A woman without her man.

I have just finished reading "My Grammar and I (or should that be 'Me'?)" by Caroline Taggart and J.A.Wines. I have always liked grammar because it is full of little jokes.

Take the section on tautology, for example. What could be funnier than 'honest truth'? Dishonest truth? Similarly what nonsense are 'PIN number', 'HIV virus', 'new innovation', 'free gift', 'skin rash', 'unconfirmed rumor', '8 p.m. in the evening', 'climb up' and 'fall down'!

Indeed, the examples scattered through the pages make us want to laugh out loud.

The longest sentence in English literature is spoken by Molly Bloom in James Joyce's Ulysses. It contains 4,391 words, which makes it far too long to be quoted here, even if the subject matter were not a bit dodgy (but it is).

Note the use of the subjunctive!

As far as I am concerned, whom is a word invented to make everyone sound like a butler.

A college professor wrote on a blackboard: A woman without her man is nothing.
He then asked the class to punctuate it. All the men in the class wrote: A woman, without her man, is nothing. All the women wrote: A woman: without her, man is nothing.

A linguistics professor was lecturing to his English class.
"In English," he said, "a double negative forms a positive. In some languages, though, such as Russian, a double negative is still a negative. However, there is no language where a double positive can form a negative."
"Yeah, right," piped a voice from the back of the room.

But my main purpose of this article is a plea in favor of retaining the semi-colon, which is going out of fashion.

It is there to connect two or more independent clauses that don't quite justify being sentences in their own right. For example: 'I have tickets for the match. I bet it rains.' This is correct, but an immature, jerky style makes it unattractive. 'I have tickets for the match, but I bet it rains' is clumsy. Far better is, 'I have tickets for the match; I bet it rains.'

Semi-colons can also be used to break up items in a long and complicated list. An example from Charles Dickens's A Christmas Carol illustrates this.
'... there were bunches of grapes, made, in the shopkeeper's benevolence, to dangle from conspicuous hooks, that people's mouths might water gratis as they past; there were piles of filberts, mossy and brown, recalling, in their fragrance, ancient walks among the woods, and pleasant shufflings ankle deep through withered leaves; there were...'; I am sure you get the idea. It is especially useful when a list has too many commas for comfort.

The semi-colon is in danger of being usurped by the dash (an en-dash in British English and an em-dash in American English).

Finally, readers always like to catch out grammarians at their own game. I have found an error in this book. When talking about the apostrophe, they say that it's is only correct when it is short for it is. Not quite right. In the sentence clause 'it's been said' it's is short for it has.

Respect authority; do good. 1 Peter 2:13-17

Is our society breaking down? I remember getting the cane at school. The headmaster had made a new rule which I and several of the boys thought unreasonable. We deliberately flouted it in front of the teachers to demonstrate that whatever they said about it we didn't agree. We were not sly or underhand about it, we were not deceitful; we did not lie about it. The consequence was that we were all caned to demonstrate that there was a certain hierarchy in the school and we had to submit to it.

On another occasion a boy in my class deliberately flouted a rule that said we couldn't buy ice creams from a van parked outside the school gates. He didn't even want an ice cream; he just wanted to demonstrate that he didn't think the rule was reasonable. He too got his comeuppance.

This was back in the 1950s when society was more ordered. Today we tolerate campaigners for the environment breaking into power stations and chaining themselves to railings with their posters and slogans. We acquiesce to demonstrators shouting abuse at the police. Recently, individuals who have attempted to stop queue-jumpers or litter louts have found themselves cautioned by the police. We are supposed to allow this sort of societal disorder.

When they made the film Titanic they showed the 1st Class passengers behaving like louts, elbowing others out of their way as they made for the lifeboats and having to be restrained by a crew member firing his revolver. In fact it never happened. The 'toffs' of Edwardian society behaved impeccably, holding back to ensure that women and children were saved. Rich men like Colonel John Jacob Astor IV and Benjamin Guggenheim stood aside. Guggenheim and his manservant helped women and children into lifeboats. When all the boats had gone they changed into their best clothes and prepared to "Die like gentlemen." Astor kissed his wife good-bye as she was put in the lifeboat. Astor said: 'I resign myself to my fate' and saluted in farewell." Of the 175 male first class passengers, only 57 survived whereas 140 of the 144 women and 5 of the 6 children lived. Such acts of heroism and self sacrifice were omitted from the movie because they did not fit the spirit of the age, where only the steerage class could be heroes. A contemporary witness wrote, "A third-class passenger who tried to climb in the boats was shot and killed by a steward. This was the only shooting on board I know of." Another said, "The behavior of the men was magnificent. They stood back without murmuring and urged the women and children into the lifeboats. A few cowards tried to scramble into the boats, but they were quickly thrown back by the others. Let me say now that the only men who were saved were those who sneaked into the lifeboats or were picked up after the Titanic sank."

This sort of historical forgetfulness is an indication of how society has changed and it is with this in mind that I hesitate to open up the next passage in 1 Peter chapter 2.
Submit yourselves for the Lord's sake to every authority instituted among men: whether to the king, as the supreme authority, or to governors, who are sent by him to punish those who do wrong and to commend those who do right. For it is God's will that by doing good you should silence the ignorant talk of foolish men. Live as free men, but do not use your freedom as a cover-up for evil; live as servants of God. Show proper respect to everyone: Love the brotherhood of believers, fear God, honor the king.

Submission is not something we take easily to. In a rather strange passage in Matthew 17 (24-26) Jesus argues that sons of the king are exempt from tax. Some have argued that the sons of the King of Kings should not be under the authority of earthly kings. But Jesus has them pay the Temple tax so as not to give offence, and here Peter exhorts us to submit to earthly rulers. The authorities in Peter's day would have been Nero and Claudius - hardly benevolent dictators. In fact they were two of the most arbitrary and cruel kings that have ever lived. Yet Peter tells us to submit. We are free of earthly ties, yet for the Lord's sake we should submit. AS we proceed we will see how it is in the Lord's interest that his servants should submit.

The NIV translation here is a paraphrase. Literally, we are to submit to every 'human creation'. But the word 'creation' has within it the implication of a formed building, something constructed according to rules and physical law. Not a tumbledown shack made of grass and bamboo, but a brick built construction with foundations and perpendicular walls. Thus, the KJV has every human ordinance, the RSV and ASV and NEB 'institution' and the NIV and Good News Bible have 'authorities'. The emphasis is on an ordered society.

As members of a society, we must obey its laws. If women go to Saudi Arabia they should cover their head, not because covering the head is honoring to God, but because it is the local law and to flout authority is to dishonor God. Incidentally, we should expect Muslims coming to Europe or the US to obey our laws. There are indeed somethings in which we must choose to obey God rather than men, but we must recognise that if we do so and fall foul of what we see a an unjust law, we must accept the consequences. While we may detest abortion and we may protest against it inasmuch as the law allows, we should not break the law in our protests. By all means lobby Congress or Parliament. March or wave a placard, but don't shoot abortionists or blow up clinics.

In Ephesians 5:21 Paul writes "Submit to one another out of reverence for Christ." It is this basic politeness that is crucial to an ordered society. I once read a book about the cardinal virtues, written by an atheist. He proposed that the first basic virtue was politeness, because without it no society could exist. How can you hold a conversation unless you allow the other fellow to speak?

A child in arms who grabs candy at the supermarket checkout must submit to his mother; she must not submit to him. The meter maid who hands you a ticket when you park illegally must be submitted to. She doesn't have to submit to you. The soccer player must submit to the referee. It is positively evil when players crowd round him in an attempt to force him to change his mind. It is not that the child is worth less to God than his mother, or the motorist than Rita, or the footballer than the referee. There is a hierarchy of authority not of value. The footballer may be paid millions of dollars every year, far more than the referee, but on the pitch the player must submit to the authority of the ref.

The other night was Guy Fawkes night when we celebrate the uncovering of the Gunpowder Plot of 1605, when Catholic revolutionaries attempted to blow up parliament. With the recent scandals concerning MPs expenses where they have used taxpayers money to have their moats dredged or to build duck islands on their lakes, some have wished that Guy Fawkes had succeeded. But Parliament legitimately has authority over us. That doesn't make them better than us or of more value to God, but we have to submit to them. A famous blogger has called himself Guido Fawkes after the revolutionary bomber, but he restricts himself to lampooning the government - a legitimate tactic. We will have the opportunity to vote this government out if we disapprove of it, but blowing them up is not honoring to God. Even petty bureaucrats are part of the governing machine. Their pettifogging restrictions have to be submitted to. Protest and point out their deficiencies all you like, but in the end you must submit.

But it is more than submitting. Verse 15 tells us that it is also God's will that we do good. Why? To silence foolish men.

Have you read recently how commentators equate evangelical Christians with fundamentalist Muslims? They would not have done so in the nineteenth century, when the evangelical Christian William Wilberforce was battling to abolish the slave trade and the evangelical Lord Shaftesbury (incidentally a local family) reformed society with the Ten Hour Bill; the 1842 Mines Act; reform of the lunacy laws; abolition of child chimney-sweeping; improvements in public health and slum housing; institution of ragged schools; improvements in the the plight of agricultural labourers; and training for destitute children, when the evangelical William Booth rescued people from alcoholism and prostitution and Dr Barnardo established orphanages. Foolish men who equate suicide bombers with works of charity, selflessness and goodwill are foolish indeed.

Do we keep up the good work? Modern evangelicals sometimes criticise good works as 'the social gospel', which they despise. We do not criticise liberal Christians for their opposition to cruel regimes, for fighting hunger, disease, oppression and slavery, for their zeal in rescuing women from servitude to their husbands, children from sexual abuse, people from poverty and prisoners from torture. We approve and join them as co-belligerents against evil. No, we criticise their neglect of the gospel and their subjugation of men's souls to their bodies. It is not a question of either preach the gospel or do good works. We should do good works because of the gospel.

We are free men, but we must never abuse that freedom. We are free to do good, not to do evil. We are free from the subjection of men, but we are slaves of God. The Roman soldier had the authority to compel any citizen to carry his load for a mile, but after a mile he had no right to compel that individual further. A christian, according to Jesus, should offer to go an extra mile, not because he is a slave of the Roman soldier, but because he is a slave of Christ.

We should show respect to everyone. A story is told of a missionary waiting in his house while murdering rebels outside went through the town killing civilians for the fun of it. When the dread knock at the door came he invited them in for a meal. Because he showed them respect they left his home intact. A soft answer turns away wrath. You must have found it so. Bullies complain "He never showed me no respect!" as they shoot an adversary. Show proper respect for everyone.

But love the brethren, and fear God. Because you fear God, you will honor the king.

Other trials in CLL

I managed to attend my first Committee meeting yesterday. I went to London to meet with other CLL experts to discuss the forthcoming British CLL trials.

If anti-CD20 antibodies add so much to CHOP, CVP and now FC, does it work for other forms of chemotherapy and for other anti-CD20 antibodies? There are several trials taking place in various countries to answer these questions. One such is the use of FC plus or minus Ofatumumab. This is having some difficulty getting off the ground. It intends to recruit 352 patients from 67 centers in 15 different countries. So far it has only recruited 30 patients. In the UK this will be an unpopular trial because the F and C have to be given intravenously whereas we give both orally. Oral fludarabine has been approved for use in the USA by the FDA. Of course the oncologist is paid less for giving out tablets than for giving an infusion, so we wait to see if it will prosper.

But another reason for its unpopularity may be the phase II study organized by Genmab. Patients in this open label study were randomized into two treatment groups. Each patient was to receive one infusion of 300 mg of ofatumumab in combination with FC followed by 5 monthly infusions of either 500 or 1000 mg of ofatumumab in combination with FC. Disease status was measured every 4 weeks until week 24 and every 3 months thereafter until disease progression or 24 months. Treatment response was assessed according to the 1996 National Cancer Institute Working Group guidelines by an Independent endpoints Review Committee. Patients not having
progressed on their disease at 24 months will be followed for disease progression at 6 month intervals until 60 months.

A total of 61 patients were treated in the study. The complete remission rate was 32% in patients who received 500 mg of ofatumumab (n=31) and 50% in patients who received 1000 mg of ofatumumab (n=30). The overall response rate was 77% in the 500 mg treatment group and 73% in the 1000 mg treatment group. Although these figures age good, they are not as good as have been achieved with FCR. Now this is not a head-to-head comparison with FCR and we know that it is dangerous to compare one phase 2 trial with another, but it does look likely that FCO will not be superior to FCR, so unless it has other advantages it doesn't look to be replacing rituximab any time soon. Of course when the trials mature it may turn out to have other advantages. The problem at the moment is that FCR is going to be a hard act to beat. This is one reason for going for MRD negativity as an end-point, as this is one area where FCR might be beaten.

Yet another reason for its unpopularity is that the comparison arm, FC, is no longer standard of care. The only possible trial is FCO versus FCR which no-one is going to fund.


Two current trials in the UK which might add something are ADMIRE and ARCTIC. ADMIRE stands for ADdition of Mitoxantrone to Improve REsponse. This is a randomized phase 2 study the main aim of which is to see whether adding mitoxantrone to FCR gives a deeper response - does it produce more MRD negativity? If it does it will be exopanded into a phase 3 trial with progression-free survival as primary end-point. (Just to remind readers about trials: phase 1 determines the dose of a drug it is safe to give, phase 2 determines whether it has an effect and phase 3 determines whether it improves survival compared to standard treatment.) 218 patients recruited over 18 months are needed for the phase 2 but more will be needed if it is expanded into a phase 3.

ARCTIC stands for Attenuated dose Rituximab with ChemoTherapy In CLL. This is the trial that tests out the 'shaving' hypothesis. Is it true that most of the rituximab that we give is ineffective because the first 100mg removes the CD20 from the surface of the cells? The comparison is between FCR and FCM-miniR. The endpoints are the same as for ADMIRE and 206 patients will be recruited in 18 months. Again it will be expanded into a phase 3 trial if the response rates are equivalent to FCR. The advantage of this regimen are completely a matter of cost. It is being funded not by Big Pharma, but by the NHS to see whether there are cheaper ways of doing the same thing.

A Phase 2 study of chlorambucil plus rituximab has been completed and an interim analysis of the first 50 patients will be presented at ASH. It shows an overall response rate of 84%. Although the CLL4 trial treated rather younger patients, it had a chlorambucil only arm and the response rate for these was 66.7%. So the the next move will be a phase 3 trial looking at the effect of adding rituximab in patients treated with chlorambucil. 100 patients have been recruited in total.

A randomized phase 3 trial comparing chlorambucil with chlorambucil plus ofatumumab is recruiting well with 114 / 444 patients already recruited. A quarter of these will be from the UK.

A further chlorambucil plus antibody phase 3 study with 800 patients is about to start. It will have 800 patients and compare chlorambucil alone with the addition of rituximab or the new Roche antibody GA-101.

It looks like GA-101 and ofatumumab will be competing for the same market.

For patients who fail to achieve MRD negativity, a consolidation stage of treatment is necessary. This is best done with alemtuzumab. A Phase 2 trial is attempting to recruit 54 patients. So far 44 have been recruited and there are another 14 patients registered. The trial closes in March 2010. This is a preliminary study to determine whether using alemtuzumab in this way is safe and efficacious. Analysis of the first 24 patients showed that 18 became MRD negative. Remember a similar CALGB trial showed 5 deaths from infection with this strategy and a German trial had to be stopped because of pancytopenia. It is clear that this sort of approach is littered with danger. So far there have been two deaths in patients who didn't live long enough to get the treatment. There have been 19 serious adverse events in this trial which include a number of viral infections and reactivations. I think there was a single death from parainfluenza - always a hazard with immunodeficient patients. This trial will proceed to a randomized phase 3 comparison between no further treatment and alemtuzumab consolidation if the safety profile is satisfactory.

For the treatment of high risk disease we are looking at the possibility of alemtuzumab, dexamethasone and Revlimid. We have switched from high dose methylprednisolone to dexamethasone partly because it is oral but mainly because of glucocorticoid effects like muscle wasting and hypertension which are less with dexamethasone. The HDMP + Campath trial was presented at EHA in the summer and will be published shortly.

Another approach to high risk disease will be the combination of Revlimid and Dexamethasone without Alemtuzumab.

For patients with stage A disease we are dividing them into those with two or more adverse markers, who will be started immediately on Revlimid, even though they do not meet the criteria for treatment. For those without high risk markers they will be given two weeks of broad spectrum antibiotics against the possibility that like marginal zone lymphoma, CLL is initiated by bacterial infection.

All patients in all trials will have their cells banked and categorized according to prognostic markers. Untreated patients will be followed in the pan-European data-collection study.

Finally, for Richter's syndrome, a trial of CHOP plus ofatumumab with antibody maintenance is to be started shortly.

MRD now

In the previous article I mentioned the value of becoming MRD negative. I should stress that the method used to determine MRD negativity is crucial. Not all PCR methods or 4 color flow cytometry methods are reliable. Most people use this method . which is straightforward and reliable, having been tested in many laboratories. Please beware of tests for MRD developed locally in individual labs that have not been subjected to this many-lab scrutiny.

Yesterday, at the UK CLL Forum Clinical Trials Group we took an important step in deciding to design trials around an end-point of achieving minimal residual disease negativity. One of the real problems we have with CLL trials is that they take so long. There are currently about 1000 CLL trials going on on the world and John Byrd recently identified 107 new drugs at various stages of testing. We have already accepted progression-free survival as a surrogate for overall survival in trials, but even this means that a clinical trial takes several years to complete. Now with the German CLL8 trial demonstrating that MRD negativity is a surrogate for overall survival for both FC and FCR, we are able to shorten the time it takes to reject a new drug or drug combination very considerably. With FCR we are talking about 48% of those tested achieving marrow MRD negativity with FCR. Of course, not everybody was tested so we need the greater detail of a peer-reviewed published report rather than the answer to a question at a meeting, but the German CLL8 trial will produce a standard to be bettered by other combinations.

The other combinations might include adding mitoxantrone, substituting Ofatumumab for rituximab or indeed the new fully glycosolated antibody, GA-101. There are quite a few other agents currently being considered.

The advantages of considering MRD negativity as an end-point include the fact that it can be assessed at 3 months after (starting - sorry this is an error) completing treatment and this can be used at interim assessments which will lead to abandonment of ineffective treatment at an early stage; trial results will be reportable within 12 months of completing recruitment rather than after several years; we will be able to answer induction and consolidation questions in the same trial; and trials may well be smaller and therefore less expensive.

Potential disadvantages include failure of a clear bone marrow to reflect the presence of disease elsewhere in the body. This is certainly true in follicular lymphoma, where it is possible to have residual disease in lymph nodes and elsewhere despite having a clear marrow. This is not true for CLL, even when treatment is with Campath which is notoriously unable to clear large lymph nodes despite having spectacular success in the marrow. As far as our experience allows us to say, if there is CLL in lymph nodes it will always be detectable in the peripheral blood by four-color flow.

It is also conceivable that an agent that is active against rapidly dividing cells would both lead to the rapid clearance of such cells but also rapid relapse after treatment is finished - just because the cells were rapidly dividing. At the same time slower growing cells might not be completely eliminated by such a drug yet because they are slowly growing, relapse might be delayed. The German trial suggests that this is not a problem as MRD negativity correlates with overall survival.

This is therefore an encouraging step. It looks as though we might have a chance of testing all the potential drugs an combinations for CLL.

Who now should get FCR?

The German CLL8 trial continues to give us useful information. For the first time one treatment arm has lead to an improvement in overall survival. Previously, in, for example, the British CLL4 trial, while one of the arms (FC) showed a higher response rate and longer progression-free survival, the overall survival for the different arms was exactly the same. However, in CLL8, FCR gives a statistically longer overall survival than FC. Another gem to come from the trial is the evidence that achieving minimal residual disease (MRD) negativity is associated with longer survival no matter how it is achieved. In other words, if you got MRD negativity from FC you did just as well as if you got it from FCR - it's just that you are more likely to get it from FCR.

The third gem is that while other trials have shown the deleterious effect of having del 11q23 or an ATM mutation, FCR abolishes the ill-effect and such patients have the same survival curve as those with trisomy 12 or no karyotypic abnormality.

What does all this mean for the CLL community? I think it is now clear that if you of an age where a 10 year survival is important to you then your best chance of getting one is to be treated with FCR - provided you are robust enough to withstand the side effects. Rather than decide who should get FCR we are now trying to decode who should not.

If you are aged over 70, then FCR may not to be the way to go. It is unlikely that you will be able to withstand the whole 6 courses that give the best effect and you are likely to have co-morbidities that will make FCR too toxic. The sort of co-morbidities that I am talking about would be a degree of impairment of kidney, heart or liver, any evidence of bone marrow failure, and a history of unusual infections, in particular fungal pneumonias.

Co-morbidity is not confined to the over-70s, but it is commoner at this age.

If you have FCR you should be aiming at MRD negativity. If you don't achieve it then you should think about further treatment - likely to be one of three drugs at present: high dose steroids, alemtuzumab or Revlimid. Ideally this should be in the context of a clinical trial, because their utility in this setting is still in doubt.

The group with del 17p13 or a p53 mutation, while only 5% of those needing treatment for the first time will almost certainly fail to respond to FCR and these should have a different approach.

For the very elderly, many find that a gentler approach gives a better quality of life. Remember, that not everybody who meets the IWCLL Guidelines indications for treatment will feel ill. A lowish platelet count, a biggish spleen, a fast lymphocyte doubling time, may all be without symptoms. Even a large lymph node may cause no problems other than the fact that you notice that it is there. If you are 82 years old and quite well, why would you need a treatment that certainly involves trips to hospital and will probably make you feel unwell? At that age your life probably won't be shortened by CLL, so what benefit will you get from the treatment?

The only cure of CLL is a bone marrow transplant, but most centers would be unwilling to enroll a patients for the program who has not had FCR - unless they had del 17p13.

You may see this as a change in attitude on my part. Well when the evidence changes, I change my mind. Don't you?

Nostalgia

DO YOU REMEMBER WHEN . . . ?

All the girls had ugly gym uniforms instead of leotards?
When it took five minutes for the TV to warm up and the picture was black and white?
When nearly everyone's Mum was at home when the kids got home from school?
When all dogs were mongrels? When pocket money was a shilling (a quarter) and you'd reach into a muddy gutter for a penny?
When nylons came in two pieces and all your male teachers wore ties and your female teachers had their hair done every day and wore high heels?
When you got your windshield cleaned, oil checked, and gas pumped, without asking, all for free, every time?
And you didn't pay for air? And, you got Green Stamps to boot?
When laundry detergent had free glasses, dishes or towels hidden inside the box?
When they threatened to keep kids back a grade if they failed . . . and they meant it?
When boys and girls went steady?
When no one ever asked where the car keys were because they were always in the car, in the ignition, and the doors were never locked?
When you could lie on your back in the grass with your friends and say things like,” That cloud looks like a ..."
When you could play soccer with no adults to help kids with the rules of the game or to argue with the referee, because there was no referee?
When stuff from the store came without safety caps and hermetic seals because no one had yet tried to poison a perfect stranger?
When being sent to the headmaster’s office was nothing compared to the fate that awaited the student at home? Our parents and grandparents were a much bigger threat! But we survived because their love was greater than the threat.
When Saturday Morning Pictures showed Nancy Drew and the Hardy Boys, Laurel and Hardy, the Lone Ranger, Roy Rogers and Flash Gordon, and not extended commercials for toys?
And the long hot summers were filled with bike rides, pick-up games, Hula Hoops, swimming in the river, sucking sherbet through a liquorice straw, and sharing Tizer with your friends.

How many of these do you remember: sweet (or do you say candy) cigarettes, soda pop machines that dispensed glass bottles, coffee shops with tableside jukeboxes, penny chews, home milk delivery in glass bottles with cardboard stoppers and newsreels before the movie? How about telephone numbers with a word prefix (Mayfair 601), party lines, peashooters, home perms, 45 RPM records metal ice cubes trays with levers, carbon paper, roller-skate keys, cork pop guns, washtub wringers, reel-to-reel tape recorders, slide rules, Hornby wind-up train sets, Meccano, lead soldiers, cigarette cards, best friends, wooden dolls houses, catapults, Airfix kits and five-stones (or perhaps you called them dibs).

I remember saving a penny by walking one bus stop nearer to home and spending it on an apple. I remember when a foot of snow was a dream come true. I remember when the fat kid was always the last to be picked. I remember fixing a card to the spokes of my bicycle to make it sound like a motor-bike. I remember when you’d see soldiers in the street in uniform. I remember sitting in a pub garden drinking Vimto with the mums who were drinking milk stout while the dads were inside drinking mild and bitter. I remember Dandelion and Burdock delivered by the Corona lorry. I remember the ice truck taking two foot cubes of ice to the ice cellar belonging to the big house on the corner. I remember chimneys catching fire. I remember giving up my seat on buses to ladies and being thanked by being told she would pray for me. I remember chimney sweeps with soot-black faces. I remember holding a newspaper up against the fire-grate to make it draw. I remember second-hand bikes and hand-me-down clothes. I remember bomb sites. I remember slums.

It was a different world then – as different as the worlds of Isaac Asimov, James Blish and Theodore Sturgeon.

Drugs and scientists

Drugs are in the headlines again. Professor David Nutt, Chairman of the body advising the government on the misuse of drugs has been fired for campaigning for the legalisation of certain drugs like Cannabis and Ecstasy. He had previously advised the government that Cannabis and Ecstasy were less dangerous than tobacco and alcohol; advice which the government rejected.

The issue is a complex one. If a government appoints you to an Advisory Council, have they bought your opinion? Clearly if you worked for Roche and you went around campaigning against the use of Roche drugs, they would be right to fire you, but the government only pays you for a day a month, surely your opinion is your own for the rest of the month. No. If your opinion is different from the government's and you voice it about, then they have every right not to employ you again. Let's be clear, scientists get a lot of kudos from chairing government committees. Sometimes they get a CBE or other award for doing so. If Professor Nutt says something, nobody listens, especially with a name like that, but if the Chairman of the Drugs Advisory Council says something the Government disapproves of then everybody listens.

But shouldn't an expert scientist's opinion be listened to? I have some sympathy with this point of view. After all, science is very hard. Students study the humanities rather than science in many cases because they can't do the Math. In the humanities, as the post modernists have told us, there is no correct answer, only opinions. You can't be post-modern about 2+2=4. The problem is that scientists are human too. Science varies. Mathmatics may be very pure, but in the applied sciences intellect is contaminated by emotion. It took many years to convince people that smoking causes lung cancer. Why? Because many people didn't want to believe; they liked their cigarettes. I have no idea whether Professor Nutt smokes pot at the weekend or whether he did at University, but if he did and he enjoyed it, his way of looking at the evidence might be a bit selective.

If a new law were to take pennies from your pocket, your view of it might not be objective. Who believes the evidence of the oil companies on global warming? Who believes Greenpeace on the virtues of vegetarianism? When we look at clinical trials, we know that some trial evidence is smothered at birth because it doesn't give the answer the pharmaceutical companies wanted. So who is doing the smothering here, Nutt or Brown?

An article in today's Times suggests that Nutt hasn't done the science correctly. The author, Robin Murray, is Professor of Psychiatric Research at the Institute of Psychiatry, King’s College London and a specialist in schizophrenia. He believes that Professor Nutt underestimates the risk of cannabis users developing schizophrenia. He states, "In his lecture last week Professor Nutt contrasted a 2.6-fold increase in the risk of psychosis from using cannabis with a twentyfold increase in the risk of lung cancer if one smokes cigarettes. Unfortunately he was not comparing like with like here. The twentyfold increased risk does not come just by being a smoker but by being a long-term heavy smoker. For cannabis, the risk of schizophrenia rises about sixfold if one is a long-term heavy user."

David Nutt is also a psychiatrist, in particular a neuropsychopharmacologist specialising in the research of drugs which affect the brain and conditions such as addiction, anxiety and sleep. He is a professor at the University of Bristol heading their Psychopharmacology Unit and also holds the Edmond J Safra chair in Neuropsychopharmacology at Imperial College, London. So we have two eminent psychiatrists falling out over the effect of drugs on the mind.

The point is that psychiatry is one of those half-sciences like economics. It is still permissable to have opinions about things.

Margaret Thatcher once said, "Advisors are there to advise; it's up to politicians to make decisions." The problem arises when politicians try to wriggle out of the decisions they have made.

On the substantive issue of whether illicit drugs should be legalized there are differing opinions. Prohibition of alcohol was tried in the USA for several years and is generally held to have been unsuccessful. Supply of alcohol became criminalized and many ordinary people broke the law with impunity. Lack of respect for the law may have been a long-lasting consequence. Many argue that the same situation exists today with drugs. Supply is by criminal gangs. Much police time is spent trying to enforce the law. Prisons are filled with drug addicts. Middle class people ignore the law with impunity.

Although banning alcohol didn't work, neither did unbanning it. More people die from alcohol-related diseases than ever before. The social consequences of alcohol abuse - wife-beating, poverty, child-neglect, public order offences, violence on the streets, football hooliganism, motor accidents, murder and mayhem - are there for all to see. Tobacco consumption is decreasing, but it has taken nearly 60 years since the first evidence linking smoking with lung cancer appeared. Price hikes, advertising bans and public education campaigns have still left is with one man in five smoking.

We do not have long term studies of people who take Ecstasy or Cannabis. Although legalising drugs might have some benefits - less spread of viruses, less contamination of the drugs that addicts take and even tax revenue for the government - we really can't begin to count the downsides.

Offensive PC

A lot of comment about what gives offence recently. In general, it is good manners not to give offence unless you mean to and it is also good manners not to take offence unless a verbal slight was intended.

Recently, scriptwriters for the BBC are protesting that they are not allowed to use the phrase "Sweet Jesus" as an expletive in a sit-com. Of course, this phrase is offensive to Christians when used in this way and the BBC Trust is responding to complaints. Surely there are other phrases commonly used that do not give offence. Deliberate use of this phrase after notice has been given that it is offensive must mean that the writer intends to give offence.

I am offended my the PC use of 'partner' instead of 'wife'. I heard recently of a young widow whose husband was killed a few years ago in Iraq and had now remarried being asked at an antenatal clinic, "It is a long time since your last child; are you in a new relationship?" To her it placed her among a group of women who flitted from one man to another and she was offended by the implication.

Those anxious to be PC seem unaware of the offence they are giving. Christmas Greetings are now Seasonal Greetings or Happy Holidays! Muslims and Hindus were never offended by the Christmas holiday. They were happy to join in in many cases. I know some extreme puritans who insist that Christmas is just a Christianized pagan festival and will have nothing to do with it, but that's their choice. they certainly don't spoil it for everybody else. (At least not since Oliver Cromwell.)

So, lets have a backlash. When you spot a PC statement that offends you, don't be held back by good manners. Let them know how offensive it is. In a polite sort of way.

The Good Life - 1 Peter 2:11-12.

There is a current controversy in Norfolk. Norfolk is a very rural county. Apart from in the county town of Norwich, most people seem to be engaged in agriculture and even the local football team is nicknamed "The Tractormen". It is one of those places about which townies make lewd jokes suggesting that there are a lot of brother-sister marriages. The implication is that people who live there are a few ants short of a picnic in their mental capacity. It is said that when a cerebrally challenged child is admitted to hospital, the doctors talk about it as NFN which stands for "normal for Norfolk". These slurs are, of course, completely untrue, but are typical of metropolitan prejudice.

The problem is that the local Conservatives have selected a parliamentary candidate with a reputation. In 2005 she was in the newspapers having conducted an extra-marital affair with a Tory MP. Following this exposure she returned to her husband while the MP divorced his wife and has since remarried. Now, she has since been selected as a parliamentary candidate, but her selection has now been challenged on the grounds that she never told the selection committee of her former indiscretion. Since this is the first thing that comes up when you Google her name, one might argue that the omission was that of the selection committee rather than hers, but the bigger question is should it count against her that she has been an adulteress?

On Jeremy Vine's Radio 2 program, a discussion took place on the merits of the case between Iain Dale, a well known blogger and Anne Atkins, a well known columnist. These two come from widely different backgrounds. Dale is gay, and his stand is libertarian, Atkins is the wife of a Church of England vicar and stresses 'family values'. Should a Christian protest at the morality of our elected representatives? The argument is that if you can't trust them to keep a solemn vow made before God at their marriage, how could you trust them with their electoral promises? The counter argument is, shouldn't a Christian be willing to forgive an adulteress, just as Jesus did in John chapter 8?

In 1 Peter 2 verse 11, the apostle begins to tell us how we should live in the world we are in. He writes to Christians, not to pagans. He tells us that we are aliens and strangers in the world. "Dear Friends" as the NIV translates it is too weak. "Dear loved ones" would be nearer. He is assigning us to the team made up of those for whom Christ has died. And though we are loved by Christ we are not playing at home; we are the away team. We are aliens and strangers in the world.

Go to any Premier division football match and you will understand what this means. Among a crowd of 50,000 you may be among 1000 cramped in the visitors' enclosure. Even the word 'enclosure' makes you sound like an animal in a zoo. You are certainly treated like one. The majority in the crowd sing their chants at you, mocking you and making you feel small. They are trying to intimidate you. But minority that you are, you are still part of a team. You sing back, determined not to be silenced. Imagine yourself to be the one Spurs supporter sitting among the Arsenal fans. You would certainly keep quiet. When they sang "You're not singing any more!" it would be true for you. But here in the visitor's enclosure you are among friends, your team is all around you. Though you may be a minority you are encouraged by their presence. Your church may be a minority in your town, but you have colleagues who are covered by the same insignia.

Elijah was alone. He had defeated the prophets of Baal, but then he had run away, and here beneath the Juniper tree he was all by himself, afraid and in despair. When he finally is confronted by God at Horeb, he is told, "I reserve 7000 in Israel - all whose knees have not bowed down to Baal." He is not alone. He is part of a team with a captain who cannot be defeated. Go to Spring Harvest or Keswick. Feel the strength of the team around you.

Fighting Mike Tyson must be one of the most intimidating things in the world. Evander Holyfield did it twice. He is the only man to have won the world heavyweight championship four times. Holyfield claims to be Christian. He has "I can do all things through Christ who strengthens me" embroidered on his fight dressing gown. As he trained for the fight he had sparring partners who mimicked Tyson's style. He was determined in his training.

We have to be determined in our training to live the Christian life. We have to abstain from sinful desires that war against our soul. We are waging a war against sin, not against sinners. Were it against sinners we would have to fight our friends, because the one criterion for becoming a Christian is to be a sinner. All those without sin need not apply. Christians are not defined by what they do not do. The reason we have something to say to the world is that we are sinners just like them. Our only difference is that someone has fished us out of the water. Those sitting wrapped in a blanket at the bottom of a lifeboat have no sense of superiority over those still in the sea. Our only plea is "Save them too!"

Not all desires are sinful. Sex is a wonderful gift from God. It is not sinful so long as it is confined to marriage and used to reinforce the structure of the family. It is a sin to misuse it. How destructive it can be when it is misused! To earn money is not a sin, even if you earn a great deal of it. But to use it to puff ourselves up and to oppress others is sinful. From him to whom much is given, much will be required. It is not a sin to live in a big house; but what an opportunity to give hospitality! Do you have a big car? The more people you can take to church.

Anne Atkins was wrong to expect the Tory candidate to live up to Christian standards unless she had been a Christian. People who live in the world of politics don't do God, said Tony Blair's presence on Earth, Alistair Campbell. We have no right to hold the world to account. The world will do worldly things. Being a member of the Church of England, Anne probably assumed that every English person is also a member unless specifically opted out. In that case they should behave like Christians. It is a delusion. We Christians are few in England today.

Our ambition should be to live such good lives among the pagans that, though they accuse us of doing wrong, they may see our good deeds. To what end? So that they may glorify God on the day that he visits us. To do that they will have to change before he returns for there is no mind changing after death.

Evander Holyfield claimed to be a Christian, but then it comes out that he had 5 kids out of wedlock with 4 different women; that he had been 'healed' by televangelist, Benny Hinn, who received an alleged $265,000 “donation” for the healing; that he has been linked to alleged usage of performance enhancing drugs; that his house is 54,000 square feet with 104 rooms and a bowling alley and that he has failed to pay child support for one of his 9 kids.

Live such good lives among the pagan...

Iain Dale was also wrong to assume that a Christian must be all forgiving. The offer of forgiveness is there from God. Sufficient grace is available. No more restitution needs to be made to God. No more bulls to be slaughtered or lambs killed. All that is needed is repentance. "Neither do I condemn you," said Jesus, "go and sin no more."

He wants a God who:
Shows complete, benevolent blindness
To our foibles.
Who does not notice when we err.
Forty-winks at deviation,
Falling short or reprobation.
Wouldn’t make a fuss
About us.

Because we stress the forgiveness of God, the world thinks that God doesn't mind sin. Because we stress the love of God, the world things that God is not also terrifying. Because Jesus told us in the Sermon on the Mount to "judge not that ye be not judged", the world thinks that it will not be judged on the last day.

We must expect the world to accuse us of doing wrong. How could it not when the world operates according to a different set of principles to us. We will not convince the Dawkins of this world by the force of our arguments. Few have been forced into heaven by the weight of logic. But many have looked at the likes of John Newton, William Wiberforce, Eric Liddell and others and asked, "What have they got in their lives that is missing from mine?"

We don't do good works to make us feel good, to repay the Lord for what he has done for us, to satisfy our conscience, to earn merit or to impress other Christians. We want to glorify God and have others do so too.

Th17 cells

I can well remember when immunologists did not know what the lymphocyte did - our anatomy professor was certain that they turned into red cells. I remember the excitement when Roger Taylor and others set about separating lymphocytes into T cells and B cells. It wasn't long before T cells were divided into helper cells and cytotoxic cells. Then more recently T helper cells were separated into Th1 which helped the cellular immune response and Th which helped the antibody response.

I was sitting in a lecture 10-15 years ago when I heard Ethan Shivak explain that there was a regulatory T cell that was CD4+, CD25+ (and later FOXP3+). Well more recently three more types of T cells have been described: Th17, Tfh and Th. A recent review of T cells can be found here .

Th17s are cells that produce interleukin (IL) 17A, IL-17E and IL-17F. These are pro-inflammatory cytokines. They also produce IL-21 and IL-22. What are they for? They seem to be involved in fighting off certain unusual infections. For example, Th17 cells have been suggested to contribute to the resistance to Listeria, Salmonella, Toxoplasma, Cryptococcus, Leishmania and Francisella. A significant and specific role for the Th17 response has been shown for Klebsiella infection in the lung, intravenous Candida albicans infection, and infection of the natural rodent pathogen Citrobacter rodentium in the gut. In addition, the preferential production of IL-17 by T cells during infection with Bacteroides fragilis, Borrelia burgdoferi, Mycobacterium tuberculosis and fungal species suggests that Th17 responses are triggered by specific pathogens and are required for their clearance. Older readers may recognise that some of these these are important in immunodeficient individuals.

In addition to controlling infection, Th17 cells play an important role in autoimmunity. IL-17 expression has been associated with autoimmune diseases such as multiple sclerosis, Rheumatoid Arthritis, psoriasis and Inflammatory Bowel Disease, as well as with allergic responses. In particular, Th17 cells are critical for the development of experimental autoimmune encephalomyelitis and an experimental Rheumatoid Arthritis, whose development was originally attributed to Th1 cells before the discovery of Th17 cells.

How are Th17 cells produced? We know that TGF-β and IL-6 act together (and both are necessary) to commit naive T cells to develop into Th17 cells. and MyD88-dependent signaling, which proved to be IL-6. TGF-β alone tends to favor the production of Tregs but the addition of IL-6 redress that tendency and pushes the cells toward Th17 development.

IL-23 and IL-21 are cytokines shown to be important for Th17 differentiation. IL-23 is currently thought to be critical for promoting the survival and proliferation of differentiated Th17 cells. IL-23 uses one of the same chains as IL-12 and in some respects as reciprocal activity. It binds to the IL-23R complex composed of IL-12Rβ1 chain and a novel receptor chain (IL-23R) related to IL-12Rβ2 and gp130. Jak2/Tyk2-STAT1, 3, 4, and 5 are involved in its intracellular signal transduction. In contrast to IL-12, IL-23 predominantly activates STAT3, but not STAT4.

IL-21 is an IL-2 family member that was recently found to be highly produced by Th17 cells. IL-21 can substitute for IL-6 to induce Th17 cells along with TGF-β. IL-21-activated signaling pathways critical for Th17 differentiation and its biological function under physiological and pathological conditions remain to be established.

Retinoic acid-related orphan receptors (ROR) are the key transcription factors in Th17 differentiation.

Soon after the discovery of Th17 cell scientists wanted to know how it related to other Th cells. Based mostly on the studies in vitro, Th17 and iTreg were found to be mutually exclusive. Following activation in the presence of TGF-β, CD4 T cells differentiate into Foxp3-expressing iTreg without IL-17 expression. However, if IL-6 is also present, activated CD4 T cells deviate to Th-17 cells without Foxp3 expression. The mechanism of such a mutual exclusion could be owing to Foxp3 expression in iTreg and ROR-t expression in Th17 cells. It appears that high-level Foxp3 expression leads to the repression of ROR-t and thus Th17 differentiation, and ROR-t expression inhibits Foxp3 and prompts IL-17 production.

Recently, emerging evidence suggests that under certain conditions, seemingly committed T cells possess plasticity and may convert into other types of effector cells. Tregs can become Th17 cells in the presence of activated inflammatory Dendritic Cells through the action of IL-6. Seemingly fully differentiated Th17 cells were also shown to convert into Th1 cells in the absence of TGF-β.

I suggest a good read of the article I cited if you want to find out about Th9 and Tfh cells. indeed it will bring you up to date on T cells activity.

Falkirk Wheel

The year 2000 marked the end of the second millennium since the supposed date of the birth of Christ. The British government set aside money from the National Lottery for several engineering works to mark the year. The best known is the Millennium Dome in London's east end, but there are others. Today I came across one I had not heard about, The Falkirk Wheel . What I like about it is that it uses engineering principles from Archimedes and cost only $25 a day to run.

P53 explored

Of all the malign features of CLL, damage to the p53 pathway is the most serious. Most drugs used in CLL work by invoking the p53 pathway to destroy the CLL cells. A recent paper in Blood has examined the p53 pathway in patients entering the German CLL2H trial.

In this trial patients who required treatment but were refractory to at least one fludarabine containing regimen were treated with subcutaneous Campath. Tests were done to determine whether the patients had a loss of part of the short arm of chromosome 17 (where the p53 gene resides) or if the p53 gene was mutated or if the p53 was functionally intact by generating p21 after irradiation of the CLL cells.

The study asked two main questions: 1]what is the contribution or p53 pathway defects to fludarabine refractory CLL? and 2]what are the clinical implications of
p53 mutations in the setting of fludarabine refractory CLL treated with Campath?

The answer is that 36% of those with fludarabine refractory CLL do not have a defect in the p53 pathway. Only 32% of the patients had del 17p. 37% had mutations of the p53 gene. Most of these (68%) were in patients who had lost 17p, but the other third were in patients whose FISH test did not give any warning of fludarabine refractoriness. In other words looking for p53 mutations in patients who are refractory to fludarabine and will uncover another 12% who have a defect in the p53 pathway. Or put it another way, 18% of those who do not have del 17p will have a p53 mutation. Or if you like, 44% had a defect of p53. In addition, 19% had an 11q deletion, which leaves 36% with no obvious poor risk factor. (Note that the German CLL8 trial - which obviously came after this one - shows us that del 11q patients can be brought back into the standard risk fold by using FCR rather than FC).

So what happens to patients who are refractory to fludarabine when they are treated with Campath? Thew answer is that they don't do all that well. The average survival is about 18 months. This trial showed it to be worse for those with p53 mutations (13 months against 21 months) but this was not statistically significant - they would have needed to study more patients to be sure. Time to treatment failure was the same for both groups which tends to suggest that those without mutations will respond to something else for a while. What can be said is that despite all this, about a quarter of those with p53 mutations were still alive at 4 years.

Don't get confused; the mutations I am talking about in this article are nothing to do with the mutations of the IGHV genes that I normally write about.

My health once more

Sorry for the silence. We have been under the influence of the electrician who has been rewiring the house. There have been a few technical hitches that have needed sorting, but I trust that all is now working.

Our church has been holding an evangelistic outreach and on the last day I was interviewed on how I became a Christian, how I faced my cancer, and why bad things happen to Christians.

For those who haven't found how I became a Christian, you can read about it on this blog at http://mutated-unmuated.blogspot.com/search?q=how+i+became+a+christian .

When I first heard that I had got cancer I was shocked and frightened. I was also in considerable pain. My post-operative course was rocky and yet I was able to be content. a verse of Scripture cam to me "Thou wilt keep him in perfect peace whose mind is staid on thee." I put everything else out of my mind and just thought about what the Lord had done for me. There was a time when I thought that I would die in hospital, but that passed and I gradually recovered.

Because I had such a slow recovery from the post-operative ileus, the surgeon was keen to start chemotherapy as soon as possible. I think he half believed that it was the cancer that was stopping my bowel working properly. Perhaps I started too soon. The chemotherapy was difficult to bear. At first I thought that I would have a few days of ill health followed by a recovery period in which I would be able to live normally. In fact, although I was able to cope with nine courses of treatment, they came every second week and I had no time to recover before the next course was due. for much of the 20 weeks of treatment I was confined to the sofa, too sick to do very much. Even walking across the road left me breathless and exhausted.

I spent a lot of the time in Bible study and prayer and I was encouraged by the hundreds of people from all over the world who sent messages of encouragement. I even managed to write a couple of hymns, although I couldn't have found the energy to rewire a plug.

Since the chemotherapy was completed a couple of months ago I have gradually improved. I have had some problem with my tummy, and of course, being a doctor, I have easily found symptoms to indicate that the cancer has returned. I presume that the symptoms have other causes since my weight is increasing and my appetite has improved. Gradually the symptoms are abating.

The worst problem has been the neuropathy caused by the Oxaloplatin. This mainly manifests as numbness and tingling in my hands and feet. There is some difficulty in doing up shirt buttons and tying shoelaces, but I manage. A less well recognised side effect is autonomic neuropathy. This means that the function of the nerves that go unnoticed is affected. My blood pressure has fallen. Previously I had to take blood pressure tablets, but even having stopped them my pressure is so low that in Germany (where low blood pressure is recognised as a disease) I would be given stimulants to raise it. The autonomic neuropathy also affects the temperature control of my hands so that I have to wear gloves on quite warm days, and it affects the motility of my bowels. It is this latter affect that can easily be confused with a return of the cancer. I have a CT scan again in a couple of weeks so this should give me an insight into whether I am right in my diagnosis.

In a couple of days I will make my first trip to London to examine a PhD. This will be a significant milestone for me.

BNP - the TV debate.

Last night on Question Time, Nick Griffin, leader of the British National Party, appeared for the first time. The audience was packed with his opponents, rent-a-mob besieged the BBC studio and four panelists appeared with him, all strongly opposed to his views.

Griffin is reputedly a fascist, yet his party won two seats at last year's European Elections and many councillors at local elections. I am not a BNP supporter.

As I have posted before, I supported the BBC in giving him the opportunity to present his views. In fact they had no choice. Their Charter demands that they be impartial and in the past they have given a voice to the Green Party, George Galloway's Respect Party and to UKIP, all of which are parties with a small and patchy following, that have won seats in Europe.

In the 1930s Oswald Moseley split from the Labor Party to form the British Union of Fascists, which allied with the Nazi Party in Germany and fought pitched battles on the streets of London with those on the Left. After the war, this brand of politics was taken up by the League of Empire Loyalists and then by the National Front. In the 1979 general election, the National Front polled 191,719 votes, 0.6% of the vote overall. Although it still exists, its current membership is 150. Nick Griffin is a former national organizer of the National Front and claims to be moving the British National Party in a more moderate direction. In the 2005 general election the BNP polled 0.7% of the total vote, but in 2008 got 5.2% of the votes in the London Mayoral election and in the same year had 2 MEPs elected and many local councillors to bring their total representation locally to 56 seats. The also have one of the 25 seats on the London Assembly. The BNP has increased its electoral influence despite well documented instances of racism, homophobia and antagonism to Islam. The general public has not been deterred from voting for them.

The rise of the BNP has been attributed to many factors. The scandal about MPs overclaiming expenses sowed distrust among voters for mainstream politicians, the recession has led to unemployment so that workers have become obsessed by immigrants 'taking our jobs', immigration has definitely increased leading to predictions that Britain's population will go from 60 to 70 million in the next 20 years, there is widespread discontent that even those illegal immigrants who are caught are seldom deported to their country of origin and the Labor government seems to keep no record of whether those on temporary visas (visitors of students) ever return to their own countries. Finally Europe is a dirty word to most Britons and many are angry that the promised referendum on the Lisbon Treaty never emerged, despite it being a Manifesto commitment by New Labor.

The TV program proved a disappointment. No political issues were discussed; instead the BNP was attacked for its previous statements (some of them mythical) rather than its present policies. Griffin was not a smart performer and some of his unpleasant beliefs were drawn out of him, but the atmosphere of intimidation was such that some will undoubtedly have felt sorry for him. One Afro-Caribbean member of the audience came over as a coherent and eloquent defender of Black Englishmen who was proud of his country and the same could be said of a South Asian who spoke with a London accent.

Griffin got in one barb at Jack Straw, the Labor Minister for Justice, by pointing out that Griffin's father had fought the Nazis in the RAF, while Straw's father (though part-Jewish) had registered as a conscientious objector. Had he wished to be nasty he could have had fun with Straw's previous views as a Marxist and with his son's conviction as a drug dealer. Griffin himself has been accused of inciting racial hatred but was not convicted of it when tried.

The only question that did not attack the BNP was "Is the rise of the BNP due to to government's handling of immigration?" The audience certainly thought so.

In summary, a debate on the BNP should certainly be held. There are issues which the main parties are afraid to approach for fear of being thought racist, homophobic or anti-Islamic. Many people are anxious about the loss of English cultural identity. Politicians are distrusted as self-serving crooks. A change of government is coming, but may be elected on a diminishing plebiscite which will allow minor parties undue influence.

The Crusades

When I was young I used to read about the Crusades in the way I used to read about Biggles. While Biggles was shooting down the Hun, Richard Coeur de Lion and Ivanhoe were cutting down the Infidel in Palestine. Revisionist historians have cast Biggles as a warmonger and Palestinian Muslims as victims. Just how correct are these recent pictures of what went on?

Were the Crusades the brainchild of an ambitious Pope or rapacious knights intent on booty? Hardly. They were a response to more than four centuries of conquests in which Muslims had already captured two thirds of the old Christian world. If you read about Paul's missionary journeys you will find that Christianity had spread from Jerusalem to Judea and Samaria, then on to Asia Minor and thence to Europe. It quickly dispersed throughout the Roman Empire. But here's the point: Christianity was not spread by armed force; it spread by word of mouth and the evidence of changed lives.

In contrast, Islam was born in war and grew the same way. From the time of Mohammed,
Muslim expansion was always by the sword. In a manner reminiscent of Hitler's Blitzkrieg, beginning shortly after the death of Mohammed, the warriors of Islam struck out against the Christians . Palestine, Syria, and Egypt - once the most heavily Christian areas in the world - quickly succumbed.

By the eighth century, Muslim armies had conquered all of Christian North Africa (where St Augustine had been bishop) and even into Spain. In the eleventh century, the Seljuk Turks conquered Asia Minor. Go to Capodocia in modern Turkey and see where the Christians were driven from their homes to live in caves. The Muslim invasion is sometimes regarded as just a fact of history while the Christian response is vilified as full of atrcoities, cannabalism and brutality. In my opinion this is a false antithesis. The Muslim invasion was brutal as were the Christian crusades; but many of the stories are exaggerated and some are entirely mythical.

At some point, European culture had to defend itself or be subsumed by Islam. The Byzantine Empire - the eastern half of the Holy Roman Empire was reduced until little more than Greece remained. In desperation, the Emperor in Constantinople sent word to the Christians of western Europe asking them to aid their brothers and sisters in the East. One factor that contributed to the decision in the West to respond to that request came from an incident in the year 1009, when the Fatimid Caliph al-Hakim bi-Amr Allah ordered the destruction of the Church of the Holy Sepulchre. In 1039 his successor, after requiring large sums be paid for the right, permitted the Byzantine Empire to rebuild it. Pilgrimages were allowed to the Holy Lands before and after the Sepulchre was rebuilt, but for a time pilgrims were captured and some of the clergy were killed. Destruction of the Holy Places and the murder of pilgrims gave an incentive that was not easily resisted.

The Muslim conquerors eventually realized that the wealth of Jerusalem came from the pilgrims and with this realization the persecution of pilgrims stopped. However, the damage was already done, and the violence of the Seljuk Turks became part of the concern that spread the passion for the Crusades. By the time the first crusaders arrived in Jerusalem persecution of pilgrims had long stopped but of course in those days there was no 24-hour news service.

In retrospect, we can see the slow corruption of the Christian church, which probably dates from the conversion of the Emperor Constantine, which led to the identification of the spiritual with the secular power. The church grew rich and powerful with positions of authority in the church being given to relatives of the secular rulers. The people were sold myths and bribed or frightened into obedience. People who are coerced into one faith can easily be coerced into a different one when the balance of power changes.

Recently the war in Yugoslavia saw a sort of re-enactment of the crusades. The Roman Catholic Croatians were set against the Greek Orthodox Serbs, who clashed with the Muslim Bosnians; yet as was stated by a UN general on the spot; racially they are all Serbs.

Jesus never endorsed war of any physical kind. "My Kingdom is not of this world," he said, "If it were, my servants would fight." He repudiated Peter's sword thrust to take off the Temple servant's ear. "All who draw the sword will die by the sword." Yet he realised that his message would lead to battles. "Do not suppose that I have come to bring peace to the earth. I did not come to bring peace but a sword." His message would set people against people. Because some would reject his message there would inevitably be conflict. In preparation for that conflict he advised his disciples "If you don't have a sword, sell your cloak and buy one." Yet when the disciples volunteered, "See, Lord, here are two swords," he was quick to reply, "That is enough."

I interpret that as his saying my kingdom is to be spread by word of mouth, not by violence, but such will be the opposition from unbelievers that you will need to defend yourselves. The Apostle Paul, gives us an example of someone who uses the secular law to protect himself when as a Roman citizen he is arrested in Philippi and when brought before the Roman authorities in Jerusalem he appeals to Caesar (who as he tells us in the letter to the Romans, 'bears the sword' for the protection of those who have not broken any law).

Pope Gregory VII struggled with reservations about the doctrinal validity of a holy war and the shedding of blood for the Lord and had, with difficulty, resolved the question in favour of justified violence, especially given the fact that the pilgrims to the Holy Land were being persecuted. Saint Augustine of Hippo, Gregory's intellectual model, had justified the use of force in the service of Christ in The City of God, and a Christian "just war" in defence of the sacred sites in Palestine might well be contemplated. As it happened it was Gregory's successor who initiated the First Crusade.

Looking back we can see other considerations that may have weighed with the papacy, though how much is difficult to be sure of at this distance. The Christianization of the Vikings, Slavs, and Magyars, had produced a large class of armed warriors whose energies were misplaced fighting one another and terrorizing the locals. The Christian princes of northern Iberia had been fighting their way out of the mountains of Galicia and Asturias, the Basque Country and Navarre, with increasing success, for about a hundred years. The fall of Moorish Toledo to the Kingdom of León in 1085 was a major victory and an obvious sign that the Muslims could be defeated. The Norman adventurer Robert Guiscard had conquered Calabria in 1057 and was holding what had traditionally been Byzantine territory against the Muslims of Sicily. The maritime states of Pisa, Genoa and Catalonia were all actively fighting Islamic strongholds in Majorca and Sardinia, freeing the coasts of Italy and Catalonia from Muslim raids. It appeared the tide was turning and there seemed to be a possibility of ending the schism between the eastern and western Christian church.

However, trying to apportion blame for the Crusades is a lost cause. Just try reading the Wiki article and then click on the areas that are disputed. At the time of the crusades many of the cities of Palestine, such as Antioch, had a mainly Christian population. The stories of atrocities cannot be referenced to first-hand sources and have the stench of propaganda about them. Undoubtedly there were atrocities on both sides and no Geneva convention applied. It is futile to look at past wars through the eyes of Amnesty International.

The end of the Crusades at the end of the fifteenth century did not signal the end of bloodshed. France and England had already given up crusading and were fighting each other and after the Turks were held back at the gates of Vienna, Muslims went back to fighting each other too. Religious wars continued, pitching Catholic against Protestant and Sunni against Shiite.

The word 'Crusader' has perjorative overtones for Muslims but quite the opposite for Christians. To say the crusades, a multi-century initiative by Europe, was either "good" or "bad" raises the question of "for whom?" Without the Crusades, Europeans might still being counting using Roman numerals! We might have lost Aristotle for another few centuries. The Crusades prevented further Muslim expansion into Christian territory (on as great a scale as had previously been seen) for hundreds of years; good for Christians: bad for Muslims. It is too simple to sum up with "good" or "bad". Any historian who does so is almost automatically biased.

What gives offence.

Following on from the last post, I have tried to imagine what sort of things I would like people arrested for because they have offended me. Here is a random list.

Bad language - not only the words employed to describe sexual and excretory functions but particularly "Jesus" and "Christ" used as expletives, and when I am in a bad mood, grammatical solecisms, misplaced apostrophes and interpolated aitches at the beginning of the word 'aitch'.

Homosexual activity in public places. Come to think of it, heterosexual activity in public places. No snogging in church!

Bullying, particularly racist bullying, whether it be white on black or black on white or black on Asian. But not just racism. Bullying of girls by boys, women by men, the old by the young, the poor by the rich, the ugly by the beautiful, workers by management, homosexuals by heterosexuals, red-haired people by those with other hair colors, and vice-versa for all of these categories, since we should never assume that bullying is always one-way.

Cheating. I am offended by those who dissemble to obtain benefits that they are not entitled to as well as those who fail to pay their taxes; by those who call a ball 'out' when it is 'in' at tennis, who feign injury in football, who claim a catch in cricket when they know it had already hit the ground before it ended up in their hands, who land low-blows in boxing, who use hands in the ruck in rugby, by card sharps, hucksters, charlatans, scientific frauds, adulterers and advertisers of face creams (no, you're not worth it).

Arrogance. This is a major temptation in everyone who is powerful including politicians, physicians and preachers.

Rudeness. In a way this is a form of bullying. You can either be rude back which is bad manners or you can cower under it, which means you are being bullied. In Western culture it is rude to hide your face in public. Whether you are wearing one of those all-over crash helmets, a balaclava or a niqab, it is impolite to wear one in Western society unless you are riding a motor cycle or robbing a bank. It is only because correcting people in public is regarded as rude that you haven't be told before.

In religion I am offended by baptismal regeneration, papal infallibility, the idea of Mary's immaculate conception or bodily assumption, the idea of priests as a separate category of Christians, drawing attention to yourself by waving your hands in the air, the prosperity gospel, denying the communion table to anyone who is not a member of your group, denial of the existence of either hell or heaven, lack of generosity, the idea that you can work your way to heaven, the denial of the deity of Christ, the creation of sainthood as a special category of 'super Christians', the worship of many gods, atheism, deism, denial of the resurrection of Christ, deliberate distortions of the Trinity, female circumcision, jihads and suicide bombers.

You might think I am easily offended.

Free speech

There is a row in the UK at the moment about freedom of speech. Two incidents have triggered it. The first was the decision of the BBC to invite Nick Griffin, the leader of the British National Party, to appear on their flagship political program, Question Time, and the second was an article in the Daily Mail about the death of a pop singer.

The British National Party (BNP) is the spiritual descendant of Oswald Moseley's pre-war fascists. They wish to preserve Britain from immigration, particularly from those whose skin is of a darker hue. They draw their support from the white working classes who have traditionally supported the Labor Party.

Overt racism is, of course, denigrated in Britain and the BNP have tried to distance themselves from that charge. Recent mass immigration to Britain has come from Poland, the Baltic countries, Romania and Bulgaria, all countries with white populations (though Romanian gypsies, a persecuted people in their own country, are somewhat swarthy). There are certainly racists among BNP members, though their electoral support - they have two members of the European Parliament and many local councillors - does not imply more than a million racists in England. They have been campaigning on the dilution of British "Christian" heritage and the intrusion of traditions from other countries, particularly Muslim countries.

Certainly a large number of immigrants have entered Britain, putting strain on the NHS and education system. Many of the immigrants have been illegals - Commonwealth citizens outstaying their visitor or student visas, Afghan and Iraqi men hitching a lift under trucks on ferries and trains from France, Chinese peasants packed 57 deep into secret compartments in trucks, and many foreign nationals taking part in fake marriages to British citizens. Although the number of black and Asian immigrants does not constitute anything like the proportion of non-whites to be found in America, being less than 10% of the population, they tend to be concentrated in certain areas, particularly in London, around Manchester and in midland industrial towns like Leicester.

With the recession it has been fairly easy to blame the immigrants for difficulties in finding a house, large classes in schools where few speak English, loss of jobs, and long waiting times in hospitals. The Unions are in decline and the Labor Party is in disarray. Consequently, many of the white working classes find the BNP an attractive home.

Another factor has been the pushing of political correctness by New Labor. To be blunt, the working man has been given to making offensive jokes against foreigners, homosexuals, vicars and Manchester United supporters ever since I worked in a factory some 50 years ago and probably before that. I honestly don't believe he meant any harm by it. Anybody from the Indian subcontinent was called "Paki" to his face, any Afro-Caribbean individual was called "Darkie", any Scot "Jock", any Welshman "Taffy" and any Irishman "Paddy". Though not that common, anyone from Eastern Europe was known as "Boris". These were terms of affection. I realise that in other strata of society these words may be offensive, but to be culturally sensitive you have to be sensitive to all cultures including that of the white working class. It is this neglect of this political base by New Labor that has allowed the BNP to flourish.

Apparently the singer from Boyzone was in a homosexual relationship. He died at a very young age on a Spanish holiday island from pulmonary edema. This is very unusual, though one does see it in young athletes because of an unsuspected cardiac condition. Given the reputation of pop singers one would immediately suspect that drugs might have been involved and as I understand it the toxicology report is not in yet. The Daily Mail columnist, Jan Muir has caused offence by suggesting that the man's lifestyle precipitated his early death. I have no idea whether she is right as I know nothing about his lifestyle. He does not seem to have died from AIDS or hepatitis, two diseases commoner among homosexuals, and I have no idea whether he fitted into the stereotype of people in his profession in overindulging in drugs and alcohol. However, writing an article in Britain's most popular daily newspaper that besmirches the reputation of a popular entertainer who has just died was, as Sir Humphrey used to put it on 'Yes Minister', courageous.

Stephen Fry, the comedian and presumed polymath, who himself has had an irregular lifestyle, has orchestrated a protest on Facebook to try and get Jan Muir dismissed (though the Daily Mail is probably revelling in her notoriety). Some 21,000 letters of protest have been received. Peter Hain, ex-minister in the Labor government who came to fame as a protester against Apartheid in South Africa, and himself forced to resign over financial irregularities, has been campaigning to get the BNP uninvited from Question Time. It would be surprising if either of them succeeded. The principle is one of free speech. In the UK no-one is prevented from speaking their mind unless they incite violence. Even minor violence is tolerated (viz. the recent occupation of a coal-fired power station by green campaigners). It is generally thought that unsavoury people will condemn themselves out of their own mouths.

One of the tenets of the politically correct is that a racist or homophobic remark is regarded as such if the object of the jibe feels offended by it. This is such utter nonsense as to be untenable. People take offence at imagined slights. There are many things that offend me but no-one is prosecuted. One law for one section of society and a different law for another? It won't do.

The Wire

What does a retired university professor do with his time? He certainly spends a lot of time on the Internet reading the newspapers and his favorite blogs. He answers the telephone and fends off people who want to sell him insurance, double glazing, new kitchens and magazine subscriptions. He goes supermarket shopping with his wife. He has a break for coffee mid-morning and a break for tea mid-afternoon. He does at least 6 crosswords a day with his wife. He tries to write something on his blog. He listens to some music - keen on adagios at the moment. He puzzles over Bayesian statistics. He sporadically polishes brass doorhandles and fits new toilet seats. He edits his journal. He reads. Currently, in various degrees of the partially read are Planet Narnia, Terry Pratchett's Unseen Academicals, Keller's The Reason for God, My Grammar and I, The Saga of the Sydney Opera house, CS Lewis's The Discarded Image, David Wilkerson's Man Have I Got problems, FF Bruce's Men and Movements in the Primitive Church, Alec Moyter's Look to the Rock and Assist Me to Proclaim, the Life and Hymns of Charles Wesley.

And he watches television. My purpose in this blog is to review The Wire.

Claimed by some to be the best show on television for a decade or more, most Christians would avoid this show like the plague. The language is revolting and there are lurid sex scenes that would be a temptation for many. So this series comes with a health warning.

That said, I have watched all five seasons with the subtitles turned on, mainly because the African-American patois was unintelligible to me, but also because you need to know what is being said to follow the plot.

On the other hand this work of fiction is extremely moral. It teaches us that the heart of man is desperately wicked. Corruption permeates every element of society. It begins by showing how drugs have wormed their way into the fabric of society, so much that for portions of the community drugs represent the basic way of making a living. The drug culture is steeped in crime with murders and beatings being the commonplace consequence of imagined slight. The cops have the closest contact with the drug world, and guess what the cops are corrupt, indeed all branches of law enforcement: judges, lawyers, prosecutors, prison staff are all corrupt. The ordinary working man in the docks is corrupt; he also drinks too much. The church is corrupt. The schools are corrupt, the politicians are corrupt, the newspapers are corrupt.

There are some people who honestly want to make a difference. We see a couple of policemen who have been sidelined because they were incorruptible. We see a politician who really cares about his community. We see a police lieutenant who wants to police the city correctly, we see a newspaper man who not only understands the rudiments of grammar but also believes in the truth. But what happens is you either play the game or you die (or at very least are demoted). An ex-killer starts a boxing gym to attract young blacks away from drugs. He is kneecapped for his trouble. A teacher wants to befriend his pupils in order to teach them the basics of reading, writing and arithmetic. He is bullied into teaching to the test, supplying them with model questions and answers that will closely resemble the test. A honest editor wishes to expose a reporter who is fabricating stories; he is demoted. A senior policeman cuts crime by isolating the drug trade to a deserted area and turning a blind eye to drug supply to addicts. It allows social workers to get into help the addicts. The politicians find out and he is demoted, losing pension. Two honest cops game the system to get funds they have been denied to catch multiple murders. Politicians and senior policemen, themselves up to their elbows in muck discipline the cops and then take personal credit for the success. The DA cuts a crooked deal with a crooked defence lawyer to allow the prosecution of murderers to go ahead.

We are left with a straight policeman who is already compromised by youthful indiscretion and by an adulterous affair resigning from the force rather than join in the morass of decay.

The acting and production values are superb, but how people need a savior!

New ways of doing trials

I met Eli Estey on a trip to MD Anderson in Houston. I found him to be a charming and thoughtful guy. He has now moved to the 'Hutch' in Seattle and has penned an interesting article entitled "Do commonly used clinical trial designs reflect clinical reality?" in the journal Haematologica.

We normally rely on randomized phase III clinical trials which compare two treatments using endpoints like overall survival, progression-free survival or time to next treatment. We rely heavily on p<0.05 which means that there is less than a 1 in 20 chance that any difference between the two could have occurred accidentally. In other words we are pretty sure that any positive result is not a false positive. In leukemia trials there is a tradition, which comes from St Jude's Memphis, that we inch forwards in our improvements. Childhood ALL is curable in the majority of cases. Treatment involves the use of several drugs in a particular order over a couple of years. Successive trials made small changes to the protocol that gave small improvements in survival. In order to be sure that these small improvements were not false positives the trials needed to utilize large numbers of patients so that a 'p' value of <0.05 could be obtained. Childhood ALL trials started with drugs that gave a high rate of complete remissions (vincristine and prednisone) so there was a good chance that adding more chemotherapy would improve things, but not by much. Hence, it was necessary to be certain that adding these new drugs did make a difference and were not false positives.

With adults, the problem is not that we are doing pretty well already, but that we don't cure very many at all. Therefore, our problem is not that we have too many false positives; it is that there may be drugs out there that help, but we reject them because we have too many false negatives.

The cure rate for CLL and adult AML is so poor that we are not really interested in drugs that make a small difference - we want agents that make a big difference - we should be willing to accept a higher risk of a false positive.

When trials are designed the numbers needed in each arm are partially determined by the power calculation. Traditionally an 80% power is required. What does this mean? It is actually the false negative rate. It means that one trial in five is discarding a treatment incorrectly because the negative answer was a false one.

Estey argues that this way of doing things is not clinically relevant. On the contrary there have been quite massive improvements in adult leukemia that did not come from these sorts of trials at all. He cites the value of imatinib in CML, CDA in hairy cell leukemia, arsenic trioxide and ATRA in acute promyelocytic leukemia and high-dose ara-C for core-binding factor AML as examples where the effect was so large that it didn't need an enormous trial to detect its value.

I raise this problem for CLL recently in this way. John Byrd recently reported that there are 107 different agents being studied at teh preclinical and clinical level for teh treatment of CLL. The typical phase III trial in CLL requires 800+ patients. There are simply not enough patients to test all those agent singly let alone in combination. WE must find a better way of doing things.

The better way that Estey proposes is the use of Bayesian statistics. Thomas Bayes (c. 1702 – 17 April 1761) was a British mathematician and Presbyterian minister, known for having formulated a specific case of the theorem that bears his name: Bayes' theorem, which was published posthumously. I have read the paper several times but I am none the wiser. Would someone please explain Baysian statistics to me.

The Bridesmaids