There has been a bit of discussion about transformation of CLL to PLL. I have been saying that it doesn't happen. This has caused some confusion, so let's see if I can straighten things out.
Prolymphocytic leukemia is quite a different disease from CLL. It has bright surface Ig, it is CD5 negative, CD23 negative, FMC7 positive, CD22 positive and it has more than 55% prolymphocytes on the blood film. Often there is a paraprotein and while the spleen is enlarged, the lymph nodes are not. It is also very rare. I have 7 cases on my books, compared to over 800 CLLs.
Most of the confusion arised from a condition known as CLL/PLL. This condition has between 15% and 55% prolymphocytes in the blood but the cell markers are those of CLL, not PLL. In the 1980s the FAB group (nothing to do with the fab four, it stands for French-American-British) having divided up the acute leukemias and MDS, decided to have a go at the chronic lymphoproliferative disorders. They divided up CLL into typical and two types of atypical CLL. One sort of atypical CLL was CLL/PLL. In a big series of patients, my group and Danny Catovsky's group demonstrated that there was a close correlation between atypical CLL and trisomy 12.
Although people talk about prolymphocytoid transformation of CLL, which seems to imply increasing numbers of prolymphocytes over time, this does not really happen with trisomy 12. There are variable numbers of increased prolymphocytes, but this is a pretty permanent state. I followed one such woman for 20 years with no change in the percentage of prolymphocytes. She had a big spleen, a high white count, a paraprotein, but CLL type cell markers and mutated VH genes. She was non-progressive. If we go back to the papers in Brit J Haem by Junia Melo and David Galton that described CLL/PLL we find that this is just what they descibed.
Here is a section of a paper that I wrote which reviewed the Melo papers:
"Contrary to the common perception, in a study of 55 cases of CLL/PLL half showed a stable picture without a progressive increase in prolymphocytes. The prognosis of this group was similar to that of stable CLL without prolymphocytes. In one third of cases the increase in prolymphocytes was unsustained and in only 18% was there a definite progression towards a more malignant phase of the disease."
In other words a third of patients had a transient increase in prolymphocytes - perhaps triggered by infection or vaccination, and only 18% had a real prolymphocytoid transformation to a more malignant phase. 18% of 55 is 10 cases.
So what was going on with these 10? Trisomy 12 is not the only chromosomal abnormality found in atypical CLL. The very rare t(14;19) translocation involving bcl3 has an excess of prolymphocytes anda poor prognosis. But 80% of patients with p53 mutations or deletions also have atypical morphology. P53 aberrations are likely to occur as a form of chromosomal evolution, and are associated with an increased aggressiveness. I have certainly seen this effect. But note this is not prolymphocytic, but prolymphocytoid transfomation. The cell markers remain typical of CLL.
Part of the confusion lies in the rather atypical immunophenotype of trisomy 12 cells. The surface Ig is rather stronger than normal in CLL and CD20 is also stronger. FMC7 is also moderately positive. These markers have a superficial resemblance to those of PLL but they are quite distinct.
Just to confuse matters more, a minority of PLLs are CD5 positive. We published a paper from my group and the French group from Nantes which exposed these as a variant form of mantle cell lymphoma. They are not the blastic form of MCL that has been described previously, but what appears to be PLL with mantle cell markers including the cyclin D1 and the t(11;14) translocation. They have a dreadful prognosis on the whole.
Is everybody thoroughly confused? Well that's better than being so sure of yourself that you treat zebras like white horses that have caught the sun behind prison bars.
Thursday, March 30, 2006
Wednesday, March 29, 2006
Chauvinism
Arsenal 2 Juventus 0. A masterly display by the London soccer team left the team from Torino reeling as the Italians had two men sent off for foul play in the last five minutes. Such was the speed and movement of the former English Champions that the Italian league leaders resorted to ugly lunges and wild kicks as the Arsenal forwards sailed by them. A real triumph for England.
Except that there were no Englishmen in the London team. Plenty of players from France and Spain and the Ivory Coast, and one from Germany and one from Holland and even one from Belarus. The coach, too, is French. Mind you, the Torino team only had four Italians.
It got me thinking about our laboratory which contains Chinese, Russians, Iraqis, Jordanians, Egyptians, Mexicans, Canadians, Australians, Belgians, Dutch, Germans, Italians, Irish, Indians and Pakistanis. Any achievements will be credited to the Welsh charity that supports us.
If you go into the Jardin des Plantes in Paris through the entrance nearest the Gare d’Austerlitz.you will see a statue of the “Father of Evolution”. How generous, I thought, of the French to so honor an Englishman. But the statue bore not the bearded visage of Charles Darwin, but the bewigged features of Jean Baptiste Pierre Antoine de Monet Chevalier de Lamarck, the Frenchman who went down the blind alley of inheritance of acquired characteristics.
Chauvinism meaning “bellicose patriotism” derives from Nicolas Chauvin a highly decorated veteran of Napoleon’s army, and the French are particularly good at it. You can read about him at http://www.chauvin.org.uk/story.htm .
We often hear arguments about the superiority of this of that economic system and this or that health service. I remember president Clinton trumpeting American achievements in science. He included in his list the splitting of the atom, which every school child knows was achieved at the Cavendish laboratory, Cambridge (that’s England not Massachusetts) by Sir Ernest Rutherford, a New Zealander.
Now New Zealand has a lot to feel chippy about. Apart from Rutherford there is a whole list of famous New Zealanders who are generally assumed to come from somewhere else, especially (perish the thought) Australia. The first man to climb Mount Everest, Sir Edmund Hillary, was from New Zealand. Film directors Jane Campion and Peter Jackson (remember Lord of the Rings) as well as actors Sam Neill and Anna Paquin are well known. Golfers will know Bob Charles, the left-hander and Michael Campbell, and equestrians, Mark Todd. Kiri Te Kanawa is one of the world’s greatest opera singers. The first surgeon I worked for, Harry Espiner, was a New Zealander and so are Myf Spellerberg and Adrian Copplestone who appear as a co-authors on some of my papers. Bruce Maclaren founded the Maclaren racing car company, Ngaio Marsh is a well known author though Katherine Mansfield is more important. Jack Lovelock was the first record breaking runner, but he was followed by Peter Snell, Murray Halberg and John Walker. William Pickering from Wellington was the man behind America’s first space satellite, Explorer 1. Keith Park, the RAF commander at the Battle of Britain was from New Zealand, as was Charles Upham, one of only three soldiers to win the Victoria Cross twice. We all know about Crick and Watson, the discoverer of DNA, but there was a third member of the team who won the Nobel Prize with them. Maurice Wilkins was a New Zealander. Harold Gillies was the maestro of plastic surgery who repaired the burned faces of Battle of Britain fighter pilots. He was from New Zealand. Robert Burchfield, the Editor of the Oxford English Dictionary was from New Zealand. Oh, and Xena, the Warrior Princess is from New Zealand. I believe there is also a promising young actor called Russell Crowe. However, he has moved to Australia, perhaps trying to emulate the actor who appears to be his hero, who hailed from there, one Errol Flynn.
The thing is that many of the above were New Zealanders when New Zealand was a British colony and were this British subjects, as were Oscar Wilde, James Joyce and WB Yeats, though the Irish claim them all. So, of course, were George Washington and Thomas Jefferson before they rebelled. So was Ghandi, whether in South Africa or India. Just as all Pakistanis were once Indians. Thought for the Day this morning on Radio 4 was taken from the Hindu scriptures and warned us of the danger of assuming that we all see things from the same viewpoint. The speaker also warned us about assuming that today’s historical assumptions applied when the events were taking place. I am sure Keith park thought of himself as both British and New Zealander. To suggest that Paul Revere’s message was “The British are coming” is crass. They were all British at the time. His message was “The regulars are out” or something similar.
It is an interesting question of where we get our drugs from. Monoclonal antibodies, for example, were developed by an Argentinean and a Swiss working in a British laboratory and funded by the British government which declined to patent them, reasoning that such a discovery should be for the whole world. The development of rituximab began with an Australian working in a British laboratory and funded by a Welsh charity who then passed the idea on to a Californian who also picked up a discovery of a man from Boston. A small biotech company in California was set up to develop the drug which is marketed in the rest of the world by a giant Swiss company.
Campath was originally developed in the same British lab that discovered monoclonal antibodies. It was originally developed and marketed by a British company before that company was taken over by another British company that wasn't interested in developing it further because it was more interested in AZT for AIDS which the first company had also developed, so it was sold to a German company that now markets it in America through its wholly owned subsidiary, but is currently fighting a take-over by the German subsidiary of an American pharmaceutical company.
One of the biggest sellers among drugs is Viagra which was discovered by British scientists working in the laboratories of the British subsidiary of an American company. Chlorambucil is British, but cyclophosphamide was discovered by an Austrian Jew who had escaped to Australia where he was working on a chemical to put a permanent kink in wool. He was invited to England and there pursued an illustrious career in cancer research. He was my friend.
My point is that we shouldn't get too Chauvinistic about scientific discoveries. Science is international and knows no boundaries. Though I sometimes joke that according to the Japanese 55% of all useful discoveries were made in Britain, I have to admit that like Arsenal we have often employed foreign mercenaries, and now that America has more money the mercenaries are playing for America.
Except that there were no Englishmen in the London team. Plenty of players from France and Spain and the Ivory Coast, and one from Germany and one from Holland and even one from Belarus. The coach, too, is French. Mind you, the Torino team only had four Italians.
It got me thinking about our laboratory which contains Chinese, Russians, Iraqis, Jordanians, Egyptians, Mexicans, Canadians, Australians, Belgians, Dutch, Germans, Italians, Irish, Indians and Pakistanis. Any achievements will be credited to the Welsh charity that supports us.
If you go into the Jardin des Plantes in Paris through the entrance nearest the Gare d’Austerlitz.you will see a statue of the “Father of Evolution”. How generous, I thought, of the French to so honor an Englishman. But the statue bore not the bearded visage of Charles Darwin, but the bewigged features of Jean Baptiste Pierre Antoine de Monet Chevalier de Lamarck, the Frenchman who went down the blind alley of inheritance of acquired characteristics.
Chauvinism meaning “bellicose patriotism” derives from Nicolas Chauvin a highly decorated veteran of Napoleon’s army, and the French are particularly good at it. You can read about him at http://www.chauvin.org.uk/story.htm .
We often hear arguments about the superiority of this of that economic system and this or that health service. I remember president Clinton trumpeting American achievements in science. He included in his list the splitting of the atom, which every school child knows was achieved at the Cavendish laboratory, Cambridge (that’s England not Massachusetts) by Sir Ernest Rutherford, a New Zealander.
Now New Zealand has a lot to feel chippy about. Apart from Rutherford there is a whole list of famous New Zealanders who are generally assumed to come from somewhere else, especially (perish the thought) Australia. The first man to climb Mount Everest, Sir Edmund Hillary, was from New Zealand. Film directors Jane Campion and Peter Jackson (remember Lord of the Rings) as well as actors Sam Neill and Anna Paquin are well known. Golfers will know Bob Charles, the left-hander and Michael Campbell, and equestrians, Mark Todd. Kiri Te Kanawa is one of the world’s greatest opera singers. The first surgeon I worked for, Harry Espiner, was a New Zealander and so are Myf Spellerberg and Adrian Copplestone who appear as a co-authors on some of my papers. Bruce Maclaren founded the Maclaren racing car company, Ngaio Marsh is a well known author though Katherine Mansfield is more important. Jack Lovelock was the first record breaking runner, but he was followed by Peter Snell, Murray Halberg and John Walker. William Pickering from Wellington was the man behind America’s first space satellite, Explorer 1. Keith Park, the RAF commander at the Battle of Britain was from New Zealand, as was Charles Upham, one of only three soldiers to win the Victoria Cross twice. We all know about Crick and Watson, the discoverer of DNA, but there was a third member of the team who won the Nobel Prize with them. Maurice Wilkins was a New Zealander. Harold Gillies was the maestro of plastic surgery who repaired the burned faces of Battle of Britain fighter pilots. He was from New Zealand. Robert Burchfield, the Editor of the Oxford English Dictionary was from New Zealand. Oh, and Xena, the Warrior Princess is from New Zealand. I believe there is also a promising young actor called Russell Crowe. However, he has moved to Australia, perhaps trying to emulate the actor who appears to be his hero, who hailed from there, one Errol Flynn.
The thing is that many of the above were New Zealanders when New Zealand was a British colony and were this British subjects, as were Oscar Wilde, James Joyce and WB Yeats, though the Irish claim them all. So, of course, were George Washington and Thomas Jefferson before they rebelled. So was Ghandi, whether in South Africa or India. Just as all Pakistanis were once Indians. Thought for the Day this morning on Radio 4 was taken from the Hindu scriptures and warned us of the danger of assuming that we all see things from the same viewpoint. The speaker also warned us about assuming that today’s historical assumptions applied when the events were taking place. I am sure Keith park thought of himself as both British and New Zealander. To suggest that Paul Revere’s message was “The British are coming” is crass. They were all British at the time. His message was “The regulars are out” or something similar.
It is an interesting question of where we get our drugs from. Monoclonal antibodies, for example, were developed by an Argentinean and a Swiss working in a British laboratory and funded by the British government which declined to patent them, reasoning that such a discovery should be for the whole world. The development of rituximab began with an Australian working in a British laboratory and funded by a Welsh charity who then passed the idea on to a Californian who also picked up a discovery of a man from Boston. A small biotech company in California was set up to develop the drug which is marketed in the rest of the world by a giant Swiss company.
Campath was originally developed in the same British lab that discovered monoclonal antibodies. It was originally developed and marketed by a British company before that company was taken over by another British company that wasn't interested in developing it further because it was more interested in AZT for AIDS which the first company had also developed, so it was sold to a German company that now markets it in America through its wholly owned subsidiary, but is currently fighting a take-over by the German subsidiary of an American pharmaceutical company.
One of the biggest sellers among drugs is Viagra which was discovered by British scientists working in the laboratories of the British subsidiary of an American company. Chlorambucil is British, but cyclophosphamide was discovered by an Austrian Jew who had escaped to Australia where he was working on a chemical to put a permanent kink in wool. He was invited to England and there pursued an illustrious career in cancer research. He was my friend.
My point is that we shouldn't get too Chauvinistic about scientific discoveries. Science is international and knows no boundaries. Though I sometimes joke that according to the Japanese 55% of all useful discoveries were made in Britain, I have to admit that like Arsenal we have often employed foreign mercenaries, and now that America has more money the mercenaries are playing for America.
Monday, March 27, 2006
Not Spring yet
I won't say Spring has arrived, because it certainly hasn't. But the weather has changed. It is certainly warmer, but not at all pleasant. The wind is strong, the sky is overcast and the rain spits, drizzles, seeps, stops, starts and sets in.
The daffodils are out but bedraggled, the crocuses have fallen over. We have some impressive catkins on the twisted hazel. Today I saw a jay on a leafless branch; a glimpse of tan that first I thought was the remains of last Fall's leaves, but he seemed to be shivering, and surely if the wind were doing that it would have blown away any leaf.
Driving home from Tunbridge Wells last evening was a trial. 20 mph on the M25; four lanes nose to tail; the sky full of grey warnings gradually intensifying as we stuttered along. Driver behavior was very good; no lane hopping or tailgaiting. It was as if we were all in the same boat so we'd better stick together.
The daffodils are out but bedraggled, the crocuses have fallen over. We have some impressive catkins on the twisted hazel. Today I saw a jay on a leafless branch; a glimpse of tan that first I thought was the remains of last Fall's leaves, but he seemed to be shivering, and surely if the wind were doing that it would have blown away any leaf.
Driving home from Tunbridge Wells last evening was a trial. 20 mph on the M25; four lanes nose to tail; the sky full of grey warnings gradually intensifying as we stuttered along. Driver behavior was very good; no lane hopping or tailgaiting. It was as if we were all in the same boat so we'd better stick together.
Selling Honors
Tony Blair is in trouble. Time was when the funding of political parties was straightforward. The Tories were funded by big business and Labour by organised labour. Corporations are no longer allowed to fund the Tories and the Unions have insufficient funds to pay for New Labour - and in any case New Labour wants to distance itself from the Unions. Both parties turned to rich individuals -but the Labour Government discouraged that by making such gifts public, exposing some Tory donors as tax exiles.
To get round the regulations, both Parties solicited loans, that don't have to be declared, but may never be repaid. But if you loan a million pounds and don't want to be repaid, what do you want?To be called Sir?
A knighthood is all very well if you want to think of yourself dressed up in armour and riding a horse, but a Lordship carries a seat in the House of Lords. When Baron Sausagemaker sat in his country seat and was content to Lord it in the County where he rode to hounds and Lady Sausagemaker entertained the County Set, and the only time he used his vote was when they threatened to abolish foxhunting, it was sort of alright. There was no great threat to the Constitution in buying and selling honours. The House of Lords is the best gentleman's club in London (some say the world); the booze is cheap, the view marvellous and they even pay you a couple of hundred quid for turning up. There is a long tradition; Lloyd George even had a price list: so much for a marquis, so much for a duke. And all those hereditary peers got their gongs by being a crony of Charles the first or the illegitimate son of Charles the second or some other reward for services rendered.
What's different now is that Tony Blair has reformed the House of Lords. Most of the hereditary peers have lost the right to vote, but the newly created ones haven't. They are not just getting a nice restaurant by the Thames, they are buying a vote; instead of being one in 40 million when it comes to having their say, they are becoming one in 600.
Selling honours may sound pretty crass and venial, but it is better than selling influence. Dressing up in ermine and going on parades is pretty harmless. Paying a million to influence decisions or change the law isn't.
So, completing the reform of the House of Lords becomes urgent. The Prime Minister's patronage has to be removed. A major elected element is vital. But if both houses are elected, which will have supremacy? Both can claim electoral legitimacy; the more recently elected will have to win.
The Upper House is supposed to be a Reforming Chamber; somewhere where legislation can be scrutinized and revised. It needs thought and common sense; not emotion. From somewhere it has to recruit experts and the worldly wise. These are not necessarily the skills of politicians.
To get round the regulations, both Parties solicited loans, that don't have to be declared, but may never be repaid. But if you loan a million pounds and don't want to be repaid, what do you want?To be called Sir?
A knighthood is all very well if you want to think of yourself dressed up in armour and riding a horse, but a Lordship carries a seat in the House of Lords. When Baron Sausagemaker sat in his country seat and was content to Lord it in the County where he rode to hounds and Lady Sausagemaker entertained the County Set, and the only time he used his vote was when they threatened to abolish foxhunting, it was sort of alright. There was no great threat to the Constitution in buying and selling honours. The House of Lords is the best gentleman's club in London (some say the world); the booze is cheap, the view marvellous and they even pay you a couple of hundred quid for turning up. There is a long tradition; Lloyd George even had a price list: so much for a marquis, so much for a duke. And all those hereditary peers got their gongs by being a crony of Charles the first or the illegitimate son of Charles the second or some other reward for services rendered.
What's different now is that Tony Blair has reformed the House of Lords. Most of the hereditary peers have lost the right to vote, but the newly created ones haven't. They are not just getting a nice restaurant by the Thames, they are buying a vote; instead of being one in 40 million when it comes to having their say, they are becoming one in 600.
Selling honours may sound pretty crass and venial, but it is better than selling influence. Dressing up in ermine and going on parades is pretty harmless. Paying a million to influence decisions or change the law isn't.
So, completing the reform of the House of Lords becomes urgent. The Prime Minister's patronage has to be removed. A major elected element is vital. But if both houses are elected, which will have supremacy? Both can claim electoral legitimacy; the more recently elected will have to win.
The Upper House is supposed to be a Reforming Chamber; somewhere where legislation can be scrutinized and revised. It needs thought and common sense; not emotion. From somewhere it has to recruit experts and the worldly wise. These are not necessarily the skills of politicians.
Monday, March 20, 2006
Spring Tomorrow
No Spring has been as late as this since 1964. Temperatures hover between 0 and 5 degrees Celcius. Going outside requires a scarf, thick gloves and an overcoat. A few straggly snowdrops have appeared and a smattering of draggly crocuses. The daffodills have been tight buds for weeks now. No sign of the grape hyacinths. The ornamental cherry that often flowers in December shows just a faint haze of pinkness on the twig tips. Some days a few Great Tits visit the peanuts hanging from the May tree and we have had one nut attack from a newly awoken squirrel. The grass is yellow-green, but the moss is dying. There are faint white buds on the magnolias. A flame-of-the-forrest has wispy pink flowers, but no red bracts.
But, astonishingly, one camellia is smothered with bright red blooms; a gory gash against the shiny green; a defiant statement of scarlet promise.
But, astonishingly, one camellia is smothered with bright red blooms; a gory gash against the shiny green; a defiant statement of scarlet promise.
Saturday, March 18, 2006
Drug trials - what went wrong.
The clinical trials disaster in London has intimidated people from taking part in future clinical trials. A recent poll in AOL indicated that 80% would not take part in a drug trial. It is important to look at what happened.
The drug being tested was a monoclonal antibody directed at a molecule on the surface of T cells called CD28. It is one of the co-stimulatory molecules on T cells. Normally in order to stimulate T cells you need to stimulate both the T-cell receptor (TCR) complex (usually done with anti-CD3 in the test tube) and a co-stimulatory molecule. However, there is a subclass of anti-CD28 antibodies known as superagonists which can stimulate T cells without involving the TCR. They do this by binding to a different site on the CD28 molecule, so that adjacent molecules are lined up in a linear array on the cell surface, which facilitates signaling.
An important property of CD28 stimulation is that it is crucial for the survival and proliferation of regulatory T cells. Regulatory T cells have suddenly assumed a great importance in immunology. They are recognised by being positive for CD4 and CD25 and have a main function in preventing the growth of autoreactive T cells. Mice that lack regulatory T cells develop autoimmune disease. Administration of superagonistic anti-CD28 to mice with autoimmune diseases produces remissions. There is also some suggestion that these T cells have a role in controlling the growth of lymphoid tumors.
In CLL patients with autoimmune disease like AIHA and ITP the regulatory T cells are suppressed. Not only did this antibody appear promising in autoimmune diseases like rheumatoid arthritis and diabetes, but in CLL it might controle AIHA and ITP and possibly the CLL itself.
So what went wrong? One of the problems of stimulating T cells is that they release cytokines. Among these is interleukin-2, which is licensed for the treatment of melanoma and kidney cancer. It is extremely toxic. It cause a high fever, shivering attacks, diarrhea, low blood pressure and makes the patient feel dreadful. So-called capilliary-leak syndrome develops. Fluid leaks from the capilliaries of the lungs, which become waterlogged, so that breathing is difficult. The blood pressure falls so that the kidneys shut down and renal failure develops. Other effects include damage to the liver and bone marrow. The activated lymphocytes visit the heart, so that sometimes heart attacks occur. Interleukin-2 induces the relase of other cytokines - the so-called cytokine storm. To me this sounds like what has happened to these volunteers. Interleukin-2 stays in the blood for 7 minutes. Humanized monoclonal antibodies hangs around for an average of three weeks.
When the anti-CD28 was given to mice there was no evidence of cytokine storm. Mouse CD28 is very similar to human CD28, and the human anti-CD28 cross-reacts with the mouse molecule. As far as I can tell it had been safe also in primates, probably macaques. Nevertheless, in the trial, just to be safe the volunteers were injected with one five hundredth the dose of what was safe in the mouse. No-one was expecting it to be anything other than safe in the volunteers.
Is there any evidence that the trial was improperly conducted? This was a phase I trial intended to test the safety of the drug and to determine a safe dose. Often cancer drugs are tested on patients who are terminally ill who have a slight chance of benefitting from the drug; here a decision was made to use healthy volunteers. In retrospect, using sick patients might have resulted in them all dying of the side effects. The drug was given to eight volunteers with a new volunteer being started every few minutes. This seems foolhardy, but is a common practice. Obviously, had they been injected on successive days the trial would have stopped after one volunteer. But with the background of a safe animal trial behind them, no-one was expecting anything untoward. The volunteers were paid £2000 each. It is not surprising that eight healthy young men felt the risk worth taking. One young man testified in the newspapers that he had paid off his mortgage by taking part in phase I trials.
Does this invalidate the use of animal trials? There is no point in protesting that animals are identical to humans. If that were so there would never be any need to test on humans after a drug has been shown to be safe in animals. Clearly there are diferences. But hundreds of drugs have never been tested on humans because they were too toxic to animals. If the animal tests were omitted there would be many more like the London Six.
My conclusion is that this was an idea with great potential benefit. So far the only criticism that I can make was that they should have staggered the doses so that the side effects would have affected fewer volunteers, but hindsight is fine thing.
The drug being tested was a monoclonal antibody directed at a molecule on the surface of T cells called CD28. It is one of the co-stimulatory molecules on T cells. Normally in order to stimulate T cells you need to stimulate both the T-cell receptor (TCR) complex (usually done with anti-CD3 in the test tube) and a co-stimulatory molecule. However, there is a subclass of anti-CD28 antibodies known as superagonists which can stimulate T cells without involving the TCR. They do this by binding to a different site on the CD28 molecule, so that adjacent molecules are lined up in a linear array on the cell surface, which facilitates signaling.
An important property of CD28 stimulation is that it is crucial for the survival and proliferation of regulatory T cells. Regulatory T cells have suddenly assumed a great importance in immunology. They are recognised by being positive for CD4 and CD25 and have a main function in preventing the growth of autoreactive T cells. Mice that lack regulatory T cells develop autoimmune disease. Administration of superagonistic anti-CD28 to mice with autoimmune diseases produces remissions. There is also some suggestion that these T cells have a role in controlling the growth of lymphoid tumors.
In CLL patients with autoimmune disease like AIHA and ITP the regulatory T cells are suppressed. Not only did this antibody appear promising in autoimmune diseases like rheumatoid arthritis and diabetes, but in CLL it might controle AIHA and ITP and possibly the CLL itself.
So what went wrong? One of the problems of stimulating T cells is that they release cytokines. Among these is interleukin-2, which is licensed for the treatment of melanoma and kidney cancer. It is extremely toxic. It cause a high fever, shivering attacks, diarrhea, low blood pressure and makes the patient feel dreadful. So-called capilliary-leak syndrome develops. Fluid leaks from the capilliaries of the lungs, which become waterlogged, so that breathing is difficult. The blood pressure falls so that the kidneys shut down and renal failure develops. Other effects include damage to the liver and bone marrow. The activated lymphocytes visit the heart, so that sometimes heart attacks occur. Interleukin-2 induces the relase of other cytokines - the so-called cytokine storm. To me this sounds like what has happened to these volunteers. Interleukin-2 stays in the blood for 7 minutes. Humanized monoclonal antibodies hangs around for an average of three weeks.
When the anti-CD28 was given to mice there was no evidence of cytokine storm. Mouse CD28 is very similar to human CD28, and the human anti-CD28 cross-reacts with the mouse molecule. As far as I can tell it had been safe also in primates, probably macaques. Nevertheless, in the trial, just to be safe the volunteers were injected with one five hundredth the dose of what was safe in the mouse. No-one was expecting it to be anything other than safe in the volunteers.
Is there any evidence that the trial was improperly conducted? This was a phase I trial intended to test the safety of the drug and to determine a safe dose. Often cancer drugs are tested on patients who are terminally ill who have a slight chance of benefitting from the drug; here a decision was made to use healthy volunteers. In retrospect, using sick patients might have resulted in them all dying of the side effects. The drug was given to eight volunteers with a new volunteer being started every few minutes. This seems foolhardy, but is a common practice. Obviously, had they been injected on successive days the trial would have stopped after one volunteer. But with the background of a safe animal trial behind them, no-one was expecting anything untoward. The volunteers were paid £2000 each. It is not surprising that eight healthy young men felt the risk worth taking. One young man testified in the newspapers that he had paid off his mortgage by taking part in phase I trials.
Does this invalidate the use of animal trials? There is no point in protesting that animals are identical to humans. If that were so there would never be any need to test on humans after a drug has been shown to be safe in animals. Clearly there are diferences. But hundreds of drugs have never been tested on humans because they were too toxic to animals. If the animal tests were omitted there would be many more like the London Six.
My conclusion is that this was an idea with great potential benefit. So far the only criticism that I can make was that they should have staggered the doses so that the side effects would have affected fewer volunteers, but hindsight is fine thing.
Friday, March 17, 2006
Chai Patel
Tony Blair is under fire. As a third term prime minister he is vulnerable. He has already announced that he will go before the next election, so his patronage has diminished. Despite a majority of 70 he is having difficulty in getting his legislation through parliament. This is probably because his agenda is not traditionally Labor.
Britain has a long tradition of preferring well spoken, well dressed, well mannered leaders. Tony Blair, the ex-public school lawyer easily beat the grammar school, Johnny-come-lately, John Major in 1997; but Blair was an anomaly. Previous Labor leaders like Welsh windbag Kinnock, scruffy Michael Foot, Yorkshire pipeman Wilson, did not have Blair's polish, and it is doubtful if anyone other than Blair would have won that election for Labor. In subsequent elections the Conservatives but up their own blunt Yorkshireman, Haigh (who in any case was bald) and the ageing Howard (who was both bald and Jewish). Now they have selected Cameron, a well dressed, well spoken, well mannered Old Etonian who is both younger than Blair and looks it. It takes no crystal ball to recognise that Cameron will walk the next election, especially against the miserable Scotsman Brown, who is respected for his efficiency but liked by virtually no-one.
The cracks in the Labor cause are already appearing. The Labor left are fed up with Blair's middle class values. The education Bill only got through with Tory support and the Health Bill will be attacked for similar reasons. It is unlikely that the Identity Cards legislation will pass unscathed. But before all that we have the tang of sleaze. John Major's Tories were tainted with sleaze. No that's unfair. The Tories were no more sleazy than any other government. It was just that people decided that it was time for them to go. In Blair they saw a better model. Now the same thing is happening in reverse. The focal point at the moment is Chai Patel. He among others lent the Labor Party over a million pounds to fight the last election. The terms of the loan are vague, but it seems apparent that it was a disguised gift. Certainly the Party is in no position to repay the £10 million that they borrowed from him and other donors. They owe more than that to the bank who will not be so forgiving. No, it was expected that after a while the "loan" would be quietly forgotten about. But being a loan rather than a gift it didn't have to be declared to parliamentry scrutiny.
Why would the donors do this? In return they were expecting peerages. Entry to the smartest club in London, and the right to call yourself Lord. It looks good on the Business stationery and the wife likes to be called Lady (though she would settle for a knighthood - she would still be a Lady). It was only when someone queried Chai's fitness to be a Lord that the fiddle was revealed.
I knew Chai in the 1980s. He was a junior doctor in my hospital. He was very good. Smart, organized, efficient, very bright; he rescued one of my acute leukemia patients at a time when we had inadequate antibiotics and poor supportive care. After he left us I heard that he had been headhunted by a major investment company. He had been investing for himself on the stock market while a junior doctor, and made a good profit. He has since made a lot more money by running a chain of nursing homes.
I was sorry to see him the subject of such adverse publicity. I liked and admired him. He is a severe warning to stay clear of politicians. The dirt rubs off.
Britain has a long tradition of preferring well spoken, well dressed, well mannered leaders. Tony Blair, the ex-public school lawyer easily beat the grammar school, Johnny-come-lately, John Major in 1997; but Blair was an anomaly. Previous Labor leaders like Welsh windbag Kinnock, scruffy Michael Foot, Yorkshire pipeman Wilson, did not have Blair's polish, and it is doubtful if anyone other than Blair would have won that election for Labor. In subsequent elections the Conservatives but up their own blunt Yorkshireman, Haigh (who in any case was bald) and the ageing Howard (who was both bald and Jewish). Now they have selected Cameron, a well dressed, well spoken, well mannered Old Etonian who is both younger than Blair and looks it. It takes no crystal ball to recognise that Cameron will walk the next election, especially against the miserable Scotsman Brown, who is respected for his efficiency but liked by virtually no-one.
The cracks in the Labor cause are already appearing. The Labor left are fed up with Blair's middle class values. The education Bill only got through with Tory support and the Health Bill will be attacked for similar reasons. It is unlikely that the Identity Cards legislation will pass unscathed. But before all that we have the tang of sleaze. John Major's Tories were tainted with sleaze. No that's unfair. The Tories were no more sleazy than any other government. It was just that people decided that it was time for them to go. In Blair they saw a better model. Now the same thing is happening in reverse. The focal point at the moment is Chai Patel. He among others lent the Labor Party over a million pounds to fight the last election. The terms of the loan are vague, but it seems apparent that it was a disguised gift. Certainly the Party is in no position to repay the £10 million that they borrowed from him and other donors. They owe more than that to the bank who will not be so forgiving. No, it was expected that after a while the "loan" would be quietly forgotten about. But being a loan rather than a gift it didn't have to be declared to parliamentry scrutiny.
Why would the donors do this? In return they were expecting peerages. Entry to the smartest club in London, and the right to call yourself Lord. It looks good on the Business stationery and the wife likes to be called Lady (though she would settle for a knighthood - she would still be a Lady). It was only when someone queried Chai's fitness to be a Lord that the fiddle was revealed.
I knew Chai in the 1980s. He was a junior doctor in my hospital. He was very good. Smart, organized, efficient, very bright; he rescued one of my acute leukemia patients at a time when we had inadequate antibiotics and poor supportive care. After he left us I heard that he had been headhunted by a major investment company. He had been investing for himself on the stock market while a junior doctor, and made a good profit. He has since made a lot more money by running a chain of nursing homes.
I was sorry to see him the subject of such adverse publicity. I liked and admired him. He is a severe warning to stay clear of politicians. The dirt rubs off.
Sunday, March 12, 2006
Steroids 1
Corticosteroids are so called because they are made by the cortex of the adrenal gland. The gland makes a number of steroid hormones. Rarely the gland stops working - in the past it was usually secondary to TB; nowadays it is usually caused by an autoimmune process. People without functioning adrenal glands have Addisn's disease, named after Thomas Addison, a physician at Guy's Hospital in London from 1824 to 1860. Addison was a contemporary at Guy's of Thomas Hodgkin who decribed Hodgkin's disease. As well as hypoadrenalism Addison also described pernicious anemia.
If you lack adrenals you become weak and watery, you lose weight, your blood pressure falls, your muscles waste and you get a low blood sugar. The clue to diagnosis is to look for brown pigmentation of the skin creases of the palm. I remember in the days when doctors did house calls being asked to see a middle aged woman in bed with lassitude because her doctor thought she was anemic. A glance at her skin creases made the diagnosis for me and made me some sort of genius in the eyes of her doctor. I have to confess to missing the diagnosis in my next door neighbor. She became increasingly suntanned and all I could think of was how they could afford so many foreign holidays.
What is lacking in Addison's disease are the adrenal hormones, cortisone and aldosterone. Cortisone is called a glucocorticoid, because it particularly affects blood sugar, and aldosterone a mineralocorticoid because it controls the balance between sodium and potassium in the body, causing sodium retention and potassium loss by the kidneys, and thus affecting the blood pressure - if you don't have enough of it your blood pressure falls and if you have too much of it your blood pressure rises. Although cortisone is mainly a glucocorticoid it does have some mineralocorticoid effects.
Too much cortisone production is known as Cushing's syndrome, though strictly speaking this should refer only the the form that is caused by the production of too much adrenocorticotrophic hormone (ACTH) by a pituitary tumor. Harvey Cushing, perhaps the greatest of neurosurgeons, was an American pioneer first at Johns Hopkins and later at Harvard with an interlude at Oxford with Sir William Osler. He died of a heart attack in 1939 at the age of 70.
In Cushing's syndrome there is typically a moon face and a change in body shape. A 'buffalo hump' is part of a round body, but the arms and legs are spindly. The shape has been describes as a 'lemon on matchsticks'. The muscles are wasted and weak, the skin is thin with stretch marks, there is often blleding into the skin. The bones become weakened with crush fractures of the spine. Often the patient becomes diabetic as the blood sugar gets out of control and the blood pressure may also be high. Sometimes there are masculizing effects becuse the adrenals also make a certain amount of testosterone, and this is probably the reason for the rise in hemoglobin. Finally the brain is also affected with inability to sleep, enormous energy, emotional lability, and even psychosis.
This disease is important because although Cushing's syndrome is rare, when steroids are used in treatment the side effects are the same.
The adrenal gland makes cortisone, but it is converted in the liver to hydrocortisone. The relationship between prednisone and prednisolone is the same. Today neither cortisone nor prednisone is much used, we use hydrocortisone and prednisolone almost exclusively. In Addison's disease replacement of the missing steroids requires 20 to 30 mg of hydrocortisone a day given in a divided dose morning and evening with the larger portion in the morning because that is how the body manages it. We need a big dose of steroids to get us out of bed in the morning. To replace the missing aldosterone a small dose, 50-300 micrograms, of the mineralocorticoid, fludrocortisone, is given.
Hydrocortisone is also used intravenously in acute situations like shock or asthma, but generally most people requiring treatment have prednisolone for small to moderate doses and either methylprednisolone or dexamethasone when larger doses are needed. This is because prednisolone has less mineralocorticoid activity (and therefore less fluid retention) than hydrocortisone and dexamethasone less still. Betamethasone and Beclametasone have very high topical effects without being absorbed systemically and are therefore often used on the skin or in the lungs (as an inhaler).
It is important to recognise the dose equivalants for the various types of steroids.
20 mg of hydrocortisone is equivalent to 5 mg of prednisolone is equivalent to 4 mg of methylprednisolone is equivalent to 750 micrograms of dexamethasone.
If you lack adrenals you become weak and watery, you lose weight, your blood pressure falls, your muscles waste and you get a low blood sugar. The clue to diagnosis is to look for brown pigmentation of the skin creases of the palm. I remember in the days when doctors did house calls being asked to see a middle aged woman in bed with lassitude because her doctor thought she was anemic. A glance at her skin creases made the diagnosis for me and made me some sort of genius in the eyes of her doctor. I have to confess to missing the diagnosis in my next door neighbor. She became increasingly suntanned and all I could think of was how they could afford so many foreign holidays.
What is lacking in Addison's disease are the adrenal hormones, cortisone and aldosterone. Cortisone is called a glucocorticoid, because it particularly affects blood sugar, and aldosterone a mineralocorticoid because it controls the balance between sodium and potassium in the body, causing sodium retention and potassium loss by the kidneys, and thus affecting the blood pressure - if you don't have enough of it your blood pressure falls and if you have too much of it your blood pressure rises. Although cortisone is mainly a glucocorticoid it does have some mineralocorticoid effects.
Too much cortisone production is known as Cushing's syndrome, though strictly speaking this should refer only the the form that is caused by the production of too much adrenocorticotrophic hormone (ACTH) by a pituitary tumor. Harvey Cushing, perhaps the greatest of neurosurgeons, was an American pioneer first at Johns Hopkins and later at Harvard with an interlude at Oxford with Sir William Osler. He died of a heart attack in 1939 at the age of 70.
In Cushing's syndrome there is typically a moon face and a change in body shape. A 'buffalo hump' is part of a round body, but the arms and legs are spindly. The shape has been describes as a 'lemon on matchsticks'. The muscles are wasted and weak, the skin is thin with stretch marks, there is often blleding into the skin. The bones become weakened with crush fractures of the spine. Often the patient becomes diabetic as the blood sugar gets out of control and the blood pressure may also be high. Sometimes there are masculizing effects becuse the adrenals also make a certain amount of testosterone, and this is probably the reason for the rise in hemoglobin. Finally the brain is also affected with inability to sleep, enormous energy, emotional lability, and even psychosis.
This disease is important because although Cushing's syndrome is rare, when steroids are used in treatment the side effects are the same.
The adrenal gland makes cortisone, but it is converted in the liver to hydrocortisone. The relationship between prednisone and prednisolone is the same. Today neither cortisone nor prednisone is much used, we use hydrocortisone and prednisolone almost exclusively. In Addison's disease replacement of the missing steroids requires 20 to 30 mg of hydrocortisone a day given in a divided dose morning and evening with the larger portion in the morning because that is how the body manages it. We need a big dose of steroids to get us out of bed in the morning. To replace the missing aldosterone a small dose, 50-300 micrograms, of the mineralocorticoid, fludrocortisone, is given.
Hydrocortisone is also used intravenously in acute situations like shock or asthma, but generally most people requiring treatment have prednisolone for small to moderate doses and either methylprednisolone or dexamethasone when larger doses are needed. This is because prednisolone has less mineralocorticoid activity (and therefore less fluid retention) than hydrocortisone and dexamethasone less still. Betamethasone and Beclametasone have very high topical effects without being absorbed systemically and are therefore often used on the skin or in the lungs (as an inhaler).
It is important to recognise the dose equivalants for the various types of steroids.
20 mg of hydrocortisone is equivalent to 5 mg of prednisolone is equivalent to 4 mg of methylprednisolone is equivalent to 750 micrograms of dexamethasone.
Friday, March 10, 2006
Expert Witnesses
I have spent most of the day working on a report for a medico-legal case. I feel sorry for the poor woman who has had her life spoiled by a mishap during her first pregnancy. She suffered a rare complication of pregnancy that was nobody's fault. It was treated as well as it could be in the 1970s, but she was left with a disability that has persisted. A couple of years ago she suffered an exacerbation of her original problem so that the resulting disability got worse. My role in this as an expert witness was simply to dismiss a red herring that someone had raised as a possible cause.
Reading through the whole thing it seems to me that there is no reason to blame anyone for what happened. Everyone acted throughout according to the guidelines available at the time. At least some of the deterioration can be put down to the patient's lifestyle choices, but I doubt whether she made those choices with any inkling of the likely outcome. I guess she is looking round for someone to blame for her predicament and her doctor was a likely candidate.
Patients sometimes have unreasonable expectations of modern medicine. Such are its successes that it is expected always to come up with the goods. But life doesn't work like that. Even if doctors did the right thing every time patients would still die. And no-one could expect doctors to do the right thing every time. To err is human. The standard by which British doctors are judged is would an ordinary doctor (not an expert or specialist) be expected to act in a different way. We are judged against our peers not against the best.
Being an expert witness is a hazardous business these days. Professor Meadows was struck from the Medical Register for misleading the court because of his misunderstanding of statistics in the Sally Clark case. He has now been re-instated and the judge had harsh words for the Disciplinary Committee of the General Medical Council. Doctors had been deterred from acting as expert witnesses for fear of making a mistake. It seemed to me that it was the court that had made the mistake, not the witness. In an adversarial system an expert witness gives what he thinks is the correct interpretation of the evidence. If the opposition thinks he is wrong then they put up another expert to refute what he says. If Meadows' statistical error was so childish, why did nobody dispute it at the time?
Reading through the whole thing it seems to me that there is no reason to blame anyone for what happened. Everyone acted throughout according to the guidelines available at the time. At least some of the deterioration can be put down to the patient's lifestyle choices, but I doubt whether she made those choices with any inkling of the likely outcome. I guess she is looking round for someone to blame for her predicament and her doctor was a likely candidate.
Patients sometimes have unreasonable expectations of modern medicine. Such are its successes that it is expected always to come up with the goods. But life doesn't work like that. Even if doctors did the right thing every time patients would still die. And no-one could expect doctors to do the right thing every time. To err is human. The standard by which British doctors are judged is would an ordinary doctor (not an expert or specialist) be expected to act in a different way. We are judged against our peers not against the best.
Being an expert witness is a hazardous business these days. Professor Meadows was struck from the Medical Register for misleading the court because of his misunderstanding of statistics in the Sally Clark case. He has now been re-instated and the judge had harsh words for the Disciplinary Committee of the General Medical Council. Doctors had been deterred from acting as expert witnesses for fear of making a mistake. It seemed to me that it was the court that had made the mistake, not the witness. In an adversarial system an expert witness gives what he thinks is the correct interpretation of the evidence. If the opposition thinks he is wrong then they put up another expert to refute what he says. If Meadows' statistical error was so childish, why did nobody dispute it at the time?
Thursday, March 09, 2006
Regulations
About the curdled clouds
The careless kiwis fly
Above the jostling crowds
That watch the hopeful sky.
Unknown the ban on flight,
Aerodynamic too;
They never hoped they might;
They simply went and flew.
The careless kiwis fly
Above the jostling crowds
That watch the hopeful sky.
Unknown the ban on flight,
Aerodynamic too;
They never hoped they might;
They simply went and flew.
Wednesday, March 08, 2006
Forgiveness.
A Church of England vicar has resigned because she cannot forgive the London 7/7 bombers who murdered her daughter.
Should a Christian always forgive? A simple reading of the Bible shows that it is not so. Universal forgiveness is a modern heresy. In John 3:16 we are told that God so loved the world that he gave his only begotten son that whosoever believes in him should not perish but have everlasting life. Universalists emphasize the fact that it is the whole world and major on the 'whosoever'; but it should be noted that this forgiveness is conditional. The words 'believes in him' are not decoration; they are the condition. Two verses later it says, "he who does not believe is condemned already."
In I John 1:9 we learn, "If we confess our sins he is faithful and just to forgive us our sins and to cleanse us from all unrighteousness." Note the condition: 'if we confess our sins.'
On the cross Jesus said, "Father forgive them for they know not what they do." Was this a prayer for all mankind or merely for the soldiers who were carrying out the crucifixion? You only have to read his confrontations with Herod and Pilate, Annas and Caiaphas to realise that they knew what they were doing. Caiaphas was the one who had advised the Jews that it would be good if one man died for the people. (John 18:14) They at least were not included in any general forgiveness. And what about Judas? We are told that the devil entered into him.
Jesus tells us to love our enemies and to pray for those who persecute us. Paul expands on this in Romans chapter 12. He tells us to bless those who persecute us. We should not repay evil for evil. We should not take revenge. He quotes from Proverbs chapter 25, "If your enemy is hungry, feed him; if he is thirsty, give him something to drink. In doing this you will heap burning coals on his head." In other words doing good to one's enemy might bring him to repentance.
In the parable of the unmerciful servant the man who had been forgiven a great debt is condemned when he fails to forgive the smaller debt of a fellow servant (Matthew 18:21-35). But note verse 29: his fellow servant fell to his knees and begged him, "Be patient with me, and I will pay you back." This story exorts us to forgive those who beg forgiveness, for we have been forgiven much more.
Forgiveness is available for everybody. "While we were still in our sin, Christ died for us." (Romans 5:8) There are countless exortations for brother to forgive brother. Those who have placed themselves under the covenant of Christ have an absolute obligation to forgive others under the same blanket. But those who reject the love of God and his priceless gift of grace put themselves beyond forgiveness.
Even if we are able to overcome our own grief and for our own benefit are able to come to terms with the hurt that has been done to us - and this always takes time and prayer - the perpetrator remains unforgiven because God's forgiveness is conditional on repentance. Forgiving those who do not repent does no good. It only encourages them to go on sinning.
Suicide bombers remove themselves from the possiblity of forgiveness. Man is destined to die once and after that to face judgement. (Hebrews 9:27) What they did in London was unspeakably evil. It cannot be forgiven and the bombers are beyond forgiveness. It is absolutely right for a Christian to hate evil. A bereaved mother can sympathize with the mothers of the bombers that their children should have been lost to them; she can pity the fact that they were led astray by evil men; but of their own volition they did this evil thing and then removed themselves from the possibility of repentance. There is now no-one for her to forgive. What remains for her is to cleanse her soul of bitterness. It's not easy. Who can say that they would not feel bitter in such a situation? But it is certainly true that when the bitterness goes she will be healed.
Should a Christian always forgive? A simple reading of the Bible shows that it is not so. Universal forgiveness is a modern heresy. In John 3:16 we are told that God so loved the world that he gave his only begotten son that whosoever believes in him should not perish but have everlasting life. Universalists emphasize the fact that it is the whole world and major on the 'whosoever'; but it should be noted that this forgiveness is conditional. The words 'believes in him' are not decoration; they are the condition. Two verses later it says, "he who does not believe is condemned already."
In I John 1:9 we learn, "If we confess our sins he is faithful and just to forgive us our sins and to cleanse us from all unrighteousness." Note the condition: 'if we confess our sins.'
On the cross Jesus said, "Father forgive them for they know not what they do." Was this a prayer for all mankind or merely for the soldiers who were carrying out the crucifixion? You only have to read his confrontations with Herod and Pilate, Annas and Caiaphas to realise that they knew what they were doing. Caiaphas was the one who had advised the Jews that it would be good if one man died for the people. (John 18:14) They at least were not included in any general forgiveness. And what about Judas? We are told that the devil entered into him.
Jesus tells us to love our enemies and to pray for those who persecute us. Paul expands on this in Romans chapter 12. He tells us to bless those who persecute us. We should not repay evil for evil. We should not take revenge. He quotes from Proverbs chapter 25, "If your enemy is hungry, feed him; if he is thirsty, give him something to drink. In doing this you will heap burning coals on his head." In other words doing good to one's enemy might bring him to repentance.
In the parable of the unmerciful servant the man who had been forgiven a great debt is condemned when he fails to forgive the smaller debt of a fellow servant (Matthew 18:21-35). But note verse 29: his fellow servant fell to his knees and begged him, "Be patient with me, and I will pay you back." This story exorts us to forgive those who beg forgiveness, for we have been forgiven much more.
Forgiveness is available for everybody. "While we were still in our sin, Christ died for us." (Romans 5:8) There are countless exortations for brother to forgive brother. Those who have placed themselves under the covenant of Christ have an absolute obligation to forgive others under the same blanket. But those who reject the love of God and his priceless gift of grace put themselves beyond forgiveness.
Even if we are able to overcome our own grief and for our own benefit are able to come to terms with the hurt that has been done to us - and this always takes time and prayer - the perpetrator remains unforgiven because God's forgiveness is conditional on repentance. Forgiving those who do not repent does no good. It only encourages them to go on sinning.
Suicide bombers remove themselves from the possiblity of forgiveness. Man is destined to die once and after that to face judgement. (Hebrews 9:27) What they did in London was unspeakably evil. It cannot be forgiven and the bombers are beyond forgiveness. It is absolutely right for a Christian to hate evil. A bereaved mother can sympathize with the mothers of the bombers that their children should have been lost to them; she can pity the fact that they were led astray by evil men; but of their own volition they did this evil thing and then removed themselves from the possibility of repentance. There is now no-one for her to forgive. What remains for her is to cleanse her soul of bitterness. It's not easy. Who can say that they would not feel bitter in such a situation? But it is certainly true that when the bitterness goes she will be healed.
Monday, March 06, 2006
Physician assisted suicide.
This evening I attended a seminar on physician assisted suicide. Lord Joffe's Bill is due to be debated in the House of Lords in May.
I am against the Bill for the following reasons:
It negates what doctors are there for. I went into medicine to save lives not to dispense with them. Although there would be an opt out clause for concientious objectors, the Bill would fundementally change the relationship between doctors and their patients.
It underestimates the ability of palliative medicine. The Hospice movement begun by Cicely Saunders (whose Memorial Service in tomorrow in Westminster Abbey) has had remarkable success in aleviating suffering. there is no reason why anybody should be in pain.
It is a slippery slope. In 1967 I fought a losing battle against the Abortion Act. The propaganda told us it was to prevent back-street abortions of which there were supposedly 100,000 a year. When the Bill was enacted the British birth rate fell by the number of legal abortions. How could it have done do if it was simply replacing the back-street abortions? In fact today 20% of all pregnancies end in legal abortions; virtually none because the life of the mother is threatened; virtually none because the mother has already had 7 pregnancies and she can't manage an eighth; virtually all because it is not the woman's choice to have a baby now. Once the door is open a chink, experience tells us that it will be forced wide open.
It is not safeguarded by having two doctors agreeing to do it. It was necessary for two doctors to sign a cremation form, but this did not stop Dr Harold Shipman from murdering more than 250 of his heartsink patients and then covering up his crime by having the body burnt.
It puts unfair pressure on the old and sick. Old people may feel that their lives are useless and opt for a pill to end it all simply because they are lonely.
It assumes that doctors know when patients are about to die. This is plain arrogance. Predicting death is like the weather forecast; you can be fairly accurate about today's outlook, less so about tomorrow's and after that it's largely guesswork.
It takes no account of medical discoveries. I have been continually surprised by medical advances that have turned terminal ilnesses into treatable conditions. A good example would be the treatment of pulmonary hypertension in babies. Previously it was rapidly fatal. Now we know it responds to Viagra. Who'd have thunk it?
It puts intolerable temptation in the hands of relatives. I have never been asked by a patient if I would kill her/him. But relatives have asked me to put gran out of her misery. With many having to sell the family house in order to pay nursing home fees, it doesn't take much to persuade a frail old lady that she would be doing everybody a favor by popping her clogs.
It devalues human life and dignity. I wouldn't allow a dog to suffer like that. You hear it said all the time. But a human being is not a dog. All human lives mean more than that. Just as the real response to an unwanted pregnancy should be care and support for the mother, so the correct response to the old and the dying should be care and support. Everybody has to die. But nobody should die alone, in pain and in sorrow. Shame on us that some should do so.
It smacks to me as a cost saving measure by a government strapped for cash. A famous "Yes Minister" TV program had the civil servants insisting that the most efficient hospital was one that didn't open to patients who would undoubtedly spoil the place. It may be a cheap way out to bump off these difficult patients, but that rather misses the point about what doctors are for.
I guess I could think of more reasons, but that should do.
I am against the Bill for the following reasons:
It negates what doctors are there for. I went into medicine to save lives not to dispense with them. Although there would be an opt out clause for concientious objectors, the Bill would fundementally change the relationship between doctors and their patients.
It underestimates the ability of palliative medicine. The Hospice movement begun by Cicely Saunders (whose Memorial Service in tomorrow in Westminster Abbey) has had remarkable success in aleviating suffering. there is no reason why anybody should be in pain.
It is a slippery slope. In 1967 I fought a losing battle against the Abortion Act. The propaganda told us it was to prevent back-street abortions of which there were supposedly 100,000 a year. When the Bill was enacted the British birth rate fell by the number of legal abortions. How could it have done do if it was simply replacing the back-street abortions? In fact today 20% of all pregnancies end in legal abortions; virtually none because the life of the mother is threatened; virtually none because the mother has already had 7 pregnancies and she can't manage an eighth; virtually all because it is not the woman's choice to have a baby now. Once the door is open a chink, experience tells us that it will be forced wide open.
It is not safeguarded by having two doctors agreeing to do it. It was necessary for two doctors to sign a cremation form, but this did not stop Dr Harold Shipman from murdering more than 250 of his heartsink patients and then covering up his crime by having the body burnt.
It puts unfair pressure on the old and sick. Old people may feel that their lives are useless and opt for a pill to end it all simply because they are lonely.
It assumes that doctors know when patients are about to die. This is plain arrogance. Predicting death is like the weather forecast; you can be fairly accurate about today's outlook, less so about tomorrow's and after that it's largely guesswork.
It takes no account of medical discoveries. I have been continually surprised by medical advances that have turned terminal ilnesses into treatable conditions. A good example would be the treatment of pulmonary hypertension in babies. Previously it was rapidly fatal. Now we know it responds to Viagra. Who'd have thunk it?
It puts intolerable temptation in the hands of relatives. I have never been asked by a patient if I would kill her/him. But relatives have asked me to put gran out of her misery. With many having to sell the family house in order to pay nursing home fees, it doesn't take much to persuade a frail old lady that she would be doing everybody a favor by popping her clogs.
It devalues human life and dignity. I wouldn't allow a dog to suffer like that. You hear it said all the time. But a human being is not a dog. All human lives mean more than that. Just as the real response to an unwanted pregnancy should be care and support for the mother, so the correct response to the old and the dying should be care and support. Everybody has to die. But nobody should die alone, in pain and in sorrow. Shame on us that some should do so.
It smacks to me as a cost saving measure by a government strapped for cash. A famous "Yes Minister" TV program had the civil servants insisting that the most efficient hospital was one that didn't open to patients who would undoubtedly spoil the place. It may be a cheap way out to bump off these difficult patients, but that rather misses the point about what doctors are for.
I guess I could think of more reasons, but that should do.
Maverick
All my life I have been regarded as a maverick. I prefer to say I have an independent mind. The term comes from Samuel A Maverick, a Texan cattle raiser, who did not bother to brand his cattle. Thus he could claim that all unbranded cattle belonged to him. Later on it was applied to politics; someone who was unbranded, who did not acknowledge any party leadership.
It's probably fair to categorise me like this, because I like to think things out for myself rather than rely on other people's opinions. When I was first appointed as a hematologist I refused to be confined to the laboratory but went about actively treating patients others thought untreatable. I took on diseases that the internal medicine specialists didn't understand like SLE and scleroderma. I thought the hematology textbooks of the day were full on nonsense. I started reporting what I saw rather than what the textbook told me I ought to be seeing.
Then I turned myself into a medical oncologist. I had trained as a hematologist and as an immunologist, but it became apparent the principles used to treat leukemias and lymphomas could be applied to solid tumors like breast and bowel cancers. At the time the only people claiming to be oncologists outside major cancer centers were radiotherapists. When surgeons began to refer patients with solid tumors to me rather than them they began to resent it and called me a cowboy oncologist. Rather childishly I responded by devising a regimen for bladder cancer that I named "Blazing Saddles".
I raise this subject because of something I picked up from a televison program. I don't know whether Inspector Frost is required watching in many households, but I am a sucker for TV detectives. Frost is an awkward customer who can't fit in with what his bosses want. His superintendant warns him, "It's alright being a maverick, Frost, as long as you keep coming up with the goods; but one failure and you're vulnerable"
Later Frost accepts an apology from his subordinate. " We can't have out of order, son, but out of step - that's another thing. If you're out of step you step on things that other people miss.."
It's probably fair to categorise me like this, because I like to think things out for myself rather than rely on other people's opinions. When I was first appointed as a hematologist I refused to be confined to the laboratory but went about actively treating patients others thought untreatable. I took on diseases that the internal medicine specialists didn't understand like SLE and scleroderma. I thought the hematology textbooks of the day were full on nonsense. I started reporting what I saw rather than what the textbook told me I ought to be seeing.
Then I turned myself into a medical oncologist. I had trained as a hematologist and as an immunologist, but it became apparent the principles used to treat leukemias and lymphomas could be applied to solid tumors like breast and bowel cancers. At the time the only people claiming to be oncologists outside major cancer centers were radiotherapists. When surgeons began to refer patients with solid tumors to me rather than them they began to resent it and called me a cowboy oncologist. Rather childishly I responded by devising a regimen for bladder cancer that I named "Blazing Saddles".
I raise this subject because of something I picked up from a televison program. I don't know whether Inspector Frost is required watching in many households, but I am a sucker for TV detectives. Frost is an awkward customer who can't fit in with what his bosses want. His superintendant warns him, "It's alright being a maverick, Frost, as long as you keep coming up with the goods; but one failure and you're vulnerable"
Later Frost accepts an apology from his subordinate. " We can't have out of order, son, but out of step - that's another thing. If you're out of step you step on things that other people miss.."
New wine
See how the sick need a doctor!
The children are dying for bread;
The Devil delights in his bombs and hatred
As panic and terror are spread.
The Church still debates its tradition,
Recalling the days that are dead,
When into the tumult there strides the Bridegroom
Demanding His Bride to be wed.
The trumpet sounds;
Listen to the shout!
Heaven opens wide;
Hear the angels sing!
All shall rise!
It’s the voice of victory
Raise your lamps to light
The coming King!
See how the world needs a Saviour!
The children are shrivelled and bored;
And mothers despair for their sons and daughters
As claims of the Christ are ignored.
But these are the days of new wineskins;
We watch as new wine is outpoured,
And see in the stretching out hands of Jesus
The joy of the world is restored.
The trumpet sounds;
Listen to the shout!
Heaven opens wide;
Hear the angels sing!
All shall rise!
It’s the voice of victory
Raise your lamps to light
The coming King
The children are dying for bread;
The Devil delights in his bombs and hatred
As panic and terror are spread.
The Church still debates its tradition,
Recalling the days that are dead,
When into the tumult there strides the Bridegroom
Demanding His Bride to be wed.
The trumpet sounds;
Listen to the shout!
Heaven opens wide;
Hear the angels sing!
All shall rise!
It’s the voice of victory
Raise your lamps to light
The coming King!
See how the world needs a Saviour!
The children are shrivelled and bored;
And mothers despair for their sons and daughters
As claims of the Christ are ignored.
But these are the days of new wineskins;
We watch as new wine is outpoured,
And see in the stretching out hands of Jesus
The joy of the world is restored.
The trumpet sounds;
Listen to the shout!
Heaven opens wide;
Hear the angels sing!
All shall rise!
It’s the voice of victory
Raise your lamps to light
The coming King
Thursday, March 02, 2006
Bible reading
We had an interesting discussion on how to study the Bible tonight. Some people feel guilty if they don't read a chapter a day. Others swear by Bible Reading Notes. Some follow a system devised by CH Spurgeon, Alan Stibbs or IVP. I find the best way is to have to preach on a passage.
One thing I have tried is to write a hymn around a section of scripture. Those readers who liked my hymn "A precious people" might care to know that it comes from Colossians chapter 3 verses 12-17.
One thing I have tried is to write a hymn around a section of scripture. Those readers who liked my hymn "A precious people" might care to know that it comes from Colossians chapter 3 verses 12-17.
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