Town and Country

The hot weather finally broke today with a torrential downpour lasting three hours. I spent the day in London at a GTAC meeting. Yesterday, Diane and I took the day off and went for a walk around Kingston Lacey. This is a large house owned by the National Trust, but previously in teh hands of the Bankes family. Joseph Bankes was the most famous of these; a naturalist and collector of the nineteenth century who got into trouble for doing something disgusting with a guardsman. Rather than face the death penalty, he fled the country.

He was the MP for the area in the days when being MP was a sort of hereditary position. There were several generations of Henry, Joseph or Ralph Bankes MP. In the other half of Dorset the Weld family had a similar grasp of office.

I visited the last Ralph Bankes (not an MP) in the late 1970s. He was someone else's private patient and I had been requested to take blood for a CBC. It's an hour's drive, there and back. I remember I charged him £8. He was a tall, thin man with enormous hands and very large veins. The house was in poor order; he was land rich but income poor. He died in 1981, and being a homosexual, he left no issue. Instead of inheritance tax, his sister gave the house and grounds to the nation, together with Studland, a huge area of coastland between Poole and Swanage.

Anyway, the National Trust has renovated the house and laid out the gardens, and on a day when Bournemouth beach was crowded with bodies smelling of suntan oil, we walked round the country estate admiring the wild flowers and butterflies for about 4 hours in perfect solitude.

I didn't see much of London. We met at Wellington House, just a couple of minutes from Waterloo station, next door to the Old Vic, where Kevin Spacey is the actor/manager. Some of these gene therapy protocols are extremely difficult to understand. Today we had several new members of the committee and they were all a bit reticent in giving their opinions. There was also a division between scientists and doctors, with the scientists wanting more pre-clinical models and the doctors realising that eventually it has to go into man, and that more animal experiments won't change the human experiments. The TeGenero experience also weighs heavily on us, as two of the protocols involved going into normal volunteers. These volunteers are paid $4000 for a week's submission to the experiment. You can understand how young men would be attracted. Especially with that "It couldn't happen to me" attitude.

There are many clinical trials units springing up as commercial concerns now. The question is how they are regulated. All national health service hospitals, all private hospitals, all ambulance services, all general practioner services are regulated by the Health Commission (the organisation that my son works for). It ensures that appropriate standards are met, that patients' rights are upheld, that pharmacy standards are appropriate, that properly qualified staff are employed etc, etc. As far as we can discover, these clinical trials units are not regulated at all. Perhaps that is the lesson of TeGenero.

Injustice

Having so many books to read makes deciding what to read next a diffcult choice. After three weeks of many away days with a lot of strenuous preparation, traveling, and speaking, I relaxed with a PG Wodehouse, 'Right Ho! Jeeves'. Entertaining enough with many a chortle, but I wanted something more substantial so I am now getting into 'Arthur and George' by Julian Barnes. It is the story of Sir Arthur Conan Doyle and his fight for justice for an Anglo-Indian solicitor who was falsely accused of a disgusting crime. It is about injustice and celebrity. It resulted in the establishment of the Court of Appeal. I've only read about 50 pages, so more about Conan Doyle later.

The newspapers are full of stories of injustice at the moment. The broadsheets are rumbling on about the Supreme Court's decision to rule the Military Tribunals at Guantanamo invalid, the red-tops are complaining about Rooney's sending-off at the World Cup.

Both these issues are complex and admit to no easy answer. Read Mark Steyne's essay here , or for more considered conservative response try this . The extreme liberal view is that Guantanamo should be closed down, President Bush leads a nest of criminals who seek to impose authoritarian rule, and the troops should come home now. Perhaps in between the extremes there will be a decision that suits all, or perhaps inflames everybody equally.

On Rooney's sending off the views are just as polarized. Anybody with a computer can re-run the incident. Rooney was sent off by the Argentinian referee for violent conduct. Watch the video and you will see that Rooney receives the ball, but is immediately tackled by three opponents. Remarkably, he does not fall over as most forwards are prone to do (prone being a good adjective for World Cup footballers) but fights for the ball. In the turmoil he clearly steps back on Carvalho's balls as he lies on the ground behind him. The referee is immediately surrounded by Portuguese players who encourage hime to give Rooney a card. Rooney is seen to push away Cristano Ronaldo, the ringleader of this group. The referee then fourishes a red card at Rooney who is thus dismissed the field. As he walks away, Ronaldo is seen to wink at the bench.

There is a subtext here. All three of the principals play for English clubs. Rooney and Ronaldo for Manchester United, Carvalho for their bitter rivals and the current champions, Chelsea. Rooney is well known to have a short temper and opponents use this to rile him in the hope that he will disgrace himself. Ronaldo has a reputation as a sly player who falls over to easily in the hope of fooling the referee.

As for Argentinian referee - there is a long record of rancour between England and Argentina. In 1966 the England manager called the Argentinian players animals because of their brutal fouls. Then there was the Falklands. Last time out Argentina was knocked out by England in the group stages and this time in the quarter finals by Germany. And who could forget the 'hand of God'; Maradonna'a handball that scored an illegal goal in a previous tournament

The crux of the matter is whether Rooney stamped on Carvalho's balls deliberately or trod on them accidentally as he sought to regain his balance. Rooney says it was the latter, the referee the former. Viewers of the video must judge for themselves. For what it's worth I think it is impossible to be sure, but I think it was an accident. The point is that it is impossible to give an unbiased opinion. That's why we have the rule of law and an independent court of appeal.

In English law a person is innocent until proved guilty, and the level of proof is 'beyond reasonable doubt'. There is a tendency for officialdom to believe its officials. In the Conan Doyle case the injustice was perpetrated by a policeman and endorsed by the Chief Constable. We have the principle that no body should investigate itself. On past form Rooney might banned by FIFA and be unavailable for England for their next several matches. With Beckham and Owen both injured this would place them under a handicap. FIFA are unlikely to overrule the referee since thgis would place the validity of their competition in jeopardy. It has been sugested that were Rooney to apologise he would receive leniency. That is the Shawshank Redemption catch - you never get parole until you admit your guilt, even if you are innocent. There is so much money in the game that someone might decide to sue FIFA. The decision then would be on the balance of probabilities.

Children everywhere utter the refrain,"It's not fair."

Have you ever thought why we think it should be?

Summer Saturday

It's been a beautiful day in Bournemouth. The temperature is in the mid-eighties, but it's not humid and there is a gentle breeze to stop us scorching. As I sit on the lawn in the shade of the apple trees I can smell the jasmine and the lavender, unadulterated by the whiff of singed goat. The barbecuers are not out tonight.

I know where they are though; I can here the strains of Elton John coming through the trees. He is playing tonight at the local football ground and both my daughters have gone.

Talking of football; England are out of the World Cup. As usual they have lost on penalties. Just as two years ago in the European Championships, they lost to Portugal. Just as 8 years ago their golden boy has been given a red card; then it was Beckham, today it was Rooney. England raise their game as they played the last half of the match with 10 against 11, but they couldn't score. Once again they go out in the quarter finals. For England that is par for the course. It is what they expected; no better, no worse. More shocking for Brazil to go out. The last four are France, Germany, Portugal and Italy. Four European sides and no South Americans; the balance of power has changed.

It's the second pop concert my daughter has been to this week. Earlier she was listening to the Pet Shop Boys at the Tower of London. It's something I've never done - been to a pop concert. Can't say I'd really want to.

Andy Murray beat Andy Roddick at Wimbledon. The young Scot gives the Glaswegians a double celebration: England defeated and a Scotsman making the second week in the tennis.

Freddie Trueman dies from lung cancer at the age of 75. England's fiery fast bowler from the fifties has bowled his last over. I guess he couldn't stand the England one day team being whitewahed by Sri Lanka.

All is quiet, now. I have been studying that remarkable poem. It keeps coming back.

The cells divide. The cells that will not die
divide too well and so they multiply.
They kill the host to keep themselves alive

In America

At the end of a busy three weeks I take a trip to Boston to advise Big Pharma about the unmet needs in hematological oncology. Since the success of imatinib in CML everyone is into targeted therapy. It sounds good, but when it comes down to it there are just too many targets, and the drugs that are the excitement of the moment, Velcade and Revlimid, seem to block just about every pathway. So despite the brilliance of molecular biologists it is the clinicians who can point to where the effort should be focused. Readers of this blog could probably write their own script for CLL. We need something that doesn't also wipe out the T cells and we need something that kills cells that have lost their p53 genes.

The first thing that struck me about Boston was the new tunnel that moves you out onto the freeway in double quick time. The second thing was the weather. Almost as hot and humid as Singapore. The East Coast has been having tropical rainstorms and flooding, though it didn't rain in Boston while I was there. I flew business class by BA. The flight is less than seven hours so the red-eye doesn't take long enough to get a good night's sleep, even in those clever electric chairs that turn into beds. Instead, BA serves you dinner in the lounge before you fly so can at least get 5 hours shut-eye.

American television is never so good in America as it is in England. The News channels are parochial and everything is constantly interrupted by advertisements. Even on PBS you get thanks to all our sponsors, who are often the same people who advertise on the commercial channels. I enjoy watching House, ER and Gray's Anatomy. I was always a sucker for medical detective stories. I can leave aside the smooching and concentrate on the cases. My daughter is fan of CSI. But these shows take forever in America because of the adverts. At home I VCR them and fast-forward over the ads.

Americans are as friendly as ever and opinionated about their President (and his team/henchmen - strike one for whichever side you are on). I think this is new. It used to be that the President always attracted goodwill because of the office (like our Queen - we may rant about Prince Charles, but when he becomes King [Heaven forfend]we will revere him) but now somepeople haven't a good word for Mr Bush, and those that do haven't a good word for his opponents.

One of my correspondents, a poet with CLL, has written a new poem about the disease and posted it here. I think it captures very well the pathology of CLL and is very clever in relating the life of the tumor cell to the life of the patient.

The verse form is called a villanelle - you can Google it for an explanation - but he has departed from the strict rhyming structure. The best known example is 'Do not go gentle into that good night' by Dylan Thomas. I think that by using this verse structure he is evoking the memory of Dylan Thomas's poem, and expressing what most CLL patients feel - I shan't let this disease beat me without a fight.

There is a strange resistance in America to soccer and the World Cup. This quote from Andrew Sullivan's blog "Soccer is the perfect game for the post-modern world. It's the quintessential expression of the nihilism that prevails in many cultures, which doubtlessly accounts for its wild popularity in Europe,"

I guess this fits in with Gary Lineker's description, " Some guys in shorts and long hair run around in the sun for a couple of hours chasing a ball, then the Gemans win on penalties." It's certainly how the host nation beat the Argeninians this afternoon.

Cruciates

Michael Owen has ruptured his anterior cruciate ligament. The cruciate ligaments are the fibrous strands that hold the knee together, joining the femur (the upper bone) to the tibia (the lower bone). They cross over each other, which is why they are called cruciate. It is almost always the anterior one that gets torn. Typically the injury involves a twisting of the knee with the foot anchored and the weight of the body falling in such a way as to lever open the knee joint. It is extremely painful. I tore my left one in 1960 at the age of 17; it was the end of my chance of playing soccer seriously. In those days there was no treatment, though when I tore the right one in 1966 at least the doctors knew what it was and first aid allowed the inflammation to settle down more quickly. Brian Clough had his footballing career ended in 1962 when he ruptured his in a league game against Bury. Clough was the most prolific goalscorer for Middlesborough and Sunderland, and might have been England's greatest center forward had it not been for the injury. He went on to be one of teh greatest soccer managers England has ever seen, If not the greatest, thesn certainly on a short list of one.

Paul Gascoigne famously tore his in the 1991 FA Cup Final when attempting a high tackle on Nottingham Forest's Gary Charles. He was out for 16 months, but it was repaired and cape back to score that wonder goal against Scotland in 1996.

Alan Shearer did his in 1997, but after the repair he was back playing in 4 months and went on to become the greatest goalscorer in English football, though everbody said he had lost a yard of pace.

Prospects for Michael Owen are perhaps more dubious. He is a striker who relies on pace. He doesn't have the immense quadraceps of Alan Shearer and may find it harder to regain his winning ability.

England did enough to top their group and in patches showed how good they can be, but schoolboy defending allowed the Swedes to gain a draw. Their equalising goal in the last minute was remarkable. A throw-in from the left bounced over everybody into the right hand corner of the goal. It seemed to touch either Mellberg or Henrik Larsson on the way in. That touch was important; otherwise it would have gone in dirct from the throw, and been disallowed.

Volunteering for a phase 1 trial.

One of the interesting questions about the TeGenero trial was why it was conducted in normal volunteers. In fact why are any trials conducted in normal volunteers? Increasingly new medicines are targeted towards specific abnormalities that are often only present in a particular group of patients; it would be folly to use the agent in people who did not have the target lesion.

However, there are some agents that are aimed to be used in everybody - flu vaccines, for example, and normal volunteers could be expected to benefit.

But if there is no possible benefit, why would a normal person vulunteer?

It was a great suprise that after the Northwick Park incident, far from our seeing a reduction in volunteers, there was actually an increase. The reason is very clear; people became aware of how much money there was to be made from volunteering.

If money is the motive, or if there is some coercion (such as PhD students in the lab being asked to 'volunteer') then I think the trial is unethical. Patients who might have some small chance of benefiting from a phase 1 trial might well volunteer and those whose relatives or friends have suffered from the targeted condition might reasonably volunteer. Those who claim to be altruistically motivated should have their expenses reimbursed, but nothing that resembles a bribe must be given. It should be remembered that to impecuneous students a bribe doesn't have to be very great.

In my experience cancer drugs are never given to normal volunteers. Although the TeGenero antibody was possibly targeted at CLL, the company was mainly interested in rheumatoid arthritis, hoping that it would switch on regulatory T cells and so switch off the autoimmune process. Boosting regulatory T cells might not have been a good idea in cancer. On the other hand boosting normal T cells in normals turns out not to have been a good idea either. Had rheumatoid arthritis patients been used the effect might have been worse.

Clearly, testing 6 volunteers together was a mistake, but it is exactly how phase 1 trials of small molecules are usually done. The likelihood of serious toxicity is so small that the lower doses are hurried through. The problem here was unexpectedly the dose was very wrong. Whether this was a Siglec5 effect remains to be determined. I think a general lesson is that the first time a new molecule goes into man it should be into a man (or woman).

When we calculate the dose to be used, we estimate the number of target molecules on the cell and the number of target cells in the body, and calculate a dose necessary to saturate them. This rule of thumb methode can be substantially and unexpectedly awry.

Body of a girl

My latest reading is a novel by Leah Stewart - Body of a Girl. It is told in the first person by a female crime reporter and tells the story of a promising young daughter of a well known doctor, who is found raped and murdered. The reporter inveigles her way into the dead girl's life by fair means and foul, looking for a suspect among friends and relatives, and uncovering an unsavory background of drug abuse and incest. The punch line is that none of this is true. She was killed by a stranger bent on robbery. The unsavory 'facts' are from false assumptions made by the reporter.

An antidote to investigative reporting.

Northwick Park

Tomorrow I have to give evidence at the enquiry about what went wrong at the Northwick Park Phase 1 study of the TeGenero superagonistic anti-CD28 antibody in March, when 6 normal volunteers suffered a severe systemic reaction that put them into the intensive care unit and almost killed them.

For those who haven’t been following the story, anti-CD28 is a costimulatory molecule on the surface of T cells. It is normally involved in the interaction between T cells and dendritic cells in an immune response. A protein antigen taken up by the dendritic cell is broken down into peptides which are then presented in a groove in the class II major histocompatibility (MHC) molecules on the surface of the dendritic cell. In performing the two functions, antigen capture and peptide presentation, the dendritic cell has to mature, losing its phagocytic function and developing the costimulatory molecules, CD80 and CD86, on its surface.

CD4 positive T cells are committed to react with specific antigens. The commitment lies within the T cell receptor (TCR) on the surface (this is the counterpart of the immunoglobulin molecule on B cells, and like immunoglobulin it is a different shape for every antigen). A CD4 positive T cell recognises the peptide in the MHC groove and moves in to dock with it. As the TCR engages with the MHC, various other surface molecules also link up, chief of which is CD80 with CD28. Stimulation and costimulation of the CD4 positive T cell cause it to proliferate and secrete cytokines like interleukin-2. The CD4 positive T cells is known as a helper cell and it aids other cells like B cells and cytotoxic (CD8+) T cells to attack the invader. The CD4+ reaction is controlled by a similar mechanism. When activated the CD4+ T cells produces a molecule CTLA-4 on its surface. This also reacts with CD80 on the dendritic cell, but this reaction has a suppressive effect. CTLA-4 is also expressed by CD4+, CD25+ T cells known as regulatory T cells, which also suppress an immune response by the same interaction.

Stimulating CD28 by itself does not stimulate T cells, the interaction of the TCR and MHC is also required. Instead of CD80, CD28 can be bound by antibodies to CD28, but most antibodies bind to a single CD28 molecule at a time and this is insufficient to build up a lattice of molecules on the surface of the T cells that causes stimulation. Antibodies against the TCR complex given together with an anti-CD28 can help to build the lattice. What TeGenero were able to do was produce an antibody that crosslinked CD28 and thus stimulate T cells without the need to ligate the TCR. In the event the antibody stimulated T cells too well and the volunteers almost died of an overactive immune system.

My contribution to this inquiry stems from experiments that we did in the 1990s. For many years my colleagues in Southampton, George Stevenson and Martin Glennie, have been working with antibody molecules, using chemical reactions to engineer the antibodies into different shapes (George worked in Oxford with Rodney Porter who won the Nobel Prize for discovering the structure of antibodies.) Antibodies have three business ends, 2 for attacking the target (known as Fabs) and one to bind to the various effector mechanisms that antibodies use to kill invaders with (such as killer cells, macrophages or complement). This end is known as Fc. You can think of three double pointed probes sticking out from a central hinge. A fairly simple chemical reaction will make them come apart at the hinge, and then they can be stitched together again, but not necessarily in the combinations that they were in originally. This we have made bispecific antibodies by taking one Fab from an anti-CD20 and one from an anti-CD16, and these can be made with or without an Fc.

The particular molecule that we tested was a trispecific with Fabs from anti-CD3, anti-CD2 and anti-CD28 stitched together. CD3 and CD2 are part of the TCR complex, and the purpose was to activate T cells by forming the lattice that I mentioned earlier. We examined this antibody in the test tube, and sure enough it was excellent at stimulating T cells. Both at making T cells divide and in making them secrete interleukin-2, it was 5 times as good as PHA, which is the standard reagent for stimulating T cells in the test tube.

We intended to use it in patients with melanoma, since we know that this is one of the few cancers in man that are definitely under immune control, and one of the few that responds to large doses of interleukin-2. We had experience of using interleukin-2 and we knew it produces very severe side effects. So we started our first-in-man tests at a very low dose. We decided to treat a patient with advanced melanoma who had no other available treatment and who had an obvious tumor on his skin that we could measure.

You all know the dose of rituximab – around 500 mg. Our starting dose was less than one two thousandth of that – 200 micrograms. Like rituximab, we gave it by slow intravenous infusion. It produced no effect. We gradually raised the dose to 1.2 mg. At this dose he had interleukin-2 type side effects – rash, fever, rigors, hypotension, muscle pain and rising serum creatinine. We stopped the trial. Although there was a marginal improvement in his tumor, it was clear that this treatment was no better than interleukin-2.

In our studies using various engineered antibodies, we have occasionally found other severe side effects. With an anti-CD37 x anti-CD64 bispecific used in advanced CLL we saw a patient with a similar cytokine storm, and with an anti-CD38-saporin immunotoxins used in intractable myeloma we saw transient blindness lasting 36 hours.

Of course none of this explains why the TeGenero antibody was so toxic in the volunteers when it was so harmless in mice and monkeys (which had a 500 times greater dose). I think that the answer to this lies in a paper from Nguyen et al in PNAS (May16 2006, 103:7765-70) They describe a molecule, Siglec-5, which is present on all animal T cells including chimpanzees, gorillas and orang-utans. Siglec-5 is an inhibitor of T-cell activation via the TCR.

From this I have drawn up some principles for the testing of biological agents in man.

1. Good as animal experiments are, there is no animal perfect model.
2. Biological therapy is increasingly targeted. There is no point in applying it in people who lack the target. It follows that trials in normal volunteers are inappropriate.
3. Agents are used first in incurable patients suffering from the target illness
4. Since the trials take place in individuals that have the target, they are designated phase I/II trials and look both at safety and efficacy.
5. One patient at a time is treated with time taken to evaluate the response
6. We give antibodies by slow intravenous infusion
7. We start at very low doses

Twins

We have been having a mini-heat-wave in England with temperatures in the eighties. I had to spend a couple of days in Holland, where it was cold and wet. An interesting event on the plane home. I flew in a turbo-prop with only 27 seats, but the flight attendent calculated that we had 22 passengers instead of 21. She had a roll-call instead and found two passengers with exactly the same name who had been allocated the same seat. Somehow they had been assumed to be the same person when they were booking in.

There was a similar story in one of the medical journals last week. Sitting in an out-patient clinic the doctor asked for the next patient. When he came in he was accompanied by another man who sat silently beside him throughout the whole consultation. The doctor thought this a little strange, but knowing today's society assumed that this was his 'partner' with whom he had had a lover's tiff.

At the end of the consultation the patient left the room, but the other man stayed on. "Did you want to ask me something about the consultation?" asked the doctor.

"Yes," replied the man. "When are we going to talk about my case?"

It transpired that this man and the other patient had the same name and both had entered the clinic room when the name was called.

When I was much younger I had two patients with the same name. Their surname is the commonest in England, and both being children of the Victorian age, they had been named after the Queen's late consort. They had also been both born on the same day, though in different parts of the country. Strange to say, they had both at one time lived at the same address, one had sold the house to the other. Finally, they had both had a prostatectomy from the same surgeon.

There the resemblance ended. One was short and fat and the other tall and gaunt. One had CLL and the other polycythemia. I had been seeing them for several years at staggered three monthly intervals when I realized that they had been given the same hospital number and were sharing the same set of hospital notes.

World Cup

Good to see Australia beating Japan in the World Cup. I am glad that Tim Cahill scored a couple; he has been playing very well for Everton. No disgrace for the USA to be beaten by the Czech Republic, probably the best team in Europe; Eddie Johnson was the best American player. The biggest surprise so far has been Trinidad holding Sweden to a 0-0 draw.

England looked very good in the first half against Paraguay, but tailed off in the second when the 80 degree heat got to them. Hot weather doesn't suit the English style which relies on high energy, closing down the man on the ball amd much running off the ball. This is all much easier to do in a cold climate. England's only success in 1966 was played in England. Playing the game in June doesn't really suit the British players. In fact about the only venue that would really provide the weather they prefer would be New Zealand, preferably South Island. Pategonia would probably suit. Still, I'd like to see these South American Fancy Dans on a November evening in Newcastle. In two pairs of leggings and woolly gloves their delicate touches would be ever so slightly less likely to come off. They's be also put off by the Newcastle supporters who prefer to go bare chested throughout the winter.

Freaky Deaky

Elmore Leonard is over 80 and I've just got around to reading my first novel by him. Get Shorty and Jackie Brown were both based on his work, so it was about time I read him. Freaky Deaky is a cops and robbers novel that is amazingly well written. It moves so fast that you need to take time to appreciate the craft. There is no message and the characters are all various shades of pond scum, but they are well drawn and rounded. The plot is preposterous, but it hangs together and you could really believe it happening in such an exotic place as Detroit.

Detroit exotic? Hey, to a resident of sleepy old Bournemouth Detroit is exotic.

The characters are all left-overs from the sixties; still doing grass and acid. Even those with straight jobs have been left with a hanker after devilment. In a way, the characters all get what they deserve, so there is a pleasant sense of completeness when you finish it. What's nice about it is to enter the thinking of one character after another and watch each of them develop of strategy that trumps the last one.

Will I read another? Probably not, at least for a while. AW Tozer was once asked his reading strategy. "Don't read good books," he said. "There's not enough time." Read only great books."

Freaky Deaky was a good book.

Cheaper by the dozen

I've just watched a DVD of "Cheaper by the dozen". This was a popular movie that got sniffy reviews by the critics.

I rather enjoyed it. Of course, it was a farce and a lot of people think farce is beneath them. It had the full panoply of slapstick and a lot of people don't like slapstick. But I think the real reason the critics didn't like it was that it portrayed an unpopular message. It said that you can't have it all. You can't have a family and a big career. No matter how hard you work, something has to go. Or you have to be married to a saint.

A successful marriage has to be built on compromises as well as promises. It is about putting other people in the family first. A successful career depends on putting the business first. That is too big a price for a happy family to bear.

Apparently 27% of evangelical pastors a suffering from burn out. The symptoms are failure to pray, failure to read the Bible, failure to fully prepare sermons. The consequences are yielding to sexual temptations. And if pastors suffer from burn out, what about the lay-leadership, who have a career to maintain as well as church responsibilities?

Burn out comes from over-commitment; taking on too much and never learning to say, "NO". I once took a time management course which instructed me to never commit more than 40% of my work time. The rest must be for thinking. I never knew a doctor who could comply with these instructions.

In the feeding of the 5000, Jesus had compassion on the multitude who had chased after them. He had first shown compassion for the emotional well-being of his disciples by taking them to a secluded. When the crowds turned up he had compasiion for the intellectual well-being of the crowd and taught them, then he had compassion for their physical well-being and fed them. A Christian doctor must follow this example, but guard against burn out.

Guantanamo

Three inmates commit suicide at Guantanamo: how should we regard that? If one had killed himself, we might have put it down to being held in oppressive conditions, or cruelty by the guards. If three had killed themselves at intervals of a month or so, this point of view would have been endorsed. But three killing themselves at the same time sounds like a conspiracy. Remember these are people who regularly kill themselves as terrorist acts. Suicide bombers don't kill themselves to damage property or to kill a few American troops, they do it to push home a propaganda message, to attack allied morale, to sap the will of the American people. The suicides at Guantanamo have the same motive.

I was beginning to think that Guantanamo would have to be closed, but I have changed my mind. It may be that some of those locked up there were innocent by-standers, but these suicides make clear that among those imprisoned are some of the right people. If they are willing to engage in a suicide conspiracy to make a propaganda point, these are seriously dangerous people; the kind that become suicide bombers if they are let out.

Viet Nam became a media war in which the Americans were defeated because their public opinion was more tender-hearted. Iraq could go the same way. Whatever the reasons for toppling Saddam, Iraq has turned into a surrogate war between the forces of oppression and those of democracy. It may surprise some readers to learn that the oppressors are not the Americans but the Islamists who oppress people in the following ways: they do not allow women to dress the way they want to or to have an independent existence apart from that of their fathers or husbands; they do not allow the practice of any religion except their own and in particular do not allow those whose background was Muslim to choose a religion for themselves; they do not allow freedom of expression; they do not allow freedom of sexual orientation; they commend murderers; they dop not respect the human rights of their prisoners.

The new chairman of the East London Mosque, Dr Muhammad Abdul Bari, has given an interview to the Daily Telegraph. In it he praises Britain's tolerance, education system, innovation and hard work, but criticises drunkenness, gambling and divorce. Such critisism would not come amiss from the Archbishop of Cantebury, but not Dr Bari's proposed remedy - arranged marriages. Nevertheless, I applaud Dr Bari's approach to evangelism; he tries to convert people by reasoned arguement, not with bombs and bullets. It goes to show that Muslims should not all be tarred with the same brush. I think their religion is wrong and misleads millions, but in matters of religion people must be allowed to make their own mistakes. A coerced conversion is no conversion at all.

There is a natural tendency for the Press to stand up for the underdog. Enemies of America receive an oversympathetic treatment by the media because of this. People should realize that Amrica can be defeated only by propaganda. The enemy realizes this and all his fire is directed in this way. Journalists should apply the same scrutiny to allegations against the US government that they rightly apply to statements by the US government. Scientific journals now insist that authors declare their interests before publishing their papers. Newspapers should ask their informants to do the same. They are quick to declare when the Army is the source. Of course, there is no journalistic advancement in regurgitating government handouts, but a native source gains kudos. The native source recognizes how useful gullible idiots can be to its cause.

Just think for a moment what Guantanamo would be like if it were run by the Islamists. Hooded men would gloatingly behead the prisoners in front of the television cameras.

Summer rambles.

Summer has undoubtedly arrived. Most of England is sweltering under cloudless skies with temperatures in the eighties. A drought order is being applied for in London. Here in Bournemouth we benefit from sea breezes that make the heat bearable. The garden is lit up by a haze of purple geraniums, all buzzing with visiting bees. Our plum tree bears fruit for the first time, though several leaves are speckled with tiny green bumps like ants eggs. I suspect an insect attck.

The small fountain is running, endlessly recycling the same few liters of water over pebbles and porcelain frogs. Once a pond was there, rich with water lillies in pink, red and white. Alas we had to drain it lest our grandchildren became pond life.

Clock golf was difficult. We secretly cut the grass without the gardener's permission, but our lawn lacks the smoothness of a putting green. When asked how the Wimbledon courts were kept so perfect the greens-keeper replied, "It's a simple process, sir, you plant the seed, then water, roll and cut for about three hundred years."

Our lawn has only been down for thirty years so it lacks the smoothness required.

It has been an eventful week. My daughter has been away in Budapest for a few days on holiday. I don't think she was very impressed. It was expensive and run down. Also cold and wet. My other daughter returned from her honeymoon in Mauritius. The weather was wonderful, but she was concious of the poverty of the locals who were providing her with luxury.

The disparity between rich and poor in the world seems an insoluble problem. I remember during the 1950s - a time of grim grime and hardship in England - watching the output of Hollywood with considerable envy. Watching smartly clad, beautiful people driving large cars, living in well-appointed, well-furnished apartments, going to night clubs clad in white tuxedos, drinking martinis with gorgeous women dressed in low-backed, sequined dresses emphasized how poor we were.

Men in England seemed always to wear grey shapeless jackets that were too short in the sleeve, uncreased trousers and down-at-heel, skuffed shoes. They couldn't even afford ready-made cigarettes, but smoked roll-ups constructed from the remnants of other people's smokes.

Of course, that picture of America was just as false as that in the mind of today's would-be Indian immigrant who regards Paddington, Edgeware Road, Tooting Bec and Streatham as magical places.

The English Flag of St George has been rehabilitated. Once it was only flown by far-right, anti-immigration political parties, but it has been redeemed by football supporters. It flies from every flagpole, every gas-station, almost every automobile. The World Cup began yesterday with Germany showing attacking flair but a leaky offside trap and Ecuador unexpectedly defeating the Poles. Perhaps the temperature had something to do with it. Isn't ecuador Spanish for equator? England play today against Paraguay. The form book says England should walk it, but I remember when Bournemouth beat Manchester United.

I guess the big news of the week has been the killing of Al-Zarqawi. Hard to think of anyone who deserved it more. The only dissenting voice seems to come from a Mr Berg, whose son was murdered in Iraq and who is running for office somewhere in America on an anti-war ticket. I guess that grief makes some men less objective than would otherwise be the case. In many ways I favor the death-penalty, but I have become convinced that enough mistakes have been made as to render it an impractical solution to the problem of murder. I do not consider it an immoral response by a community to the most heinous crimes, and I have no sympathy for those who are clearly guilty. Its great flaw is that it cannot be undone if a mistake is made, and it is a human inevitability that mistakes will be made.

What has changed from those grim days of the fifties is an enormous lessening of the fear of punishment. I used to have dreams - nightmares - about being hanged. I imagined that something that I might do might lead me to kill somebody. No doubt we are less deterred by the fear of punishment today. The number of homicides in Britain before the end of the death-penalty was about 160 a year: now it is about 1000; still rather few by American standards but continuing to increase. Can it be reversed?

Almost every day the TV News carries and item about one young person killing another with a knife - this is in a country where hand-guns are banned. You can't ban knives, people need them to cut their food with. At the moment the Police are running a knife amnesty. Among the items handed in was a Klingon Batalith (is that the right spelling? One of those double-handed battle axes from Star Trek). However, the dangerous weapon is the hand that wields it, not the sharp implement. To remedy that requires a change of heart.

In the BMJ there is an obituary of Jean Bernard, the French Hematologist who has died in his 99th year. Apart from describing a rare platelet disorder (the Bernard Soulier syndrome), he also introduced the anthracyclines (daunorubicin, adriamycin) for the treatment of leukemia. The BMJ credits him with diagnosing CLL in the Shah of Iran. It claims it was the admission of the Shah to America for medical treatment by President Carter, that prompted the Iranians to storm the American emabassy and take the hostages. If this is the case then it provides a stark contrast between the motives of the Christian Mr Carter and the Islamists in Iran.

By the way, Bernard got the diagnosis wrong. It was almost certainly splenic lymphoma with villous lymphocytes - or splenic marginal zone lymphoma as it is now called. It is said that the Shah failed to take the chlorambucil he was prescribed for fear of showing weakness. It would probably have made no diference.

Mercury fillings

Have you heard about all those people who've had their mercury fillings removed? Have you ever thought of doing the same? Can't decide?

Well, you'll be glad that the latest news will help you decide. I'm sure you've seen it splashed all over the newspapers. It wasn't in your paper? That's funny, it wasn't in mine either. Here's a summary:

The first large scale randomised control trials on the safety of mercury fillings were published just two weeks ago. They studied more than 1,000 children, some were given mercury fillings and some mercury-free fillings. Then they measured kidney function and various neurodevelopmental outcomes such as memory, coordination, nerve conduction, IQ, and so on, over several years. There were no significant differences between the two groups.

Not good news for dentists, I'm afraid. A lady I saw this afternoon told me that she's just seen a private dentist. On her first visit he offered to remove all her mercury fillings and relace them with 'safe' ones. That's strange, she thought, he didn't offer to do that when he was my NHS dentist. So she sacked him.

This is such important news that I'm surprised it wasn't in the newspapers. But then good news is no news, as the saying almost goes.

Vioxx

An important meta-analysis has appeared in the BMJ.

When COX-2 inhibitors appeared they were seen as an answer to one of the real problems of pain relief. For years gastroenterologists have been plagued by hospital admissions for haematemasis (bleeding from the stomach) following treatment with non-steroidal anti-inflammatory drugs (NSAIDs). Drugs like Vioxx and Celebrex seemed to reduce the risk of bleeding. Alas, they also increased the risk of clotting. Vioxx, in particular has been blamed for causing heart attacks.

The meta-analysis looks at the thrombotic risk of COX-2 inhibitors compared to placebos and also old fashioned NSAIDs.

Sure enough there is a risk for all COX-2 inhibitors. Compared to placebos the risk of myocardial infarction went from 0.3% per year to 0.6% per year - an increased risk of 86% (confidence interval 33% to 159%). However, the striking thing was that compared to old fashioned NSAIDs there was no statistically significant increased risk.

This should not be too surprising. We know that the old fashioned NSAIDs inhibit both COX1 and COX2 to varying degrees. In fact, diclofenac (volterol or diclomax or motifene or arthrotec) is a very good COX-2 inhibitor. Even ibuprofen, widely available over-the-counter in various guises, carries the same risk. What stands out is that one particular NSAID seems to carry no increased risk of thrombosis. Naproxen (naprosyn or synflex or napratec) is an excellent COX1 inhibitor. Unfortunately, it seems to be the NSAID with the worst reputation for bleeding from the stomach.

What should we learn from this?

First, that the media hype and the compensation culture, directed at Vioxx was an over-reaction. For a start half the myocardial infarctions that occurred on Vioxx would have occurred if a placebo had been given, and as many would have happened if a standard over-the-counter pain killer had been used. It is also hard to blame a drug company for Vioxx if similar problems have been going unnoticed with the old fashioned NSAIDs for more than 20 years.

Second, we may ask why there has not been a similar outcry against the use of NSAIDs causing stomach hemorrhage.

Third, we are going to have to be more circumspect in our use of these drugs in future. I take ibuprofen in 800mg doses for my arthritis, but only once or twice a week. An editorial in the BMJ is entitled "Life without COX2 inhibitors" spells out the risk.

Pentecost

The latest possible date for Pentecost is June 13th, so June 4th is a relatively late date for it, though three years ago it was on June 8th. Pentecost is 50 days (hence the “pent”) after Easter and occurs at the same time as the Jewish Shavuot, variously known as the Feast of Weeks (Deuteronomy 16:10), the Feast of Harvest (Exodus 23:16) or First Fruits (Numbers 28:26). For Christians it celebrates the coming of the Holy Spirit (Acts Chapter 2), seen as a fulfilment of the prophecy of Joel (2:28-32).

In England we no longer celebrate Whit Monday, which since 1967 has been replaced by the Spring Bank Holiday, which occurs on the last Monday in May. I guess that it was seen as more vulnerable than Easter, but with the introduction of the Communist May Day as a public holiday it now means that we have a cluster of Spring Holidays and then a long summer without one until the last Monday in August. Whit Monday was vulnerable because the Church had forgotten about Pentecost. One of the reasons for this was that the Church of England wished to distance itself from Pentecostal denominations that majored on Pentecost.

Pentecostal Churches associate the Holy Spirit with the spectacular gifts poured out on the Church: speaking unlearnt foreign languages, miracles of healing, visions and prophecies. I think that these churches made the error of not appreciating the significance of Shavuot. It is the Feast of First Fruits. The first fruits are a particularly Mediterranean phenomenon. Harvest does not normally occur in May – this is the early harvest, an earnest, (if you like a deposit) of what is to come later. It is clear that the miraculous gifts of the book of Acts were short lived. In Acts 91:12 we read of Paul’s handkerchiefs touching the sick and healing them, but later on he writes to Timothy to take a little wine for his stomach’s sake and his many ailments. Why didn’t he send a handkerchief?

The miraculous gifts were the first fruits. To pretend that they are still present is technically known as realized eschatology; the idea that the ‘last things’ are already here. Concentrating on the gift of tongues misses out on what it was there for. The point about Acts chapter 2 is that everybody present heard them speaking in his own language. It was the message that was important not the medium.

The Jews of the Gospels were notoriously insular. There had long been strictures about marrying out for fear of foreign gods. In the conquest of Canaan no prisoners were taken. But as God’s chosen people they were chosen for a purpose – to let the world know about Him. So the Deuteronomy passage about Shavuot specifically mentions foreigners among the blessed. Jesus’ first sermon (Luke Ch 4:14-28) raised the anger of his listeners because he spoke of God helping the Gentiles giving examples of Elijah helping a widow from the region of Sidon and Elisha curing the leprosy of a Syrian rather than an Israelite.

When modern Biblical critics consider the two feeding miracles in the Gospels (of the 5000 in Mark 6 and 4000 in Mark 8) they assume that this is the same event somehow confused, but they fail to notice the differences between them. The 5000 took place on Jewish territory in Galilee and the 4000 in Gentile territory in the Decapolis. In explaining their meaning in Mark 8 Jesus harks on about the numbers of baskets. “Do you still not understand?” he asks.
The numbers give the clue. Many people are sceptical about numerology, but without doubt numbers had an important significance in Biblical times. The Jewish feeding is full of Jewish symbolism. 5000 refers to the Pentateuch, the 5 books of Moses; note also there were 5 loaves. Arranging the people in groups of 50 and 100 harks back to Moses in the Wilderness. The 12 baskets refer to the 12 tribes of Israel. The Greek word for basket used here is a specific term for a small lunchbox sized basket used by the Hebrews. On the other hand the word for basket used for the feeding of the 4000 refers to a hamper sized receptacle used by Jews and Gentiles alike. The 4000 is symbolic of everyone – the 4 points of the compass. The 7 baskets refers to the ‘perfect number’ representing all nations; note also there were 7 loaves.

All through the Old Testament there are signs that the Jews were to share ‘their’ God with the rest of the world. Abram is renamed Abraham, the father of many nations. Isaiah talks of his servant being a light for the Gentiles (44:6, 49:6), and Zechariah 8:22 has “many peoples and powerful nations will come to Jerusalem to seek the Lord Almighty.”

Finally Jesus gives the Great Commission, “Go and make disciples of all nations…”

Pentecost is about evangelism … and it worked. Three thousand converted in a single day; evangelists spilled out all over the Roman Empire and beyond,.all preaching a message of a suffering saviour who died to save us and rose to free us and will return to take us home.

My Lord what love is this
That pays so dearly,
That I, the guilty one,
May go free?
Amazing love,
O what sacrifice!
The Son of God given for me.
My debt he paid
And my death he dies
That I might live

Graham Kendrick

This is a true story.

This is a true story. My memory was prompted by Jenny Lou's posting that a watery discharge from the eye turned into white pus after steroids.

It happened about 20 years ago, before we had acyclovir. In those days I had a patient with a very high white count, well over 400K, with massive lymphadenopathy - glands in the armpits about 15cm in diameter - but a normal haemoglobin and platelet count. His serum immunoglobulins were just about undetectable; this was also before iv Ig. Every time we tried to give him chemotherapy he developed widespread herpes simplex lesions all over his body.

In desparation we turned to leucocytapheresis to control his disease. This was quite an ordeal for him as he was 87 years old, but he bore it patiently and even developed an interest in teh creamy solution we were extracting from his blood.

After several session he approached me after the nurse had gone home for the afternoon. "Doctor, I think I have discovered why I have this CLL."

I'm always interested in new theories, so I played along with him, "What do you think it's caused by then?"

"I haven't had sexual intercourse with my wife for 37 years," he said, "it's back pressure."

Nutlin

We have all heard of p53, usually in a negative way. We know that cancer patients whose p53 has gone missing have bad news disease. It is the gene that is most commonly disrupted in cancer. In CLL deletion of 17p13, where the p53 gene is located, or mutation of the gene so as to make it non-functional, leads to poor prognosis, drug-resistant disease. So what does p53 do?

It is often called the Guardian of the Genome, meaning that it's role is to guard against copying errors in the DNA. The idea is that it recognizes when a mistake is made, puts the cell into stasis to see if it can be repaired, and if it can't, orders the cell to kill itself. It's a dangerous molecule to have around; kept on a leash doing what it's told it serves an essential function; let loose, like the dogs of war, it could cause untold damage.

One of the ways of controlling p53 is through the molecule MDM2 (it stands for Murine Double Minute - a reference to the mouse chromosome it is found on). In humans mdm2 is on the short arm of chromosome12. MDM2 is the master regulator of p53. (By the way, if you are getting confused by the use of italics, the covention is that the gene is in italics and small letters whereas the protein is not italicized and often capital letters are used. p stands for protein and the 53 refers to the molecular weight in kiloDaltons. there are other important molecules called p21 and p16 etc.)

MDM2 controls p53 in several ways, including blocking its transactivation domain so that it blocks its ability to activate transcription, also by aiding the nuclear export of p53 and by acting as a ubiquitin ligase to promote p53 degradation by proteosomes. Normally a cell has very low levels of both p53 and MDM2. It has been well demonstrated that disruption of p53-MDM2 interaction leads to activation of p53 and tumor suppression, but until recently disrupting this interaction has been very difficult. The breakthrough came from examining the crystal structure of MDM2 which showed that there is a relatively deep hydrophobic (= water repelling) pocket in the molecule which raised the possibility that small molecular weight molecules might be able to block the interaction with p53. Scientists at Roche have been screening molecules that might do this. They hit upon a series of molecules called cis-imidazolines (Chaya will understand precisely what this means) which they named Nutlins. The name puzzled me for a while until I realized that the Roche Research Institute is based at Nutley, New Jersey. Thus Nutley inhibitors.

The nutlins have been shown to activate the p53 pathway and to have anti-tumor effects in tumor cell lines, especially in those that over-express MDM2. and including some cell lines derived from acute myeloid leukemia and myeloma. In fresh CLL cells the nutlins activate the p53 pathway and induce apoptosis. They synergize with fludarabine and chlorambucil and they are much less toxic to noemal T cells.

They seem to have great promise in CLL; they are orally available and they penetrate cell membranes. Of course they have yet to be tried out in patients, but it can't be long before they are in clinical trials. In order to act they require an intact p53 pathway, so they will of no use in drug resistant CLL, but nevertheless to have a non-toxic agent in CLL that works will be a great boon.

Trading estate shopping

We have blue tits nesting in the bird box in the garden, which means no more football on the lawn. With eldest grandson coming on Monday this presents a problem - how to entertain him all day with no soccer. The solution we hit upon is clock golf. But where to buy a clock gold set? None of the local stores can help, so we resort to the internet. We find that they are made by the ancient firm of Jacques - who made John Prescott's croquet set. We find a site who will sell us a set, but they suggest delivery will take 5-7 days. That will not guarantee that we will get it in time, but the site also suggests "If you are local, drop in and see us."

They are based in Downton, a small village between here and Salisbury. It's a nice drive that takes half an hour or so along country lanes. We arrive at a rather forbidding and deserted trading estate amd enter what seems to be a block of offices. Yes, they'd be happy to sell us a clock golf set and immediately produce one. They have a staff of five very pleasant people who do most of their business over the web, but have about seven customers a week who call in, so it is an event when someone does. Their main business is kitchenware so I ask them if they have a carving dish with rubber feet that won't slide all over the working surface in the kitchen. Not only do they have one, but it doubles as a chopping board and has a heat retaining block to stop the meat cooling while cutting. They have another sale. We are very popular when we leave.

We proceed to another trading estate in Poole, looking for an art gallery. We have been through the yellow pages looking for art galleries because we want to give out daughter a present reminding her of home when she returns from her honeymoon in Mauritius. All the galleries in Bournemouth have large tasteless paintings that are massively overpriced. At the Poole trading estate he has thousand of pictures - prints and originals - and hundreds of choices of frame. He shows us a set of watercolors of Christchurch harbour by Christopher Hollick, a local artist who has now moved to Norfolk and won't be painting any more Dorset views. We purchase three.

I don't like shopping as a rule. I mainly visit the internet when I want to buy something, but trading estate shopping seems tolerable. The man at the art gallery gave us a book about the Dorset Art Fair. Local artists are exhibiting in their own homes for the next month. It is an opportunity to see what they have to offer. The first one we must visit lives 5 doors away from us. After 30 years at this address it is a wonderful excuse to meet out neighbours.

St Pierre

The venue for my daughter's wedding was just over the old Severn Bridge into Wales. Well, I say Wales, but when I went to school Monmouthshire was part of England, but it became Gwent and part of the Welsh Principality. The old Severn Bridge was built in 1966. Diane and I walked over it in November that year, but the more direcct route into Wales (and the M4) takes the new Severn Bridge, built in 1996.

The church of St Peter was built around 1100 AD, although there was probably an even older Saxon church there. It was restored by the Victorians (at the cost of £1000) but incorporated a wooden chancel screen from 1400 and two stone coffin lids from the 13th century. The manor of St Pierre is first mentioned in 1340, but the house was built in 1475 and has been added to and improved ever since.

Ownership of the estate changed hands many times, and in 1946 it fell into the hands of the National Association of Boys Clubs. When they moved elsewhere it was eventually established as St Pierre Golf and Country Club. It became the site of the Welsh Open in 1971 and the Dunlop Masters was played there the same year. In 1973 it was acquired by Whitbread Hotels and in 2005 it became part of the Marriott chain. In 1996 the Solheim Cup was held there and in 2000 the Welsh Masters.

Today the house is a hotel and leisure center with two 18 hole golf courses, swimming pool, gym and tennis courts. There are 143 rooms many of them as appartments and small cottages. A very pleasant place to spend a few days.

Spring

This really has been a cold spring in England. We have our first blue geraniums out in the garden, the pink ones have been out for a couple of days. We have blue tits and their fledgelings in our nesting box, the lilac is well advanced, small Bramly apples have formed on the trees; but it has been the wettest May since 1983 and one of the coldest. Last year we had a week in May when the temperature touched 80 degrees. This year it has been mainly in the fifties.

Everything is very green. The trees are in full leaf and growing quickly. The oil seed rape is glowing luminous yellow in the fields. We certainly have bright and sunny days; but a North wind is blowing.

I wonder if Nature is confused by this weather? The vigorous growth of vegetation seems like an overreaction. The grass needs cutting twice a week. Plants we had forgotten about are growing stronger than we ever remember them. The Christmas Cactus that we moved into the greenhouse is flowering six months early.

I've put on a thick pullover and gone back to thick woolly socks. If Nature isn't confused, I certainly am.

Harry Potter

I have just watched the DVD of Harry Potter and the Goblet of Fire. I thought it very well done. My usual complaints that the music was too loud, muffling the dialogue, and everything was too dark to see properly applied, but I turned the subtitles on and was able to follow it.

The young actors have much improved since the first film, Ralph Feinnes was excellently evil, but Michael Gambon is still a disappointment after Richard Harris. Brendan Gleeson was fun. Spotting the uncredited actors was interesting. No John Cleese this time, but veteran comedian, Eric Sykes put in an appearance at the beginning and the new Dr Who, David Tennant played the part of the villain, Barty Crouch Junior.

Fludarabine and prednisolone

This is the comparison of two phase II trials at MDACC showing no benefit from adding prednisolone to fludarabine.

Steroids 3

After a long interval, I want to complete this subject with an essay on how steroids are used in CLL.

First, it goes without saying that where steroids are used in autoimmune diseases, they are also used in autoimmune disease associated with CLL. Thus for AIHA and ITP, and for paraneoplastic pemphigus steroids are used in a conventional way starting with a dose of 1 mg/kg and tailing off once the complication is controlled.

But steroids are also used as a treatment for CLL, either alone or in combination with chemotherapy or antibody therapy. Early studies showed no benefit from adding steroids to chemotherapy. The British CLL2 trial, for example, compared chlorambucil 20 mg/sq m for 3 days every 4 weeks with the same dose plus prednisolone 40mg/sq m for 5 days ever 4 weeks. There was no significant difference in response rates (74% v 80%) or in overall survival. After this study the recommendation was made that steroids only be used in patients with anemia or thrombocytopenia for the first or second course as anecdotally it was thought that such an approach afforded some protection from the potential marrow damaging affect of chlorambucil.

At the MD Anderson Cancer Center they don’t do comparative trials, but they compare successive phase II studies. The combination of fludarabine at 30 mg/ sq m/d for 5 days combined with prednisone at 30 mg/sq m/d for 5 days every 4 weeks was certainly no improvement on fludarabine alone, and may well have been worse, although with historical controls such a comparison lacks authority.

The use of high dose methylprednisolone with a dose of 1g/ sq m/ d for 5 days – about 30 times the dose that was used with chlorambucil in CLL 2 – was a development from the Royal Marsden Hospital, in London. They found that most patients responded to this, even those who were resistant to chlorambucil or fludarabine.

How does high dose methylprednisolone work? It seems to have a direct lympholytic effect that does not depend on the presence of steroid receptors, and does nor depend on the presence of p53.

Recently, two trials of high dose methylprednisolone (HDMP) and monoclonal antibody have begun. In Britain the combination of Campath and HDMP is being trialled, and in America HDMP plus rituximab. The logic of using Campath with HDMP is that both agents are effective in CLL with a crippled p53 pathway, the commonest cause of drug resistance. Rituximab is ineffective in these patients, but perhaps the combination is more effective. Both these studies are phase II trials, so we will not discover whether either combination is better than single agent treatment.

The suggestion has been made that steroids will render the effector cells used in ADCC ineffective. Although theoretically this seems to be a problem, in practice it does not seem to matter. Perhaps the other methods of killing that antibodies invoke synergize with the effects of the high dose steroids.

It is important to remember that high doses of steroids have major side effects. In diabetics there will be immediate loss of control of blood sugar and sometimes in pre-diabetics the existence of this precursor condition will be revealed. It is important therefore to monitor blood sugar. There is likely to be a change in psyche. Some patients are unable to sleep, others weep in an uncontrolled manner. Others are on a permanent high. Appetite is markedly increased. Blood pressure often goes out of controlled. Some patients will suffer bony collapse – crush fractures of the vertebrae are a possibility, and necrosis of the femoral head (hips) both occur, though usually only after repeated doses and with other auxiliary factors.

Infections are a real possibility. Reactivation of herpes infections such as zoster, herpes simplex and CMV, infections with Pneumocystis, Listeria monocytogenes, Aspergillus and other fungi, are a real possibility and therefore patients on these regimens need to be carefully monitored by doctors with experience of these complications.

In conclusion, steroids clearly have a role in CLL, but that role is not clearly defined. Apart from their use in the autoimmune complications, they are useful in displacing cells from relatively inaccessible sites like bone marrow and lymph nodes, and in high doses for their lympholytic effect which is active even in drug-resistant cases.

Sean Bean

For the past couple of days I have been attending the wedding of my eldest daughter in Wales. They decided to be married at the golfing resort of St Pierre near Chepstow. It was well organized by the hotel staff and I can give them a hearty recommendation. But the most remarkable thing about the couple of days occurred because the actor Sean Bean was making a film there.

My 87-year old mother doesn't get around very well these days, and seeing her struggling with a few stairs, the actor gallantly gave her his arm. It really made her day. At breakfast the next morning next morning she had to endure some gentle ribbing about baked Beans and whether the tomatoes weren't too Sharpe for her, but as she was sitting in the lobby afterwards, the actor came up and greeted her again. I guess she'll be talking about this for the rest of her life.

Monoclonal antibodies in CLL

On May 4th this year the UKCLL Forum held a meeting in London. The topic was "Monoclonal Antibodies in the Treatment of CLL" I have written a report of the meeting and the first part is reproduced here.

Monoclonal antibodies were one of the first attempts at targeted therapy. Two monoclonal antibodies, rituximab (anti-CD20) and Alemtuzumab (anti-CD52) are currently widely used in the treatment of CLL. Lumiliximab (anti-CD23), and HuMax (a fully humanised anti-CD20) are in clinical trials. Although the response to single agent Rituximab in previously treated patients is only 13%, in untreated patients it is 51%. The response in untreated patients to single agent Alemtuzumab is even better at 87% and patients whose disease shows deletions of p53 respond well even though this defect defeats most other therapeutic agents, but Alemtuzumab also kills T cells and engenders immunodeficiency. Used in combination with chemotherapy, the response to rituximab approaches 100%, though the use of chemotherapy detracts from the specificity of the targeting.

According to Professor Martin Glennie, University of Southampton, CD20 is in many respects the ideal target. Compared with most other antigens on the surface of CLL cells antibodies that target it are much more effective killers. It is believed that rituximab kills in three different ways: 1] antibody dependent cellular cytotoxicity (ADCC) in which macrophages, NK cells and possibly granulocytes recognise the Fc portion of cell-bound antibody through their FC receptors, and this invokes killing and ingestion of the CLL cell; 2] complement dependent killing (CDC) – either tumbling the complement cascade right up to the membrane-attack-complex that punches a hole in the CLL membrane or, more likely, opsonizing the cell so that a derivative of the third component of complement, C3b, sits on the cell surface to be recognized by the C3b receptor of macrophages; 3] direct killing by cross-linking adjacent CD20 molecules into lipid rafts which sends a signal through the cell to self-destruct, either through apoptosis or through some other, as yet unclear, process. It is probably true that all three mechanisms play a part in real life, but experiments have revealed two quite distinct types of anti-CD20s. Most are rituximab-like and kill by ADCC and CDC – these are known as type I anti-CD20s – type II antibodies like B1 the original antibody produced in Boston, and the one used in Bexxar, kill by a mixture of ADCC and direct killing. The acute reactions seen after rituximab are cause by the release of C3a, an anaphylactoid, after the fixation of complement, but these also act as chemo-attractants for effector cells.

Dr Glennie also spoke about HuMax, a fully humanized anti-CD20 developed in his lab and currently undergoing clinical trials. This is a type I antibody, but it has certain advantages over rituximab. It is directed against a slightly different portion of the CD20 molecule from rituximab, and a slower off-rate (it stays on the cell longer) so that it is more effective at killing cells with lower quantities of CD20 on the surface.
Dr Josee Golay from Bergamo, Italy stressed the importance of complement in rituximab killing. In animal models lacking complement no killing occurred. Other models emphasize the importance of effector cells, both NK cells and macrophages being required. She went on to stress the importance of the interaction of various killing mechanisms. Fixation of anti-CD20 leads to the upregulation of the chemokines CCL3 and CCL4, which attract and activate a number of cell types including mononuclear phagocytes, NK cells, T cells and granulocytes through interaction with their CCR1 and CCR5 receptors. Which killing mechanisms are predominant depends on which tumor is being attacked and in which body compartment – blood, marrow, spleen or lymph nodes.

Dr Ron Taylor from the University of Virginia, Charlottesville also stressed the importance of complement fixation in rituximab-induced killing and added the information that complement could be consumed. Post-rituximab-infusion sera lacks complement activity, principally through consumption of the C2 component of complement. Although this might be overcome by the infusion of fresh plasma or of recombinant C2, a more important barrier to successful immunotherapy was also revealed. Antigen shaving is another mechanism for antigenic modulation. Antigenic modulation was seen as a potential barrier to antibody therapy in the 1980s. Fixation of antibody led to movement of the antigen in the lipid cell membrane – patching and capping – which in turn led to pinocytosis (internalization) of the antigen/antibody complex so that the cell became naked of antigen. One of the reasons that CD20 was chose was that it is not subject to antigenic modulation. However Dr Taylor has shown that after exposure to quite small amounts of antibody CLL cells are cleared from the circulation, to shortly reappear, this time bereft of surface CD20. The antigen had not been internalized, but phagacytosed by macrophages. It appears that the capacity of macrophages to ingest antibody coated tumor cells is soon exhausted and thereafter as the antibody binds to the macrophage Fc receptor, the most that can be accomplished is the stripping of the immune complex from the tumor cell – antigen shaving – and its ingestion by the phagocytic cell.

The choice of 375 mg per square meter as the dose of rituximab was quite arbitrary, dependent on the amount of antibody available and the number of patients needed to be treated. It may be that most of this antibody is wasted. Dr Taylor suggested that smaller doses given fairly frequently might be more effective. A dose between 20 and 60 mg was suggested, given once or twice a week

On a clear day

Last night I watched an interesting movie. Entitled "On a Clear Day" it won a Scottish BAFTA for best film last year. It stars Peter Mullen as a redundant Glasgow shipbuilder who decides to swim the English Channel. It uses this plot device to explore his relationships with his wife (played by Brenda Blethyn) and the other characters. He keeps the swim secret from his wife, just as she keeps secret from him the fact that she is training to become a bus driver.

Three of his workmates and fellow swimmers at the local baths also feature. One has retained his job but at the expense of his manhood; he is now required to clean the bosses' lavatories. The other two have women problems. The young guy (played by Billy Boyd, who was Merry or Pippin in Lord of the Rings and was also in Master and Commander) looks up to our hero as a father, recognising him as a strong and principled character whom he wishes to emulate, but is afraid to ask out the young girl who serves at the local sweet shop. The older chap was once married but his wife left him for a jam salesman and he has steered clear of women ever since lest history repeat itself. There is also a Chinese Chippy (fish and chip shop owner - not carpenter) who never says a word and cowers when the potato delivery man regularly drops the sack on the floor of the shop, splitting the sack and spilling the spuds. When he speaks it is a surprise because he has a broad Glaswegian accent and is highly intelligent.

But the main broken relationship is with his thirty-something son. He had been a twin but his brother had been lost in a swimming accident when he was a child. The son now has twin boys himself, but his father has pushed both son and grandchildren out of his life. The son feels rejected and thinks his father blames him, whereas in fact the father blames himself and keeps his family at bay to protect them from him.

The channel swim (22 miles in the busiest shipping lane in the world) becomes the talisman for all these people. If he succeeds it will restore all of their lives. The swim is their collective Redeemer.

Here is a movie that won't break box office records, didn't cost a mint to make, doesn't display spectacular scenery or exotic locations, but will reward you more on seeing it than almost any Hollywood spectacular. The acting was fine; the sound balance was perfect - despite the Scottish accents I could hear every word.

It won't be appearing at a cinema near you, but if it comes on cable try to catch it, or try and find it on DVD.

London

Today was my day at a major London Teaching Hospital. Practically the whole team had decamped to America with management consultants to inspect the transplant set-ups at Dana Farber and the Hutch. So it was rather lonely there.

One particularly difficult case was a patient with ATLL, the strange and intractible T-cell leukemia caused by the HTLV-1 virus. She was Jamacian and an illegal immigrant, but she had been in the UK for 17 years and had a son who was a student in College. The leukemia was in her brain and she has perhaps 6 months to live. She could go home, but she has given up her lodgings since she has been in hospital. Social Services, who have the responsibility of finding the homeless somewhere to live don't want to know. Two adjacent areas each claim that she is the responsibility of the other. My suggestion was to contact the Pastor of her local church and ask them to care for her for her last few months, on the Christian principle of "I was a stranger and you took me in." Failing that I suggested that they contact the MP in whose constituency the hospital is and who also happens to be a Government Minister, and complain that a valuable transplant bed in the biggest marrow transplant center in the UK is being blocked by an illegal immigrant that nobody wants to own.

Another problem was a 59 year old patient with CLL who had been in hospital for nearly a year since his low intensity mini-transplant. His problem was chronic graft versus host disease. He receives phototherapy for his skin GVHD and this is improving but he still has diarrhea and abnormal liver function. On large doses of steroids to control his GVHD his CMV had reactivated and for this he takes gancyclovir. I asked how common was severe GVHD in the mini-transplants. The answer was 15% unless they also need donor lymphocyte infusions, when it rises to 30%.

Apparently the patient looks like Gollum from Lord of the Rings. For light relief, I informed the meeting that Andy Serkis, who plays Gollum, also played Bill Sykes in the BBC's early Oliver Twist and the gorilla in King Kong. "That was before he had his marrow transplant," opined some wag.

I also learned that once you have had Hepatitis B, the virus remains in your liver for life, ready to be awakened by immunosuppression. I caught Hepatitis B from a needle stick injury when I was a Fellow. Another good reason why I don't ever want a bone marrow transplant. Or fludarabine.

For relief from the doom and gloom I picked up this story from the Internet:
A man came across a striking brass rat in an antique store and decided it would look great on his desk. He paid $100 for it but was surprised when the proprietor insisted it was non-returnable. He said, "It's been returned twice already, and I don't want to see it again." Leaving the store, the man saw a couple of rats scurrying around the corner; several more were near his car. As he drove, rats appeared from the gutters and side streets until he was nearly overwhelmed. In panic, he threw the brass rat over a bridge railing into a river, and witnessed the army of live rats follow into the depths. The man hurried back to the store, but the owner cut him short, saying, "Look, I told you there would be no returns." The man quickly replied, " Oh no, that's fine. I was just wondering if you had a brass lawyer."

The Constant Gardener

I have just watched the Constant Gardener on DVD. Now this was a movie worth watching, and beautifully transferred to the screen by Fernando Meirelles. Le Carre's books are all about betrayal, and frequently he mixes sexual betrayal with betrayal of country, friends, class, whatever. There were stunning perfomances from Ralph Fiennes and Rachel Weisz, and good supporting roles for Bill Nighy, Pete Postlethwaite, Danny Houston and Juliet Aubrey. The photography is spectacular. There are no green screens, and the single car chase is sinister rather than exciting. * The plot is just the Maguffin; probably preposterous and hardly likely to be true. Pharmaceutical firms may do some dreadful things, but hanging out so far that they are likely to get caught by a idealistic girl is unlikely in their risk averse culture. But that is beside the point, in this sort of literature you need a evil-enough villain, and now the communists have gone, the white South Africans have been defeated and the Moslems blow you up if you attack them, who is there left but big Pharma? It's also hard to believe that you could buy the British government for 1500 jobs in Wales. A peerage perhaps. But the enemy is frightening, fearful and foreboding. Fiennes is just right for the part. Diffident, gentlemanly, polite and dogged. He bears his suspicions of his wife's infidelity with grace and when he discovers her utter faithfullness he breaks down and weeps with both shame and joy. Rachel Weisz is the best pregnant performance since Fargo, but this shameless display fitted so well with her fearless character. All in all a film worthy of the awards it garnered.

Ministry of Unintended Conseqences

If I were Prime Minister I would set up a Ministry of Unintended Consequences. One of New Labor's trumpeted achievements was the incorporation of Human Rights Legislation into UK law. It sounded good at the time, but it has had the unintended consequence of empowering the judges to frustrate the will of Parliament.

Wicked men from other countries, many of them illegal immigrants, commit crimes in the UK, and are recommended for deportation after they have been released from prison. In many cases pure indolence on behalf of the prison authorities and the immigration department has prevented this from happening, but where they do try and carry this out judges rule that it would infringe the human rights of the individual to send him back to Somalia. It's too dangerous for him. It doesn't seem to occur to the judge that it's a dangerous place because it's full of people like the man we want to deport there.

Human rights legislation is unworkable without a written constitution, something Britain lacks. Our rights are founded on the Common Law and legal precedent. The European Convention of Human Rights might fit with the Napoleonic code, or in countries with an elected judiciary, but judges are supposed to interpret the law as parliament intended, they get above themselves when they interpret it as they think Parliament ought to have intended it.

They need to remember the sovereignity of the people in all this is paramount.

This is not the first time that government action has had unintended consequences. Targeting funding to elective surgery had the unintended consequence of starving acute illness of funds. Setting up unitary local authorities had the unintended consequence of reducing the size of social services departments, ending sub-specialisation in social workers, delaying the discharge of elderly patients from hospital, causing a back-up of emergency patients in Emergency Rooms, thus delaying elective surgery. In schools, in hospitals, in prisons, in road building, in energy policy, in Iraq; whatever the government attempts has unintended consequences. What would my minister do? He would say don't legislate, don't interfere; small government is best.

Reading novels

I have 115 unread novels on my bookshelves. Even if I buy no more (and I shall certainly but the new Discworld) it will take me more than two years to complete them. Perhaps I should be a bit more choosy in what I read.

I am currently comparing Kathy Reichs and Patricia Cornwell, the queens of gory fiction. Both have female protagonists who are experts in forensic pathology, which was always the best attended of undergraduate lectures at medical school.

“Reichs is not just ‘as good’ as Cornwell, she has become a finer writer” says the Daily Express on the back cover. One is tempted to ask how they would know. It is certainly not true. Cornwell at least writes mostly in sentences; Reichs writes in phrases. She even has sentences comprising a single word. Really! Many paragraphs consist of a single sentence, sometimes without a verb.

Here’s an example picked at random:

“Flashbulb memory. Gran, shuffling to bed with her Dearfoam slippers and her chamomile tea.

My gaze shifted to the body.

Parent looked small and pitiful on the perforated steel. So alone. So dead.

Stab of sorrow.

I pushed it down.”

I am tempted to put it down.

Although both ‘Blow Fly’ and ‘Monday Mourning’ are a similar size and weight, Cornwell fits over 300 words on the page; Reichs fewer than 200. This is not to say that Cornwell doesn’t go for the one-word, verbless sentence, but she holds it in check and uses it for effect. Reichs comes over as in a breathless panic, and Tempe Brennan, her heroine, as an empty headed woman ruled by her emotions. Scarpetta, who I guess is the prototype for this type of fiction, has become world-weary. No, I think it is Cornwell who is bored with it all; all the characters are tired of life. They have been around too long. Like the regular actors in a TV soap they need killing off and burying under the patio and some fresh blood introduced (pun intended).

What did I get from reading them? A snippet of information about carbon dating and the strontium content of teeth, which I guess I would not have picked up otherwise.

The success of this kind of book is that it sticks to a formula. Every book is the same. We know that Brennan will never settle down with Ryan, that there will always be trouble between Scarpetta and Benton; that Chardonne, like Moriarty before him, will keep escaping. And why not? Dick Francis wrote the same short book about 20 times and each one was a best seller.

FA Cup Final

The FA Cup Final was a football match worth watching. I have been to Wembley - I watched West Bromwich Albion beat Preston North End in 1954. My father was the Secretary of the Aldershot Town FC supporters club, and as all league clubs were allocated small numbers of tickets for the final, he was able to obtain a ticket. He had been at the 1953 final when Blackpool came back from the dead to beat Bolton Wanderers 4-3. This was Stanley Matthews' final. Some regard Matthews as the greatest footballer ever better even than Pele. He was known as the wizard of the dribble. He played on the right wing and had the beating of every full back. On this great day he provide crosses from the right to enable Stan Mortenson to score three goals. No-one has scored a hat-trick in a Cup final since. Matthews went on playing top football until the age of 53!

The other great winger of that era was Tom Finney who played for Preston North End. In 1954 we thought that Finney might repeat Matthews's feat and win a medal. Alas West Brom won. I was taken to the match by Mr Calton, my headmaster. My father had obtained a ticket for him too. Astute readers will realise that this was the year that I took the 11+ exam. I hope that the bribe wasn't necessary.

Yesterday's match began with defences on top, with very little activity in the first twenty minutes. Then in eleven minutes came three goals. First, West Ham, the underdogs, struck. Ashcroft, the mid-season signing from Norwich, put through a well-timed pass to the overlapping full back, Scolari, who centered immediately. It was the goalkeeper's to deal with, but needing a shout, Jamie Carragher in attempting to clear, shinned the ball into the net with his trailing leg. Minutes later, a shot from Etherington was blocked by Raina, but the goalie lost control of the rebound and Ashcroft punced to slide it home.

West Ham looked to be cruising, but Steven Gerrard, the Liverpool captain, as so may times before, rescued his side. A cross pitch pass cut out both full back and center back, allowing Djibril Cisse to steal in and volley home Liverpool's first.

Peter Crouch is a skinny giant who wins everything in the air. He nods down a high ball for Gerrard to equalize with a screamer from the edge of the penalty area. Within a few minutes West Ham are ahead again. Kanchesky atempts a cross from the left, but he overhits it. Raina misjudges it and it flies over his head and into the net; 3-2.

Time passes. On the stroke of 90 minutes, just as the announcer lets us know there will be 4 minutes of overtime for injuries, Stevie Gerrard lets loose abeauty from even further out and it scorches into the net; 3-3. West Ham are stunned. The cup was theirs. But as teams prepare for extra time it is West Ham who are on their feet and eagar; Liverpool are in agony, cramps and crocks everywhere lying spreadeagled on the pitch.

Overtime: only one incident: a West Ham corner bounces off the back of o0ne of their players. Liverpool cannot clear and the pull falls to Harewood, the West Ham forward who is barely able to stand with a sprained ankle, but all the substitutes have been used and he must soldier on half crippled. Harewood swipes at the ball, but it trickles feebly past the post.

And so to the penalty shoot out. Raina, responsible for two and possibly all three of West Ham's goals become a hero. Only 40 year old Teddy Sherringham's nerve holds for the Hammers. Raina saves three and Liverpool win the cup.

Narnia

I finally got around to watching Narnia. Was it worth the wait?

I have to say that I was disappointed. It was given the Lord of the Rings treatment and turned into a cinema blockbuster, but I think this was a mistake. The book is a smaller, less complex opus than TLOR - it can easily be read in an afternoon. It is much more a domestic story that doesn't need the opening out to the plains and mountains of New Zealand. The BBC made a television version of it some years ago that in many ways was better, though I couldn't really enthuse about that. Much better to read the book.

To get down to specifics. First, the music was too loud for the speech - and with CS Lewis the words are important. Second, the acting was nothing to write home about. On the whole the children were adequate - Lucy a bit more than adequate, Peter a bit less. Tilda Swinton, who got rave reviews, was, in my view, poor as the White Witch. She was neither frightening nor evil - just some second rate crook with a stick that turned people into statues. Mr Tumnus was good, but the beavers didn't really work and although Aslan was well visualized he never captured the essence of being 'good, but not safe'. Third, the CGI was OK, but after TLOR rather commonplace.

Of course you can't extinguish the wonderful story, even with a below par film. In the BBC series it all went rather downhill for the later books and I don't hold out too much hope for the other six in the manifetation. I would predict that they don't all get made.

But don't let me put you off reading CS Lewis. Try 'Out of the Silent Planet', 'A Gruef Observed' and 'The Problem of Pain'.

Food for thought

One of the strangest sights I ever saw occurred during the Manchester Uunited versus Charlton Athletic football match last week. Rio Ferdinand, the United and England center-back, collapsed to the ground apparently injured. The referee called on the United physiotherapist who supplied Ferdinand with a packet of McVitie's Chocolate Digestive biscuits to eat. It seems that the cause of his distress was that he was hungry, poor thing.

I wondered at the time whether this was an advertising stunt. Would we see in days to come advertisments for McVitie's biscuits showing Ferdinand revived on the field by their miraculous confectionary? But reflecting on it, I have seen tennis players at Wimbledon eating bananas between sets. Is their something wrong with the diets of modern atheletes?

The current popular injury among English footballers is a fractured metatarsal. So far the following have suffered: Michael Owen, David Beckham, Ledley King, Gary Neville, Ashley Cole, and Wayne Rooney (twice). The boots are blamed. Not for them the heavy leather clod-hoppers, smeared with dubbin, and soaked in the bath to shrink them to their feet; todays carpet slippers with studs don't protect the feet. But we don't see the same injury in Spain or Italy.

Perhaps the answer lies in the diet. The only food item that impacts on bones is Vitamin D. This vitamin is found in dairy food and is also manufactured in the skin when it is exposed to sunlight. One serious possiblitity being looked at by experts is that cows in Britain don't get enough sunshine. In Spain or Italy the sun always shines, but the murky skies over Britain deny the cows the opportunity to make vitamin D. Added to this the curent crop of youngsters never got their school milk the way we did. When she was education minister Margaret Thatcher thought this was an extravagance and took it away (Margaret Thatcher-milk snatcher).

So England may fail to win the World cup next month because of Mrs Thatcher and the murky skies of the North West where little Wayne grew up.

The Citadel

I have been reading the autobiography of AJ Cronin. It was written in 1952, and I guess that as an author he is not read much today. Yet Dr Finlay's Casebook was a weekly television duty when I was younger and The Citadel, not only a wonderful film starring Robert Donat, but also a book that almost evrybody read that went through over 30 impressions.

It becomes apparent that both Dr Finlay and The Citadel are intensely autobiographical. There really was a Dr Cameron and a Janet at Tanochbrae.

Cronin was a rather unobservant Catholic and his wife a strict Presbyterian, yet they had a long and happy marriage. He gives a picture of what medicine was like during the early part of the 20th century. Lobar pneumonia ran its course without antibiotics and was expected to be fatal. Scarlet fever was an epidemic to strike terror into families. Syphilis an incurable scourge bringing madness to the next generation. Doctors sold tea and sympathy for pennies, wise words and good advice for nothing or strychnine tonics and bogus diagnoses for guineas.

Just as now they got paid more for injections.

For those who made it in this Darwinian struggle there were servants, fine clothes, a Rolls or a Bentley, a gentleman's club and invitations to sup with the high and mighty. For those who failed, there was scraping a living in a lock-up surgery, a dismal two room Bayswater flat and cheap whisky.

Cronin knew both lifestyles, but Providence intervened to deflate his ego whenever he got to thinking that his success was down to him, and the daily degradation that he saw around him caused him to remember his roots.

Life has certainly changed in the last 60 years and all of us in the Western world are affluent and well taken care of, but when I read this book I remembered why I became a doctor.

Diagnosing ITP

A low platelet count is an indication for treatment in CLL according to the NCI guidelines. However, this is only true if the cause is bone marrow suppression. There are two other fairly common causes in CLL: immune destruction (ITP) and hypersplenism (a big spleen).

The diagnosis of ITP is not easy. There is not a simple test like the Coombs test for AIHA that you can do. It is not easy to measue how long the platelets survive. Often the answer can only be determined by a bone marrow aspirate and biopsy. What you see in ITP are increased numbers of megakaryocytes (the cell that makes platelets). Thes often appear immature - their nuclei are not lobulated and there are no platelets budding off their cytoplasm.

This picture needs to be differentiated from MDS, another cause of thrombocytopenia, in which increased non-lobulating megakaryocytes may also be seen. It requires examination by an experienced pathologist who understands bone marrow - not someone whose day-to-day work is examining vasectomy specimens and breast cancer.

Bob Dylan

I have been reading Bob Dylan's 'Chronicles'.

This is not a celebrity autobiography ghosted by a professional writer. Dylan can write. The style is engaging.

Bob Dylan was an early favorite of mine. I never thought much of his voice or harmonica playing, but his words were new and courageous and his tunes catchy. In the book he tells us that he never wanted to be a leader of the protest movement of the 1960s. He was a perfomer and a song writer - who cared what he thought about politics. Too bad that modern celebrities don't follow his example. Actors who have appeared in a TV series or singers who have made a hit record are supposed to have been endowed with superior wisdom on the merits of teh death penalty or the Iraq invasion. Says who?

I suppose he could be accused of name dropping, but after all he is more famous than most of the names he drops. His narrative is full of facts and sometimes the minute detail is tedious, but in a funny sort of way he paints a picture of what it was like to be a young singer in New York. Folk singing was an arcane art that shied away from commercial records. Dylan admires all types of music from Sinatra to Neil Diamond to Woody Guthrie and Leadbelly and even Beethoven. There is no clear timeline in this book. We skip from the young man who hitched across from the mid-west to New York admiring the humdrum with wide open eyes, to the married man with five children trying to find something new in a recording studio in New Orleans. Its line is thematic not chronologic.

I guess he's a grandfather now. The fresh-faced youngster of the record sleeve is long gone. The tone of the book is experience, but now and then the innocent ingenue appears