Monday, February 27, 2006

Cricketers falling apart

England's cricketers seem to be falling over like drunks at a party. Yesterday they said they would soldier on with the squad they had; today they are sending for replacements. Last week Alan Smith suffered a fracture dislocation of his ankle while playing for Manchester United against Liverpool. He had only been on the pitch for a few minutes. Had he warmed up properly?It is hardly surprising that injuries are common when you see the speed that games are played at. As I watched the Chelsea v Barcelona match last week the speed and ferocity of the tackles was frightening. The Scotland v England rugby match was even more furious. Watching men of 6 ft 5 inches and weighing around 250 pounds smash together in the scrums was intimidating; no body armor as in the flashy American version, just raw flesh and bones grinding together. They have this rather quaint rule that a player may be temporarily replaced if he is bleeding. I would have thought that AIDS was the least of their worries.Today's teams are cosseted by physiotherapists, sports' surgeons and sports' psychologists, yet they continue to damage themselves. Several leading soccer players have been out with fractured metatarsals - that has to be down to the very light footwear that they wear. The game has developed differently in Latin countries and northern Europe. The Latin countries are full of tricks, clever ball control and conning the referee by falling over as if assassinated as soon as they are touched. In northern Europe it is regarded as a man's game. Tackling is part of it. Those who fall over are expected to bounce back up or be jeered as girls.In yesterday's Carling Cup final Manchester United trounced Wigan 4-0. United have both robust tacklers and clever ball players. At one stage Ronaldo, the Portugese winger, started taunting the Wigan team by playing keepy-upy in the middle of the park. He was sharply spoken to by Ryan Giggs, the Welsh veteran. It is not the gentlemanly thing to do to poke fun at losing opponents. Ronaldo is full of tricks and prone to falling over when breathed upon by the opposition. He has no need. When he scored his goal he stripped off his jersey to reveal a waxed chest and rippling muscles that a porn star would be proud of. Of course, being in England he received a yellow card for this display.I have had my share of injuries. As a young man I tore both anterior cruciate ligaments playing soccer, one in a school match following a clumsy tackle on me by a boy called Maynard, and the other kicking a ball about with my nephew in a roughly tuffeted field. I also managed the Alan Smith injury - fracture dislocation of my right ankle. I was playing cricket for the church against the Plymouth Brethren. We had won the match easily and we were having a silly game of tip-and-run afterwards. I was about to take a catch at silly mid-on when I caught my spikes in the turf and toppled over, twisting my ankle. I was surprised to see the bone sticking out from the skin. It hardly hurt and I dropped the catch. It was at a time when I was very busy. I was due to fly to Budapest the next day and I guess my body thought it was time for a break.

Saturday, February 25, 2006

Spleen 3

In Spleen 2 we saw that the circulation of the spleen was so designed that it acts as a filter to stop damaged red cells from continuing to circulate. Red cells last for 120 days and then they run out of energy and can't maintain their structure. The dying red cells can't escape the Cords of Bilroth and get eaten by macrophages.

Platelets live for much shorter periods - around 9 days, but they die, not from old age, but by being used as plugs in the holes in capillaries. Antibody coated platelets (as in ITP) just like antibody coated red cells (as in AIHA) also get trapped in the Cords of Bilroth,

But in this section I want to talk about the lymphocytes. Remember, they were skimmmed off in the penicillate arteries with the plasma, and this then enters the white pulp of the spleen. The white pulp of the spleen is the largest accumulation of lymphoid tissue in the body; about 25% of the T cell pool and 15% of the B cell pool are there. They are there to react to all the antigens processed by the macrophages lining the Cords of Bilroth. You can think of the white pulp as a gigantic lymph node attached to the circulation. The spleen is especially important as a defence against bacteria that circulate in the blood.

In some people the spleen atrophies. Adults with sickle cell disease have lost theor spleens because of infarction. Patients with systemic lupus erythematosus (SLE) and celiac disease suffer from shrinking spleen. In other condition the spleen has to be removed. Following trauma to the spleen it often has to be removed to stop bleeding. Some surgical operation - say for stomach cancer - require the spleen to be removed to get access to the cancer. Sometimes it is necessary to remove the spleen to stop the destruction ofred cells or platelets. On other occasions the spleen is large and overactive and the removal of the spleen becomes a matter of judgement.

What are the complications of splenectomy? The most serious is overwhelming pneumococcal septicemia, (although other bacteria - Hemophilus Influenzae and meningococcus - can cause a fatal septicemia). To guard against this I prefer belt and braces. I vaccinate against the three bacteria and prescribe penicillin (or erythromycin in the penicillin allergic). This is especially important in CLL where response to vaccination is at best uncertain.

It is also important to take antimalarial prophylaxis in malarial areas.

Another complication is a marked rise in platelet count sometimes to over a million. Some patients have had thromboses at the level and a watch need to be kept. Aspirin may be necessary to prevent thrombosis. We sometimes see an abcess under the diaphragm where the spleen used to be, but I have to admit that it's been a very long time since I have seen one of those.

Finally, nowadays my surgical colleagues have usually performed laparoscopical splenectomy whenever they could.

Friday, February 24, 2006


She smiled at me,
Her fair and swinging
Straight hair hanging,
And wrinkled up her nose
Like a white soft rabbit
Culled from Alice.
She talked, an earnest seventeen,
Of God and Beethoven,
And pointed to her scar
And how it wouldn’t show
On next year’s beaches.
While I, who knew the worst,
Forgot my pretty speeches
Lest the bubble burst
And gaily smiled at her instead;
Laughter smothering the dread.

Thursday, February 23, 2006

Spleen 2

What is unusual about the spleen is its blood supply. Normally arteries branch into smaller arterioles which branch into leaky thin-walled capillaries. From the capillaries fluid and white cells leak, but red cells remain contained and are collected into venules that coalesce into veins which return the blood to the heart. Fluid and lymphocytes that have left the capillaries are collected by lymphatics which return to the heart via the thoracic duct and the way stations situated on the lymphatics and known as lymph nodes.

In the spleen things are different. First there is a mechanism known as plasma skimming. Small arterioles known as penicillate arteries skim off the plasma and lymphocytes sideways, leaving the splenic arteries with red cells, platelets and much less plasma. The hematocrit rises from 40% to 80%. The arterioles drain not into capillaries but into sinusoids known as the Cords of Bilroth. Theodor Bilroth (1826-1894) is the father of abdominal surgery. His operations for stomach ulcers (Bilroth I and Bilroth II have only recently gone out of fashion). He was a great friend of Johannes Brahms and might have been a musician had it not been for his success in medicine.

These Bilroth Cords are lined with macrophages, and red cells delayed within them tend to get eaten. Escape from the Cords is through very narrow apertures only 1-2 microns in diameter. A red cell is 7 microns in diameter, but extremely flexible. Its shape as a biconcave disc means that it is able to squeeze through the opening. As a red cell ages it gets less flexible (like us all) and gets delayed. Red cells from some hereditary hemolytic anemias are less distensible - for example hereditary spherocytosis or pyropoikilocytosis - and tend to get trapped and eaten.

The macrophages that line the Cords have receptors for immunoglobulin. One of these receptors, FCR1 (or CD64) binds very avidly to immunoglobulin, but all the normal immunoglobulin in plasma tends to shield cells that are covered with antibody from binding to them. In the spleen the high hematocrit means that there is less plasma protecting antibody- coated red cells, and the macrophages start nipping off pieces of antibody-coated red cell membrane. Left with the same content but a smaller membrane, the red cell assumes the shape that contains the largest volume for the smallest surface area; in other words a sphere. Spheres cannot escape from the Cords of Bilroth.

Thus it is that taking out a spleen cures the hemolysis of hereditary spherocytosis and autoimmune hemolytic anemia.

When a spleen enlarges a much greater proportion of the red cells in the body are within it at any time. A normal spleen contains perhaps 100 mls of blood, a very large spleen ten times that amount. Platelets fare even worse; a very large spleen can contain 90% of the platelets in the body. There is no discernable pool of neutrophils in the spleen, however.


As I arrived in London today I was met by large posters that told me that Microsoft Office has evolved. Are they sure? Isn't it possible that they had some Intelligent Designers?


The Welsh windbag, as former Labor party leader, Neil Kinnock, was known, became one of Britain's European Commisioners. In Brussels he went native. Now he is calling for the UK to abandon miles and go for kilometres. The cost of changing all the road signs has been estimated to cost £700 million.

British roads are nowhere contiguous with European roads and anyway like most of the rest of the world we drive on the left. It was only those countries that were conquered by Boneparte (and his allies including the USA) who changed to driving on the right, and he did it out of hatred of everything British. The Chinese, Japanese, Indians and most of Africa all drive on the left. (The Swedes changed in the 1950s but they only had 117 cars on their roads then).

The Japanese have estimated that more than 50% of all useful inventions have come out of Britain - and that includes monoclonal antibodies, CT scanners and MRI scanners. The reason for this inventiveness is the Imperial system of weights and measures. Where most of the world does its mathematics by thinking in base 10, we have learned to think in base 2 (pints in a quart), 3 (feet in a yard), 4 (peck in a bushel), 6 (feet in a fathom), 7 (days in a week), 8 (pints in a gallon), 12 (pennies in a shilling), 14 (pounds in a stone), 16 (ounces in a pound), 20 (shillings in a pound), 22 (yards in a chain), 24 (hours in a day), 40 (rods in a furlong), 60 (seconds in a minute), 112 (pounds in a hundredweight), 168 (hours in a week), 1760 (yards in a mile), 2240 (pounds in a ton) and 4840 (square yards in an acre).

So when the rest of the world was doing their mundane hundreds, tens and units, we were out-thinking the world with our pounds shillings and pence.

Wednesday, February 22, 2006

Free speech

Speech is free because you don't have to listen to it. Were we forced to do so it would be intolerable. Speech can be offensive, but because we don't have to listen to it we don't have to be offended.

We do regulate what is said. If someone blackens my name by lying about me I have recourse in law to claim damages. If I lie on oath to a court, I may be sent to prison for perjury. If I steal someone's words and pass them off as my own I may be guilty of plagiarism, an offence that damages my reputation if I am caught, but also I may be liable for damages under the laws of copyright.

If I lie to the police I may be charged with perverting the course of justice or with wasting police time. If I lie to deceive others into parting with their money I may be guilty of fraud. If I incite other to kill or commit violent acts, this too is an offence.

The point is that there are limits to free speech. Society imposes those limits for its good running. Those limits cannot be fixed limits because society changes and new phenomena arise that are not covered by past limits.

I recently read a book on the great virtues. The virtue that the author chose as first, the sine qua non without which civilization cannot exist was ... politeness. I thought it a strange choice, but as I read on it became clear that without politeness we would have no discussion; only strife. No one would listen while others spoke. It would be a me-first society. The devil could take the hindermost.

Good men will not abuse their right of free speech. With every right comes a responsibilty. The responsibilty of free speech is not to use it to cause unnecessary offence. To offend deliberately is at best childish; at worst inflammatory. There is such a thing as necessarily offensive free speech: to right a wrong, to expose a fraud, to undo a lie.

How do the recent examples of "free speech" fare? David Irving's "Holocaust denial" was silly, attention seeking, and offensive to survivors of the concentration camps and the relatives of those who were killed. In Austria it was illegal, though it sounds as though the precise law against Holocaust denial was only enacted in 1992 and Irving's offence was in 1989. Making a speech retroactively illegal sems to me unjust. Austria has its own special guilt over Hitler and his cronies and I don't think it is entirely assuaged. Perhaps there is a need to have a special law for Austrians. Irving is not of course Austrian. Irving's reputation is already bust following the previous libel case. Imprisoning him only gives his vile views greater publicity.

Hamza the hooked one was prosecuted for incitement. Tapes of his sermons placed before a jury left little doubt that he had incited people to kill. People who heard him atempted or succeeded in mass murder. He clearly went beyond the limits of free speech.

The Moslem demonstrators with placards calling for the beheading of the cartoonists? I think this is a difficult one that needs to be placed in context. London marches are usually associated with inflammatory slogans. Hyperbole is rife. In the context of the London bombings; in the context of what is happening in Iraq, it was certainly unwise and a court might regard it as incitement to murder. They would have to take into account the likely effet on the observers. Even football crowds have been known to shout "Kill him!" following a perticularly bad foul. A jury might convict, though, given the current unrest. The march was certainly a foolhardy action, but I am not sure that it should be curtailed.

The cartoonists themselves? I found the cartoons poorly drawn, not funny, and for that reason I would not have published them. They were clearly offensive to Moslems; and for that reason I would not have published them. I guess they were trying to make the point that Islam is a religion of violence. That is an inaccurate charge, although for some strands of Islam it is undoubtedly true. Perhaps they were trying to make the point that no one is immune to ridicule in Western society; that Jesus can be lampooned, Jews mocked and Buddha made fun of. Why should Mohammed not be the subject of a cartoon?

Well, I am offended when Jesus is mocked, Jews are offended when Yahweh is blasphemed (they will not even say his name) and Moslems are upset when Mohammed is pictured. I feel like marching in protest at Jerry Springer the Opera. I sympathise with Moslems who protest against the cartoons. But I do not threaten to behead the actors. The Anti-Jewish placards in Moslem lands are far worse than the Danish cartoons. Moslems cannot have it both ways. In Western societies blasphemy is unlikely to be punished no matter which god is abused. I suppose we take the view that an almighty father can take silly children shaking their fists at him. If you really believe in life after death you can afford to wait for the Lord to administer justice.

Recently a street preacher in Bournemouth was arrested for reading from the Bible those passages that condemn homosexuality. That seems to be a new authoritarianism. If he were inciting violence the police might have had a point; if he were provoking a breach of the peace they might have moved him on. Merely reading aloud from the Bible is not a crime except in the old Soviet Union.

Free speech is a precious right. The government should value it even if it is not politically correct.

Tuesday, February 21, 2006

Spleens 1

The thing that surprises most patients about the spleen is how small it is. It is between 3-5 inches long, 2-3 inches wide and about an inch thick. There is this thing about what units are used to measure things. Although schoolchildren in the UK have been taught in centimetres for decades, many people still think in feet and inches. An inch is the length of the top joint of the thumb and a foot is the length of a man’s foot. A yard is a man’s pace; a metre is more than I can comfortably pace. So, a spleen is 8-13 cm long, 4.5-7 cm wide and 2-3 cm thick; I can’t visualise that.

I once had an amusing correspondence with a medical journal over units of measurement. I had described a red cell as having a volume of 105 femtolitres. A femtolitre is ten to the power of minus 15 litres. In other words extremely small. The abbreviation for femtolitres is fl. Obviously the editor had never heard of such a unit, so she chided me for this unknown abbreviation. “Do you mean fluid ounces?” she asked, “The correct abbreviation for fluid ounces is fl oz.” I was dumfounded. Try to imagine a red blood cell with a volume of 105 fluid ounces. That’s more than five pints! You want a pint of blood? That will contain one fifth of a red cell.

You can’t normally feel a spleen. It is tucked up next to the diaphragm under the ribs on the left, far beyond the reach of even a finger probing under the ribs. When you take a deep breath the diaphragm descends and the spleen moves nearer to the edge of the ribs (sometimes called the costal margin) but it still cannot be felt unless it is enlarged. What constitutes an enlarged spleen? It is said that a spleen has to be three times its size to be felt. Another textbook says spleens longer than 14 cm can be felt. What is the truth?

The truth is that spleens are different sizes in different bodies. In a small woman the spleen is normally 8 cm long. If it gets to 14 cm long, its volume will certainly be more than 3 times normal, and it will be felt coming down under the ribs as the patient takes a deep breath. For bigger people bigger numbers apply.

Patients are often confused because their spleen measurements are given in centimetres as measured on a CT scan. Whereas previously they were given according to how many centimetres the spleen protruded below the costal margin. So a 16 cm spleen sounds horrific if it’s measured below the costal margin (that’s six and a half inches!), but in a man it would mean a spleen that’s about an inch larger than normal.

Normally 5-10% of the total blood supply travels through the spleen every minute. Passage through the spleen takes about a minute if the blood takes the fast route, but there is also a slow transit route that takes about an hour. When the spleen enlarges more blood takes the slow route.

The spleen has a complicated anatomy. It is divided into the red pulp and the white pulp and my next post will describe the different functions of the two.

Friday, February 17, 2006

The Civil Servant

I know that the pill is bitter
And doubly so as you’re young
But it’s one that ought to be eaten
For the taste is just on the tongue:
And when the thing is digested,
Dispersed from your head to your foot,
You can writhe in a sea of self pity
About that, up with which, you must put.
You can tell all your friends you’re a martyr,
But comply with the rules all along
And you’ll know that the head that is severed
Won’t be yours when something goes wrong;
But, best, at the heart of the matter,
You can feel justly proud deep inside
Of the time when you acted so nobly,
Pinched your nose and swallowed your pride.

Reptiles and Raptors

A new animal home has opened up near us called Reptiles and Raptors. Technically, raptors are birds that kill with their claws, and this home is mainly about hawks, owls, eagles and vultures with a few snakes, iguanas and tortoises thrown in. Still a good place to take the grandchildren on a chilly February day.

I learned quite a bit. First that most hawks and falcons can interbreed like dogs. Breeding peregines with harriers and other falcons gives speed plus endurance or strength. Although not as refined as the breeding of dogs, there is quite a tradition in falconry.

Second, the kestrel, at least, can see in the ultraviolet range. It is able to track the urine trails of small rodents from a great height. They say it looks pink, but how would they know? Owls on the other hand, being nocturnal, have poor vision but fantastic hearing. They can distinguish the individual heartbeats of a room fulll of people. They have asymetric ears. Their left ear is located below their left eye and their right ear is above their right eye. There is a space in between, and we all know that space is the final frontier. (Boom! Boom!) Vultures rely on smell rather than either sight or hearing.

There are still working falcons. They are used to clear an area of rabbits. Rabbits are a menace for horses, which stumble in their barrows and break their legs. The New Forest (only relatively new; it was laid out 950 years ago) is full of horses, so falconry thrives.

Thursday, February 16, 2006

Gene Therapy

I spent yesterday in the Gene Therapy Advisory Committee. This is a fascinating committee. All gene therapy protocols have to come before us to be approved. The level of debate is terrific. The committee comprises molecular biologists, cancer specialists, geneticists, virologists, experts on medicinal product regukations, pathologists, immunologists, cardiologists, ethicists, patient representatives and a bishop (who has an immunology PhD). The committee might well to extend its brief to take in stem cell research and xenotransplantation (transplants from animals - and if you think that is disgusting, remember that many people are walking around with pig heart valves). Perhaps the government believes in putting all its dangerous eggs in the same basket.

Yesterday, we had a discussion on "What is gene therapy?"

Many of the studies that we scrutinize are vaccine studies. A foreign gene is introduced into the body with the purpose of getting the body to make the protein coded for by that gene, in such a way that it will be rejected by the body with a strong immune response. Should such vaccines be called gene therapy? We decide that they should. Usually the gene is placed inside a virus. The virus infects a human cell and induces this cell to manufacture the foreign protein, which is then presented to the immune system. Any therapy that induces one of your cells to make a protein encoded by a foreign gene has to be gene therapy.

There are new vaccines on the way where the foreign gene is inside a bacterium such as salmonella. The salmonella has to get inside a human cell to survive. Should this also be called gene therapy? No, because this vacine used the bacterium's machinary to make the foreign protein not the human cells. A fine difference, but you have to draw the line somewhere.

Gene therapy was all about trying to treat single gene disorders. However, two thirds of the protocols we deal with are about treating cancer. Now we have to consider a protocol designed to treat a single gene disorder. The ethical problem here is whether the risks of gene therapy outweigh the benefits in a condition where there is already a satisfactory treatment. The missing proetein can be administered intravenously twice weekly to prevent the consequences of the disease. On the other hand we have seen a young boy die in America when the therapist didn't stick to the rules, and three chillden in France have developed leukemia in a different kind of genetic experiment. Should patients be put at these risks for the convenience of not having to give themselves injections twice a week? It is impossible to calculate how big the risks are. The medical community is divided and vehemently so. Perhaps the bishop will guide us.

Tuesday, February 14, 2006

Valentine's Morning

The sun awoke
And filtered through the trees
To please the lark.

The morning spoke
In tones of warmer days
To praise the lark.

The chimney smoke
Was curled above the street
To greet the lark.

The milkman’s bottles rang
And in the sky above
The splendid skylark sang
For you alone, my love.

Monday, February 13, 2006

Fludarabine Combinations

Today I want to evaluate an important new paper published in Cancer by Bill Wierda.

It is important because it deals with overall survival rather than length of remission. It compares overall survival in relapsed and refractory patients who were treated with one of the following: fludarabine, fludarabine plus cyclophosphamide (FC) or FC plus rituximab (FCR). This information has been available on the lecture circuit for some time, but Bill has been very helpful in publishing it in a form that enables us to scrutinize it carefully. He is to be commended in publishing it without trying to hide any details and even pointing out himself some of the flaws of this kind of study.

I want to go straight to the bottom line. The median overall survival for the fludarabine group was 20 months; for the FC group it was 31 months; for the FCR group it was 49 months. The difference between F and FC had only a 1% risk of having occurred by chance, and the difference between FC and FCR had only a 5% risk of occurring by chance.

Although these figures are impressive and mean that the idea that FCR is better than FC which is better than F alone should certainly be listened to, the way that the data were collected means that the concept is not proven.

The first thing to say is that this was not a randomized trial. Randomization is a great device for ensuring that you are comparing like with like. Scientists who dissect physiological mechanisms prefer to work in inbred strains of mice. All the mice are identical, but humans have so many variables. It is usually impossible to find people who match each other. Even if you choose people with say, Stage 3 or 4, unmutated VH genes, high CD38 levels, high ZAP-70 levels, del 11q, high LDH, high serum CD23 levels, high beta-2 microglobulin levels; even then there will be considerable variation within that group. Patients are all different. Randomization means that the good and poor risk characteristics will tend to cancel each other out is the sample is large enough.

The second thing to say is that these drugs were not tested at the same time. The 241 patients given F were treated between 1984 and 1993; the 111 patients treated with FC were treated between 1995 and 1999; and the 143 patients treated with FCR began treatment between 1999 and 2001. Even if treatment of the disease had not improved in the past 20 years, there is little doubt that supportive care is better. It is admirable that the paper has given so much detail about this. For the F group, there was no routine use of prophylactic antibiotics or growth factors. In contrast some 35 of the FC group were given GM-CSF and 13 amifostine, but again prophylactic antibiotics were not used. For the FCR group Bactrim was given twice weekly and valacyclovir daily. Routine G-CSF was not given, but of course, as time passed G-CSF became much more routinely available in the community, as did better antibiotics and better antifungals.

The third thing is that these patients were not really matched. True, there were no significant differences between the FC and FCR groups in terms of them in terms of age, WBC, Hb, Platelets, beta-2M or albumin, but the F group were 2-3 years older, and had a slightly higher (10K) WBC, and lower HB (1g/dL), though the platelet count was higher (20K). Perhaps more important is what prior treatment the patients had received. 45% of the F group had received 3 or more types of treatment, compared with 31% of the FC group and 29% of the FCR group. In addition 75% of the F group were resistant to alkylating agents, compared to 46% of the FC group and 27% of the FCR group.

We know very well that outcome in CLL is chiefly determined by which ‘bucket’ the CLL falls in. The ‘gold standard’ for determining this is the VH gene mutational status. Unfortunately this was not done in any of these patients. The prognostic test that was done was beta-2M, and the median beta-2M was the same for all three groups. However, beta-2M is influenced not only by the rate of progression of the CLL, but also by the tumor mass, and simply having a lot of CLL is not life threatening.

So, what can we learn from this paper?

First, if you need treatment, and you have already had treatment previously and relapsed or failed to get even a partial remission, then FCR is better than FC in producing remissions, in producing complete remissions, in how long the remission will last and in overall survival. Although, the studies were not contemporaneous and not randomized, the two groups were very similar and the most likely explanation for the difference in outcome is that rituximab really does make a difference.

Second, the addition of cyclophosphamide to fludarabine is still an open question. The F group was more heavily treated than the other two groups, and were treated at a time when supportive care was not so good and significantly at a time when there were no rituximab-containing regimens to rescue them with. We know from another historical comparison (Byrd et al Blood 2005;105:49-53) that rituximab adds similar benefit to fludarabine alone. Although the recent German study shows that FC gives more and better remissions than F alone, so far there has been no difference in overall survival. Therefore the possibility remains that the less toxic FR is no worse than FCR in this situation.

Third, this paper does not address the question of what should be given as first line treatment for CLL. My considered view is still that treatment should be delayed as long as possible and begun with the treatment that does the least harm. But it is still possible that early effective treatment might be most beneficial in certain subgroups.

Saturday, February 11, 2006

The Scientist

If the sun’s an automatic clock
And the fields just food producers;
If the workings of my mind are matched
By digital transducers;
If the air is only there to breathe
As part of an equation
And a flower is just another type
Of by proxy copulation;
If the sky and sea aren’t really blue
And a rainbow’s just refraction
And the moon is only there because
Of gravity’s attraction;
If love is just my awkward way
Of relieving sexual tension
And my heart is just a pump for blood
And God is Man’s invention;
Why am I writing this?

More fraud

One of my hobby horses is scientific fraud. 25 years ago I wrote an article entitled "Fake" which reviewed scientific fraud through the ages. As a result I am now the major source for the realisation that there is no more iron in spinach than in lettuce leaves. This was not a fraud but a simple mistake because somebody put the decimal point in the wrong place. I have retained my interest in it and today came across this reference from COPE, the committee on publication ethics.

Manipulation of a journal’s impact factor

An editor had been recently sacked from her/his job as an assistant editor with a medical research journal. The editor stated that “s/he believed that the reason for his/her dismissal was in large part motivated by disagreements with the editor in chief over several editorial policies at the journal.”

During the review process it was common practice for the editorial staff to ask authors to add references to the journal in their submitted articles.The editorial staff sometimes asked the authors to find “pertinent” references themselves and sometimes suggested references that should be added. The editor was told by the editor in chief to imply, but not overtly state to authors, that the acceptance of their submissions depended on these additions.

Although some refused, many of the section editors of the journal—under pressure from the editor in chief—would determine possible references to be added and then state that one or more of the anonymous referees had insisted on these additions during the peer review process.
The sacked editor had archived examples of this and other policies that consistently manipulated the impact factor at the journal during her/his employment. Several previous employees have also stated their willingness to testify on this matter.

A journal's impact factor is its life blood. Researchers only get grants and promotion if they publish in journals with high impact factors. All the best papers therefore go to a few journals. Journals are in a competetive market and are therefore keen to raise their impact factor by whatever means possible.

The impact factor is determined by dividing the number of times papers published in the journal are quoted in other joournals in the first 2 years after publication divided by the number of papers published in that journal. Therefore if papers quote more papers in the references at the end it raises the impact factor of the journals that those papers were published in.

The quote from COPE names no names, but it sounds very like a case that I as editor of Leukemia Research reported to COPE in 1997 about our rival Leukemia and which was cited in both the BMJ and Lancet.

Friday, February 10, 2006

The secret life of Dr Chandra

Published today in BMJ

The Secret Life of Dr Chandra
Terry Hamblin
BMJ 2006;332:369 (11 February), doi:10.1136/bmj.332.7537.369
The colourful career of Dr Ranjit Chandra may be old news to BMJ readers. In the spring of 2000 he sent to the BMJ a paper that claimed that a mixture of vitamins and minerals could reverse dementia in elderly people. The then BMJ editor, Richard Smith, thought that it was just too good to be true and one reviewer told him that it had all the hallmarks of having being completely invented. The full story can be read at BMJ 2005;331: 288-91[Free Full Text].
Applying the old adage that a thing isn't true until it's been on television, the Canadian Broadcasting Corporation has put together a documentary on Chandra made by Chris O'Neill-Yates, and broadcast it over three successive nights last week.
The programme made for compulsive viewing. Here was an eminent academic physician, an officer of the Order of Canada, holder of five honorary doctorates, visiting professor at universities on four continents, donor of $C250 000 (£124 500; $218 000; 182 000) to his alma mater in India and of $C20 000 for a Hindu temple, and supposedly twice nominated for the Nobel prize in medicine, exposed as a fraud.
The story began with a study Chandra carried out in the late 1980s. He was retained by Ross Pharmaceuticals to test whether its baby milk would help the newborns of allergy prone parents avoid eczema. He engaged a research nurse, Marilyn Harvey, to find 288 such neonates; no mean task in a city as small as St John's, Newfoundland, where they worked. She was therefore surprised to find a year later, when she had collected only a handful of cases, that Chandra had published the results of an identical study on a similar product from Nestlé and shortly afterwards another on a product from Mead Johnson. These two studies supported the idea that the products were hypoallergenic, but the original, and almost identical, Ross Pharmaceuticals product was not.
Faced with the impossibility of Dr Chandra having recruited over 700 babies, Marilyn Harvey blew the whistle and his employer, Memorial University, carried out an investigation. Despite this investigation clearly uncovering the fraud, the university backed down, cowed by the threat of a lawsuit from Chandra. Nothing was done, but Richard Smith, having rejected the dementia and vitamins paper, suggested that Memorial investigate him afresh.
Meanwhile, the same paper had been published by the journal Nutrition, where it came to the attention of professors Saul Sternberg of the University of Pennsylvania and Seth Roberts of Berkeley. The two professors found so many glaring errors in the paper, they concluded that the most likely explanation was that Chandra had made it all up. By 2002 Memorial had asked Chandra for his raw data. He was unable to provide it, claiming it had been stolen or that the university had lost it. Memorial was relieved when Chandra suddenly decided to retire and leave Canada.
When Chandra divorced his wife it was revealed that he had 120 different bank accounts in various tax havens. He patented his multivitamin mixture and is selling it as an "evidence based" nutritional supplement for the elderly. The "evidence" is derived from his dubious clinical trials.
Scientific fraud is seldom isolated. As Richard Smith observed in 2005, there must be grave doubts about the reliability of the 200 papers published by Chandra other than the Nutrition one, and yet, to date, that is the only one to have been formally withdrawn.

Tuesday, February 07, 2006

More family matters

My eldest daughter has a new job. Instead of a 2 hour commute into the City of London, in future she will work in the charming Hampshire village of Odiham - only a 45 minute drive from her home. She will be working as a manager in a telecoms company. This is a quality of life thing.

Her story is quite remarkable. Her husband left her with two young children and no income. She took all sorts of part time jobs - selling double glazing, selling real estate, garden landscaping - before getting a full time post in a call center while we looked after the children. Within two years she had been promoted internally to European sales manager. This firm was taken over and she was one of the few who were not made redundant. She was headhunted from the firm that did the taking over to a much bigger concern in the City. Again she was promoted internally. She had a big salary, but had to make frequent trips to Europe as they decided to outsource many of their services to Eastern Europe, where labor costs were less. The attitude within the firm left a lot to be desired, so when she was invited to apply for this new job she had no hesitation in leaving. A company that treats its workers poorly does not command loyalty.

We hope for a happier future for her. She is remarrying soon.

My younger son has also been interviewed. He has applied for the post of Chief Engineer in his company. He is only 24 so it's asking a bit much, but at least he has been shortlisted. He has already designed the brakes for the new Bugati, the fastest car in the world, and also did the brakes for the Bentley that the Queen was given for her Golden Jubilee.

Monday, February 06, 2006


No light, no breath of wind;
Let night all life rescind;
Dull death all life to end.

No warmth, no fall of rain,
No struggle and no pain;
Dust dies to dust again.

No lingering, no fear,
No sting of salt, no tear,
No negatives not there.

No mightiness of men,
No strength and valour when
The worms come crawling in.


It is the 25oth anniversary of Mozart's birth. Some years ago I bought the Complete Mozart on CD. I am having fun playing them again. I started with the piano concertos and I am listening to K467 (# 21) as I am writing this. I find that I am more organized and clearer thinking when Mozart is playing.I came to classical music while I was at University. I shared lodgings with a man ccalled Richard Osborne who went on to be editor of the Gramaphone magazine. A later flat mate was a Bob Dylan enthusiast. He also introduced me to French movies. I'm not sure that my medical school was all that good, but my University course taught me a lot about what it meant to be a human being.

Integrity and altruism

Doctors should be committed to integrity, compassion, altruism, continuous improvement and working in partnership with members of the wider healthcare team. So says an article in today's Journal of the Royal Society of Medicine written by Richard Smith, previously a campagning editor of the British Medical Journal.Richard is now Chief Executive of United Health Europe, a commercial organisation founded by Simon Stevens, who from 1997-2004 was the British Government’s Health Policy Advisor, serving both as the Prime Minister’s Health Advisor at 10 Downing Street, and as policy advisor to successive Secretaries of State for Health at the Department of Health.When Stevens left for the private sector there were murmurings from various health pundits that he had decided to take the money and run. There are strictures against government advisors moving into the private sector to profit from their time in the public service. I make no comment. Let's hope that UHE conducts itself with integrity and altruism.

Blood Transfusion

Blood transfusion is one alternative for those who become anemic, but it’s not without its hazards. Chief among these is getting the wrong blood. In the UK nearly two thirds of all serious hazards are caused by the patient getting the wrong blood. It has been known for about 100 years that there are four main blood groups: A, O, B and AB. In the UK at least A is the commonest, then O then B then AB. The reason that they are important is that we have naturally occurring antibodies against these groups. Group A patients have anti-B, Group O have anti-A and anti-B, Group B have anti-A but Group AB don’t have antibodies. If you are transfused blood from a group that you have antibodies against you will have a severe reaction comprising fever, shakes, back pain, dark urine and possibly kidney failure. People still get these reactions.

I have seen these reactions twice in my career. On the first occasion the patient was in hospital for a prostate operation. It was a simple matter of the technician, who did not normally work in the blood bank, but who was an immunologist helping out, cross matching blood at night. He performed the task excellently and issued the blood. About half an hour later he double checked his work and discovered that he had cross matched the blood against a different patient’s sample. Inadvertently, he had issued Group A blood for a Group O patients. He rushed to the ward and stopped the transfusion. Only 50 ccs had gone in, and although the patient had a shivering attack and raised his temperature, no further harm was done.

On the second occasion the patient had had his hip replaced and was unconscious when he got the blood. He was one of two patients returning from the operating theater, not to the orthopedic ward, which had closed for the summer while he was being operated on, but to the general surgery ward. Because of this he was unknown to the nurses on the ward and when the ward sister told the nurse to put up a unit of blood on Mr Bloggs who had just returned from theater, she didn’t check his name on the wristband, she didn’t check the name on the bed, she didn’t get a second nurse to double check, she just gave a unit of group A blood to Mr Doe who was group O. His reaction was more severe and he went into kidney failure, but happily made a complete recovery.

The astonishing thing was that it was the same patient on both occasions. My callous colleague exclaimed, “Never mind, we’ll get him next time!”

The important point from this story was that it was not a technical error that nearly killed him, but because somebody didn’t follow the published protocol. Most wrong transfusions are because of clerical errors. Commonly an error on the ward in giving the wrong blood to the patients, next taking the sample from the wrong patient; straight laboratory errors are a minority. Note: that even applies with autotransfusions, where a patient deposits a pint of his own blood for future use. The other point is that there might have been other occasions when a patient got the wrong blood, but by luck it happened to be the right group and nobody told me about it. If instead of cross matching the blood a unit was withdrawn randomly from the blood bank, it would turn out to be compatible 64% of the time. Even when incompatible blood is given, in more than half the cases there are no clinical symptoms resulting and the death rate is only about 1 in 50.

You might ask about the other blood groups: Rhesus negative and the like. The difference is that we don’t have naturally occurring antibodies against these; we have to be sensitized. Sensitization is caused either by a previous transfusion or a previous pregnancy. The Rhesus blood groups have 5 separate antigens: c, C, D, e and E. There is no d. We normally only test for D as anti-D is the commonest acquired antibody. Consequently, we give Rhesus D negative blood to Rhesus D negative patients and give anti-D injections to Rhesus D negative mothers who have Rhesus D positive babies, to prevent sensitization. But patients do get sensitized against c, C, e and E, and against a range of other less well known antigens such as Kell and Duffy. Cross matching is done to screen out incompatibilities here, but a sensitized patient may have no detectable antibody, only producing it after re-stimulation by a transfusion. The antibodies produced then slowly (or sometimes not so slowly) destroy the transfused red cells. This is called a delayed transfusion reaction. About 10% of severe adverse complications of transfusions are delayed transfusion reactions.

One of the most serious types of reaction is called transfusion related acute lung injury or TRALI. TRALI is caused by transfusing blood that contains anti-white cell antibodies in the plasma. The usual cause of these antibodies is sensitization during pregnancy. It is not practical to exclude women who have had children from being blood donors, though in the UK women who have had children cannot donate plasma. Neutrophils are activated in the capillaries of the lungs and the resulting inflammation hurts the lung’s ability to transfer oxygen. TRALI accounts for over 150 deaths a year in the US.

Anaphylaxis after blood transfusion is rare. It usually occurs in the 1 in 500 people with selective IgA deficiency. They make anti-IgA antibodies which react with the IgA in the transfused blood. Transfusion associated graft-versus-host disease (GVHD) results because the donor lymphocytes are engrafted and recognise the recipient-host as foreign and starts to reject it. Although GVHD is common in bone marrow transplants, it is not usually lethal as it is in transfusion-related GVHD since in the former case the bone marrow is of donor origin, whereas in the latter it belongs to the host and is susceptible to attack. You can’t live long without a bone marrow. It is very rare today because we irradiate blood to stop it happening. Blood should be irradiated in patients who have had auto- or allo- marrow transplants, patients with immunodeficiency syndromes, those with Hodgkin’s disease and those who have received one of the purine analogues: fludarabine, cladribine or pentostatin.

Infection is the next problem. Hepatitis B and C, HIV, HTLV-1, CMV, are well known risks, Chagas disease and Malaria in certain parts of the world, in times past, syphilis, in times present West Nile Virus, and possibly parvovirus, Lyme disease and variant CJD are all possible hazards of transfusion. Scrupulous care is taken to avoid these problems but there is still a slight risk of acquiring HIV in one in 2-5 million transfusions. That might not seem much, but people still play the lottery with a one in 14 million chance of winning.

The final risk I want to highlight is iron overload. I will write about this separately but patients who receive 50-100 units of blood will get iron overload, which can damage skin, joints, liver, pancreas and heart and will need a special treatment.

Friday, February 03, 2006


I have spent the day correcting the proofs of an article I wrote nearly a year ago. It is part of a theme issue on CLL coming out in Seminars in Oncology. Writing for a multi-author issue is like traveling in a convoy; we all proceed at the speed of the slowest ship. I had actually forgotten about this piece.

The proof correcting was quite difficult because I had the references out of sync, and one had missing page numbers. Since the paper was from a book, Medline was no good, and my copy of this very old textbook has been long thrown away. How do you find a 1961 book reference? After trying several things on Google, I eventually found the reference cited by somebody else. So unless he got frustrated and just made up the numbers, I should be OK.

Easy to get distracted by the Danish cartoons. They are easy to find on the internet and are pretty unremarkable to a Western eye. Of course, we have to recognise that Moslems allow no representation of anything with a soul, a certainly not the Prophet. I, too, have been offended by some of the way the Media portray Jesus. However, we are living in a secular society and we have to lump it if we want to live here. In Moslem societies women have to dress in certain ways that I find offensive. Certain other behaviours are unacceptable to me. If I went to live in Saudi Arabia, I should have to put up with them. That's why I live in England. Those who don't like living in a Western democracy have the option of leaving. They can also march up and down with banners and protest. What they can't do is threaten others with violence or encourage others to be violent. And neither can I.

Free speech is a precious right. So is freedom of worship. Moslems can boycott goods from Denmark if they want to and call them names if they want to. It's a free country. But will they be content with that?

A clash between fundamentalist Islam and the West seems to be coming. Let's hope that it doesn't go nuclear.

Thursday, February 02, 2006

Scientific Fraud

Today I have been writing a review of the Canadian TV program on Dr Ranjit Chandra - the fraud who deceived the world of nutrition science for nearly 20 years. His story has been told at It appears that he has been salting money away in numbered accounts intax havens for years.

Another story that caught my eye today was about an horrific accident in which 4 childen were killed. It turns out that the mother who was the driver and seriously injured, had stolen the car. It was later reported that her partner was in prison for robbery. Career criminals commit disproportionate numbers of traffic offences.

It seems that criminality, whether it be fraud or violence is seldom an isolated incident.