compelling (it ended with a nice compensation package) that they wouldn't be swayed. This was the satisfying story.
I have a little story of my own to try out. A couple of days ago I developed swelling of my ankles. I have had it before and though it is largely unexplained I accounted for it by postulating a rare condition known as RS3PO. As I usually do, I took a furosamide tablet.
Yesterday I noticed a fine maculo-papular rash on my forehead. It didn't itch or cause me any bother; it was just there. It seems that such a rash can be an allergy to furosamide. Last night I was particularly bothered by abdominal bloating. This has been a problem since my surgery last year. I have been left with a blind loop of bowel which easily fills with air. I have got used to putting up with it. Last night it was particularly troublesome.
Here is how I put the story together. RS3PO is known to be associated with men in their sixties with malignant disease. The mechanism is unknown but s thought to be autoimmune. This perhaps makes an allergic reaction to furosamide more likely. The type of rash is associated with immune complexes.
rashes are seldom just on the surface and it is reasonable to assume that it is also on the peritoneum where it can cause edema. this could cause more problems with intestinal motility and therefore with bloating. The remedy for all this is likely to be steroids so I have increased my steroid dose for the next week.
Ths story is satisfying in that it predicts a remedy. The hypothesis can be tested.
As patients we like a narrative. Rather than have a series of blood tests we want to put together a story about our condition. Sometimes it is a wrong story, but it is more satisfying than the truth. I remember a young 35-year old man who worked on the railway. He had an accident and broke his leg. X-rays showed that it was a pathological fracture. He had been developing myeloma at the site and this had weakened the bone at the point where it had fractured. For him and his Union representative the story was that the industrial accident had caused the myeloma. This story was so compelling (it ended with a nice compensation package) that they wouldn't be swayed. This was the satisfying story.
I have a little story of my own to try out. A couple of days ago I developed swelling of my ankles. I have had it before and though it is largely unexplained I accounted for it by postulating a rare condition known as RS3PO. As I usually do, I took a furosamide tablet.
Yesterday I noticed a fine maculo-papular rash on my forehead. It didn't itch or cause me any bother; it was just there. It seems that such a rash can be an allergy to furosamide. Last night I was particularly bothered by abdominal bloating. This has been a problem since my surgery last year. I have been left with a blind loop of bowel which easily fills with air. I have got used to putting up with it. Last night it was particularly troublesome.
Here is how I put the story together. RS3PO is known to be associated with men in their sixties with malignant disease. The mechanism is unknown but s thought to be autoimmune. This perhaps makes an allergic reaction to furosamide more likely. The type of rash is associated with immune complexes.
rashes are seldom just on the surface and it is reasonable to assume that it is also on the peritoneum where it can cause edema. this could cause more problems with intestinal motility and therefore with bloating. The remedy for all this is likely to be steroids so I have increased my steroid dose for the next week.
Ths story is satisfying in that it predicts a remedy. The hypothesis can be tested.