Friday, December 31, 2010

The white plague in London

An article in today's Lancet entitled "The white plague returns to London - with a vengeance" should strike terror in the minds of our legislators. In the nineteenth century a quarter of all deaths in Europe were due to tuberculosis. Even in my youth the initials TB were only whispered in polite company. In past 60 years better housing, nutrition, and economic status, effective anti-tuberculosis drugs and BCG vaccination have reduced the incidence so that what John Bunyan called the 'Captain of these men of death' has been demoted to a mere corporal. That is true for the whole of Western Europe, but not for London, and not for the rest of the world, where 1.7 million people die annually from TB.

The problem is that London has become home to the rest of the world. The number of cases in London has increased by nearly 50% since 1999, from 2309 in 1999 to 3450 in 2009, accounting for almost 40% of all tuberculosis cases in the UK and this is certainly an underestimate. A further worry is that many of the new cases are multi-drug resistant.

The increase in the number of cases in the UK has largely been in people not born here, though 85% of them have lived here for more than two years. In 2009, there were 28% black African28%, 27% Indian, and only 10% white sufferers. Tuberculosis was commonest in London boroughs that are relatively deprived with poor housing, inadequate ventilation, and overcrowding.

London has a problem with housing. It has always been an entry point for immigrants. When I applied for the London Hospital Medical school in 1961 the Mile End Road was occupied by shops with names like Isaacs, Abrahams and Jacobs, now all the signs are Bangladeshi. The Jews now live in Enfield and Barnet, the Hindus have moved to Southall, the Afro-Caribbeans to Camberwell and Peckham - once a working-class white area. Islington and Hackney have become gentrified and the same is happening to many unfashionable areas that were once shabby Victorian terraces. Houses in Camden - once a home for the laboring Irish - now sell for over a million pounds.

Immigrants live in central London because there are many low-paid jobs there - office cleaning, care home skivvying, minicab driving, short-order cooking, clothing sweat-shop sewing, and male and female prostitution. There is even slavery in the employ of rich potentates from the Near East. Although it is poorly paid, it seems like a fortune to what they could make in Bangladesh or even Bulgaria. They feel that they ought to send money home and they do - as much as they can. What they don't realize is how much it costs to live in London. They get subsidized housing, but their landlords are unscrupulous. The greatest rents can be achieved in houses of multiple occupancy. It used to be a joke among medical students that when they had a room in the hospital so they could be on-call, they were so busy that they let their room to a family of 17 Pakistanis. That is an exaggeration, of course, but there is a nub of truth there in that immigrants put up with a good deal of overcrowding. Hot-bedding is common enough to be a cause of the spread of infectious disease.

Why is it that immigrants who have been here for greater than two years have the highest incidence of TB? Most immigrants from sub-Saharan Africa and South Asia will have been exposed to a primary infection with TB, but those that don't die and are strong enough to emigrate will have a degree of immunity. The most obvious cause for a fall in their immunity in London is infection with HIV that insidiously gets worse with time. The commonest cause of AIDS in the UK is no longer gay sex, but women having unprotected sex with a black African. However, HIV does not account for the whole of the problem.

Containment of the TB bacillus is the responsibility of the moncyte/macrophage system. It derives from the same progenitor as granulocytes. What directs the maturation down monocyte lines is vitamin D3, but dark skinned immigrants in London don't get enough vitamin D3 made from sunlight. Perhaps this is part of the problem, which would be easily remedied by vitamin D3 supplements in food?

Wednesday, December 29, 2010

Elephants more precious than people

I heard a story today from Zimbabwe. When you get out in the bush there the people are starving. They live subsistence farming that is heavily dependent on the rains.

The story concerns a village in the bush where their crops were trampled down by a rampaging elephant. The villagers were able to kill the elephant and the cry went up to the surrounding villagers that meat was available. The elephant was butchered and fed to the starving.

That is not the story. The story was what happened when the missionary who witnessed this told the story to local churches on deputation work. He was heckled and criticised because he approved of the villagers killing the elephant. The woman who criticised him was told that the villagers would die if they had no crops. "So," replied the woman, "Villagers die all the time in Africa."

Monday, December 27, 2010

Reading and Viewing

What have I been reading and watching over the Christmas period? Apart from the Peter Mandelson book which I wrote about last week, I have read the latest Lee Child which is up to his usual standard. It really carries on from 61 Hours and pits Reacher against the Italian, Arab and Iranian mafia, half a dozen American football players and a family of people traffickers. Guess who wins?

I have also started a new Minette Walters, Dorset's own writer of psychological thrillers.

Continuing our viewing of old films, we have watched two Humphrey Bogart movies, The Left Hand of God and Sirocco. In the former Bogart apparently plays an RC priest who arrives at a mission station to take up his role there. Gene Tierney plays the love interest, though what is a priest doing falling for a young girl? And what is his relationship with Lee J Cobb, the local Chinese warlord. Is he really a priest?

In Sirocco Bogart plays an American gun-runner, selling weapons to the Syrians in their uprising against the pre-war French. Lee J Cobb (again) plays the French Intelligence Officer who is hunting him. Unusual for him at this late stage in his career, Bogart plays a baddie, though will he have a self-sacrificing core to his character? What do you think?

We have also watched A Letter to Three Wives which starred Jeanne Crain, Linda Darnell and Ann Sothern as three wives who receive a letter from the local beauty telling them that she has run off with one of their husbands. One of the husbands is played by Kirk Douglas (a pedant after my own heart) but the movie is stolen by a young(-ish) Thelma Ritter.

WE are also making our way through One Foot in the Grave. Last night we watched the 1995 Christmas Special. My sides were aching with laughter.

How children became children

There is a scene in Schindler's List where Schindler is defending to the Nazis his decision to include children among the Jews he is rescuing. He says he needs their small hands to polish the inside of shell casings. It sounds strange to us and bizarre that the Nazis should accept this as a reason, yet before 1850 children were seen in just this was: bijou units of economic activity, ideal for doing those fiddly jobs that require smallness and a delicate touch - like tweezers for pulling out nasal hairs. So, children were used for crawling under the machines in the cotton mills to remove all the accumulated fluff and for working narrow seams in coal mines.

Only a few people know that the statue of Eros in Piccadilly Circus in London commemorates Anthony Ashley Cooper, the 7th Earl Of Shaftesbury, one of the greatest do-gooders of the nineteenth century. Even fewer know that it is not a statue of Eros at all but of his brother Anteros; the god of charitable love, not of sexual love. A few more people will know now if they have been watching Ian Hislop's series of TV programs, The Do-Gooders. I know that it isn't available in the US though it may be in Canada, but these things are usually marketed on DVD, so look out for it.

Shaftesbury (of Avenue fame in London's theater land) may be said to have invented childhood. He was shocked by seeing how children were used in factories and the coal mines. As a member of parliament he was able to introduce legislation to limit children's hours and stop the under-10s from working at all. There was much opposition. Shaftesbury would deprive children of a livelihood that kept their families out of the workhouse; the mining industry would collapse without their labor, so would the textile industry. The same arguments that are used today in favor of sweat shops around the world.

I am particularly proud of Shaftesbury even though he was a Lord and privileged beyond imagining, in that he was a local lad; his family seat is at Wimborne St Giles, about 15 miles from here, but he was also an Evangelical Christian with a social conscience. So many Evangelicals are concerned with their own salvation and with obscure points of doctrine (Charles Haddon Spurgeon was even told by fellow Evangelicals, "Don't preach to those who are not the 'elect' it’s a waste of time."). Often they so shrink from doing good works that they sit on their hands in the face of tragedy, for fear of propagating the 'social gospel'. Among the do-gooders were many Unitarians who did not look to Jesus as God and who tended to major on the social gospel, so that to Evangelicals, for whom salvation through Jesus, one of the persons of the triune God, was paramount, the social gospel became tainted with heresy. However, nineteenth century Evangelicals like Wilberforce and Shaftesbury, leaders of successive generations of Evangelicals saw good works as the working out of their faith. There was no thought that good works aided in their salvation or sanctification, they were with James - "Faith without works is dead."

Since they were no longer required to go down mines or crawl under Spinning Jennies someone had the bright idea that children should be educated. Of course, the children of the rich and powerful had always been educated at schools like Eton and Harrow, Winchester and Rugby. The idea of educating working class children began with Robert Raikes of Gloucester who began Sunday Schools in 1780. The movement started with a school for boys in the slums. Raikes had been involved with those incarcerated by the county Poor Law and saw that vice would be better prevented than cured. He saw schooling as the best intervention. The most available time was Sunday as the boys were working in the factories the other six days. The best available teachers were lay people. The textbook was the Bible, and the originally intended curriculum started with learning to read and then progressed to the catechism.

The movement began in July 1780 in the home of a Mrs Meredith. Only boys attended, and she heard the lessons of the older boys who coached the younger. Later, girls also attended. Within two years, several schools opened in and around Gloucester. There were disputes about the movement in the early years. The schools were derisively called "Raikes' Ragged Schools". Criticisms raised included that it would weaken home-based religious education, that it might be a desecration of the Sabbath, and that Christians should not be employed on the Sabbath. "Sabbatarian disputes" in the 1790s led many Sunday Schools to cease their teaching of writing.

By 1831, Sunday Schools in Great Britain were teaching weekly 1,250,000 children, approximately 25 percent of the population. In the late 18th century, Thomas Cranfield offered free education for poor children in London. While he was a tailor by trade, Cranfield's educational background included studies at a Sunday school on Kingsland Road, Hackney. In 1798, he established a free children's day school, located on Kent Street near London Bridge. By the time of his death in 1838, he had established 19 free schools that provided services for children and infants living in the lower income sections of London. These opportunities and services were offered on days, on nights, and on Sundays, for the destitute children of poor families throughout London.

Another separate strand of education began with John Pounds, a crippled Portsmouth shoemaker. In 1818 Pounds began teaching poor children for the whole week, not just on Sundays, without charging fees. Pounds was moved by the plight of starving and abused children in Portsmouth (also not far from here, close to where my daughters and sister live). Within the confines of his small workshop in St Mary's Street, Old Portsmouth, the old cobbler fed, nursed, clothed and taught them (often 40 at a time). He was voted Portsmouth's Man of the Millennium in 2000 (remember that Lord Nelson and Charles Dickens were also Portsmouth residents).

After Pounds' death, Thomas Guthrie wrote A Plea for Ragged Schools and proclaimed John Pounds as the originator of this idea. Guthrie started a ragged school in Edinburgh. In 1844, Lord Shaftesbury formed the Ragged School Union and over the next eight years over 200 free schools for poor children were established in Britain.

In 1841, Sheriff Watson established another school in Aberdeen, Scotland. His methods were different from his colleagues. Unlike the efforts of Raikes, Pounds, Cranfield, and Guthrie, Watson used compulsion. Watson was frustrated by the number of children who committed a petty crime and faced him in his courtroom. Instead of sending them to prison for vagrancy, he established a school for boys. As a law official, the sheriff arrested vagrant children and enrolled them in school. The Industrial Feeding School, as it was called, opened to provide reading, writing and arithmetic. Watson believed that gaining these skills would help the boys rise above the lowest level of society. Three meals a day were provided and the boys were taught useful trades such as shoemaking and printing.

In 1843, Charles Dickens began his association with the schools and visited the Field Lane Ragged School. He was appalled by the conditions and moved toward reform. The experience inspired him to write A Christmas Carol. He initially intended to write a pamphlet on the plight of poor children, but he realized that a dramatic story would have more impact. Dickens continued to support the schools, donating funds on various occasions. At one point, he donated funds, along with a water trough, stating that it was "so the boys may wash and for a supervisor" (from a letter to Field Lane).. He later wrote about the school and his experience there in Household Words. In 1837, he had used the area called Field Lane as a setting for Fagin’s den in his classic novel, Oliver Twist.

The Earl of Shaftesbury served as chairman of the Ragged Schools Union for 39 years. During his chairmanship, an estimated 300,000 destitute children received a free education. The free school movement became respectable, even fashionable, attracting the attention of many wealthy philanthropists such as Angela Burdett-Coutts who gave large sums to the Ragged Schools Union. This helped to establish 350 ragged schools by the time the 1870 Education Act was passed. Shaftesbury gave what had been a Nonconformist undertaking the cachet of his Tory churchmanship — an important factor at a time when even broad-minded (Anglican) churchmen thought that Nonconformists should be credited with good intentions, but they were not to be cooperated with.

The success of the Ragged Schools demonstrated that there was a demand for education among the poor. In response, both England and Wales established school boards to administer elementary schools. However, education was still not free of fees until 1870 when public funding began to be provided for elementary education among working people.

School boards were public bodies created in boroughs and parishes under the Elementary Education Act of 1870 following campaigning by George Dixon, Joseph Chamberlain and the National Education League for elementary education that was free from Anglican doctrine. Members to the board were directly elected, not appointed by borough councils or parishes. As the school boards were built and funded, the demand for Ragged Schools declined. The Board Schools continued in operation for 32 years until the Education Act of 1902, which replaced them with Local Education Authorities.

The Ragged School Museum is housed in a group of three canal-side buildings that once housed the largest Ragged School in London. It occupies buildings that were previously used by Dr Thomas Barnardo and is located on Copperfield Road in the London Borough of Tower Hamlets.

Thomas John Barnardo (4 July 1845 – 19 September 1905) was an Irish philanthropist. His father who was of Sephardic Jewish origin, and his mother an English woman and member of the Plymouth Brethren (to which he converted on 26 May 1862). He came to London in 1866, with plans to train as a doctor and then become a medical missionary in China. In London, he was confronted by a city where disease was rife, poverty and overcrowding endemic and educational opportunities for the poor were non-existent. He watched helplessly as a cholera epidemic swept through the East End, leaving over 3,000 Londoners dead and many destitute. He gave up his medical training to pursue his local missionary works and in 1867, opened his first Ragged School, where children could gain a free basic education.

Ten years later, Barnardo’s Copperfield Road School opened its doors to children and for the next thirty-one years educated tens of thousands of children. It closed in 1908, by which time enough government schools had opened in the area to serve the needs of local families.

Barnardo was a great showman and self-publicist but one of the great do-gooders of all time. He gave himself the title of "Doctor" despite never qualifying for such an academic degree. However, he worked as ‘doctor’ in the East End of London in 1866 during the cholera epidemic there. Encouraged by the support of the Lord Shaftesbury and the Lord Cairns, he gave up his early ambition and began what was to prove his life’s work, opening the first of the "Dr Barnardo’s Homes" in 1870 at 18 Stepney Causeway, London.

The object of these institutions was to search for and to receive waifs and strays, to feed, clothe and educate. The infants and younger girls and boys were "boarded out" in rural districts; girls above fourteen years of age were sent to the industrial training homes, to be taught useful domestic occupations; boys above seventeen years of age were first tested in labor homes and then placed in employment at home, sent to sea or emigrated; boys of between thirteen and seventeen years of age were trained for the various trades for which they may be mentally or physically fitted. Besides the various branches necessary for the work, there were also a rescue home for girls in serious danger, a convalescent seaside home and a hospital for the terribly sick. At the time of his death in 1905, there were 112 district homes throughout the United Kingdom.

Barnardo laid great stress on the religious teaching of the children under his care. Each child was brought up under the influence and teaching of the Protestant Faith. It was a condition of admission that Roman Catholic children were to be educated as Protestants by Barnardo. Children of Jewish parentage were handed over to the care of the Jewish Board of Guardians in London.

Despite founding the most famous children’s charity in the UK, Barnardo’s methods were questionable He was guilty of misleading advertising, photo-fakery and even child abduction. Yet, we owe our own concept of child protection - that children have rights independently from their parents – to him. Barnardo was perhaps the first to declare that the rights of the child were paramount and he, quite illegally, would remove children from parents whom he decided were harming a child with their bad parenting. Even Lord Shaftesbury opposed him in this. However, because the public was carried along by the rightness of his actions whatever the law said, this principle eventually became enshrined in English Law and social workers today have been criticized for not taking advantage of this provision; most recently in the notorious ‘Baby Peter’ case. The current Director of Barnardos, Martin Narey, was a prison governor in a previous incarnation, and he was once a staunch defender of the rights of parents, but his experience with the children’s charity has quite changed his mind.

Saturday, December 25, 2010

Peter Mandelson's book

I have been reading The Third Man, the autobiography of Peter Mandelson, one of the architects of New Labour, who ruled Britain from 1997 to 2005. Mandelson was a cabinet minister under Tony Blair (though twice dismissed on rather petty grounds) and effectively deputy prime minister under Gordon Brown. In between he was Britain's Commissioner at the European Union responsible for the international trade talks and the failed attempt to lower trade barriers between emerging nations and the rich. It ought to be seen as one of the most successful political careers of his generation, yet Mandelson is probably regarded as a failure.

He is a man who is regarded with suspicion; a Machiavellian character who plotted behind the scenes, open to any form of dishonest spinning of the truth. Although he is the grandson of Herbert Morrison, deputy prime minister in the 1945-51 Attlee administration, he is not a typical Laborite. His parents were upper middle class, he attended a very good Grammar School in North London and went on to Oxford University. He was aways privileged, with easy entry into the higher echelons of the Labour Party.

With Blair and Brown he set out to change the party from the unelectable, far-left, rump that supported Michael Foot in wanting to ban-the-bomb, into the progressive party of Tony Blair that wanted to occupy the middle ground. Much of what he achieved was a superficial gloss. Blair was a consummate showman; articulate with a barrister's silver tongue, he could work equally well with Clinton and Bush and was able to persuade his colleagues into several unpopular wars. But many of his ideas were impractical (taking unruly teenagers to ATMs to pay a fine on the spot to policemen, for instance) and these would irk Gordon Brown who considered himself to be the brains behind New Labour and had been in one colossal sulk since 1994. When Brown finally achieved the leadership of the Labour Party that he had always craved, he proved himself to be wholly unsuitable as Prime Minister and completely unelectable.

The picture he presents of the internecine wars within Labour during the years in government may be true, but one would have to read Blair's and Brown's autobiographies to be sure, but Mandelson has a reputation for dissembling and I wouldn't trust him to deliver the post let alone the truth.

At the end of the book he comes up with the following: the goal... is to create the sort of society in which the daughter of a Hartlepool shop assistant has as much chance of becoming a High Court Judge as the daughter of a Harley Street doctor.

This statement is so awry that it takes my breath away.

First of all, the daughter of a Grantham shopkeeper, has already become, not a High Court Judge, but Prime Minister of the UK: Margaret Thatcher.

Second, the Grammar Schools, from which he benefited, have already caused a great deal of social mobility. The writer is himself the son of a bar steward who became an internationally renowned doctor thanks to those same Grammar schools. Yet it has always been Labour Party policy to have comprehensive schools in which bright boys and girls are lost within a morass of low-achievers and instead of being stimulated by good teaching, resort to being the class clown to get attention.

Third, being a High Court Judge, takes a certain degree of brain power. Although clever people may come from any stratum of society, most clever people have already found their niche. There is not a huge reservoir of brain-boxes among the children of shop assistants. Intelligence is not entirely genetic, but it is in part. It is true that very few students at Oxford and Cambridge come from working class backgrounds, but that is not because of lack of opportunity.

Fourth, High Court Judges are hardly the example I would set before my children. A recent report of the foul language issuing from a female judge prosecuted for drunken driving is hardly what I want from my kids.

Fifth, there is a distressing tendency for people in government to rate intellectual skills above more practical ones. I would rather my son were a good carpenter than a politician with a reputation for mendacity, no matter how high and mighty he might be. Even more, I would want him to be a man of integrity even if his joints didn't fit.

Friday, December 24, 2010

christmas poem II

But here is Wendy Cope on Christmas.

At Christmas little children sing and merry bells jingle,
The cold winter air makes all our hands and faces tingle,
And happy families go to church and cheerily they mingle,
And the whole business is unbelievably dreadful, if you’re single.

christmas poem

I published this last year, but I've been too unwell to write another one.

I came to you at Christmas when the frost had fixed the grass,
When they decorate department stores with balls of coloured glass,
When the Square is lit with silver shapes and sparkles green and red
And the trees are decked with fairy lights that flicker overhead,
When the shopper-laden buses hustle down Westover Road
And you wonder if that tea set will suffice for Mrs Spode;
When the speakers blare out ‘Jingles Bells’ off-key and very loud
And the bargain hunters muscle through the shoulder-crushing crowd;
When a lady limps and lurches under purchases too large
From a bright and shiny toyshop never known to undercharge,
When you fight for bulbs and batteries and each last-minute task,
For an electronic Christmas that is all that they could ask;
And I caught your eye and thought, for a moment, you might stop;
But the fever was upon you and your only thought was,”Shop!”

I came to you at Christmas down at number thirty-four
Where the reindeer and fat Santa quite irradiate the door,
Where the presents are piled high underneath the plastic tree
And the herald angels hark from a plasma screen TV,
Where there’s whisky overflowing and a Quality Street tin
And heaps of chocolate biscuits and buckets full of gin,
Where the parsnips and potatoes are roasting in the pan
And the turkey has been cooking since before the day began,
Where the cake from Marks and Spencers will be passed off as your own,
Just like the Christmas pudding – last year’s gift from Auntie Joan;
And it’s time to do the vegetables, the peas and beans and sprouts
And the microwavable mince pies at four or thereabouts.
And I caught your eye and thought, for a moment, you might look;
But the fever was upon you and your only thought was, “Cook!”

I came to you at Christmas; but not as a masquerade,
All safely wrapped in swaddling clothes and in a manger laid.
I was not at the rehearsals; I was sorting goats from sheep
For my gaze is universal and you know I never sleep.
In Zimbabwe I was hungry; in Romania I was cold,
In Malawi I was orphaned and in Darfur I was sold;
In other lands imprisoned; in other countries stoned;
The plain facts skated over or by other means condoned.
I was there in Boscombe Crescent sleeping on that slatted seat
I was scrabbling in the rubbish bin for something fresh to eat
I was with the young offenders down at Portland on the coast
Kept away from home and family at a time that matters most.
I was sick in the Macmillan and I almost caught your eye
But the fever was upon me and, of course, I came to die.

I came to you at Christmas but not just for Christmas Day.
All through the year I’ll hunt you and I will not go away.
Though you think you do not need me, that your staying power’s too strong,
The calamities that crush you will be bound to prove you wrong.
If you think you’re irredeemable; you’ve long since burnt your boats;
The die was cast when years ago you sowed your wild oats,
Oh! Hesitate to think so for I’ve rescued worse than you,
My blood can make the foulest clean; I offer life anew.
I came to you at Calvary; to you and all mankind
To give you peace from God above; none need be left behind.
Don’t let the world distract you, don’t hanker after things,
However they attract you, they always come with strings.
My Christmas present for you is superb beyond compare;
On that Resurrection Morning won’t you meet me in the air?

Thursday, December 23, 2010

Spinach - I was right for the wrong reason

Twenty-nine years ago I wrote an article in the British Medical Journal about scientific fraud, fakes and medical mistakes in which I revealed that spinach is not a good source of iron. I further revealed that a German Chemist made a mistake by misplacing the decimal point. Here's what I wrote:

In the year that Popeye became once again a major movie star it
is salutary to recall that his claims for spinach are spurious.
Popeye's superhuman strength for deeds of derring-do comes
from consuming a can of the stuff. The discovery that spinach
was as valuable a source of iron as red meat was made in the
1890s, and it proved a useful propaganda weapon for the meatless
days of the second world war. A statue of Popeye in Crystal
City, Texas, commemorates the fact that single-handedly he
raised the consumption of spinach by 33%. America was "strong
to finish 'cos they ate their spinach" and duly defeated the Hun.
Unfortunately, the propaganda was fraudulent; German
chemists reinvestigating the iron content of spinach had shown
in the 1930s that the original workers had put the decimal point
in the wrong place and made a tenfold overestimate of its value.
Spinach is no better for you than cabbage, Brussels sprouts, or
broccoli. For a source of iron Popeye would have been better off
chewing the cans.

I was never quite sure where I got that information. At the time I was making a reputation as an author of humorous articles for the popular magazine World Medicine. I was also interested in scientific fraud and was asked to write an article on it for the Christmas edition of the BMJ by the then editor, Stephen Lock. It was to be a light hearted article without the usual scrupulous references that I would normally supply for a journal like the BMJ. Given that I was debunking a number of frauds that included examples of plagiarism, I was uncomfortable with this suggestion and we agreed that I should provide a bibliography at the end. This is what I wrote:

Having spent so much of my time talking about people whose work
was unoriginal, I should mention that little of my article is based on
original work but has been derived from the publications of others.
Among these I should particularly like to mention:
Arther Koestler: Case of the Midwife Toad. London, Hutchinson.
Malcolm Bowden: Ape Men-Fact or Fallacy. Bromley, Sovereign
William J Broad: Science 208:1438-40,209:249,210:38-41, 171-3.
Colin Tudge: World Medicine 1974 Jul 17:34.
Leon Kamin: New Society 1976 Dec 2:460-1.
Marjorie Sun: Science 1981 ;212:1366-7.
D D Dorfman: Science 1978;201:1177-88.
Ian St James Roberts: New Scientist 1976 Nov 25:466-7.
C Joyce: New Scientist 1981 Apr 9:68-9.
D Dickson: Nature 1981 ;289:227.
Nature 1980;286:433, 831-2.
Lancet 1976;ii: 1066-7.
British Medical Journal 1980 ;281 :41-2.

I have rechecked these references but none of them refer to Popeye. When people have asked me about it (including the late, great, Martin Gardiner) I have always replied that I thought I remembered reading it in Reader's Digest but I have never been able to find the article.

Now some fascinating research by Mike Sutton has found out the whole truth behind the decimal point and the iron in spinach myth and I am pleased to be able to say that I was right about spinach being useless as a source of iron, but utterly wrong about why the myth has taken hold.

Dr Mike Sutton is the originator of the Market Reduction Approach to theft. He is the General Editor of the Internet Journal of Criminology and is Reader in Criminology at Nottingham Trent University in England. He is an alumnus (BA hons. Law and PhD) of the University of Central Lancashire.

In an earlier article Dr Sutton accused me of inventing the story. I knew that to be untrue, but I couldn't remember where I had read it. I still don't remember, but I now know where the information came from although I'm sure it wasn't in the Spectator that I read it in as Dr Sutton implies. Some other author must have picked it up from the Spectator and written it down elsewhere for me to pick up.

It appears that the original published source of this story was nutritionist, Arnold E. Bender. He first mentioned it in his inaugural professorial lecture in 1972 and later in an article in the Spectator where he claimed, according to Sutton, that "a German textbook on nutrition (Noorden and Salomon 1920; 476) replicated an earlier decimal point data mistake made by generations of textbooks that unquestioningly replicated erroneous data first published in 1870 by the German scientist E. von Wolff":

“For a hundred years or more spinach has been (and clearly still is) renowned for its high iron content compared with that of other vegetables, but to the joy of those who dislike the stuff this is quite untrue. In 1870 Dr E. von Wolff published the analyses of a number of foods, including spinach which was shown to be exceptionally rich in iron. The figures were repeated in succeeding generations of textbooks – after all one does not always verify the findings of others – including the ‘Handbook of Food Sciences’ (Hundbuch der Ernahrungslehre) by von Noorden and Saloman (sic) [1] 1920.

In 1937 Professor Schupan eventually repeated the analyses of spinach and found that it contained no more iron than did any other leafy vegetable, only one-tenth of the amount previously reported. The fame of spinach appears to have been based on a misplaced decimal point.”

My article in the BMJ has been the spur to countless other articles perpetuating the decimal point myth. So what is the truth? You can read it for yourself if you click the link, but for those who don't have the time, it does seem that Emil von Wolff did over estimate the amount of iron in spinach. In 1871 he reported that fresh spinach contained 3350mg of iron per 100g. This is from Professor Bender's article in the Spectator:

One common belief, that spinach is good for you, appears to be due to experimental error since the belief predates the Hollywood nutrition films based on the muscular development of the film star Popeye. I am indebted to Professor den Hartog of Holland for tracing the possible origin of this belief. It appears to date soon after 1870 when Dr E. von Wolff published food analysis showing spinach to be exceptionally rich in iron, a figure that was repeated in many generations of textbooks; it was in the Handbook of Food Sciences (Handbuch der Ernahrungslehre) by von Noorden and Saloman in 1920. In 1937 Professor Schupan analysed spinach for its iron content with µ-µ’-dipyridyl and found the figure to be one tenth of that reported by von Wolff – the fame of spinach may well have grown from a misplaced decimal point.”

There seems no published work of Professor den Hartog that makes this claim and Sutton concludes that the information may have been conveyed in informal conversation.

Quoting Sutton: "Noorden and Salomon’s (1920 Handbuch Der Ernährungslehre Erster Band Allgemeine Diätetik. Berlin. Verlag Von Julious Springer.) figure for the amount of iron in dried spinach is 445 mg of iron per 100g. This figure is derived from Haensel, who presented the iron content of spinach in percentage terms as 0.445 per cent. To convert this figure to mg per 100g it is simply multiplied by 1000 - which is 445.

Professor Bender was completely wrong about the source of Noorden and Salomon’s data on the iron content of spinach. Absolutely none of it came from von Wolff. Not one single figure. The figure Bender thinks came from the work of Wolff in the 1870’s in fact came from Haensel (Haensel, von. E. (1909) uber den eisen- und phosphorgehalt unserer Vegetabilien. Biochem. Zeitschr 16. 9."

Sutton believes that "The source of Bender’s decimal error belief derives from the fact that accepted knowledge at the time when Bender was writing quite correctly held that dried spinach contained 44.8 mg of iron per 100g (e.g. Jackson 1938Determination of Iron in Biological Material. Industrial & Engineering Chemistry Analytical Edition. 10 (6), 302-304). Subsequent research has recorded a figure of 44.6 (Rewashdeh et al 2009 Iron Bioavailabilty of Rats Fed Liver, Lentil, Spinach and other Mixtures. Pakistan Journal of Biological Sciences. 12 (4) 367-372.) From this it is easy to see where the decimal error idea in Bender’s spinach story came from. Had Haensel (1909) moved his decimal point to give a figure of 0.0445 per cent iron he would have had an accurate figure for the amount of iron in dried spinach of 44.5 mg per 100g."

It is clear that von Woolf's result cannot be corrected by simply moving the decimal point one place - his result is at least 50 times too great. It is far more likely that the method that he employed was faulty and Sutton has discovered that other measurement made during this period was similarly awry. Certainly there has been confusion between the amount of iron in fresh spinach and dried spinach and the water content of spinach depends on how recently it was picked, nevertheless, even by the turn of the twentieth century errors in earlier measurements were readily apparent without the need to invoke decimal places.

In fact most foodstuffs whether green vegetables or meat have similar amounts of iron; what matters is whether the iron is available for absorption by the human gut. Whereas the iron in meat is readily available this is not true for green vegetables. Whatever the result of measurements of iron, you cannot prevent or cure iron deficiency by eating spinach. Meat, red or white, (but not from shellfish) is what you need.

The moral of this story is that a good story is not necessarily a true story.

Tuesday, December 21, 2010

Christmas Carols

Getting ready for Christmas, I have been playing my Christmas CDs - I have 38 of them and I've been doing some research on what I have. Altogether there are 325 different Christmas songs on them. The most popular is Silent Night, of which there are 19 versions, followed closely by O Little Town of Bethlehem, which appears 18 times. Third is O Come all ye Faithful 15, 4th is The First Noel with 13, tie 5th are Away in a Manger and Hark the Herald Angels sing on 12, tie 7th are the Coventry Carol and In Dulce Jubilo on 10 and tie 9th are I Saw Three Ships, O Holy Night and Ding Dong Merrily on High with 9. The first secular songs are Deck the Halls and White Christmas which are tie 12th with 8, the same as Once in Royal David's City, God Rest Ye Merry Gentlemen and In the Bleak Midwinter. 17th is The Christmas Song (Chestnuts roasting...) and 18th are The Holly and the Ivy and What Child is This, and 20th is Jingle Bells.

Saturday, December 18, 2010

Galatians 3:1-6. Six Questions.

The legend has it that Pheidippides, a Greek messenger, was sent from the battlefield of Marathon to Athens to announce that the Persians had been defeated in the Battle of Marathon in August or September, 490 BC. It is said that he ran the entire distance without stopping and burst into the assembly, exclaiming "Νενικήκαμεν" (Nenikékamen, 'We have won.') before collapsing and dying. The legend may be wrong since the name Pheidippides only appears 400 years after the event and other names of the hero include Thersipus of Erchius, Eucles and Philippides. In 1879, Robert Browning wrote the poem Pheidippides. Browning's poem and his composite story, became part of late-19th century popular culture and was accepted as a historic legend.

The idea of a marathon race was seen as a way of popularising the modern Olympic games, first held in Athens in 1896. The idea of organizing a marathon came from Michel Bréal and it was was heavily supported by Baron Pierre de Coubertin as well as the Greeks who staged a selection race for the Olympic marathon on March 10, 1896 over a course of about 25 miles - the approximate distance between Marathon and Athens, avoiding Mount Pentelli, which stands between them. Between 1896 and 1920 the Olympic marathon was held over a variable distance of about 25 miles, but the current distance of 26 miles and 385 yards derives from a decision in 1921 to fix on the distance used in the London Olympics of 1908. This was known as the 'Race of the Century' because a runner who was winning the race collapsed and nearly died close to the tape. The race was run from Windsor Castle to White City Stadium - a distance of 26 miles and 700 yards - but in order to give Queen Alexandra a better view of the finish from the Royal Box it was shortened to 26 miles and 385 yards.

The huge crowd, including Queen Alexandra, watched as the little Italian, Dorando Pietri, staggered round the final 385 yards, falling several times, and eventually being propelled by officials over the line as Irish-American Johnny Hayes got ever closer. Dorando was disqualified and Hayes was awarded the Gold Medal. However, Queen Alexandra was so moved by his plight that the very next day she presented Dorando with a silver-gilt cup.

Running marathons is a dangerous pursuit and there are many who have died in the attempt. Measurement of certain chemicals in the blood after marathon running indicates that the muscle of the heart is frequently damaged unless the runner has been training in excess of 35 miles a week. When I was young a strikingly similar event to the 1908 marathon took place at the Empire games of 1954 in Vancouver. Jim Peters, the English runner who had three times lowered the best time for a marathon in the previous months, entered the stadium a full 17 minutes ahead of the second placed man.

As the report in the Manchester Guardian put it at the time, 'Instinct and a misbegotten willpower under the merciless sun had Peters keeling over onto the cinder track again and again like a drunken vaudeville tumbler; each time he hauled himself up once more to stagger on in a groggy, futile nobility.' The Daily Mirror wrote, 'Two steps forward, three to the side. So help me, he is running backwards now ... oh, he's down again ... The nauseous spectacle of a semi-conscious man being allowed to destroy himself while no one had the power or gumption to intervene.'

'The ghastly, ghostly mime lasted all of 11 minutes and 200 metres, when a boxer's sprawl of surrender at the halfway mark had the England team's masseur Mick Mayes stepping in to call for stretcher-bearers. Peters, skin a deathly mottled grey and a collar of foam streaming from his mouth, was borne away on a stretcher.'

He never ran again.

I could never run a marathon. To travel from Windsor Castle to London I should take the train. It might be cheating, but I know when I need help.

Over 30 competitors in the Xiamen International Marathon in China were disqualified earlier this year after officials caught them cheating. Race organisers found video footage that revealed some runners had carried the time-recording microchips of others so that one runner would register two or more results on passing the finish line. Others made their way around at least some of the course in vehicles, while some hired impostors.

They were following an honorable (?) tradition. On 21 April 1980, Rosie Ruiz, a 23-year-old New Yorker, was the first woman to cross the finish line in the Boston Marathon. She had achieved the third fastest time ever recorded for a female runner (two hours, thirty-one minutes, and fifty-six seconds), which was made all the more remarkable by the fact that she looked remarkably sweat-free and relaxed as she climbed the winner's podium to accept her wreath. However, race officials almost immediately began to question her victory. The problem was that no one could remember having seen her during the race. Monitors at the various race checkpoints hadn't seen her, nor had any of the other runners. Numerous photographs taken during the race failed to contain any sign of her. Her absence was overwhelming. Finally, a few members of the crowd came forward to reveal that they had seen her jump into the race during its final half-mile. Apparently she had then simply sprinted to the finish line.

As race officials prepared to announce her disqualification from the race, they discovered evidence that she had also cheated during the earlier New York marathon, where she had earned the time that had qualified her to run in the Boston marathon. She had apparently achieved her time in New York by riding the subway

Before her, Fred Lorz easily claimed the men's title in the 1904 St Louis Olympics with a time of three hours, 13 minutes. Officials soon discovered the secret of his success: the 11-mile ride he received in his manager's car.

The question for Fred is, if it was so much easier to ride in your manager's car, why put yourself to the trouble of running at all?

I suppose it was a guilty conscience. He felt he he had to make some contribution to his medal. Rosie had a better idea. Take the victory as a free gift without even breaking into a sweat.

Many Christians are like Fred. Having accepted salvation as a free gift, they feel that to hang on to it they have to earn it all over again by obeying the Law. In Galatians chapter 3 Paul is at pains to negate the idea by asking six questions.

The first is, "Who has bewitched you?"

I was watching a TV detective story the other night. It portrayed Christianity in a poor light. The vicar and his curate went on Gay Pride marches together and the three Church Wardens were respectively a dying pornographer, a hanging, flogging and birching magistrate and a sanctimonious middle aged doctor who liked to 'examine' pretty young girls and ogle their naked photographs. One character claimed that the Bible told Christians to burn sinners at the stake. In fact the only mention of witchcraft in the New Testament is in Galatians 5:20 which lumps witchcraft with a good many other sins and a warning that people who live like this will not enter the the Kingdom of Heaven. No mention of burning at the stake.

I am sure Paul is using a figure of speech here. He means to ask who has led the Galatians astray and the answer is surely the Judaizers, the circumcision party, those who insisted that the Law must be obeyed.

The second question is, "Did you receive the Spirit by observing the law or by believing what you heard?" It is a rhetorical question. Receiving the Holy Spirit must have been a major event in their spiritual life. Before they were dead in trespasses and sins. The Law had not revived them - it never does. The Law crushes. Read Exodus and Leviticus. Isn't it depressing? Where can you turn and not see yourself as guilty as charged? But look at Christ and him crucified! God sent his one and only son, that whoever believes in him shall not perish but have everlasting life!

The third question is, "Are you so foolish?" You may see on wayside pulpits at this time of the year the words, "Wise men seek him still." But foolishness here is not just the opposite of wisdom; it implies moral delinquency. It is like the "Thou fool!" of the Sermon on the Mount. No one can help being a couple of teaspoons short of a canteen of cutlery. There is no blame attached to that - we can't all be Einsteins. But the foolishness here is that of disbelieving God and the cleverest people can be guilty of that. Paul has begun the chapter with, "You foolish Galatians!" And so they were.

The fourth question is, "After beginning with the Spirit, are you now trying to attain your goal by human effort?" This is where my marathon illustration comes in. There must be enormous personal pride in winning a marathon but in real life you need to be a Kenyan or an Ethiopian to do it. I heard that the Mayor of Rome was planning to cancel the Rome marathon because it was always won by Africans. When you come to think of it running 26 miles for the sake of personal pride is a pretty futile exercise. Better to take a bus. Imagine taking a trolley bus up one of those steep hills in San Francisco, but deciding to walk the rest of the way. The Galatians were doing worse than that. They were abandoning a method that worked for one that didn't.

Many of my readers will know that I am getting an electric train set for Christmas. If you have ever owned one, you will know that the only way to get the locomotive to move is applying electricity to the wheels. imagine that I do this and get the train to move out of the station, but once it gets started I switch the electricity off and decide to push it round the rest of the tract. You'd think me crazy. But that's what abandoning the Spirit and going back to the Law is like.

The fifth question is, "Have you suffered so much for nothing?" The word translated 'suffering' doesn't necessarily imply pain; it can just mean 'experienced'. Compare "Suffer little children to come unto me", which only means 'allow'. But this question sums up the the whole passage - after all you have experienced, how can you go back to the old ways?

The sixth and final question is "Does God give you his Spirit and work miracles among you because you observe the Law or because you believe what you heard?" Again, Paul is appealing to their experience. So many Christians want to separate their conversion from their sanctification as these were two different processes. We are saved by the death and resurrection of Jesus Christ. He cancels the guilt and punishment and the power of sin. Not just our past sins, but our present and future sins. Consequent upon our salvation is the gift of the Holy Spirit who takes responsibility for our sanctification. His main role is to draw attention to the Lord Jesus Christ and make him our template. He grows us closer to Jesus. How foolish (in both senses) to abandon what works and go back to what doesn't.

I sometimes hear people complain about listening to the 'simple gospel' every week. They would prefer to hear the preacher draw out some fine doctrinal point from the book of Numbers or Ezekiel. Nonsense! We should never stray too far from the cross. 'Tell me the old, old story' says the hymn. I never tire of hearing of what Jesus did for me. If I had one sermon to hear before I died it would be of how God loved me so much that he sent his son to die for me. Only Jesus. Only Jesus. Only Jesus.

Jaguar fails to return

Snow has hit Southern England again. Diane was out at 11am clearing the drive of snow that fell between 6am and 9am. I went out with her but collapsed breathless after 10 minutes.

Alas, my son David was unable to join us for the weekend. After driving in blizzard conditions for 3 hours he had to abandon hope and return home. The picture shows my Jaguar battling through the snow. The picture was taken by his girlfriend who was driving his car in tandem.

We have had a beautiful sunny day and most of the snow has melted, but the route from Oxford to Bournemouth was impassable.

rioter in a wheelchair

A Mr Jody McIntyre has complained that the police manhandled him during the recent Student riots that were ostensibly protesting against raising of the cap on tuition fees originally introduced by New Labour to pay for their policy of sending excessive numbers of people to polytechnics renamed 'Universities'.

I draw attention to a website that sees things differently though you will have to click on the link to see the photos:

A series of shots taken during the afternoon of the latest student protest in London. The young man in the shots, Jody McIntyre claims he was assaulted by the police.
This claim relates to an event later in the evening, however, these shots show the way the police dealt with Mr McIntyre in the afternoon.
At the time these shots were taken the police were under a barrage of bricks, bottles and metal fence panels, as well as being involved in hand to hand fighting with the crowd.
Mr McIntyre was in the front row of the crowd and in a very precarious position, especially as he is wheelchair bound.
It was clear from my vantage point that the police moved him as gently as possible and in doing so the officers put themselves in personal danger from the hail of missiles.
Once he had been moved away from the front line to a safe distance, the officers sat him on a low level wall. Mr McIntyre got up and started arguing with an officer. He was so wound up that he eventually tried to strike an officer and was only stopped from doing this due to the intervention of a famale passer-by.

Peruse Mr McIntyre's website and you will see what sort of specimen he is. Just as being black doesn't put you necessarily on the side of the angels, neither does being in a wheelchair. He is clearly trading on his handicap, but political correctness deters people from saying so..

Friday, December 17, 2010


I picked up this from the Open Doors website
A Christian in Afghanistan facing "apostasy" charges punishable by death is still without legal representation after authorities blocked a foreign lawyer’s attempt to visit him in prison. Said Musa (45) was arrested in May after images of Christians worshipping were broadcast on a popular TV channel.

A Christian lawyer from the region, who requested anonymity, travelled to Kabul on behalf of an American Christian legal rights organisation, Advocates International, to represent Musa, but the authorities denied him access to Musa and to his charges file.

"If a man is not entitled to define his own beliefs and to change those ideas under the existing constitutional order of Afghanistan, then how is this government more moral than the Taliban’s?", the lawyer asked.

Musa has been imprisoned for seven months, even though an accused person has the right to be released if no valid charge is brought before the courts within 15 days of arrest.

The court hearing is expected to take place imminently but because of the sensitivity of the case, Musa is still searching for a lawyer who will defend him. In a letter from prison, Musa asked Christians to pray for him and for his country. Musa is married and has six young children.

Another Afghan Christian in prison for his faith is Shoib Assadullah, 25, who was arrested on 12 October for giving a New Testament to a man who then turned him in to authorities. Shoib is in jail in northern Afghanistan and, like Musa, cannot find a lawyer to defend him. Sources close to him have said that despite everything, he is not frightened and his faith is strong, but he desperately misses having a Bible.

Source: Compass Direct News

Please pray:

1. For Musa and Shoib, that able defence lawyers will be found to represent them in court and they get a fair trial.

2. That these men will be strengthened in prison, both in mind and spirit, and they would know they are not alone.

3. That God would bless Advocates International and raise up similar organisations, so that persecuted Christians would have access to legal representation in such cases.

Health and Christmas

This has been a busy week. I had my 6th course of chemotherapy on Saturday-Monday. Side effects were unpleasant and continued until Thursday. They were mainly colic and constipation with fatigue and nausea, headache and general soreness at times. I've had a lot of visitors. The district nurse came Monday to take down my chemotherapy pump. On Tuesday my brother and mother came and brought down their Christmas presents, taking back ours to them. On Wednesday I was glad to see Dr John who always brings good cheer and spiritual support. On Thursday my brother-in-law came down for a run on the beach and a dip in the sea (in a wet suit). He also had presents to bring and retrieve. Today Jane, the MacMillan nurse, came in for a chat. She is offering some physio to strengthen my muscles and some aromatherapy. I don't expect miracles, but they tell me it is very pleasant.

Tomorrow, my younger son David is expecting to visit - I guess it all depends on the weather. We had a flurry of snow today and it is expected to be worse tomorrow. He is hoping to bring my Jaguar back, but a rear-wheel drive is not the best vehicle for slippery road. I would rather he drove his Land Rover Defender.

Our Christmas preparations are almost complete. Our tree is decorated. This year our 8ft tree is replaced by a 5ft one - I was not strong enough to manhandle it. We had to buy a small table to put it on (£4 at the Salvation Army Charity Shop) and we have had fun decorating the table with soft toys (reindeer, camels, Santas and elves). Round the tree the presents have been piled. I know that I am getting an electric train set for Christmas with lots of extra track. It's like being 12 again. We also picked up a table football game from the British Heart Foundation Charity shop. With so many Charity shop bargains, nobody need be poor any more.

We plan to go to the Carols by Candlelight service on Sunday evening if I am well enough. I am listening to carols now as I am writing this - A Christmas Album from Clare College Cambridge, arranged and conducted by John Rutter. We have a sum total of 34 CDs of Christmas carols, but last Christmas because of space problems we put them away. When we came to get them out again this year we couldn't remember where. We turned the house upside down, finding all sorts other misplaced items, including dozens of board games. Eventually the carols turned up in the loft on top of the bookcase with the CS Lewis books in it.

More on 13q14

I have been promising to write something more about the 13q14 deletion in CLL. I have already visited this subject several times and claim some ownership of it since it was in my lab that it was first discovered by David Oscier. There is a good review by Ulf Klein and Riccardo Dalla-Favera in Seminars in Cancer Biology published this month and if you can get hold of a copy I would recommend reading it. Unfortunately it is behind a paywall so I will summarise what it says about 13q14.

Based on a large number of cases of CLL it has been discovered that there is a minimally deleted region (MDR) that is always gone on at least one of the chromosomes. The amount that is missing is very variable, but this MDR is constant.

So what is it that goes missing?

1] A long non-coding RNA called deleted in leukemia (DLEU)-2. This bears no similarity to any other long non-coding RNA, but it is conserved among all vertebrates.
2] The first exon of the DLEU-1 gene; another sterile transcript, but unlike DLEU2 this gene is not evolutionarily conserved.

It was later discovered by Croce and Calin that two microRNAs, miR-15a nd miR-16-1 are found within intron 4 of DLEU2 and indeed require the DLEU2 promoter region for expression.

There are two adjacent genes that have been considered as possibly being involved in CLL, DLEU5 and KCNRG, but since these are not missing in all cases and KCNRG is not expressed in B cells, this seems unlikely.

Current thinking is that the two miR genes are implicated in the pathogenesis of CLL, either directly, or through the loss of DLEU2 promoter regions or perhaps in other cases by an epigenetic switch-off. miRs work by targeting mRNA and there is no doubt from biostatistical algorithms that there are miR-15a/16-1 binding sites in a number of mRNAs involved in proliferation and apoptosis; prominent among them have been the cyclins, CCND1 and CCND3, the cyclin-dependent kinase, CHK6, and the apoptotic gene, BCL2. After a lot of technical dispute these genes may all still be candidates, and the miR genes may target multiple regulators controling the transition of G0/G1 to S in the cell cycle.

To help sort out this problem, Klein and Dalla-Favera have created a mouse model. Mouse models have been a problem for CLL and I have already pointed out the problems with the TCL-1 mouse model produced by Croce's lab. The disease that these mice produce is like an aggressive CLL, but certainly not the indolent disease that we see in most humans.

Klein and Dalla-Favera have developed two transgenic lines, one mimicking the loss of the entire MDR and the second containing a specific deletion of miR-15a/16-1 within intron 4 of the DLEU2 gene. Both mouse lines developed clonal lymphoproliferative conditions late in life - the former with a penetrance of 40% and the second with a penetrance of 25%. Most were MBL or CLL, but occasionally CD5-negative proliferations were seen including diffuse large B-cell lymphoma.

There are two points to make obout the mouse models: first they showed the same sort of sterotypy that CLL shows and second the line with the larger deletion had the more aggressive leukemias.

Another clue that they are on the right lines comes from the CLL-like disease that is sometimes seen in New-Zealand Black (NZB) mice. These CD5+ lymphoproliferations occur at a greater age than in the miR mice and are less aggressive. Three loci have been linked with their development including a point mutation close to miR-16-1.

What this all suggests to me is that the basic lesion is a loss of control of the transition from G0/G1 to S in the cell cycle because of the loss of the genes that downregulate the entry into the cell cycle. This therefore expands the mature B-cell pool. Normally, entry into cell cycle would be in response to strong antigenic stimulation, but with loss of control, weak antigens or even self-antigens might be enough. Oligoclonality leads to monoclonality and a relatively small pool of such initiating antigens leads to stereotypy. The amount of chromosomal loss determines the aggressiveness of the proliferation. The basic miR los is sufficient to set the process going, but loss of other genes (such as DLEU5 or, further away on the chromosome, Rb1 or indeed anything in between) adds aggression to the tumor. I would predict therefore that we might see a difference between CLL with the MDR alone and CLL with a larger deletion.

Monday, December 13, 2010


There is an interesting article on placebos in last week's New Scientist.

Placebos are a vital element of Randomized Clinical Trials (RCT) because the very act of seeing a doctor and being prescribed a treatment can make a patients feel better. To avoid this placebo effect, an inert substance is given to the control group. The more spectacular the placebo procedure the more beneficial the effect. The most dramatic placebo effect I have heard about is sham plasmapheresis, where a machine with many flashing lights attended by a pretty nurse, removes the patient's plasma by a sort of spin-drying effect and replaces it with donor plasma. Twenty years ago a doctor using this technique got himself on the front page of Time Magazine because of his remarkable success in alleviating rheumatoid arthritis.

Unfortunately, it was later shown that the same effect could be obtained by sham plasmapheresis, where the patient's own plasma was returned after the same dramatic procedure. Recently sham acupuncture - where no concern was made to place the needles in the Chinese meridians - was found to be equally as effective as proper acupuncture.

So not all placebos are equal was one of the messages of the article. The other was the difficulty in keeping a trial double blinded. If patients are given an inert substance as the placebo, they will soon recognize it because they will have no side effects. One solution to this is to use a placebo that gives the side effects but not the benefit. Atropine has been suggested as a placebo in trials of antidepressants since it produces the same side effects - dry mouth, headaches, insomnia and drowsiness. But would it be ethical? I don't think so.

Perhaps it would be better simply to ask the patients whether they thought they were receiving active drug or the placebo. At least then we would know the extent of the unblinding that had taken place.

Where Mad Men came from

Pursuing my hobby of watching old movies, last night I watched The Man in the Gray Flannel Suit, starring Gregory Peck. Vintage ~ 1956 and based on a book by Sloane Wilson. It was one of those Darryl Zanuck productions from the vintage years of Hollywood. It was well written, clearly spoken and with high production values in Technicolor.

Above all it was about integrity. An ordinary office worker in a safe job earning $7000 a year (those were the days) is persuaded by his financial circumstances to go for a riskier job making $10,000. He constantly has to face challenges to his integrity. By being honest he benefits even when the easy way would be to obfuscate and 'game' the situation. In this he is supported and even cajoled into honesty by his wife played by Jennifer Jones. (Minor parts are played by Fredric March, Lee J Cobb and Keenan Wynne). Then he is confronted by the fact that he has a son in Italy - the product of an illicit affair during the war. Now, there is a test for his integrity. Should he tell his wife? And if he does, how would she, who was so keen on honesty, react?

They don't make films like that any more.

Friday, December 10, 2010

A Quiet Belief in Angels

They say that you should write about what you know. When I began this novel it irritated me. It was slow to get started and read as if it were written by a young writer trying to impress his English teacher. It was about a young writer trying to impress his English teacher. Although billed as a thriller, the thrills came out so slowly that although it was a bout a serial killer, the actual murders were almost incidental. It was really about a young boy growing into a man. It was just that his rites of passage involved being witness to a young girl being raped and dismembered - at least he was the one who found most of the body.

The killing of little girls haunts him throughout his life as tragedy piles on tragedy. It begins immediately pre-war in a small town in Georgia. The description of the environment is believable to me (though who am I to judge). the author comes from Birmingham. I thought it must be Birmingham Alabama, but no, this is Birmingham, England. The novel has won many awards, but although it held my attention, it took a lot of getting in to, and the plot denouement was too obvious. In any murder mystery there must be more than one possible solution, but if all the other suspects are eliminated with 50 pages to go, it is easy to guess the killer. You could, I guess, bring in a new character, but that would be spoiling the game, but when the answer comes not from the plot, but from the number of pages left to read, it is too disappointing for words.

Thursday, December 09, 2010


I saw the oncologist today. This course I am having an extra week without treatment to allow the side effects to abate before embarking on course #6. The colic and diarrhea continued until Tuesday (day 18), so I do think it was a good idea. I am finally able to withdraw the Buscopan, so I hope my tachycardia will diminish.

Course 6 starts on Saturday and then I get a 4-week delay before course 7. After Christmas I will revert to 2-weekly courses depending on whether I can stand the side effects. We also talked about maintenance treatment. There is some evidence that this will prolong remissions, but we must decide which regimen to use. The oncologist seems to favor irinotecan at a lower dose and less intensity. We shall see.

At least he thought that this wouldn't be my last Christmas.

Monday, December 06, 2010

Big government

"Our country is too large to have all its affairs directed by a single government. Public servants, at such a distance, and from under the eye of their constituents, must, from the circumstance of distance, be unable to administer and overlook all the details necessary for the good government of the citizens; and the same circumstance, by rendering detection impossible to their constituents, will invite the public agents to corruption, plunder, and waste."

Thomas Jefferson.

And there were only 13 states then.

Sunday, December 05, 2010

Why are Americans so different?

How many civilized countries are there in the world? How do you define civilized?

There would have to be free and fair elections, freedom of speech within reasonable laws of libel and slander, freedom of religion - and that means being able to change your religion if you want to, freedom from want - not some unreachable definition of relative poverty, but sufficient access to food and shelter, equality before the law, without fear or favor, access to education. Should it include access to health care without impossible impoverishment?

By my reckoning there are very few civilized nations. There are 27 countries in the European Union - not all of them could be described as civilized, and if you added a criterion that public officials must work for the public good rather than in their own interests, then very few of them would make the grade.

Outside the EU there are Norway and Switzerland in Europe.

Outside Europe, the USA, Canada, Australia and New Zealand. As far as I can judge none of the South or Central American states would meet the standards. In Asia, Japan, South Korea and possibly Singapore would be candidates. There are small former colonies which might qualify including Gibraltar, the Falkland Islands and possibly some of the West Indian Islands. There is no African or Middle Eastern country except, perhaps, Israel that is up to scratch.

These thoughts have been prompted by an article in the New England Journal of Medicine by Victor Fuchs

From the late nineteenth Century onwards government's role in paying for health care has increased rapidly. For most relatively rich countries there is some form of national health insurance so that virtually all the population is eligible for health care by a government-organized insurance system. America is different, but even there the government's role as paymaster has increased over the past 50 years so that the taxpayer's share of the bill has risen from 20% to nearly 50% (or perhaps less, depending how you do the calculation). The Chicago school of Economics avers "If an economic policy has been adopted by many communities, or if it is persistently pursued by a society over a long span of time, it is fruitful to assume that the real effects were known and desired." In other words people get what they want despite the unplanned-for consequences.

The most obvious difference between the US and other countries is that the US spends much more on health care whether measured per capita or as a share of the gross domestic product. The US spends 50% more than the next higher spender and twice as much as the average OECD spend.

The reason for this trend is obscure, but it is probably true to say that Americans really do want the system they have rather than a 'European' one. Sure the political system is against change, and special interests have to be humored, but Mr Joe Plumber must like what he's getting. What is he getting? Instant access is one thing. There is no delay for appointments with specialists, blood tests or imaging procedures, or even for treatment. Then there are the front of house facilities. American are more likely to choose a five star hotel-like hospital with mediocre results that an 'ordinary-looking' hospital with excellent results. "I'll have my coronary by-pass with chrome fins, please."

All insurance is redistributive. Large amount of care is used by a small proportion of policy holders and is paid for by the premiums of those who use little care. The difference for a national scheme is that premiums are not assessed on the risk of catching something, but on the ability to pay. Rich people pay more taxes - unless they cheat the taxman - but tend to use the service more. In the UK, you don't get a rebate for using the private sector rater than the NHS.

So why is the US so reluctant to adopt the more redistributive model that Europe, and the rest of the Anglosphere has acquiesced to? Perhaps because America is a nation of individuals rather than communities. I notice that the watchword for most American movies is 'Freedom' whereas in British films, certainly in those made before 1950, that word was 'Service'


I haven't said anything about the cricket. For years Australia humiliated England, and even when we won at home we were thrashed away. Now having won the Ashes at home England are making mincemeat of Australia on their home turf. Australian bowlers have been abysmal and Cook, the supposed weak link in the English batting line up can't stop making runs. What I want to know is when should we start pitying the Aussies rather than crowing over them?

Saturday, December 04, 2010

Cholera in Haiti

Before the earthquake there was no cholera in Haiti. Where did it come from? According to New Scientist it came from Nepalese peacekeeping troops. Cholera, which is carried by feces-tainted water, is endemic in Nepal: there was an outbreak in Kathmandu, the country's capital, just before the peacekeepers flew in from there between 9 and 16 October. Their camp in Mirebalais dumped sewage straight into a stream that led to Haiti's main central river. The first cases were in Mirebalais and downstream, areas barely touched by the earthquake. What is more, the DNA in Haiti's cholera shows it was a single, recent introduction of a strain from south Asia.

The UN is covering up the evidence and is in denial. UN peacekeepers around the world are largely supplied by poor countries, and of the top 15 contributors, which supply 71 per cent of UN troops, 12 harbor cholera.

The do-gooders

Ian Hislop is a funny guy. Britishers will know him as the editor of the satirical magazine, Private Eye, and team captain of one side on the comedy quiz show, Have I got news for you. He is also a Christian and a Liberal Democrat, so I was not surprised to find that he had made a TV program about the Victorian do-gooders.

He began with William Wiberforce, the godfather of all do-goodery, and not strictly a Victorian, but then related the stories of many other characters, several of whom, though not all, were, like Wilberforce, Evangelical Christians.

One story that stood out for me was about the English Civil Service. Before the 1850s it was taken as read that the purpose of seeking Office Under The Crown was to feather your own nest. Any Tudor drama you may have seen will have courtiers fluttering around the monarch seeking favors. These would often be in the form of an office with a strange name like Guardian of the King's Chamber Pot or Lady of the Queen's Bedchamber, and would usually carry some land, servants and a stipend with them.

By the Eighteenth Century, these would have more believable names, but would be equally simple sinecures. I don't suppose the Warden of the Cinque Ports would have to do much wardening. (Queen Elizabeth, The Queen Mother, was the last to hold that office and was not often seen in Rye and Winchelsea).

One must, of course, provide for one's own and if you are rich enough you can do that from your own resources. We don't see Mr D'Arcy getting much involved with Hoi Polloi in Pride and Prejudice. Pembury was self contained. If you were very kindly you might show some concern for you servants (like keeping them on when your son got them pregnant), but you showed no concern for the factory workers in your mill in Manchester, nor for your slaves in Jamaica.

The French Revolution served as a wake up call. It wasn't the Scarlet Pimpernel that saved the English aristocracy, but John Wesley. Working men turned to Christ rather than Mme Guillotine. But with the writing on the wall more of the Landed Gentry got involved in politics. The English aristocracy took great pains to preserve the status quo and one of their strategies was to place duffers from their own families in The Civil Service. If you have read or watched the TV adaptation of Little Dorritt (and if you haven't, get the DVD) you will see the inertia created by duffers in the "Circumlocution Office" - code for the Treasury.

Another example cropped up in an episode of Garrow's Law (yet another BBC period drama worth watching). In this there was concern about the conditions at Greenwich Hospital, the home for retired and disabled naval officers. Food and provisions had become so poor because the Commissioners of the Hospital were sequestering the money that should have been adequate to provide all that was needed for the gallant officers, to their own accounts. It turned out that the Commissioners were all from the small town of Huntington, which just happened to be the constituency of the Earl of Sandwich, the First Sea Lord, in whose gift was the office. A 1911 report said, "It was through his [Sandwich’s] habit, already noticed, of appointing officials not for their capacity but in return for their votes that affairs had sunk into such a deplorable state. Stores supplied to the army and navy have a queer little knack of being above the market price and below the market value.”

The idea that one should seek public office for the good of the public rather than oneself was a novel one and one that has not reached many nations in the world so far - about nine out of 200 by my calculations. The recent scandals about MP's expenses indicate that the idea has not fully taken hold in the UK. The man behind the idea was Charles Trevelyan, then Permanent Secretary at the Treasury who was commissioned by Gladstone in 1853 to look into the operation and organisation of the entire Civil Service. He made 4 recommendations:

Recruitment should be entirely on the basis of merit by open, competitive examinations

Entrants should have a good ‘generalist’ education and should be recruited to a unified Civil Service and not a specific department, to allow inter-departmental transfers.

Recruits should be placed into a hierarchical structure of classes and grades

Promotion would be on the basis of merit not on the grounds of ‘preferment, patronage or purchase’

The result was a permanent impartial Civil Service, that is able to serve political parties of either or any hue, without fear of favor.

Initial reaction to the Trevelyan report was hostile and even Queen Victoria declared herself ‘horrified’ that the running of the country might be handed to ‘professional bureaucrats’. The independent Civil Service Commissioners were established in 1855, but it wasn’t until 1870 that the main recommendations of the report were put in place and that success in a competitive examination became the primary means of entry to the Service.

Charles Edward Trevelyan was born on 2 April 1807 in Taunton where his father was a clergyman. His ability to learn foreign languages resulted in his posting as a writer to the East India Company's civil service in Bengal in 1826. A year later he was named assistant to the English commissioner at Delhi. For the next four years he made it his special work to improve the living conditions of the local population and to modernise trade, by eliminating duties on internal trade.

He was assistant secretary to HM Treasury from 1840–1859, during both the Irish famine and the Highland Potato Famine of 1846-1857. In Ireland he was responsible for administering famine relief, whilst in Scotland he was closely associated with the work of the Central Board for Highland Relief. His inaction and personal attitude towards the Irish are widely believed to have worsened the Famine. To Irishmen he is thought of as the greatest villain since Cromwell. As Assistant Secretary to the Treasury he was placed in charge of the administration of Government relief to the victims of the Irish Famine in the 1840s. In the middle of that crisis Trevelyan published his views on the matter. He saw the Famine as a "mechanism for reducing surplus population". He described the famine as "The judgement of God sent the calamity to teach the Irish a lesson, that calamity must not be too much mitigated. …The real evil with which we have to contend is not the physical evil of the Famine, but the moral evil of the selfish, perverse and turbulent character of the people". While these views appeared to be mitigated in another letter dated 29 April 1846 when Trevelyan wrote: "Our measures must proceed with as little disturbance as possible of the ordinary course of private trade, which must ever be the chief resource for the subsistence of the people, but, coûte que coûte, the people must not, under any circumstances, be allowed to starve."

One wonders whether his Evangelical Christianity, some versions of which regarded the Pope as the Antichrist, led him to such a harsh judgement, for in many other ways he showed himself to be a caring man with a warm heart for the poor.

In 1858, after the Indian Mutiny, Trevelyan returned to India as governor of Madras. He was recalled after he released some government information that was deemed an act 'subversive to all authority', but he was vindicated and returned to India as finance minister from 1862 to 1865. In his later years in England, he was involved in various charitable enterprises and supported other important reforms regarding the purchase of army commissions and advancements, as well as the organisation of the army. He died on 19 June 1886.

Lesson for do-gooders: keep your mouth shut about your opinions and let not your left hand know what your right hand is doing. Good works are nothing to boast about.

Lesson for us: don't judge the activities of the nineteenth century by the standards of the twenty-first.

Friday, December 03, 2010

Watching and reading

I suppose it is 71 years late, but over the past two evenings we have been watching Gone With The Wind. It was prompted by my wife deciding to read Scarlett the fairly recent sequel to Margaret Mitchell's magnum opus. It has been about 40 years since she read the original, so the get up to date for the start of the sequel we decided to watch the movie.

It is very melodramatic of course and the acting style is dated, but I was surprised at just how good it was. Clark Gable gives a great performance, as does Olivia de Havilland. I can't get on with Leslie Howard's tedious patrician nor Vivien Leigh's spoiled brat. But the production values were superb.

We have also watched two other films from the same era, both directed by Henry Hathaway. The House on 92nd Street and Call Northside 777 were both made in a semi-documentary style on location. The first is about the immediately pre-war and wartime FBI and German spies, and the latter about a reporter, James Stewart, who seeks to right an miscarriage of justice.

These films are to be commended because of the sharpness of their cinematography, the clarity of the plot line and the effective performances of the principals. You can hear every spoken word!

I've also been reading through some books. Another Minnette Walters, The Chameleon's Shadow, is a splendid read. The protagonist is an army captain returned from Iraq terribly injured from an IED. When someone tells him he is lucky to be alive, he reacts angrily. If he were really lucky the device would have left him intact and killed someone else. His anger does not stem from his injuries, though - he can bear them - it is a broken relationship that makes him hate women.

He gets caught up in a murder mystery - three old men have been killed, at least two of them gay. This is a psychological thriller and well up to Miss Walters' usual standard. I have also read No Country for Old Men by Cormac McCarthy. I found it hard to like at first, since McCarthy is no Jane Austen. The style is strange. It reads more like a screenplay. It is almost all spoken of unspoken dialogue and there is hardly a sentence with a verb in it. In addition it is mostly in a southern Texas dialect. A young man out hunting deer comes across 8 bodies, a load of drugs and 2.4 million dollars in a drug deal gone wrong. He takes the money and runs. Big mistake. One of the characters is the most unmitigated villain I have come across yet one of the most moral. In part it is a novel about the disintegration of western society. In part it is about the integral violence of America. In part it is about the loss of religion. In the end it is a great book, but a strange one belonging to a different literary genre than most of what passes as a novel.

Thursday, December 02, 2010


The snow that has engulfed the whole east of the country reached as far west as us overnight. My daughter was with us yesterday afternoon borrowing a suitcase to take to ASH where she has a poster to present. All UK flights to Orlando leave from Gatwick and Gatwick was snowed in. Around 500 UK haematologists go to ASH, so she was in the same boat as a lot of people. She was due to fly today but the airport was still closed. Luckily, my son bought a chocolate Labrador from someone who has inside information at BA and she was able to inform my daughter that her flight would be cancelled and to recommend an alternative route via Dallas going and via New York returning, leaving from Heathrow, which was still open.

There was still the problem of getting to Heathrow from the south coast. She looked out of the window at midnight ans saw the that it was snowing very heavily; so she decided to start then and there. The journey normally takes an hour and a half, but driving conditions were so bad that it took three and a half hours. HGV drivers were behaving like madmen with no concern for other road users. One truck jackknifed, blocking most of the motorway.

She rang a few minutes ago to let us know that she was in the process of boarding her flight, so she looks like she is going to make it. I wonder how many would have given up.

We seldom have snow in Bournemouth and I thought we were going to get away with it. My other son has not been to work since returning from Italy on Monday. He is snowed in at Tunbridge Wells.

The view from my office window is stunning and it's still snowing. I reckon I have the best office view in the world. I am separated from the 18th green of the golf course by a stand of trees. In the summer there is a magnificent sycamore, several silver birches and a smattering of different conifers, yet you can still catch glimpses of the brilliant green of the golf course and the yellow sand of the bunkers. Grey squirrels are always present (even today in the snow). The highest trees are about forty feet and the tree-rats have fun as they leap the highest branches. Seldom absent are a pair of ring doves and lately we have had an ominous black crow. Pairs of magpies and jays swing back and forth across the road between our lawn and the tall trees, but our hawthorn is home to families of blue tits. I spot sparrows diving for cover beneath our yew hedge and there is always a robin around somewhere. Our blackbirds live in the back garden and rarely venture to the front.

Today in the snow, the trees are even more attractive. Normally, I would be out clearing the drive, but my wife forbade me and set out to do it herself. It was really hard work and I was chomping at the bit to go and help, but this last course of chemotherapy has been tough to bear and I am still getting side effects on day 13 - so much so that we are delaying the 6th course by a week.

I watched her manfully shovelling from my office window, and watched lots of young men, spared school, walking by throwing snowballs. I cast my mind back to my own teenage years. I would certainly have stopped had I seen a lady in late middle age shovelling snow and offered to do it for her. No doubt she would have given me sixpence and a warm drink for my troubles. What has happened to our youth?

On local TV last evening a man was being interviewed because he had cleared a hundred yards of sidewalk as a neighborly act. Astonishingly, this had made the news headlines! We are not used to bad weather in England but instead of getting off their backsides and clearing the snow, they are complaining that the local authority has not anticipated the snow and done something about it. How did we become such a dependent culture?


I have had occasion to mention the beautiful nature pictures on the Daily Mail website. Here is another of blue tits in a bird bath.

Wednesday, December 01, 2010

vitamin D and CLL

I wrote about vitamin D in January this year, but I am prompted to write about it again by the recent announcement by the Institute of Medicine that older people should take a bigger dose, and the identification of low vitamin D levels as a poor prognostic factor in CLL by the Mayo Group. A further prompt was the suggestion by my oncologist that my steroid-induced proximal myopathy might benefit from some vitamin D, and why didn't I go outside and bear my skin to the sunlight? At minus 17 degrees Centigrade?

None of this changes what I wrote about vitamin D back in January; the idea that it can prevent or ameliorate cancer is still to be formally tested.

The level of vitamin D supplement required by most people was set at 200 iu in 1997. The new recommendation is 600 iu or 800 if you are over 70.

Although we know that apart from controlling calcium metabolism, vitamin D controls over 2000 genes and interferes with the functioning of many tissues, the Institute of Medicine, an arm of the National Academy of Sciences that sets US governmental nutrient levels, said there wasn't enough evidence to prove that low vitamin D causes chronic diseases; it based its new recommendations on the levels needed to maintain strong bones alone. The panel also raised the acceptable upper limit of daily intake to 4,000 IUs for adults, from 2,000 previously.

The panel dismissed concerns that many Americans and Canadians are vitamin D deficient, noting that there is no scientifically validated level that's considered optimum. Even so, the panel concluded that for 97% of the population, a blood level of 20 nanograms of vitamin D per milliliter is sufficient. However, several major medical groups, including the Endocrine Society and the International Osteoporosis Foundation, have concluded that a level of 30 ng/ml is necessary for optimal bone health. Others have set far higher levels.

The panel was also concerned about emerging evidence of concern about possible ill effects of too much vitamin D. Besides a risk of kidney and heart damage noted with vitamin D levels of 10,000 iu per day. They said that they had seen higher death rates from pancreatic cancer, prostate cancer and other causes in men whose blood levels were above 50 ng/ml. The link is still tentative and may never be proven.

But the real concern is about serum calcium levels, which constitute a risk for everybody. High levels of calcium cause thirst, constipation, dehydration, sleepiness and coma. In diseases like myeloma and breast cancer they are recognized as medical emergencies which could prove fatal in a day or so. Other less dramatic features of a high serum calcium are deposits of calcium in soft tissues including the prostate gland and kidney. Kidney stones are a painful complication.

A high calcium can be caused by increased resorption from the bones or increased absorption from the bowel. Vitamin D controls the absorption and parathormone the resorption. The commonest abnormal finding on blood test screening is a high serum calcium, almost invariable due to secretion of parathormone by a parathyroid adenoma. I have one of these and a consequent high calcium. One of the ways that parathormone works is by converting vitamin D into its active form of vitamin D3. So some patients are walking around with high vitamin D3 levels because their bodies are mistakenly manufacturing it.

Before embarking on a megadose regime for vitamin D, always check serum calcium first.

Now, how about the Mayo paper.

They found that low levels of serum vitamin D3 were an adverse prognostic factor in CLL. In a multivariate analysis it was independent of most of the usual adverse prognostic factors for time to treatment, though not for overall survival. The study was perhaps insufficiently powered to show that.

Several reports have suggested that low serum vitamin D3 levels may be associated with increased incidence of colorectal, breast, and other cancers. One population based, double-blind, randomized placebo-controlled trial found women who increased their daily vitamin D intake by 1100 IU reduced their risk of cancer by 60-77%.

Recent data suggest low vitamin D3 levels at diagnosis may be associated with poorer prognosis in colorectal, breast, melanoma, and lung cancer, although these data have not yet been replicated in independent cohorts.

Sounds an open and shut case, doesn't it?

The problem is that association does not prove causation.

Here is another example of an association being unrelated to causation: A low Hb is a poor prognostic factor in CLL. If you correct the Hb does it make the prognosis better? Of course not! the problem is that the CLL is destroying the bone marrow; raising the Hb artificially by blood transfusion or erythropoietin won't affect that.

One possible reason for a low vitamin D3 being a poor prognostic factor is that D3 is protective against CLL and if you have low levels it roars away. But equally it may be that aggressive CLL consumes vitamin D3 and that's why the level is low. If you give more D3 you might be feeding the flames.

Generally there seems no downside to giving megadoses of D3 as long as you keep the serum calcium in check, but so far no-one has shown any benefit in CLL. The Mayo group are right to call for clinical trials

UK CLL Trials meeting

Although I wasn't well enough to attend the last Clinical Trials meeting of the UK CLL sub-group I did receive the agenda. I was impressed by the full portfolio of trials that are available for almost all categories of patients. Here is the list:

As first line treatments:

For patients considered fit for FCR there are two randomized Phase 2 trials:
ADMIRE compares FCR with FCR plus mitoxantrone and ARCTIC compares FCR with FCM plus low dose rituximab.

For patients considered unfit for FCR The current trial, having completed a phase 2 trial of chlorambucil plus rituximab, which will be reported at ASH, is CLL7 which compares chlorambucil plus or minus ofatumumab in a randomized phase 2. After this there is RiAltO which compares chlorambucil + ofaftumumab with bendamustine + ofaftumumab. NB in the chlorambucil trials the chlorambucil is given at 70mg/sq m/month.

As consolidation therapy following first line treatment, we have already completed CLL207 and we move on to CLL8 or CLARET which compares alemtuzumab consolidation with observation.

For poor risk stage A patients who would otherwise be on watch and wait there is RESPECT, which offers Revlimid in a phase 2 study.

For good risk stage A patients, based on the finding of stereotypy, CLEAR is a trial of broad spectrum antibiotics and Helicobacter elimination as a phase 2 study.

For Richter's transformation we Have a phase 2 study of CHOP + Ofatumumab.

For relapsed disease that is not refractory FC v FCO is planned.

For refractory disease or del 17p CLL210 is a phase 2 study of alemtuzumab + revlimid + dexamethasone.

For del 11q we have PiCLLe using the new PARP inhibitor (this study also includes T-PLL and mantle cell lymphoma).

The result of the Chlorambucil + rituximab trial showed an overall response rate of 82% (compared to 66% for chlorambucil in LRF CLL4 which had rather younger and fitter patients). Median progression free survival was 23.5 months - 16% better than the matched CLL4 subset.

Results from CLL207, also to be presented at ASH. 47 patients were entered and they hadhad a median of 2 prior treatments. Alemtuzumab consolidation has a bas name following the CALGB trial. In this study alemtuzumab was give between 6 and 24 months after completing induction therapy with a fludarabine based treatment. The alemtuzumab was given at a dose of 30mg sc for 6 weeks and those who were MRD positive who had shown at least a log reduction in tumor load were continued for a further 6 weeks. There were 2 treatment related deaths (1 EBV lymphoproliferative disease, 1 parainfluenza). 45% showed reactivation of CMV, but all were successfully treated pre-emptively.

Prior to alemtuzumab 24 were in CR and 23 in PR. 13 PRs converted to CR. At the end of the alemtuzumab, 39/47 (83%) had MRD negative bone marrows. 6 months later 48% of the MRD negative patients had become positive 41% remained negative. 6 months later 8/9 were still negative.

It seems that the gratest benefit is to those who become MRD negative at 6 weeks.

A rather strange trial has been adopted. This is a novel supportive care treatment called RaBaP which will be randomized against best supportive care.The drugs are Bezafibrate and medroxyprogesteraone acetate. It is suggested that these agents will stimulate bone marrow.

The final ASH abstract concerns alemtuzumab in refractory disease. We know that about half of refractory patients have del 17p and tend to respond well to alemtuzumab, but what about the non-del 17p cases. The answer is they also do well on alemtuzumab.