Here is the attraction of stem cell transplants: they cure people. Here is the problem with stem cell transplants in CLL: they kill people. Full blown transplants for any condition are of dubious value; they work best for people under the age of 20. Hardly anybody has CLL under the age of 20 – my youngest patient was 21. The older you get the worse the problem – the total body irradiation and the high dose chemotherapy are so toxic that even the best centers in the world struggle to keep anyone over the age of 50 alive after that insult, and even 50 is stretching it. The one disease where standard transplants were absolutely the treatment of choice was chronic myeloid leukemia (CML) – until imatinib (Glivec or Gleevec) came along. When Glivec became available for CML hardly anyone continued to transplant patients over 30, even though it seemed that 10% of patients had relapsed after Glivec after the first year. Nowadays CML doctors like to confine transplants to patients under 20.
Since half of patients with CLL are aged 70 or over when they present, you can see that there was very little call for transplants in CLL. There are some younger patients of course, but the toxicity of the treatment in these was still very great. Treatment-related-mortality (defined as deaths in the first 100 days) was 40% even in the best centers.
Then along came reduced-intensity-conditioning (RIC). The idea works like this: if you have an autograft – that is your own bone marrow stem cells are taken out and frozen down and this is followed by strong chemo- or radiotherapy, after which the stem cells are returned – you get the same dose of chemo- or radiotherapy as when you are having an allograft (where the stem cells come from somebody else. Theoretically this should be better (I certainly thought so in the 1980s) since there is no bother with the immunological consequences of someone else’s bone marrow growing inside you. However, when you look at the long term consequences, for most diseases patients having allografts survive for longer than those having autografts.
There must be something special about an allograft that an autograft hasn’t got. And what could it be except that those very immunological effects that we were worried about? These immunological effects weren’t rejection (which is the problem with kidney transplants or heart transplants), but quite the reverse. The graft tries to reject the patient! This graft-versus-host disease (GVHD) can be very unpleasant. Mild acute forms just have a bit of a rash, particularly on the palms and soles, which fades after a while, but severe forms have a rash that scales and won’t heal, diarrhea that won’t stop and severe liver damage. It also damages the immune system making rotten infections more likely. With chronic GVHD the skin becomes fixed to the underlying tissue so that its like walking around in a suit of scar tissue, with loss of hair and teeth. I’ve seen an 18-year old looking like an old man of 80. I have also had patients kill themselves because their condition was intolerable. But within the GVHD there is also a graft-versus-leukaemia (GVL) effect and it is this effect that can really cure disease that doesn’t respond to anything else.
In fact it’s not the chemotherapy that cures you with an allograft, but the GVL effect. So why have the chemotherapy? Rainer Storb at the Hutch in Seattle was the person who realized this and put it into practice. Using immunosuppressive drugs rather than marrow ablative drugs an allograft can successfully be transplanted, and because the damaging chemo- or radiotherapy is not used you can give it to older patients. But you still have the GVHD problem to contend with. Usually this is done with immunosuppressive drugs after the transplant like ciclosporin and methotrexate, but one thing that has been tried for a long time is T depletion. This simply means removing the T cells from the graft. It is a very effective way of getting rid of GVHD, though if too many are removed the patient rejects the graft. The problem is that getting rid of GVHD often means getting rid of GVL, so although such grafts are safer, they are usually less effective and patients start relapsing. Theoretically, Campath ought to be a more efficient way of T-depleting because not only does it get rid of the T cells, it is also an anti-CLL drug and will get rid of any residual disease. As we saw yesterday, Campath does exactly this. Much less GVHD, but more relapses than not using it. Nonetheless, still pretty good long term survivals.
As it happens, another paper was published in the Journal of Clinical Oncology in October last year from Seattle. 82 patients aged between 42 and 72 who had CLL no longer responding to fludarabine were treated with a RIC allograft between 1997 and 2006. The conditioning regime was low dose total body irradiation (200 centiGray) with or without fludarabine. 78 patients still had measurable disease when transplanted; only four has no detectable disease. So what happened to them? Let’s take the four already in remission: one died of relapsed leukemia, two died of treatment complications while in complete remission and on remains in complete remission. But no-one should read into this that if you are in CR and have a RIC transplant you have a 75% chance of dying. The numbers are just too small to know. The next 50 patients might all survive.
What about the other 78? 55% got a complete remission and 15% a partial remission. Remember these were patients who did not respond to fludarabine, so getting any sort of remission is remarkable. There is a sort of randomization going on here, between those who have a matched sibling donor and those who don’t. Interestingly, the chance of getting a complete remission was significantly greater in those who didn’t. This suggests that a matched unrelated transplant has greater immunological power at killing the CLL than a sibling transplant.
Of the 41 patients who achieved a complete remission, 30 are still alive in CR, 8 died of the complications of the transplant and 3 relapsed (one of these still alive the other two now dead). Of the 13 who achieved PR, 4 are still alive and in PR, 3 died of the complications of the transplant and six developed progressive disease (4 of these dead, 2 still alive in PR after treatment with Campath or Rituximab). In addition there were four who died of transplant complications before their response could be assessed, three who had stable disease, two of whom died of transplant complications and one who remains alive with stable disease. 17 patients had disease progression despite the transplant; 14 of these have died of progressive disease and three are alive after antibody treatment.
To summarize all this: 23% died of the complications of transplant, 38% progressed, and the actuarial survival at 5 years was 50%, while progression-free survival was 39%.
There were no significant differences for any of these 4 measurements between those who had a sibling and those who had a matched unrelated transplant, nor between those who had their transplants at Seattle compared to those who had theirs with the same protocol at a sister organization. However, the numbers are relatively small and ‘no significant difference’ doesn’t mean ‘no difference’; it just means there were not enough numbers to demonstrate a difference. In any case even if there were differences, unless the trial was designed to look for differences, any that were found would be examples of data dredging. Data dredgers always find differences one in 20 dredges because ‘significance’ is defined as p<0/05.
Grade 3 and 4 GVHD was found in 16% of those having a sibling transplant and 23% of those with matched unrelated transplants. However, bad chronic GVHD was worse, occurring in 49% of related and 53% of unrelated transplants. The transplant-related causes of death were as follows: acute GVHD 5, chronic GVHD 6, bleeding from the lungs 1, stroke 1, cardiac arrest 2, lung cancer 1, sepsis 2, multi-organ failure after cardiac surgery 1.
A lot of factors did not affect the outcome including age, donor type, CD34+ cell dose, CD3+ cell dose, CD38 positivity, cytogenetics, splenomegaly, or time between diagnosis and transplant. The following did influence outcome: lymph nodes more than 5 cm in diameter and co-morbidities. In a univariate analysis heavier marrow infiltration, higher beta-2 microglobulin levels and higher white counts added to the prognosis but these were subsidiary to the large lymph nodes in a multivariate analysis.
What we learn from today’s posting is that RIC transplants extend the age range where transplants become a possibility, and the toxicity of the chemo-radiotherapy is removed, but people still die and/or suffer from having a transplant. The major reason for this is GVHD.
What we learned from yesterday’s posting is that we can reduce GVHD by removing the T cells with Campath. But when we reduce the graft versus host disease we also reduce the effectiveness of the transplant.
As I said at the beginning; the attraction of a transplant is that it cures. The problem with a transplant is that it kills.
Friday, January 30, 2009
Wednesday, January 28, 2009
Should I go for a transplant?
Should I go for a transplant or not? This is often a difficult question for patients with CLL. Until recently the answer was, “Not if you can avoid it,” but since the introduction of reduced intensity conditioning regimens, toxicity has been reduced and the age range for which allografting is contemplated has increased. The question has to be asked anew, and to help us with that a series of 62 patients with CLL has recently been published by a consortium of doctors from Britain and Spain.
This is not a clinical trial. Although there were two cohorts of patients, there was no randomization. It was a retrospective look-back at experience between 1999 and 2007. Four institutions were involved, and patients who were eligible were generally young, with disease refractory to chemotherapy or in early relapse, and/or had poor risk cytogenetics. All the patients had reduced intensity conditioning with fludarabine and melphalan. The results were analyzed according to whether the patient had had alemtuzumab (Campath) for prevention of graft-versus-host disease (GVHD). Unfortunately, the categories were not clean cut, which probably explains why the paper has been published in a relatively obscure journal (Biol Blood Bone Marrow Transplant 2008; 14:1288-97). In the first cohort, 40 patients received ciclosporin and alemtuzumab to prevent GVHD. The dose of alemtuzumab was 100mg given over 5 days from day -8 to -4; but 8 patients received only 60mg, 3 received 40mg, 2 got 30mg and 5 had 20mg. In the second cohort, patients with a sibling donor with a complete tissue match were given methotrexate as well as ciclosporin while those with matched unrelated donors received mycofenolate mofetil (MMF) with their ciclosporin. In addition, two patients with 1 locus mismatched unrelated donors also received anti-thymocyte globulin.
The characteristics of the two cohorts were not significantly different, though with numbers this small that statement may be meaningless. The median age at transplant was 53 (range 34-64) and 73% were male. Transplantation took place at a median of 55 months after diagnosis (range 5-132 months).
Since this was not a randomized trial, differences in outcome between the two cohorts, or indeed similarities could be due to a whole host of different causes other than the treatment protocol. The comparisons therefore cannot be used for anything other than hypothesis generating. Bearing that in mind, how did the two cohorts compare? There was no significant difference between them in terms of overall survival. For both cohorts there seems to be a plateau at 60% alive extending out from 3 years to nine years when nobody died. But the numbers are so small that this cannot be said to be predictive of what would happen to you.
In terms of progression-free survival there is again no significant difference between the cohorts, but whereas the non-Campath cohort seems to have a plateau at 50% non-progressive after 3 years, the Campath group continues to relapse. Again, because the numbers are so small this is not a statistically significant difference, but it is what you might expect – if you wipe out more of the T cells, you are more likely to relapse.
Another consequence of wiping out all the T cells might be failure to engraft. The incidence of mixed donor chimerism (this means that you have a mixture of the donor cells and the patient’s own cells) at 6 months was significantly greater in the Campath cohort (43% v 11%; p=0.03), however, most of these attained full engraftment following donor lymphocyte infusion (DLI) and the incidence of secondary graft failure was the same in both cohorts (12% v 9%).
Acute graft versus host disease was not significantly different in either cohort (37% v 57%; p=0.18) though this could be a type II error where you don’t have enough patients to detect a difference. Similarly with severe acute GVHD, 20% is not significantly different from 38% with such low numbers (p=0.14), though GVHD that didn’t respond to treatment with steroids was significantly more common in the non-Campath cohort (10% v 33%; p=0.03). Chronic GVHD was greater in the non-Campath cohort 68% v 29%; p=0.016) and extensive chronic GVHD needing systemic rather than local therapy was also greater (48% v 10%; p=0.03). Mortality from GVHD was also greater in the non-Campath cohort (33% v 10%; p=0.034)
Severe infections were common in both cohorts (73% v 67%; not significant) and 18% died of infection which was often related to GVHD. There was no difference between the two cohorts. As might be suspected there were a lot of viral infections in patients who received Campath – herpes simplex in 7, EBV in 6, adenovirus in 5, RSV in 4, influenza in 3, zoster in 2, and metapneumovirus and parainfluenza each in one. CMV reactivation occurred in 66%, neither for viral infection nor CMV reactivation did the excess in the first cohort reach statistical significance. Again, this is probably because the numbers were so small. Fungal and bacterial infections were equally distributed between the cohorts.
To summarize, reduced intensity conditioning has extended allografting into the CLL community by raising the age of eligible patients. It becomes an immunologic treatment where the graft attacks both the CLL and the patient. Reducing the number of T cells in the graft diminishes both attacks. GVHD is a dangerous thing to have: it can kill you directly, it can make infection more likely and it can make life not worth living. Getting rid of T cells (which is what Campath does) reduces the amount of GVHD but also reduces the attack on the CLL. So if you use Campath you have less GVHD but also you are more likely to have residual leukemia. Less T cells also means less able to fight virus infections, and although some of these can be withstood by other means (ganciclovir for CMV, rituximab for EBV) others can’t be resisted.
So it’s swings and roundabouts; you gain on one and lose on the other. This study identifies the problems, but because it is not a randomized prospective trial it can’t weigh up the relative risks.
This is not a clinical trial. Although there were two cohorts of patients, there was no randomization. It was a retrospective look-back at experience between 1999 and 2007. Four institutions were involved, and patients who were eligible were generally young, with disease refractory to chemotherapy or in early relapse, and/or had poor risk cytogenetics. All the patients had reduced intensity conditioning with fludarabine and melphalan. The results were analyzed according to whether the patient had had alemtuzumab (Campath) for prevention of graft-versus-host disease (GVHD). Unfortunately, the categories were not clean cut, which probably explains why the paper has been published in a relatively obscure journal (Biol Blood Bone Marrow Transplant 2008; 14:1288-97). In the first cohort, 40 patients received ciclosporin and alemtuzumab to prevent GVHD. The dose of alemtuzumab was 100mg given over 5 days from day -8 to -4; but 8 patients received only 60mg, 3 received 40mg, 2 got 30mg and 5 had 20mg. In the second cohort, patients with a sibling donor with a complete tissue match were given methotrexate as well as ciclosporin while those with matched unrelated donors received mycofenolate mofetil (MMF) with their ciclosporin. In addition, two patients with 1 locus mismatched unrelated donors also received anti-thymocyte globulin.
The characteristics of the two cohorts were not significantly different, though with numbers this small that statement may be meaningless. The median age at transplant was 53 (range 34-64) and 73% were male. Transplantation took place at a median of 55 months after diagnosis (range 5-132 months).
Since this was not a randomized trial, differences in outcome between the two cohorts, or indeed similarities could be due to a whole host of different causes other than the treatment protocol. The comparisons therefore cannot be used for anything other than hypothesis generating. Bearing that in mind, how did the two cohorts compare? There was no significant difference between them in terms of overall survival. For both cohorts there seems to be a plateau at 60% alive extending out from 3 years to nine years when nobody died. But the numbers are so small that this cannot be said to be predictive of what would happen to you.
In terms of progression-free survival there is again no significant difference between the cohorts, but whereas the non-Campath cohort seems to have a plateau at 50% non-progressive after 3 years, the Campath group continues to relapse. Again, because the numbers are so small this is not a statistically significant difference, but it is what you might expect – if you wipe out more of the T cells, you are more likely to relapse.
Another consequence of wiping out all the T cells might be failure to engraft. The incidence of mixed donor chimerism (this means that you have a mixture of the donor cells and the patient’s own cells) at 6 months was significantly greater in the Campath cohort (43% v 11%; p=0.03), however, most of these attained full engraftment following donor lymphocyte infusion (DLI) and the incidence of secondary graft failure was the same in both cohorts (12% v 9%).
Acute graft versus host disease was not significantly different in either cohort (37% v 57%; p=0.18) though this could be a type II error where you don’t have enough patients to detect a difference. Similarly with severe acute GVHD, 20% is not significantly different from 38% with such low numbers (p=0.14), though GVHD that didn’t respond to treatment with steroids was significantly more common in the non-Campath cohort (10% v 33%; p=0.03). Chronic GVHD was greater in the non-Campath cohort 68% v 29%; p=0.016) and extensive chronic GVHD needing systemic rather than local therapy was also greater (48% v 10%; p=0.03). Mortality from GVHD was also greater in the non-Campath cohort (33% v 10%; p=0.034)
Severe infections were common in both cohorts (73% v 67%; not significant) and 18% died of infection which was often related to GVHD. There was no difference between the two cohorts. As might be suspected there were a lot of viral infections in patients who received Campath – herpes simplex in 7, EBV in 6, adenovirus in 5, RSV in 4, influenza in 3, zoster in 2, and metapneumovirus and parainfluenza each in one. CMV reactivation occurred in 66%, neither for viral infection nor CMV reactivation did the excess in the first cohort reach statistical significance. Again, this is probably because the numbers were so small. Fungal and bacterial infections were equally distributed between the cohorts.
To summarize, reduced intensity conditioning has extended allografting into the CLL community by raising the age of eligible patients. It becomes an immunologic treatment where the graft attacks both the CLL and the patient. Reducing the number of T cells in the graft diminishes both attacks. GVHD is a dangerous thing to have: it can kill you directly, it can make infection more likely and it can make life not worth living. Getting rid of T cells (which is what Campath does) reduces the amount of GVHD but also reduces the attack on the CLL. So if you use Campath you have less GVHD but also you are more likely to have residual leukemia. Less T cells also means less able to fight virus infections, and although some of these can be withstood by other means (ganciclovir for CMV, rituximab for EBV) others can’t be resisted.
So it’s swings and roundabouts; you gain on one and lose on the other. This study identifies the problems, but because it is not a randomized prospective trial it can’t weigh up the relative risks.
Tuesday, January 27, 2009
The Placebo Effect
Penicillin was a wonderful discovery. Before that doctors had very few medicines that worked - morphine, aspirin, digoxin, ether, chloroform, atropine, adrenaline, cocaine, and very few others. Penicillin opened the door to a huge pharmaceutical revolution that continues to this day. Despite this, there have been doctors around for thousands of years. Whatever did they do?
Their practice was very similar to that of the purveyors of alternative medicine today. First, they had a uniform. It differed from age to age, but when I was young it included a frock coat, top hat and arrogant affect. Later doctors had white coats and other paraphernalia. Nowadays it is likely to be surgical scrubs.
Second, they had equipment. To be honest it is very hard to distinguish the various noises heard down a stethoscope - chest physicians always believe the X-ray rather than their 'tubes' and cardiologists want an ECHO whatever their stethoscope tells them. Anyone other than an ophthalmologist looking with an ophthalmoscope is probably making it up, and ophthalmologists prefer to use a slit lamp.
Third, they had a ritual. Part of this is the medical examination. We hospital doctors are apt to scoff at general practitioners who don't examine their patients, and certainly the physical is good for some things. I once was referred a case of anemia to investigate by a consultant surgeon. Imagine his embarrassment when I stuck a finger in the rectum and detected a stonking great, bleeding carcinoma. Most complicated is the neurological examination with its reflexes and finger-nose pointing. But whenever a neurologist came to see one of my patients the first thing he would do was ask for an MRI scan, no matter what we had found on examination.
The physical examination is of absolutely no use when performed by a junior doctor. They do not have sufficient gravitas. The examination should be undertaken with a serious face at a deliberate pace, with pauses for reflection and many a "Hmm" interspacing the touching. "Say '99'" is a wonderful device; it shuts the patient up and adds a sense of mystery. It is very important that the patient completely disrobes. Stethoscopes poked through a gap in the clothing do not have the same therapeutic effect.
Ritual is very important. The consultation should always begin with the doctor rising to greet the patient. Hand shaking is very effective even if it does spread germs. Eye contact is good. Taking the history well is more important than anything and it is vital to let the patient tell his or her story in his or her own words. Leading the witness misleads the physician. It is important to get the story right, but of even more meaningful is the process of instilling in the patient the feeling that he or she is of value and worth listening to. Without the enormous modern medical bureaucracy the doctor of old had time to listen and put the patient at ease.
Never let anyone tell you that alternative practitioners have nothing to offer. Of course their oils and needles have no therapeutic effect, vast doses of vitamins and strange diets are completely useless. Enemas are good for constipation and colonic washouts are useful as preparation for colonoscopy, but they incorporate no magic cures. A recent study demonstrated that acupuncture needles stuck in the wrong places were as effective as needles stuck in the proper meridians - but they were effective. Just as doctors in the 1930s were effective. They all make use of the placebo effect.
'Placebo' is Latin for 'I please'. The placebo effect is what happens when a doctor goes through all the ritual of diagnosing and treating a patient and prescribes colored water. Although this sounds like deceit and fraud, the fact is that a proportion of patients will get better from whatever they are suffering. Ye, whatever they are suffering from. You might well expect a response from patients with chronic fatigue or headaches or backache, but placebos can heal up ulcers, abolish angina and even produce remissions in cancer.
Studies have been done on the placebo. Two pills are better than one. Injections are better than pills. Green pills are better than red ones, unless you are looking for a stimulant effect when red or orange ones are best. It is even possible to cure nausea by instilling a drug designed to make you vomit, directly into the stomach if you are able to convince the patient that what you are giving is an anti-emetic rather than an emetic.
You may believe that you are immune to the placebo effect, but if you are then why do you buy branded painkillers rather than straight ibuprofen. I know they work better but why? Because of the placebo effect. And they cost more. That's part of the placebo effect; expensive placebos work better than cheap ones.
Back in 1972, that sensible physician Richard Asher (yes, he was Jane's father) wrote, "If you can believe fervently in your treatment, even though controlled tests show that it is quite useless, then your results are much better, your patients are much better, and your income is much better too. I believe this accounts for the remarkable success of some of the less gifted, but more credulous members of our profession, and also for the violent dislike of statistics and controlled tests which fashionable and successful doctors are accustomed to display."
The problem with placebos is that they involve lying to patients. Placebos don't work if you say to a patient, "I'm giving you a sugar pill. There is absolutely no reason why it should make you better except for the 'placebo effect' which no-one understands but it probably acts psychologically." Or do they? A trial of sugar pills for pain that had been diagnosed as 'neurotic' was carried out at Johns Hopkins Hospital, with just such an explanation. The patients improved considerably.
Never apologise, never explain, goes the old adage. But we can't get away with that these days. We are obliged to tell patients the truth and to explain fully what we are about to do. The Philosopher and doctor Raymond Tallis has written, "The drive to keep patients fully informed has led to exponential increases in the formal requirements for consent that only serve to confuse and frighten patients while delaying their access to needed medical attention."
Alternative practitioners are not burdened by the same restrictions. They can look into your eyes and give you an explanation that sounds sciencey, but is in fact gobbledygook. Watch the TV for adverts for anti-aging creams to see what I mean by sciencey.
Actually, I think it is possible to invoke the placebo effect without telling lies and good doctors do it all the time. After I retired I handed on my patients to other physicians. I was surprised at how many of them promptly died. There was no change in treatment, only a change of treater. One patients illustrates the case starkly. She had cancer of the body of the uterus. She had refused surgery, chemotherapy and radiotherapy and all I did was see her, take a blood test and talk to her. I was astonished that her cancer did not progress. It remained static for three years. Then I retired and six months later she died. Somehow she had fixed on me as a walking placebo.
It should be possible to say to a patient without too much mendacity, "We have exhausted the latest treatment - we must now start thinking for ourselves. This is a concoction that I have tried before in cases like yours and it sometimes works. I don't know how it works - I could make up a scientific sounding explanation if you like - but I won't insult your intelligence. It is important though that you take it in the way that it is prescribed. You must take it on an empty stomach (and here you can invoke any ritual you think they will wear - standing on one leg, facing Mecca, drinking out of the back of the cup or prunes for breakfast) and I will see you every week if you can afford it. Unfortunately, it's not cheap, but if it works it will certainly be worth it."
Some of these people could sell snow to the Eskimos.
Their practice was very similar to that of the purveyors of alternative medicine today. First, they had a uniform. It differed from age to age, but when I was young it included a frock coat, top hat and arrogant affect. Later doctors had white coats and other paraphernalia. Nowadays it is likely to be surgical scrubs.
Second, they had equipment. To be honest it is very hard to distinguish the various noises heard down a stethoscope - chest physicians always believe the X-ray rather than their 'tubes' and cardiologists want an ECHO whatever their stethoscope tells them. Anyone other than an ophthalmologist looking with an ophthalmoscope is probably making it up, and ophthalmologists prefer to use a slit lamp.
Third, they had a ritual. Part of this is the medical examination. We hospital doctors are apt to scoff at general practitioners who don't examine their patients, and certainly the physical is good for some things. I once was referred a case of anemia to investigate by a consultant surgeon. Imagine his embarrassment when I stuck a finger in the rectum and detected a stonking great, bleeding carcinoma. Most complicated is the neurological examination with its reflexes and finger-nose pointing. But whenever a neurologist came to see one of my patients the first thing he would do was ask for an MRI scan, no matter what we had found on examination.
The physical examination is of absolutely no use when performed by a junior doctor. They do not have sufficient gravitas. The examination should be undertaken with a serious face at a deliberate pace, with pauses for reflection and many a "Hmm" interspacing the touching. "Say '99'" is a wonderful device; it shuts the patient up and adds a sense of mystery. It is very important that the patient completely disrobes. Stethoscopes poked through a gap in the clothing do not have the same therapeutic effect.
Ritual is very important. The consultation should always begin with the doctor rising to greet the patient. Hand shaking is very effective even if it does spread germs. Eye contact is good. Taking the history well is more important than anything and it is vital to let the patient tell his or her story in his or her own words. Leading the witness misleads the physician. It is important to get the story right, but of even more meaningful is the process of instilling in the patient the feeling that he or she is of value and worth listening to. Without the enormous modern medical bureaucracy the doctor of old had time to listen and put the patient at ease.
Never let anyone tell you that alternative practitioners have nothing to offer. Of course their oils and needles have no therapeutic effect, vast doses of vitamins and strange diets are completely useless. Enemas are good for constipation and colonic washouts are useful as preparation for colonoscopy, but they incorporate no magic cures. A recent study demonstrated that acupuncture needles stuck in the wrong places were as effective as needles stuck in the proper meridians - but they were effective. Just as doctors in the 1930s were effective. They all make use of the placebo effect.
'Placebo' is Latin for 'I please'. The placebo effect is what happens when a doctor goes through all the ritual of diagnosing and treating a patient and prescribes colored water. Although this sounds like deceit and fraud, the fact is that a proportion of patients will get better from whatever they are suffering. Ye, whatever they are suffering from. You might well expect a response from patients with chronic fatigue or headaches or backache, but placebos can heal up ulcers, abolish angina and even produce remissions in cancer.
Studies have been done on the placebo. Two pills are better than one. Injections are better than pills. Green pills are better than red ones, unless you are looking for a stimulant effect when red or orange ones are best. It is even possible to cure nausea by instilling a drug designed to make you vomit, directly into the stomach if you are able to convince the patient that what you are giving is an anti-emetic rather than an emetic.
You may believe that you are immune to the placebo effect, but if you are then why do you buy branded painkillers rather than straight ibuprofen. I know they work better but why? Because of the placebo effect. And they cost more. That's part of the placebo effect; expensive placebos work better than cheap ones.
Back in 1972, that sensible physician Richard Asher (yes, he was Jane's father) wrote, "If you can believe fervently in your treatment, even though controlled tests show that it is quite useless, then your results are much better, your patients are much better, and your income is much better too. I believe this accounts for the remarkable success of some of the less gifted, but more credulous members of our profession, and also for the violent dislike of statistics and controlled tests which fashionable and successful doctors are accustomed to display."
The problem with placebos is that they involve lying to patients. Placebos don't work if you say to a patient, "I'm giving you a sugar pill. There is absolutely no reason why it should make you better except for the 'placebo effect' which no-one understands but it probably acts psychologically." Or do they? A trial of sugar pills for pain that had been diagnosed as 'neurotic' was carried out at Johns Hopkins Hospital, with just such an explanation. The patients improved considerably.
Never apologise, never explain, goes the old adage. But we can't get away with that these days. We are obliged to tell patients the truth and to explain fully what we are about to do. The Philosopher and doctor Raymond Tallis has written, "The drive to keep patients fully informed has led to exponential increases in the formal requirements for consent that only serve to confuse and frighten patients while delaying their access to needed medical attention."
Alternative practitioners are not burdened by the same restrictions. They can look into your eyes and give you an explanation that sounds sciencey, but is in fact gobbledygook. Watch the TV for adverts for anti-aging creams to see what I mean by sciencey.
Actually, I think it is possible to invoke the placebo effect without telling lies and good doctors do it all the time. After I retired I handed on my patients to other physicians. I was surprised at how many of them promptly died. There was no change in treatment, only a change of treater. One patients illustrates the case starkly. She had cancer of the body of the uterus. She had refused surgery, chemotherapy and radiotherapy and all I did was see her, take a blood test and talk to her. I was astonished that her cancer did not progress. It remained static for three years. Then I retired and six months later she died. Somehow she had fixed on me as a walking placebo.
It should be possible to say to a patient without too much mendacity, "We have exhausted the latest treatment - we must now start thinking for ourselves. This is a concoction that I have tried before in cases like yours and it sometimes works. I don't know how it works - I could make up a scientific sounding explanation if you like - but I won't insult your intelligence. It is important though that you take it in the way that it is prescribed. You must take it on an empty stomach (and here you can invoke any ritual you think they will wear - standing on one leg, facing Mecca, drinking out of the back of the cup or prunes for breakfast) and I will see you every week if you can afford it. Unfortunately, it's not cheap, but if it works it will certainly be worth it."
Some of these people could sell snow to the Eskimos.
Monday, January 26, 2009
More on global warming
Last week a report in Nature sought to undermine the case of the global-warming-deniers. Although there are certainly observations that suggest that, especially during the nineties the world was mostly warming up, the exception has always been Antarctica. The BBC continues to broadcast archive footage of great sheets of ice falling from Antarctica into the sea, without emphasizing that this is a particular area of the Peninsular that reaches up towards South America near to which volcanic activity is taking place undersea. It is a case of a picture being more powerful than 1000 words. In fact The vast mass of Antarctica, all satellite evidence has shown, has been getting colder over the past 30 years. Last year's sea-ice cover was 30 per cent above average.
The new paper from Eric Steig 'demonstrates' that Western Antarctica has also been warming up. At the moment I am reading a book by Ben Goldacre called 'Bad Science' in which the junior doctor and Guardian columnist takes apart the quack nutritionists and other perpetrators of media fraud, so I have my nonsense antennae primed. My suspicions are further raised when I see that one of Steig's co-workers is Michael Mann inventor of the notorious 'hockey stick' graph that has been so disparaged. So we need to examine the data.
It turns out that the data were produced by a computer model based on combining the satellite evidence since 1979 with temperature readings from surface weather stations. The problem is that there are very few surface weather stations, and those that there are are predominately on the warmer peninsular. Even arch-warmist Dr Kevin Trenberth expressed some surprise. He wryly observed "it is hard to make data where none exists". But perhaps the most telling comment comes in a letter sent to Steig by Ross Hays, an atmospheric scientist who has often visited the Antarctic for NASA.
Eric,
Let me first say that this is my own opinion and does not represent the agency I work for. I feel your study is absolutely wrong.
There are very few stations in Antarctica to begin with and only a hand full with 50 years of data. Satellite data is just approaching thirty years of available information. In my experience as a day to day forecaster that has to travel and do field work in Antarctica the summer seasons have been getting colder. In the late 1980s helicopters were used to take our personnel to Williams Field from McMurdo Station due to the annual receding of the Ross Ice Shelf, but in the past few years the thaw has been limited and vehicles can continue to make the transition and drive on the ice. One climate note to pass along is December 2006 was the coldest December ever for McMurdo Station. In a synoptic perspective the cooler sea surface temperatures have kept the maritime storms farther offshore in the summer season and the colder more dense air has rolled from the South Pole to the ice shelf.
There was a paper presented at the AMS Conference in New Orleans last year noting over 70% of the continent was cooling due to the ozone hole. We launch balloons into the stratosphere and the anticyclone that develops over the South Pole has been displaced and slow to establish itself over the past five seasons. The pattern in the troposphere has reflected this trend with more maritime (warmer) air around the Antarctic Peninsula which is also where most of the automated weather stations are located for West Antarctica which will give you the average warmer readings and skew the data for all of West Antarctica.
With statistics you can make numbers go to almost any conclusion you want. It saddens me to see members of the scientific community do this for media coverage.
Sincerely,
Ross Hays
The link is to an anti-global warming site so it has to be handled with care, but as someone with no expertise in climate science, but with a healthy scepticism about scientists, I conclude that the anthropogenic global warming case is not proven
The new paper from Eric Steig 'demonstrates' that Western Antarctica has also been warming up. At the moment I am reading a book by Ben Goldacre called 'Bad Science' in which the junior doctor and Guardian columnist takes apart the quack nutritionists and other perpetrators of media fraud, so I have my nonsense antennae primed. My suspicions are further raised when I see that one of Steig's co-workers is Michael Mann inventor of the notorious 'hockey stick' graph that has been so disparaged. So we need to examine the data.
It turns out that the data were produced by a computer model based on combining the satellite evidence since 1979 with temperature readings from surface weather stations. The problem is that there are very few surface weather stations, and those that there are are predominately on the warmer peninsular. Even arch-warmist Dr Kevin Trenberth expressed some surprise. He wryly observed "it is hard to make data where none exists". But perhaps the most telling comment comes in a letter sent to Steig by Ross Hays, an atmospheric scientist who has often visited the Antarctic for NASA.
Eric,
Let me first say that this is my own opinion and does not represent the agency I work for. I feel your study is absolutely wrong.
There are very few stations in Antarctica to begin with and only a hand full with 50 years of data. Satellite data is just approaching thirty years of available information. In my experience as a day to day forecaster that has to travel and do field work in Antarctica the summer seasons have been getting colder. In the late 1980s helicopters were used to take our personnel to Williams Field from McMurdo Station due to the annual receding of the Ross Ice Shelf, but in the past few years the thaw has been limited and vehicles can continue to make the transition and drive on the ice. One climate note to pass along is December 2006 was the coldest December ever for McMurdo Station. In a synoptic perspective the cooler sea surface temperatures have kept the maritime storms farther offshore in the summer season and the colder more dense air has rolled from the South Pole to the ice shelf.
There was a paper presented at the AMS Conference in New Orleans last year noting over 70% of the continent was cooling due to the ozone hole. We launch balloons into the stratosphere and the anticyclone that develops over the South Pole has been displaced and slow to establish itself over the past five seasons. The pattern in the troposphere has reflected this trend with more maritime (warmer) air around the Antarctic Peninsula which is also where most of the automated weather stations are located for West Antarctica which will give you the average warmer readings and skew the data for all of West Antarctica.
With statistics you can make numbers go to almost any conclusion you want. It saddens me to see members of the scientific community do this for media coverage.
Sincerely,
Ross Hays
The link is to an anti-global warming site so it has to be handled with care, but as someone with no expertise in climate science, but with a healthy scepticism about scientists, I conclude that the anthropogenic global warming case is not proven
Sunday, January 25, 2009
Mode of Baptism
As a Baptist I believe that baptism is for believers. In the Bible it comes after repentance ('Repent and be baptized, everyone of you'), and since infants can't repent, I think that paedo-baptism is a mistake. I was baptized as an infant, I am told, but I can't remember anything about it.
There are some who believe that a child becomes 'born again' through baptism. "This child is now regenerate" goes one form of words. But I cannot see how this could be so. Many who are baptized with such a ritual never give evidence of being regenerate. A whole tribe of Mafiosa has been 'done' in such away, yet turned out to be a murderous group of extortioners and crooks.
Similarly, such people have undertaken confirmation as if it, like baptism, were a ritual designed to get them to heaven rather than a life changing experience. So my first point is there is nothing magical about either ceremony. The water isn't holy; saying words over it doesn't impart a special purifying quality, even if it is done by someone who has hands laid upon him by someone who has hands laid upon him by someone ... who has had hands laid upon him by the Apostle Peter.
There used to be a tradition in neonatal units for the (usually Irish) midwife to rush off and sprinkle any newborn who looked a bit frail so that the child would not die unbaptized. Let me say that this is a cruel superstition. What does it say about the child who doesn't make it to the sink? How must such parents feel?
Some Christians of the Reformed tradition see infant baptism as a continuation of the Covenantal relationship of people within the family of God - as a replacement of the ritual of circumcision. Now, it is certainly good for children to be brought up within God's Family but nowhere in Scripture do I find circumcision being replaced by baptism. Moreover circumcision (at least in the Jewish tradition) is only for males on the eighth day of life). Both males and females are baptized and hardly ever on the eighth day.
I think it is increasingly accepted in evangelical circles that baptism is for believers. Many converts within the Church of England are now baptized as believers. This blog is not meant to be an exhaustive investigation into the Biblical basis of baptism but rather to talk about the mode of baptism.
Within the Greek Orthodox Church, while they practise infant baptism, they dunk the baby in whole, right up to his noggin. The English translators of the Bible when they came across the word for 'baptize' in the Greek original, instead of translating it, they simply transliterated it - Anglicizing the same word. Of course, this is not an option for the Greeks, as they know what the word means. It is a technical term from the dyeing industry. It means to dunk or dip in the dye so the piece of cloth is completely covered. Hence the ceremony in the Greek Orthodox Church. They would have no truck with simply sprinkling a few drops on the person's forehead. Again, whether 'dip' means 'totally immerse' is another matter, though to dye a piece of cloth leaving a small part of the cloth like the heel of Achilles out of the liquid would seem to defeat the purpose.
Evangelicals see the process of baptism as a symbol. Symbols have a power beyond an intellectual exercise. That is why the Old Testament Prophets often acted out their message. Think of Jeremiah or Ezekiel. When you take your driving test your examiner expects you to turn your head to use your mirrors and to check no one is coming from right or left. It is not good enough to protest that you made the requisite eye movements. He doesn't do this to deliberately fail you - he is looking to see if you have absorbed the ritual; do you have the body memory of safety? When I was batting at cricket I used to have a ritual after every ball of walking around the stumps. It looked like superstition, but it wasn't; it was a ritual to get me in the right position to face the next ball. It gave me a body memory of how I should settle. Baptism is a major body memory in every Baptist that reminds us that we have committed our lives to the Lord - and the symbolism has a meaning that rubs in our commitment.
So what is the symbolism? First, it is a good wash. We are acting out the fact that our sins have been washed away. We start with a clean slate; we have been washed in the waters of baptism. I think this must have been the meaning of the baptism of John the Baptist, which, of course, was how Jesus was baptized, even though we know that John thought it unseemly that he should baptize Jesus. Jesus himself needed no washing, so why was he baptized? Some have seen it as his priestly anointing.
A good example of washing as the meaning of the symbol comes from the baptism of Saul of Tarsus himself; the words of Ananias to Saul were (Acts 22.16): "Get up, be baptised and wash your sins way."
But many Baptists see another symbol. It comes from Romans 6:3-4: 'Don't you know that all of us who were baptized into Christ Jesus were baptized into his death? We were therefore buried with him through baptism into death in order that, just as Christ was raised from the dead through the glory of the Father, we too may live a new life.' It is reinforced by Colossians 2:12: 'having been buried with him in baptism and raised with him through your faith in the power of God, who raised him from the dead.' They see it as a symbol of our old life entering the grave and our new life rising from it. This could not have been the symbolism of John the Baptist, because at that time Christ had not risen from the dead.
To accept this symbolism is not straightforward, and many evangelicals see problems. Just put 'mode of baptism' into any search engine and you will come up with a myriad of opposing views. One of the most serious problems is that Jesus did not in fact go down into a grave, but his dead body was put into a tomb (probably horizontally). Our own methods of burial, which are quite different to those of First Century Palestine add to our appreciation of this symbolism, but what Paul was talking about was a spiritual union with Christ to defend against the heresy of antinomianism.
Of course, some evangelicals have abandoned all this symbolism completely. The Salvation Army, for example, has neither baptism nor Holy Communion but has adopted an entirely different symbolism that was potent for people living in the Nineteenth and early Twentieth Centuries, but is probably very dated today.
I really don't think that this is a reason for Christians to fall out and I worry when individual churches make mode of baptism a rule for church membership or holding office. There are some with physical handicaps who could not undergo baptism by immersion, for example. Should their baptism by effusion be a reason for denying them office in a church?
Jesus submitted to the baptism of John, even though it was unnecessary for him. This should be our pattern. Should we be required to be baptized in a certain way to join a church or to hold office, we should humble ourselves and obey. There should be no question of someone saying, "I have already been baptized and I don't need to do it again." That displays an arrogance that is not appropriate in a follower of Christ. Remember the Apostle Paul said, "Everything is permissible—but not everything is beneficial. Everything is permissible—but not everything is constructive. Nobody should seek his own good, but the good of others."
There are some who believe that a child becomes 'born again' through baptism. "This child is now regenerate" goes one form of words. But I cannot see how this could be so. Many who are baptized with such a ritual never give evidence of being regenerate. A whole tribe of Mafiosa has been 'done' in such away, yet turned out to be a murderous group of extortioners and crooks.
Similarly, such people have undertaken confirmation as if it, like baptism, were a ritual designed to get them to heaven rather than a life changing experience. So my first point is there is nothing magical about either ceremony. The water isn't holy; saying words over it doesn't impart a special purifying quality, even if it is done by someone who has hands laid upon him by someone who has hands laid upon him by someone ... who has had hands laid upon him by the Apostle Peter.
There used to be a tradition in neonatal units for the (usually Irish) midwife to rush off and sprinkle any newborn who looked a bit frail so that the child would not die unbaptized. Let me say that this is a cruel superstition. What does it say about the child who doesn't make it to the sink? How must such parents feel?
Some Christians of the Reformed tradition see infant baptism as a continuation of the Covenantal relationship of people within the family of God - as a replacement of the ritual of circumcision. Now, it is certainly good for children to be brought up within God's Family but nowhere in Scripture do I find circumcision being replaced by baptism. Moreover circumcision (at least in the Jewish tradition) is only for males on the eighth day of life). Both males and females are baptized and hardly ever on the eighth day.
I think it is increasingly accepted in evangelical circles that baptism is for believers. Many converts within the Church of England are now baptized as believers. This blog is not meant to be an exhaustive investigation into the Biblical basis of baptism but rather to talk about the mode of baptism.
Within the Greek Orthodox Church, while they practise infant baptism, they dunk the baby in whole, right up to his noggin. The English translators of the Bible when they came across the word for 'baptize' in the Greek original, instead of translating it, they simply transliterated it - Anglicizing the same word. Of course, this is not an option for the Greeks, as they know what the word means. It is a technical term from the dyeing industry. It means to dunk or dip in the dye so the piece of cloth is completely covered. Hence the ceremony in the Greek Orthodox Church. They would have no truck with simply sprinkling a few drops on the person's forehead. Again, whether 'dip' means 'totally immerse' is another matter, though to dye a piece of cloth leaving a small part of the cloth like the heel of Achilles out of the liquid would seem to defeat the purpose.
Evangelicals see the process of baptism as a symbol. Symbols have a power beyond an intellectual exercise. That is why the Old Testament Prophets often acted out their message. Think of Jeremiah or Ezekiel. When you take your driving test your examiner expects you to turn your head to use your mirrors and to check no one is coming from right or left. It is not good enough to protest that you made the requisite eye movements. He doesn't do this to deliberately fail you - he is looking to see if you have absorbed the ritual; do you have the body memory of safety? When I was batting at cricket I used to have a ritual after every ball of walking around the stumps. It looked like superstition, but it wasn't; it was a ritual to get me in the right position to face the next ball. It gave me a body memory of how I should settle. Baptism is a major body memory in every Baptist that reminds us that we have committed our lives to the Lord - and the symbolism has a meaning that rubs in our commitment.
So what is the symbolism? First, it is a good wash. We are acting out the fact that our sins have been washed away. We start with a clean slate; we have been washed in the waters of baptism. I think this must have been the meaning of the baptism of John the Baptist, which, of course, was how Jesus was baptized, even though we know that John thought it unseemly that he should baptize Jesus. Jesus himself needed no washing, so why was he baptized? Some have seen it as his priestly anointing.
A good example of washing as the meaning of the symbol comes from the baptism of Saul of Tarsus himself; the words of Ananias to Saul were (Acts 22.16): "Get up, be baptised and wash your sins way."
But many Baptists see another symbol. It comes from Romans 6:3-4: 'Don't you know that all of us who were baptized into Christ Jesus were baptized into his death? We were therefore buried with him through baptism into death in order that, just as Christ was raised from the dead through the glory of the Father, we too may live a new life.' It is reinforced by Colossians 2:12: 'having been buried with him in baptism and raised with him through your faith in the power of God, who raised him from the dead.' They see it as a symbol of our old life entering the grave and our new life rising from it. This could not have been the symbolism of John the Baptist, because at that time Christ had not risen from the dead.
To accept this symbolism is not straightforward, and many evangelicals see problems. Just put 'mode of baptism' into any search engine and you will come up with a myriad of opposing views. One of the most serious problems is that Jesus did not in fact go down into a grave, but his dead body was put into a tomb (probably horizontally). Our own methods of burial, which are quite different to those of First Century Palestine add to our appreciation of this symbolism, but what Paul was talking about was a spiritual union with Christ to defend against the heresy of antinomianism.
Of course, some evangelicals have abandoned all this symbolism completely. The Salvation Army, for example, has neither baptism nor Holy Communion but has adopted an entirely different symbolism that was potent for people living in the Nineteenth and early Twentieth Centuries, but is probably very dated today.
I really don't think that this is a reason for Christians to fall out and I worry when individual churches make mode of baptism a rule for church membership or holding office. There are some with physical handicaps who could not undergo baptism by immersion, for example. Should their baptism by effusion be a reason for denying them office in a church?
Jesus submitted to the baptism of John, even though it was unnecessary for him. This should be our pattern. Should we be required to be baptized in a certain way to join a church or to hold office, we should humble ourselves and obey. There should be no question of someone saying, "I have already been baptized and I don't need to do it again." That displays an arrogance that is not appropriate in a follower of Christ. Remember the Apostle Paul said, "Everything is permissible—but not everything is beneficial. Everything is permissible—but not everything is constructive. Nobody should seek his own good, but the good of others."
The DVD race
Now up to 628 films. A slight change in the running order for Directors, Steven Spielberg is now on his own at number 5 with 7 films - I just found a copy of A.I. in the garage. John Ford now has 5 and Michael Apted enters with 4. (Nell, Amazing Grace, Coalminer's Daughter and Enigma). For Male Actors Bogie is still in the lead, now with 18, Clive Owen moves into 4th place with 11, and Daniel Day-Lewis and Robert De Niro come in with 7. For Female Actors Angelina Jolie comes in in second place with 7 and Scarlet Johansson enters with 5 (Match Point, Girl with a Pearl Earring, A Good Woman [a new version of Lady Windemere's Fan], Lost in Translation, and The Horse Whisperer). I still have another cupboard full of films to add.
Look out for Al Pacino, Jack Nicholson, Judi Dench, Jake Gyllenhaal, and Kevin Spacey who are all close behind.
Look out for Al Pacino, Jack Nicholson, Judi Dench, Jake Gyllenhaal, and Kevin Spacey who are all close behind.
The Resurrection
For some time I have been taking the Sunday morning sermon from Lansdowne Baptist Church and on Sunday afternoons I meditate upon it. What comes out of that appears on my blog. A few of weeks ago we started a new series in 1 Peter. Christ Kelly preached a sermon on 1 Peter 1:3-5 and I started to think about it. You can find what I wrote here. As you can see I got stuck on the phrase "A living hope through the resurrection" which had been only mentioned in passing in the sermon. However, this turned out to be such an important topic that Chris has gone back and preached two sermons on the Resurrection. Rather than meditate on them, I will just give you the link. Here you will see what a real preacher makes of a phrase.
Friday, January 23, 2009
Favorite Film Stars
It can be measured by how many of their films I have on DVD.
1. Humphrey Bogart 16
2. Anthony Hopkins 14
3. Cary Grant 13
4=. Clint Eastwood 8
Clive Owen 8
6=. Michael Caine 7
Tom Cruise 7
Alan Rickman 7
As far as women go:
1. Cate Blanchett 8
2.= Nicole Kidman 7
Diane Keaton 7
4.= Bette Davis 6
Helen Mirren 6
Kate Winslett 6
7.= Helena Bonham-Carter 5
Jodie Foster 5
Julia Roberts 5
Ingrid Bergman 5
Susan Sarandon 5
Of course, it is not a fair comparison since there are still some films I want to own and haven't got around to buying yet and there are some series like the BBC Shakespeare where there are so many actors that my database doesn't mention them all. Nevertheless, the only surprises for me are how high Julia Roberts and Tom Cruise feature. I would have put Al Pacino higher than Cruise and Sissy Spacek higher than Roberts.
1. Humphrey Bogart 16
2. Anthony Hopkins 14
3. Cary Grant 13
4=. Clint Eastwood 8
Clive Owen 8
6=. Michael Caine 7
Tom Cruise 7
Alan Rickman 7
As far as women go:
1. Cate Blanchett 8
2.= Nicole Kidman 7
Diane Keaton 7
4.= Bette Davis 6
Helen Mirren 6
Kate Winslett 6
7.= Helena Bonham-Carter 5
Jodie Foster 5
Julia Roberts 5
Ingrid Bergman 5
Susan Sarandon 5
Of course, it is not a fair comparison since there are still some films I want to own and haven't got around to buying yet and there are some series like the BBC Shakespeare where there are so many actors that my database doesn't mention them all. Nevertheless, the only surprises for me are how high Julia Roberts and Tom Cruise feature. I would have put Al Pacino higher than Cruise and Sissy Spacek higher than Roberts.
Wednesday, January 21, 2009
Movies on DVD
I have been cataloguing my movie collection. My most popular director is Alfred Hitchcock with 17 movies, followed by Peter Weir with 9, Clint Eastwood and Ingmar Bergman with 8 each, The Coen Brothers, James Ivory, Martin Scorsese and Steven Spielberg each have 6, Billy Wilder, Francis Ford Coppola, John Huston, Mike Leigh, Stephen Frears, William Wyler, Stephen Poliakoff, and David Lean have 5 and John Ford, Steven Soderbergh, Woody Allen, Peter Jackson, Leo McCarey, Howard Hawks and Christopher Nolan have 4 each. Anyone else has three or fewer. The total number is 579, but I still have a couple of dozen still to catalogue.
Side Effects in easier language
After Paul's comment I have rewritten the last piece to make it more understandable by patients.
Recently, there has been some discussion among CLL patients about the side effects of drugs used to treat the disease. Are there any treatments that are side effect free?
Unless there were a perfectly targeted drug that killed silently and without fuss, it is inevitable that all effective drugs will have side effects. Whether the side effects really matter, is another question.
It is possible to classify side effects in a number of different ways: ones felt only by the patient versus ones that can be measured by an observer; ones that last for a limited time versus ones the patient is left with after the treatment stops; short or long lived; rare or common; caused by the treatment in everyone to some degree or only rarely and in particular patients.
Let's take the individual drugs that are used in CLL.
Chlorambucil (Leukeran) has been around the longest and has relatively few side effects compared to most of the others. It works by damaging the DNA of the CLL cell. This sets going a process known as ‘programmed cell death’. There are two programs on offer, and most chemo-drugs use the same program. It doesn’t just kill CLL cells; any cell that is dividing is at risk; this means the cells of the bone marrow, the immune system, the skin and hair, and the lining of the stomach and guts are in danger.
Compared to other anti-cancer drugs Leukeran is pretty free of side effects. Many patients take it and don’t notice anything different than if they were taking a sugar pill. The larger the dose the more likely it is that you will feel something, most commonly a metalic taste in your mouth. Some patients will feel sick, but it is very rare for it to make you vomit. Even if it does, most patients get relief by dividing up the dose during the course of the day or even taking the monthly dose over more days (14 instead of 7 for instance). You won’t lose your hair. Rashes are also rare – if you get one it is more likely to be due to a drug that you are taking at the same time like Zyloric (allopurinol), but some (very few) people are genuinely allergic to Leukeran.
What about the silent side effects that you can’t feel? It can certainly damage your bone marrow. Damaged bone marrow means you can’t make enough red cells, neutrophils (these are the white cells that eat bacteria) and platelets (needed to make the blood clot). The marrow can be damaged in two ways: either the stem cells are killed so that there aren’t enough of them to make the red cells, white cells and platelets, or the stem cells are damaged so that the red cells, white cells and platelets that are made don’t work properly. This second type of damage is known as the myelodysplastic syndrome (lets call it MDS so we don’t have to remember the long word). MDS can turn into acute leukemia (AML), so it is a worry.
Undoubtedly Leukeran can kill stem cells, but this is a slow process and it is pretty rare that it is a problem. It is hard to be sure because the very presence of the CLL seems to switch stem cells off so in any patient who has anemia (lack of red cells) , lack of white cells or platelets it might be due to remaining CLL cells in the bone marrow or due to the toxic effect of drugs. Nevertheless patients who have had a lot of Leukeran over a long period do run out of stem cells.
Leukeran also sems able to cause MDS. I have seen it in patients with ovarian cancer treated with Leukeran, but I have never seen it (or AML) caused by Leukeran in CLL. Neither has Danny Catovsky and between us we have seen more cases in the UK than anyone else. Occasionally untreated CLL develops MDS or AML, but we don’t know why. It is very rare.
Leukeran can also damage the immune system. Since the CLL cell is part of the immune system, you would expect it to, and it is true to say that all treatments that kill CLL cells also kill their ormal counterparts and thus make the poor immunity of CLL worse – at least temporarily.
Very simply, the immune system consists of B cells that make antibodies (CLL cells are B cells) and T cells that kill viruses and fungi, reject transplants and also control immunity. (They are like the conductor of the symphony orchestra). T cells are in fact very complicated; as well as helping B cells and other T cells to do their job, they are also the cells that switch off an immune response when it is no longer needed.
Leukeran kills both B cells and T cells, but again not so you’d notice – at least at first. This is because like the bone marrow, the immune system has a ‘full tank’ and it isn’t until you are running on empty that you begin to notice a problem. Drugs empty your tank at different rates, and Leukeran is one of the slowest.
Many years ago it was noticed that Leukeran could trigger a type of anemia called autoimmune hemolytic anemia (AHA). This is where the body makes an antibody to kill its own red cells. We now know that what happens is the T cells that are supposed to switch off an immune response are killed. AHA occurs in about 15% of patients with CLL and it is quite unusual for treatment with Leukeran to be the trigger, but almost any type of chemotherapy can do it.
The only other thing I want to say about Leukeran is that you can’t give it intravenously (iv). Some people see this as a disadvantage, though I think most people would rather take a pill than have a jab.
Because it has been around for so long (more than 50 years) Leukeran is the standard that other drugs are compared against.
There are other drugs that are chemically similar to Leukeran. They were all derived by chemists from Mustard Gas, which was used in the First World War to kill an injure soldiers. None of them are that toxic, but it is a warning that we are not dealing with sweeties. The most commonly used of these Leukeran lookalikes is cyclphosphamide. This has many trade names as it has been off patent for many years. We generally refer to it as Cyclo. Cyclo was invented by a wool chemist in Australia who was trying to alter the kinks in wool fiber. It is not usually used alone but as part of a combination (it is the ‘C’ in FCR, CHOP and CVP). It is very similar to Leukeran but it can be used iv as well as in pill-form. It has these differences. It is much more likelyto make you lose your hair. It is much more likely to make you feel sick and to vomit. It is less likely to kill stem cells but more likely to cause MDS. It tends not to supress T cells, but attacks B cells more. Because of this it tends to be a remedy, not a trigger of AHA. There don’t seem to be any comparisons with Leukeran on whether it makes you more likely to get an infection.
The other drug we have from mustard gas is bendamustine (Treanda). The publicity for Treanda suggests that it also has a chemical formula like fludarabine. This is partly true, but I have not seen any evidence that it acts like fludarabine. It is best to regard it as a Leukeran look-alike that has become very popular because the pharmaceutical company can make a big profit from it, which they can’t do with either Leukeran or Cyclo. There is also the dose thing. Increasing the dose of any of these drugs makes them both more effective and more toxic. So comparisons should be between equally toxic doses of the drugs. When this is done they all seem equally effective, but mostly they are compared with a low dose of Leukeran because doctors have often settled on a low non-toxic dose since they are not aiming to cure the disease, merely control it.
The list of side effects of Treanda given on the packet insert: nausea, vomiting, diarrhea, tiredness, itching, weight loss, headache, shortness of breath, fast heartbeat, dizziness, pale skin, confusion, hives, rash, difficulty breathing or swallowing, swelling of the face, excessive tiredness or weakness, fever, chills, cough, or other signs of infection, unusual bleeding or bruising and inferility in men are the same as are seen with all of this class of drug. Whether they occur or not is all about dose. The only controled trial comparing Leukeran with Treanda showed more benefit for Treanda but more toxicity. But the Leukeran results were particularly poor compared with other trials. I am waiting for a comparison with a bigger dose of Leukeran before I give a judgement.
Treanda can only be given iv.
Although fludarabine (Fludara) is not a member of the Mustard Gas family it still uses the same killing program kill CLL cells and in the test tube it has the same sensitivity pattern as Leukeran. It has roughly the same pattern of toxicity as Leukeran only more so. In the LRF CLL4 trial it was equally efficient as a larger dose of Leukeran than is usually used in clinical trials, but was more toxic, being more likely to allow a severe infection to take hold.
Fludara is much more toxic to T cells, knocking the T helper cell levels to about the same level as is seen in AIDS patients and for two years or more. As a consequence shingles is commoner and AHA more severe.
Shingles is caused by a herpes virus that we catch as chicken pox and thereafter lives in our nerve cells, but never comes out to harm us unless our T cells begin to fail. There are other viruses that are similar including CMV and EBV. These can also be reactivated after Fludara treatment (especially when it is given in combinations like FC or FCR) but this is rare. Another problem is lung infection with a fungus like aspergillus or pneumocystis. These are very difficult to treat once they get hold, and many people advocate using drugs to prevent these infections including, acyclovir, itraconazole and Bactrim.
A transfusion into someone who has had Fludara can be very dangerous. Fludara is used as an immunosuppresive drug to prepare a patient for a stem cell transplant. Blood transfusions are not matched for tissue type, just for red cell types. Therefore, white blood cells in the transfusion will recognise the patient as foreign and because they are not rejected by the patient’s damaged imune system they will try to reject the patient causing ‘transfusion related graft-versus-host disease’. This is uniformly fatal. For this reason, we recommend that patients who have ever had Fludara who need a blood transfusion should have the transfusoion irradiated to kill the white cells.
Fludara was originally just iv, but an oral preparation is now available even in the US, which was last to see the convenience of this.
Fludara is often used with cyclo. It is certainly more effective when they are used together, but also more toxic. We insist that a blood test is taken two weeks after the combination starts because the incidence of severe neutropenia is so great that G-CSF or prophylactic ciprofloxacin might be needed to protect the patient from a serious bacterial infection capable of killing the patient within a few hours. However, this combination is less likely to trigger AHA.
Prednisolone (or other steroids like dexamethasone and methyl prednisolone) is not a cytotoxic drug though it can kill CLL cells by the other program pathway. In high doses it kills even cells with the del17p (p53) lesion. But it has a whole set of different side effects. When given for a short time it causes fluid retention, diabetes, high blood presure and mood changes that are quite severe, but when continued for longer periods steroids cause muscle wasting and thinning of the bones as well.
Vincristine is a cytotoxic drug that is not very toxic to the bone marrow, and it is not much use against CLL either, even though it is used in the CVP and CHOP combinations. It does have quite unusual side effects though. It causes a peripheral neuritis. Everyone loses some nerve function; when you knock their ankle tendons with a hammer you don’t get the familiar twitch. Some people are get worse than this, even paralysis. More troubling is damage to the nerves of the stomach which cause bad bellyache and constipation.
Doxorubicin, also known as Adriamycin, causes hair loss and vomiting that are much worse than with any other CLL drug, but it is also toxic to the heart in a cumulative way. No more than 9 courses can be given else heart failure or abnormal heart rhythms will follow. If there is pre-existing heart disease even fewer courses are safe. Mitoxantrone (Novantrone) is a drug with similar qualities and similar side effects. It is used in FCR-M. We recommend that anyone having either Adriamycin or Mitoxantrone should have a heart Echo scan or MUGA scan first to see that their heart is working properly
The monoclonal antibody rituximab (Rituxin or MabThera) is not marrow suppressive and does not cause AHA. Its main side effect is an infusion reaction with flushing, shivering attacks, low blood pressure leading to fainting or collapse, changes in the pulse rate and possibly breathlessness. By giving the infusion more slowly this side effect can be avoided. Occasionally, patients become allergic to rituximab, but this is very, very rare.
Alemtuzumab (MabCampath or just Campath) is less well directed than rituximab since CD52 is also on T cells. It too can cause infusion reactions, but these can be avoided by subQ administration. Instead it causes local skin reactions at the injection sites. These can be unpleasant, but they are not serious. The main side effect is suppression of T cells so that infections with viruses and fungi become a problem. Bactrim and acyclovir prophylaxis is necessary, but because reactivation of CMV is a real possibility, it is necessary to do weekly tests for CMV antigen by PCR. Ganciclovir is given if two successive tests are raised, even if there are no symptoms. Untreated CMV can be fatal. The T cells recover about 6 months after stopping Campath.
Any effective treatment can cause tumor lysis syndrome (TLS). this means that release of toxins from the dying CLL cells are not cleared quickly enough and can damage or even kill the patient. The main toxins are potassium and uric acid. Prevention of TLS is by allopurinol for the uric acid and lots of fluids for the potassium.
Lenolidamide (Revlimid) is one of the drugs that cause TLS. It can also cause marrow suppression and it has a strange complication known as tumor flare, where a lymph node mass increases in size and may become painful. This can be suppressed by steroids, but it usually means that the treatment is working.
If there are any other side effects that I have not mentioned, please ask.
Recently, there has been some discussion among CLL patients about the side effects of drugs used to treat the disease. Are there any treatments that are side effect free?
Unless there were a perfectly targeted drug that killed silently and without fuss, it is inevitable that all effective drugs will have side effects. Whether the side effects really matter, is another question.
It is possible to classify side effects in a number of different ways: ones felt only by the patient versus ones that can be measured by an observer; ones that last for a limited time versus ones the patient is left with after the treatment stops; short or long lived; rare or common; caused by the treatment in everyone to some degree or only rarely and in particular patients.
Let's take the individual drugs that are used in CLL.
Chlorambucil (Leukeran) has been around the longest and has relatively few side effects compared to most of the others. It works by damaging the DNA of the CLL cell. This sets going a process known as ‘programmed cell death’. There are two programs on offer, and most chemo-drugs use the same program. It doesn’t just kill CLL cells; any cell that is dividing is at risk; this means the cells of the bone marrow, the immune system, the skin and hair, and the lining of the stomach and guts are in danger.
Compared to other anti-cancer drugs Leukeran is pretty free of side effects. Many patients take it and don’t notice anything different than if they were taking a sugar pill. The larger the dose the more likely it is that you will feel something, most commonly a metalic taste in your mouth. Some patients will feel sick, but it is very rare for it to make you vomit. Even if it does, most patients get relief by dividing up the dose during the course of the day or even taking the monthly dose over more days (14 instead of 7 for instance). You won’t lose your hair. Rashes are also rare – if you get one it is more likely to be due to a drug that you are taking at the same time like Zyloric (allopurinol), but some (very few) people are genuinely allergic to Leukeran.
What about the silent side effects that you can’t feel? It can certainly damage your bone marrow. Damaged bone marrow means you can’t make enough red cells, neutrophils (these are the white cells that eat bacteria) and platelets (needed to make the blood clot). The marrow can be damaged in two ways: either the stem cells are killed so that there aren’t enough of them to make the red cells, white cells and platelets, or the stem cells are damaged so that the red cells, white cells and platelets that are made don’t work properly. This second type of damage is known as the myelodysplastic syndrome (lets call it MDS so we don’t have to remember the long word). MDS can turn into acute leukemia (AML), so it is a worry.
Undoubtedly Leukeran can kill stem cells, but this is a slow process and it is pretty rare that it is a problem. It is hard to be sure because the very presence of the CLL seems to switch stem cells off so in any patient who has anemia (lack of red cells) , lack of white cells or platelets it might be due to remaining CLL cells in the bone marrow or due to the toxic effect of drugs. Nevertheless patients who have had a lot of Leukeran over a long period do run out of stem cells.
Leukeran also sems able to cause MDS. I have seen it in patients with ovarian cancer treated with Leukeran, but I have never seen it (or AML) caused by Leukeran in CLL. Neither has Danny Catovsky and between us we have seen more cases in the UK than anyone else. Occasionally untreated CLL develops MDS or AML, but we don’t know why. It is very rare.
Leukeran can also damage the immune system. Since the CLL cell is part of the immune system, you would expect it to, and it is true to say that all treatments that kill CLL cells also kill their ormal counterparts and thus make the poor immunity of CLL worse – at least temporarily.
Very simply, the immune system consists of B cells that make antibodies (CLL cells are B cells) and T cells that kill viruses and fungi, reject transplants and also control immunity. (They are like the conductor of the symphony orchestra). T cells are in fact very complicated; as well as helping B cells and other T cells to do their job, they are also the cells that switch off an immune response when it is no longer needed.
Leukeran kills both B cells and T cells, but again not so you’d notice – at least at first. This is because like the bone marrow, the immune system has a ‘full tank’ and it isn’t until you are running on empty that you begin to notice a problem. Drugs empty your tank at different rates, and Leukeran is one of the slowest.
Many years ago it was noticed that Leukeran could trigger a type of anemia called autoimmune hemolytic anemia (AHA). This is where the body makes an antibody to kill its own red cells. We now know that what happens is the T cells that are supposed to switch off an immune response are killed. AHA occurs in about 15% of patients with CLL and it is quite unusual for treatment with Leukeran to be the trigger, but almost any type of chemotherapy can do it.
The only other thing I want to say about Leukeran is that you can’t give it intravenously (iv). Some people see this as a disadvantage, though I think most people would rather take a pill than have a jab.
Because it has been around for so long (more than 50 years) Leukeran is the standard that other drugs are compared against.
There are other drugs that are chemically similar to Leukeran. They were all derived by chemists from Mustard Gas, which was used in the First World War to kill an injure soldiers. None of them are that toxic, but it is a warning that we are not dealing with sweeties. The most commonly used of these Leukeran lookalikes is cyclphosphamide. This has many trade names as it has been off patent for many years. We generally refer to it as Cyclo. Cyclo was invented by a wool chemist in Australia who was trying to alter the kinks in wool fiber. It is not usually used alone but as part of a combination (it is the ‘C’ in FCR, CHOP and CVP). It is very similar to Leukeran but it can be used iv as well as in pill-form. It has these differences. It is much more likelyto make you lose your hair. It is much more likely to make you feel sick and to vomit. It is less likely to kill stem cells but more likely to cause MDS. It tends not to supress T cells, but attacks B cells more. Because of this it tends to be a remedy, not a trigger of AHA. There don’t seem to be any comparisons with Leukeran on whether it makes you more likely to get an infection.
The other drug we have from mustard gas is bendamustine (Treanda). The publicity for Treanda suggests that it also has a chemical formula like fludarabine. This is partly true, but I have not seen any evidence that it acts like fludarabine. It is best to regard it as a Leukeran look-alike that has become very popular because the pharmaceutical company can make a big profit from it, which they can’t do with either Leukeran or Cyclo. There is also the dose thing. Increasing the dose of any of these drugs makes them both more effective and more toxic. So comparisons should be between equally toxic doses of the drugs. When this is done they all seem equally effective, but mostly they are compared with a low dose of Leukeran because doctors have often settled on a low non-toxic dose since they are not aiming to cure the disease, merely control it.
The list of side effects of Treanda given on the packet insert: nausea, vomiting, diarrhea, tiredness, itching, weight loss, headache, shortness of breath, fast heartbeat, dizziness, pale skin, confusion, hives, rash, difficulty breathing or swallowing, swelling of the face, excessive tiredness or weakness, fever, chills, cough, or other signs of infection, unusual bleeding or bruising and inferility in men are the same as are seen with all of this class of drug. Whether they occur or not is all about dose. The only controled trial comparing Leukeran with Treanda showed more benefit for Treanda but more toxicity. But the Leukeran results were particularly poor compared with other trials. I am waiting for a comparison with a bigger dose of Leukeran before I give a judgement.
Treanda can only be given iv.
Although fludarabine (Fludara) is not a member of the Mustard Gas family it still uses the same killing program kill CLL cells and in the test tube it has the same sensitivity pattern as Leukeran. It has roughly the same pattern of toxicity as Leukeran only more so. In the LRF CLL4 trial it was equally efficient as a larger dose of Leukeran than is usually used in clinical trials, but was more toxic, being more likely to allow a severe infection to take hold.
Fludara is much more toxic to T cells, knocking the T helper cell levels to about the same level as is seen in AIDS patients and for two years or more. As a consequence shingles is commoner and AHA more severe.
Shingles is caused by a herpes virus that we catch as chicken pox and thereafter lives in our nerve cells, but never comes out to harm us unless our T cells begin to fail. There are other viruses that are similar including CMV and EBV. These can also be reactivated after Fludara treatment (especially when it is given in combinations like FC or FCR) but this is rare. Another problem is lung infection with a fungus like aspergillus or pneumocystis. These are very difficult to treat once they get hold, and many people advocate using drugs to prevent these infections including, acyclovir, itraconazole and Bactrim.
A transfusion into someone who has had Fludara can be very dangerous. Fludara is used as an immunosuppresive drug to prepare a patient for a stem cell transplant. Blood transfusions are not matched for tissue type, just for red cell types. Therefore, white blood cells in the transfusion will recognise the patient as foreign and because they are not rejected by the patient’s damaged imune system they will try to reject the patient causing ‘transfusion related graft-versus-host disease’. This is uniformly fatal. For this reason, we recommend that patients who have ever had Fludara who need a blood transfusion should have the transfusoion irradiated to kill the white cells.
Fludara was originally just iv, but an oral preparation is now available even in the US, which was last to see the convenience of this.
Fludara is often used with cyclo. It is certainly more effective when they are used together, but also more toxic. We insist that a blood test is taken two weeks after the combination starts because the incidence of severe neutropenia is so great that G-CSF or prophylactic ciprofloxacin might be needed to protect the patient from a serious bacterial infection capable of killing the patient within a few hours. However, this combination is less likely to trigger AHA.
Prednisolone (or other steroids like dexamethasone and methyl prednisolone) is not a cytotoxic drug though it can kill CLL cells by the other program pathway. In high doses it kills even cells with the del17p (p53) lesion. But it has a whole set of different side effects. When given for a short time it causes fluid retention, diabetes, high blood presure and mood changes that are quite severe, but when continued for longer periods steroids cause muscle wasting and thinning of the bones as well.
Vincristine is a cytotoxic drug that is not very toxic to the bone marrow, and it is not much use against CLL either, even though it is used in the CVP and CHOP combinations. It does have quite unusual side effects though. It causes a peripheral neuritis. Everyone loses some nerve function; when you knock their ankle tendons with a hammer you don’t get the familiar twitch. Some people are get worse than this, even paralysis. More troubling is damage to the nerves of the stomach which cause bad bellyache and constipation.
Doxorubicin, also known as Adriamycin, causes hair loss and vomiting that are much worse than with any other CLL drug, but it is also toxic to the heart in a cumulative way. No more than 9 courses can be given else heart failure or abnormal heart rhythms will follow. If there is pre-existing heart disease even fewer courses are safe. Mitoxantrone (Novantrone) is a drug with similar qualities and similar side effects. It is used in FCR-M. We recommend that anyone having either Adriamycin or Mitoxantrone should have a heart Echo scan or MUGA scan first to see that their heart is working properly
The monoclonal antibody rituximab (Rituxin or MabThera) is not marrow suppressive and does not cause AHA. Its main side effect is an infusion reaction with flushing, shivering attacks, low blood pressure leading to fainting or collapse, changes in the pulse rate and possibly breathlessness. By giving the infusion more slowly this side effect can be avoided. Occasionally, patients become allergic to rituximab, but this is very, very rare.
Alemtuzumab (MabCampath or just Campath) is less well directed than rituximab since CD52 is also on T cells. It too can cause infusion reactions, but these can be avoided by subQ administration. Instead it causes local skin reactions at the injection sites. These can be unpleasant, but they are not serious. The main side effect is suppression of T cells so that infections with viruses and fungi become a problem. Bactrim and acyclovir prophylaxis is necessary, but because reactivation of CMV is a real possibility, it is necessary to do weekly tests for CMV antigen by PCR. Ganciclovir is given if two successive tests are raised, even if there are no symptoms. Untreated CMV can be fatal. The T cells recover about 6 months after stopping Campath.
Any effective treatment can cause tumor lysis syndrome (TLS). this means that release of toxins from the dying CLL cells are not cleared quickly enough and can damage or even kill the patient. The main toxins are potassium and uric acid. Prevention of TLS is by allopurinol for the uric acid and lots of fluids for the potassium.
Lenolidamide (Revlimid) is one of the drugs that cause TLS. It can also cause marrow suppression and it has a strange complication known as tumor flare, where a lymph node mass increases in size and may become painful. This can be suppressed by steroids, but it usually means that the treatment is working.
If there are any other side effects that I have not mentioned, please ask.
Monday, January 19, 2009
Side effects
Recently, there has been some discussion among CLL patients about the side effects of drugs used to treat the disease. Are there any treatments that are side effect free?
Unless there were a perfectly targeted drug that killed silently and without fuss, it is inevitable that all effective drugs will have side effects. Whether the side effects matter, is another question.
It is possible to classify side effects in a number of different ways: subjective versus objective; transient versus permanent; short or long lived; rare or common; intrinsic to the treatment or to the patient; inevitable or idiosyncratic.
Let's take the individual drugs that are used in CLL.
Chlorambucil has been around the longest and has relatively few side effects. It is an alkylating agent and as such it interferes with the integrity of DNA, causing breaks that often can't be repaired. These go on to induce apoptosis through the mitochondrial pathway. Its activity is not confined to the CLL cells, but it kills any dividing cell. Unlike many alkylating agents it doesn't cause hair loss, and it can be given quite safely by mouth. It does kill normal bone marrow cells but at the doses used in CLL this effect is not too severe. It kills normal lymphocytes too, but again the effect is much less than with other drugs. Its effect on the bowel is also not marked, though this is the effect most reported by patients. They often mention a metallic taste in the mouth and in about a quarter of patients nausea is mentioned. In a very small number of patients an allergic rash is seen.
Chlorambucil can be used as a pattern for the other drugs used in CLL. Many of them work like chlorambucil by targeting dividing cells so all dividing cells will be damaged, not only CLL cells but also hair, skin, bowel, red cells, platelets and neutrophils, T and B lymphocytes. Because these cells are dividing they are usually rapidly replenished, so although with all chemotherapy there is a tendency for the patient to become anemic, thrombocytopenic and neutropenic, these usually recover within a week or so. When hair loss occurs it is also transient, but recovery takes longer, usually not occurring until all courses of treatment have finished. Gut and bowel symptoms, on the other hand, are usually much shorter-lived, lasting only a few days.
On these transient symptoms, chlorambucil scores very well. Nausea may occur but it is seldom sufficient to cause the use of anti-nausea pills. Hair loss hardly ever occurs. Transient suppression of the bone marrow is mild and does not require the use of G-CSF to stimulate the neutrophils, Epo to stimulate the red cells or transfusions of either red cells or platelets. Damage to the skin only occurs in the rare case of allergy. There is some suppression of T lymphocytes, but this is seldom a problem unless the patient is severely immunosuppressed by his CLL or there have been many courses of treatment beforehand. The commonest T cell effects are triggering of shingles (or Zoster) and triggering of autoimmune hemolytic anemia (AHA).
Can there be permanent damage? Probably, though this is seldom a problem. Bone marrow stem cells can be damaged so that either the patient has long term bone marrow cytopenias or develops myelodysplastic syndrome which can transform to acute myeloid leukemia. It is always hard to be sure of these complications because if the marrow remains full of CLL it is difficult to know whether the CLL is suppressing the bone marrow or the chemotherapy. Of all the chemotherapeutic drugs that we use chlorambucil is least likely to cause these problems. I have never seen MDS or AML develop in CLL because of chlorambucil, though I have seen both develop in untreated patients.
The other alkylating agents that we use in CLL are cyclophosphamide and bendamustine. Compared to chlorambucil, cyclophosphamide is more likely to make you sick, much more likely to make your hair fall out, but less likely to cause bone marrow suppression. However, it is more likely to cause long term damage to the bone marrow and myelodysplastic syndrome and acute leukemia definitely occur. It seems less likely to cause AHA, perhaps because it targets B cells more than T cells. Cyclophosphamide can be given either by mouth or intravenously.
Bendamustine is still a bit of an unknown quantity, but it seems more toxic than chlorambucil under all headings, though we have to suspend judgment a little. It is likely that many of these drugs have very similar effects as long as they are given in equally effective doses. It then becomes a matter of which drug has the fewer side effects at equally effective doses. Unfortunately, manufacturers want their drug to look good so they compare it with suboptimal doses of chlorambucil. At these doses chlorambucil has fewer side effects, but how would these compare if enough chlorambucil were given? With fludarabine, we know that it is more toxic than chlorambucil when the latter is given in an equally effective dose, but we don't know about bendamustine.
Although fludarabine is not an alkylating agent it still makes use of the same mitochondrial apoptosis pathway to kill CLL cells and in in vitro testing it has the same sensitivity pattern as chlorambucil. It has roughly the same pattern of toxicity as chlorambucil only more so. However, it is much more toxic to T cells, knocking the T helper cell levels to about the same level as is seen in AIDS patients for two years or more. As a consequence shingles is commoner and AHA more severe. There are also occasional cases of CMV reactivation and pneumocystis pneumonia occurs. A transfusion into someone who has had fludarabine can allow the donor lymphocytes to remain alive and attack the bone marrow causing transfusion associated graft versus host disease, which is uniformly fatal. For this reason, we recommend that patients on fludarabine receive prophylactic Bactrim and acyclovir and any transfusion they require should be irradiated. Fludarabine was originally just intravenous, but an oral preparation is now available even in the US, which was last to see the convenience of this.
Fludarabine is often used with cyclophosphamide. It is certainly more effective when they are used together, but also more toxic. We insist that a blood test is taken two weeks after the combination starts because the incidence of severe neutropenia is so great that G-CSF or prophylactic ciprofloxacin might be needed to protect the patient from gram negative septicemia (which can kill in a few hours). However this combination is less likely to trigger AHA.
Prednisolone (or other steroids like dexamethasone and methyl prednisolone) is not a cytotoxic drug though it can kill CLL cells by a pathway different from the mitochondrial apoptosis pathway. In high doses it kills even cells with the del17p lesion. But it has a whole set of different side effects. Transiently it causes fluid retention, disturbances in the control of blood sugar, hypertension and labile mood, but when continued for longer periods steroids cause muscle wasting and thinning of the bones as well.
Vincristine is a cytotoxic drug that is not very toxic to the bone marrow, and it is not much use against CLL either even though it is used in the CVP and CHOP regimens. It does have quite unusual side effects though. It causes a peripheral neuropathy. Everyone loses their ankle jerks, but some people are paralyzed. More troubling is autonomic neuropathy, which causes problems with bowel movement leading to abdominal pains and constipation.
Doxorubicin, also known as Adriamycin, causes hair loss and vomiting that are much worse than with any other CLL drug, but it is also toxic to the heart in a cumulative way. No more than 9 courses can be given and fewer if there is pre-existing heart disease. Mitoxantrone is a drug with similar qualities and similar side effects.
The monoclonal antibody rituximab is not marrow suppressive and does not cause AHA. Its main side effect is an infusion reaction with flushing, shivering attacks, low blood pressure leading to fainting or collapse, changes in the pulse rate and possibly breathlessness. These symptoms are caused by the consumption of complement and the release of complement fragments that are vaso-active peptides. By giving the infusion more slowly this side effect can be avoided. Occasionally, patients become allergic to rituximab, but this is very, very rare.
Campath is less well directed that rituximab since CD52 is also on T cells. It too can cause infusion reactions, but these can be avoided by subQ administration. Instead it causes local skin reactions at the injection sites. These can be unpleasant, but they are not serious. The main side effect is suppression of T cells so that infections with viruses and fungi become a problem. Bactrim and acyclovir prophylaxis is necessary, but because reactivation of CMV is a real possibility, it is necessary to do weekly tests for CMV antigen by PCR. Ganciclovir is given if two successive tests are raised, even if there are no symptoms. Untreated CMV can be fatal. The T cells recover about 6 months after stopping Campath.
Any effective treatment can cause tumor lysis syndrome (TLS). this means that release of toxins from the dying CLL cells are not cleared quickly enough and can damage or even kill the patient. The main toxins are potassium and uric acid. Prevention of TLS is by allopurinol for the uric acid and lots of fluids for the potassium.
Revlimid is one of the drugs that cause TLS. It can also cause marrow suppression and it has a strange complication known as tumor flare, where a lymph node mass increases in size and may become painful. This can be suppressed by steroids, but it usually means that the treatment is working.
If there are any other side effects that I have not mentioned, please ask.
Unless there were a perfectly targeted drug that killed silently and without fuss, it is inevitable that all effective drugs will have side effects. Whether the side effects matter, is another question.
It is possible to classify side effects in a number of different ways: subjective versus objective; transient versus permanent; short or long lived; rare or common; intrinsic to the treatment or to the patient; inevitable or idiosyncratic.
Let's take the individual drugs that are used in CLL.
Chlorambucil has been around the longest and has relatively few side effects. It is an alkylating agent and as such it interferes with the integrity of DNA, causing breaks that often can't be repaired. These go on to induce apoptosis through the mitochondrial pathway. Its activity is not confined to the CLL cells, but it kills any dividing cell. Unlike many alkylating agents it doesn't cause hair loss, and it can be given quite safely by mouth. It does kill normal bone marrow cells but at the doses used in CLL this effect is not too severe. It kills normal lymphocytes too, but again the effect is much less than with other drugs. Its effect on the bowel is also not marked, though this is the effect most reported by patients. They often mention a metallic taste in the mouth and in about a quarter of patients nausea is mentioned. In a very small number of patients an allergic rash is seen.
Chlorambucil can be used as a pattern for the other drugs used in CLL. Many of them work like chlorambucil by targeting dividing cells so all dividing cells will be damaged, not only CLL cells but also hair, skin, bowel, red cells, platelets and neutrophils, T and B lymphocytes. Because these cells are dividing they are usually rapidly replenished, so although with all chemotherapy there is a tendency for the patient to become anemic, thrombocytopenic and neutropenic, these usually recover within a week or so. When hair loss occurs it is also transient, but recovery takes longer, usually not occurring until all courses of treatment have finished. Gut and bowel symptoms, on the other hand, are usually much shorter-lived, lasting only a few days.
On these transient symptoms, chlorambucil scores very well. Nausea may occur but it is seldom sufficient to cause the use of anti-nausea pills. Hair loss hardly ever occurs. Transient suppression of the bone marrow is mild and does not require the use of G-CSF to stimulate the neutrophils, Epo to stimulate the red cells or transfusions of either red cells or platelets. Damage to the skin only occurs in the rare case of allergy. There is some suppression of T lymphocytes, but this is seldom a problem unless the patient is severely immunosuppressed by his CLL or there have been many courses of treatment beforehand. The commonest T cell effects are triggering of shingles (or Zoster) and triggering of autoimmune hemolytic anemia (AHA).
Can there be permanent damage? Probably, though this is seldom a problem. Bone marrow stem cells can be damaged so that either the patient has long term bone marrow cytopenias or develops myelodysplastic syndrome which can transform to acute myeloid leukemia. It is always hard to be sure of these complications because if the marrow remains full of CLL it is difficult to know whether the CLL is suppressing the bone marrow or the chemotherapy. Of all the chemotherapeutic drugs that we use chlorambucil is least likely to cause these problems. I have never seen MDS or AML develop in CLL because of chlorambucil, though I have seen both develop in untreated patients.
The other alkylating agents that we use in CLL are cyclophosphamide and bendamustine. Compared to chlorambucil, cyclophosphamide is more likely to make you sick, much more likely to make your hair fall out, but less likely to cause bone marrow suppression. However, it is more likely to cause long term damage to the bone marrow and myelodysplastic syndrome and acute leukemia definitely occur. It seems less likely to cause AHA, perhaps because it targets B cells more than T cells. Cyclophosphamide can be given either by mouth or intravenously.
Bendamustine is still a bit of an unknown quantity, but it seems more toxic than chlorambucil under all headings, though we have to suspend judgment a little. It is likely that many of these drugs have very similar effects as long as they are given in equally effective doses. It then becomes a matter of which drug has the fewer side effects at equally effective doses. Unfortunately, manufacturers want their drug to look good so they compare it with suboptimal doses of chlorambucil. At these doses chlorambucil has fewer side effects, but how would these compare if enough chlorambucil were given? With fludarabine, we know that it is more toxic than chlorambucil when the latter is given in an equally effective dose, but we don't know about bendamustine.
Although fludarabine is not an alkylating agent it still makes use of the same mitochondrial apoptosis pathway to kill CLL cells and in in vitro testing it has the same sensitivity pattern as chlorambucil. It has roughly the same pattern of toxicity as chlorambucil only more so. However, it is much more toxic to T cells, knocking the T helper cell levels to about the same level as is seen in AIDS patients for two years or more. As a consequence shingles is commoner and AHA more severe. There are also occasional cases of CMV reactivation and pneumocystis pneumonia occurs. A transfusion into someone who has had fludarabine can allow the donor lymphocytes to remain alive and attack the bone marrow causing transfusion associated graft versus host disease, which is uniformly fatal. For this reason, we recommend that patients on fludarabine receive prophylactic Bactrim and acyclovir and any transfusion they require should be irradiated. Fludarabine was originally just intravenous, but an oral preparation is now available even in the US, which was last to see the convenience of this.
Fludarabine is often used with cyclophosphamide. It is certainly more effective when they are used together, but also more toxic. We insist that a blood test is taken two weeks after the combination starts because the incidence of severe neutropenia is so great that G-CSF or prophylactic ciprofloxacin might be needed to protect the patient from gram negative septicemia (which can kill in a few hours). However this combination is less likely to trigger AHA.
Prednisolone (or other steroids like dexamethasone and methyl prednisolone) is not a cytotoxic drug though it can kill CLL cells by a pathway different from the mitochondrial apoptosis pathway. In high doses it kills even cells with the del17p lesion. But it has a whole set of different side effects. Transiently it causes fluid retention, disturbances in the control of blood sugar, hypertension and labile mood, but when continued for longer periods steroids cause muscle wasting and thinning of the bones as well.
Vincristine is a cytotoxic drug that is not very toxic to the bone marrow, and it is not much use against CLL either even though it is used in the CVP and CHOP regimens. It does have quite unusual side effects though. It causes a peripheral neuropathy. Everyone loses their ankle jerks, but some people are paralyzed. More troubling is autonomic neuropathy, which causes problems with bowel movement leading to abdominal pains and constipation.
Doxorubicin, also known as Adriamycin, causes hair loss and vomiting that are much worse than with any other CLL drug, but it is also toxic to the heart in a cumulative way. No more than 9 courses can be given and fewer if there is pre-existing heart disease. Mitoxantrone is a drug with similar qualities and similar side effects.
The monoclonal antibody rituximab is not marrow suppressive and does not cause AHA. Its main side effect is an infusion reaction with flushing, shivering attacks, low blood pressure leading to fainting or collapse, changes in the pulse rate and possibly breathlessness. These symptoms are caused by the consumption of complement and the release of complement fragments that are vaso-active peptides. By giving the infusion more slowly this side effect can be avoided. Occasionally, patients become allergic to rituximab, but this is very, very rare.
Campath is less well directed that rituximab since CD52 is also on T cells. It too can cause infusion reactions, but these can be avoided by subQ administration. Instead it causes local skin reactions at the injection sites. These can be unpleasant, but they are not serious. The main side effect is suppression of T cells so that infections with viruses and fungi become a problem. Bactrim and acyclovir prophylaxis is necessary, but because reactivation of CMV is a real possibility, it is necessary to do weekly tests for CMV antigen by PCR. Ganciclovir is given if two successive tests are raised, even if there are no symptoms. Untreated CMV can be fatal. The T cells recover about 6 months after stopping Campath.
Any effective treatment can cause tumor lysis syndrome (TLS). this means that release of toxins from the dying CLL cells are not cleared quickly enough and can damage or even kill the patient. The main toxins are potassium and uric acid. Prevention of TLS is by allopurinol for the uric acid and lots of fluids for the potassium.
Revlimid is one of the drugs that cause TLS. It can also cause marrow suppression and it has a strange complication known as tumor flare, where a lymph node mass increases in size and may become painful. This can be suppressed by steroids, but it usually means that the treatment is working.
If there are any other side effects that I have not mentioned, please ask.
Sunday, January 18, 2009
Inverting the Pyramid
The grandfather of my former Pastor's wife played football for England.
William John "Billy" Wedlock (28 October 1880 – 25 January 1965), also known as "Fatty" or the "India Rubber Man", was a footballer who played for Bristol City in 1900–01 and from 1905 until his retirement in 1921. He was a centre-half whose his short and stout stature belied his natural talent. He won 26 England caps between 1907 and 1914,[1] his only rival for the centre-half position being Charlie Roberts of Manchester United, his opposite number in the 1909 FA Cup Final. The East End of Bristol City's ground at Ashton Gate is named the Wedlock Stand in his honour. Wedlock's pub (currently closed) opposite the ground was where he lived and worked for 43 years. He was born in Bedminster, south of the River Avon. He started playing football with Masonic Rovers before joining the Bristol City amateurs, who played as a branch called Arlington Rovers. When he did not make the transition to professional, he transferred to Gloucester County and then joined Aberdare in Wales. Only in 1905 did he return to Bristol City FC, where he stayed until 1921. During the 1905/06 season he won the second-division championship with the “Robins”, and during the following season even were English runner-up. “Billy” Wedlock made a late start, but upon his return became a mainstay right away and went on to become one of the best English centre-halves.
He made his full international début against Ireland on February 16, 1907, and then played for the English national team without a break until 1912. Up to 1914 he played a total of 26 full “A” internationals. Yet from the 1911/12 season onwards, he languished in the second division with his club. “Billy” Wedlock was an excellent centre half-back, outstanding both in attack and in defence. He was very elastic, and popularly known as “India Rubber Man”. Although he was not particularly tall, he had an amazing energy. He reached the Welsh Cup final with Aberdare in 1904 and 1905, and the English Cup final with Bristol City in 1909. When he concluded his active career at the age of 39, he was granted a licence to open a pub in the immediate vicinity of Ashton Gate, the stadium of his club.
What surprised me about this story was the fact that Billy Wedlock was only 5 foot three inches tall. Centre halves are usually six foot two or more. Their role is to be the stopper who prevents the big centre forward from scoring. It wasn't until I read this book, "Inverting the Pyramid" that I understood. It is written by Jonathan Wilson, the football corespondent of the Financial Times and it is a history of playing formations in football. It sounds incredibly boring, but it gives a fascinating insight into social history. I began watching football in 1948 and at that time everybody used the W-M formation developed by Herbert Chapman at Huddersfield and then Arsenal in the 1930s, but before that football had been developed as an attacking game with the teams lined up in the shape of a pyramid. In front of the goalkeeper were two full backs. In front of them were three half backs and in front of them five forwards. At that time the centre half was the play maker - like a quarter-back in American Football. What Chapman did was to withdraw the centre half to be a third defender, and he also withdrew the inside forwards to link with the two remaining half backs. This was the age of the tricky winger exemplified by Stanley Matthews.
My father was at the 1953 Cup Final when Blackpool beat Bolton 4-3. Known as Matthews' Final, it highlighted the skill of the right winger who danced along the right touchline mesmerizing the opposing full back and then sending a high cross over for centre forward Stan Mortenson to head into the net. I attended the Cup Final the following year when everybody expected the other great winger of the period, Tom Finney, to repeat Matthews' triumph. But it wasn't to be. Finney's Preston North End were beaten by West Bromwich Albion 3-2 with a winning goal in the last minute. Something remarkable had happened in the meantime. Hungary had beaten England 6-3 at Wembley in a match that spelled the end of W-M.
Hungary's formation relied on a withdrawn centre-forward with four attackers, but the key was fluidity. Players played for each other rather than for themselves. Even though the players were among the most skilled the world had yet seen, their success was how they moved when they didn't have the ball. Pass the ball the run into space was their watchword. They didn't have the physique of the English players but they had a system.
I'll leave you to read the book if you are interested, but the story is fascinating when seen as a Hegelian dialectic with each thesis met by antithesis and the synthesis becoming the new thesis.
The Brazilians and the Dutch both made their contribution and today we see Manchester United playing without any forwards but with two backs, two wing-backs and seven midfielders becoming world champions.
William John "Billy" Wedlock (28 October 1880 – 25 January 1965), also known as "Fatty" or the "India Rubber Man", was a footballer who played for Bristol City in 1900–01 and from 1905 until his retirement in 1921. He was a centre-half whose his short and stout stature belied his natural talent. He won 26 England caps between 1907 and 1914,[1] his only rival for the centre-half position being Charlie Roberts of Manchester United, his opposite number in the 1909 FA Cup Final. The East End of Bristol City's ground at Ashton Gate is named the Wedlock Stand in his honour. Wedlock's pub (currently closed) opposite the ground was where he lived and worked for 43 years. He was born in Bedminster, south of the River Avon. He started playing football with Masonic Rovers before joining the Bristol City amateurs, who played as a branch called Arlington Rovers. When he did not make the transition to professional, he transferred to Gloucester County and then joined Aberdare in Wales. Only in 1905 did he return to Bristol City FC, where he stayed until 1921. During the 1905/06 season he won the second-division championship with the “Robins”, and during the following season even were English runner-up. “Billy” Wedlock made a late start, but upon his return became a mainstay right away and went on to become one of the best English centre-halves.
He made his full international début against Ireland on February 16, 1907, and then played for the English national team without a break until 1912. Up to 1914 he played a total of 26 full “A” internationals. Yet from the 1911/12 season onwards, he languished in the second division with his club. “Billy” Wedlock was an excellent centre half-back, outstanding both in attack and in defence. He was very elastic, and popularly known as “India Rubber Man”. Although he was not particularly tall, he had an amazing energy. He reached the Welsh Cup final with Aberdare in 1904 and 1905, and the English Cup final with Bristol City in 1909. When he concluded his active career at the age of 39, he was granted a licence to open a pub in the immediate vicinity of Ashton Gate, the stadium of his club.
What surprised me about this story was the fact that Billy Wedlock was only 5 foot three inches tall. Centre halves are usually six foot two or more. Their role is to be the stopper who prevents the big centre forward from scoring. It wasn't until I read this book, "Inverting the Pyramid" that I understood. It is written by Jonathan Wilson, the football corespondent of the Financial Times and it is a history of playing formations in football. It sounds incredibly boring, but it gives a fascinating insight into social history. I began watching football in 1948 and at that time everybody used the W-M formation developed by Herbert Chapman at Huddersfield and then Arsenal in the 1930s, but before that football had been developed as an attacking game with the teams lined up in the shape of a pyramid. In front of the goalkeeper were two full backs. In front of them were three half backs and in front of them five forwards. At that time the centre half was the play maker - like a quarter-back in American Football. What Chapman did was to withdraw the centre half to be a third defender, and he also withdrew the inside forwards to link with the two remaining half backs. This was the age of the tricky winger exemplified by Stanley Matthews.
My father was at the 1953 Cup Final when Blackpool beat Bolton 4-3. Known as Matthews' Final, it highlighted the skill of the right winger who danced along the right touchline mesmerizing the opposing full back and then sending a high cross over for centre forward Stan Mortenson to head into the net. I attended the Cup Final the following year when everybody expected the other great winger of the period, Tom Finney, to repeat Matthews' triumph. But it wasn't to be. Finney's Preston North End were beaten by West Bromwich Albion 3-2 with a winning goal in the last minute. Something remarkable had happened in the meantime. Hungary had beaten England 6-3 at Wembley in a match that spelled the end of W-M.
Hungary's formation relied on a withdrawn centre-forward with four attackers, but the key was fluidity. Players played for each other rather than for themselves. Even though the players were among the most skilled the world had yet seen, their success was how they moved when they didn't have the ball. Pass the ball the run into space was their watchword. They didn't have the physique of the English players but they had a system.
I'll leave you to read the book if you are interested, but the story is fascinating when seen as a Hegelian dialectic with each thesis met by antithesis and the synthesis becoming the new thesis.
The Brazilians and the Dutch both made their contribution and today we see Manchester United playing without any forwards but with two backs, two wing-backs and seven midfielders becoming world champions.
iPray
There has been a proliferation of iProducts: iPods, iTrips, iTunes and iPhones. Let me suggest another: iPray.
I'm not sure what the 'i' stands for, I guess 'intelligent'. All these iProducts are about communication so I suggest that iPrayer fits neatly into the pattern since prayer is all about communication. The thing about iPrayer is you don't need to spend $100 on an electronic device to do it nor do you have to walk around with those silly little ear-buds stuck in your pinnas. iPrayer is available to everybody, instantly and free.
Here are some things you might want to iPray about:
The cease-fire in Gaza.
Famine in Zimbabwe.
Greed in Wall Street.
iPrayer should be a spur to action. So when you've finished complaining to God about the mess we have made of the world, how are you going to answer Him when he asks, "What are you going to do about it?"
1 The cease-fire in Gaza. I am reminded of a story about John Major, Prime Minister of the United Kingdom between 1990 and 1997. He was a great peacemaker - it was he that started the Northern Ireland peace process that Tony Blair took the credit for. The story goes that he found an ancient glass bottle that he rubbed and out popped a genie. "I am the genie of the bottle; you can have two wishes." "Two wishes," said John, "I thought it was supposed to be three." "No," said the genie, "That's lamps. Bottles only have junior genies and you only get the two."
"Fine, said John, fetching a map of the Middle East from his briefcase, "look at this map. I would like to bring peace between Israel and Palestine, but history is against me, what with 1948, 1967, 1973, the intifada, the settlements and real hatred between the two sides."
"Hang on a minute, " complained the genie, "I'm only a junior genie. That would be a tough one for the King of the genies. Haven't you got something a little simpler?"
John Major thought for a moment. He had been a supporter of Chelsea Football Club all his life, but they hadn't been Champions since 1955. "For my second wish I'd like to see Chelsea champions again."
The genie looked nonplussed. "Let me see that map again," he said.
The thing is Chelsea were champions again in 2005. How did it happen? Roman Abramovitch, the Russian Billionaire bought the club and ploughed a large fortune into it. One player alone cost him $50 million. I heard today that the British government is going to give £20 million in aid to Gaza. It sounds a lot of money until you compare it to the attempt by Manchester City football club to buy Kaka from AC Milan for £108 million plus £25 million for his agent and half a million a week for his wages.
Northern Ireland was solved because a lot of money was thrown at it. The EU subsidized the Irish Republic so that the Government there became confident enough to repeal the clauses in its constitution which laid claim to the North, and the US threw enough money at Northern Ireland so that there were jobs for Catholics as well as Protestants. The Palestinian problem will not go away until the Palestinians become prosperous.
2. Famine in Zimbabwe. Several solutions have been proposed. Quite a lot of Britishers would volunteer for an army to invade the country to remove the ruling elite. I remember seeing a television film starring Peter O'Toole called Rogue Male, based on the novel by Geoffrey Household. In it the O'Toole character tries to 'take out' Hitler with a rifle in 1939. You may remember that he failed, but many have proposed this solution for Mugabe. We have to remember that however brutal
Mugabe is now he was once the hero who forced the removal of the notorious Smith regime that had unilaterally declared independence from Britain. This racist regime is how the white man is seen in a lot of Africa. The country has just issued a one hundred trillion pound note which is worth about a dollar. Next week it will be worth less.
Again, whatever the political solution that eventually emerges in Zimbabwe, the people will need feeding, the infrastructure will need to be recreated, jobs will need to be provided. It will cost a lot of money.
3. Greed in Wall Street. The papers today are talking about a £200 billion bail out for British banks from the taxpayer. They are in trouble because of foolish lending, 80% of it going abroad. Bernie Madoff made off with $50 billion. Banks paid their executives crazy salaries and even larger bonuses. Those who were prudent and frugal are now paying the bills of those who were incautious and profligate. As ever people were seduced by the thought of easy money. The Bible says 'The love of money is the root of all evil'.
I am not against money, but it is simply a tool to make service go round. It is just a device to keep a record of what you have done for others and what they have done for you. When it becomes an end in itself disaster follows.
Do pray for all these issues but remember that as we point to others with our index finger, our middle and ring fingers and our pinkie point back at ourselves. Do we have the right attitude to money?
I'm not sure what the 'i' stands for, I guess 'intelligent'. All these iProducts are about communication so I suggest that iPrayer fits neatly into the pattern since prayer is all about communication. The thing about iPrayer is you don't need to spend $100 on an electronic device to do it nor do you have to walk around with those silly little ear-buds stuck in your pinnas. iPrayer is available to everybody, instantly and free.
Here are some things you might want to iPray about:
The cease-fire in Gaza.
Famine in Zimbabwe.
Greed in Wall Street.
iPrayer should be a spur to action. So when you've finished complaining to God about the mess we have made of the world, how are you going to answer Him when he asks, "What are you going to do about it?"
1 The cease-fire in Gaza. I am reminded of a story about John Major, Prime Minister of the United Kingdom between 1990 and 1997. He was a great peacemaker - it was he that started the Northern Ireland peace process that Tony Blair took the credit for. The story goes that he found an ancient glass bottle that he rubbed and out popped a genie. "I am the genie of the bottle; you can have two wishes." "Two wishes," said John, "I thought it was supposed to be three." "No," said the genie, "That's lamps. Bottles only have junior genies and you only get the two."
"Fine, said John, fetching a map of the Middle East from his briefcase, "look at this map. I would like to bring peace between Israel and Palestine, but history is against me, what with 1948, 1967, 1973, the intifada, the settlements and real hatred between the two sides."
"Hang on a minute, " complained the genie, "I'm only a junior genie. That would be a tough one for the King of the genies. Haven't you got something a little simpler?"
John Major thought for a moment. He had been a supporter of Chelsea Football Club all his life, but they hadn't been Champions since 1955. "For my second wish I'd like to see Chelsea champions again."
The genie looked nonplussed. "Let me see that map again," he said.
The thing is Chelsea were champions again in 2005. How did it happen? Roman Abramovitch, the Russian Billionaire bought the club and ploughed a large fortune into it. One player alone cost him $50 million. I heard today that the British government is going to give £20 million in aid to Gaza. It sounds a lot of money until you compare it to the attempt by Manchester City football club to buy Kaka from AC Milan for £108 million plus £25 million for his agent and half a million a week for his wages.
Northern Ireland was solved because a lot of money was thrown at it. The EU subsidized the Irish Republic so that the Government there became confident enough to repeal the clauses in its constitution which laid claim to the North, and the US threw enough money at Northern Ireland so that there were jobs for Catholics as well as Protestants. The Palestinian problem will not go away until the Palestinians become prosperous.
2. Famine in Zimbabwe. Several solutions have been proposed. Quite a lot of Britishers would volunteer for an army to invade the country to remove the ruling elite. I remember seeing a television film starring Peter O'Toole called Rogue Male, based on the novel by Geoffrey Household. In it the O'Toole character tries to 'take out' Hitler with a rifle in 1939. You may remember that he failed, but many have proposed this solution for Mugabe. We have to remember that however brutal
Mugabe is now he was once the hero who forced the removal of the notorious Smith regime that had unilaterally declared independence from Britain. This racist regime is how the white man is seen in a lot of Africa. The country has just issued a one hundred trillion pound note which is worth about a dollar. Next week it will be worth less.
Again, whatever the political solution that eventually emerges in Zimbabwe, the people will need feeding, the infrastructure will need to be recreated, jobs will need to be provided. It will cost a lot of money.
3. Greed in Wall Street. The papers today are talking about a £200 billion bail out for British banks from the taxpayer. They are in trouble because of foolish lending, 80% of it going abroad. Bernie Madoff made off with $50 billion. Banks paid their executives crazy salaries and even larger bonuses. Those who were prudent and frugal are now paying the bills of those who were incautious and profligate. As ever people were seduced by the thought of easy money. The Bible says 'The love of money is the root of all evil'.
I am not against money, but it is simply a tool to make service go round. It is just a device to keep a record of what you have done for others and what they have done for you. When it becomes an end in itself disaster follows.
Do pray for all these issues but remember that as we point to others with our index finger, our middle and ring fingers and our pinkie point back at ourselves. Do we have the right attitude to money?
Saturday, January 17, 2009
Aphorisms 5
Don’t forget in the darkness what you learned in the light.
When you start worrying about the absence of God, perhaps he is thinking about the absence of you.
If you want to make God laugh, tell him your plans.
Lord may my heart be broken by what breaks your heart.
There is no future in relying on fate.
Educate without the Bible: you end up with clever devils.
Children once wanted to be doctors or lawyers when they grew up, or at least firemen and engine drivers: now, they just want to be famous.
When you start worrying about the absence of God, perhaps he is thinking about the absence of you.
If you want to make God laugh, tell him your plans.
Lord may my heart be broken by what breaks your heart.
There is no future in relying on fate.
Educate without the Bible: you end up with clever devils.
Children once wanted to be doctors or lawyers when they grew up, or at least firemen and engine drivers: now, they just want to be famous.
Wednesday, January 14, 2009
Vitamin A
By 1906 it was known that factors other than carbohydrates, proteins and fats were necessary to keep cattle healthy. In 1917 one such substance was independently discovered by two American research groups, Elmer McCollum at the University of Wisconsin, and Lafayette Mendel and Thomas Osborne at Yale University. McCollum recognised that there were more than one of these substances and designated the fat soluble entity Vitamin A and the water soluble factor Vitamin B. In 1934 Wald isolated from animal retina a substance he called retinene. Morton in 1944 suggested that this compound was the aldehyde of vitamin A, and called it retinaldehyde (rather than retinal). The correct structure of vitamin A was deduced in 1931 by Karrer who proposed the name axerophthol (Axerophtol in German), based on its action in preventing the eye disease xerophthalmia. The first synthesis was in 1947 by two Dutch chemists, David Adriaan van Dorp and Jozef Ferdinand Arens.
Vitamin A found in foods that come from animals is called preformed vitamin A. It is absorbed in the form of retinol, one of the most usable forms of vitamin A. Sources include liver, whole milk, and some fortified food products. Retinol can be made into retinal and retinoic acid in the body. Provitamin A is found in colorful fruits and vegetables and is called carotenoid. It can be made into retinol in the body. Common provitamin A carotenoids found in foods that come from plants are beta-carotene, alpha-carotene, and beta-cryptoxanthin. Among these, beta-carotene is most efficiently made into retinol. Alpha-carotene and beta-cryptoxanthin are also converted to vitamin A, but only half as efficiently as beta-carotene.
Actually, of the 563 identified carotenoids, fewer than 10% can be made into vitamin A in the body. Some provitamin A carotenoids have been shown to function as antioxidants in laboratory studies; however, this role has not been consistently demonstrated in humans. Antioxidants protect cells from free radicals, which are potentially damaging by-products of oxygen metabolism that may contribute to the development of some chronic diseases.
Vitamin A is interesting for hematologists. The cell line HL60 is a myeloid leukemic cell line much loved by experimental hematologists. These blast-like cells can be made to differentiate into neutrophil granulocytes if exposed to vitamin A (vitamin D on the other hand turns them into monocytes) It appears that developing white cells have a receptor specifically designed for vitamin A.
Vitamin A deficiency is common in developing countries but rarely seen in the United States and Europe. Approximately 250,000 to 500,000 malnourished children in the developing world become blind each year from a deficiency of vitamin A. In Western countries, vitamin A deficiency is most often associated with strict dietary restrictions and excess alcohol intake. Strict dietary restrictions can also lead to zinc deficiency. Zinc is required to make retinol binding protein (RBP) which transports vitamin A. Therefore, a deficiency in zinc limits the body's ability to move vitamin A stores from the liver to body tissues.
Night blindness is one of the first signs of vitamin A deficiency. In ancient Egypt, it was known that night blindness could be cured by eating liver, which was later found to be a rich source of the vitamin. Vitamin A deficiency also contributes to blindness by making the surface of the eye very dry, thus it damages both the retina and the cornea.
As with other vitamins there has been interest in low storage levels of vitamin A that do not cause obvious deficiency symptoms. This supposedly mild degree of vitamin A deficiency is said to increase children's risk of developing respiratory and diarrheal infections, decrease growth rate, slow bone development, and decrease likelihood of survival from serious illness. Children living at or below the poverty level, who have children with inadequate health care or immunizations, especially those from immigrant communities and those with abnormalities of fat absorption are believed to be especially at risk.
Unless a person falls into one of these groups it is entirely likely that a normal diet will provide sufficient vitamin A. Three ounces of liver, for example, provides five times the daily requirement. Vegetarians and those who do not take dairy products will have to rely on the conversion of pro-retinoids from vegetables like carrots, cabbage, spinach or broccoli.
For those who like to take megadoses of vitamins, Vitamin A is one to be wary of. Overdoses are possible and can cause birth defects, liver abnormalities, reduced bone mineral density that may result in osteoporosis, and central nervous system disorders. The pro-retinoids have also been recommended as a prophylactic against cancer. A very large study of the use of beta-carotene had to be stopped when it was found that there was a 46% increase in lung cancer in those taking beta-carotene compared with controls.
However, retinoids can be used as medicines. For about 15 years synthetic retinoids (Roaccutane® or Accutane®)) have been used to treat certain skin diseases such as acne and psoriasis, and another retinoid, all trans retinoic acid (ATRA) is used to treat acute promyelocytic leukemia. Nevertheless, even these drugs should be avoided by those likely to get pregnant, and liver function tests should be monitored.
The daily requirement for vitamin A depends on your body size, but it is about 3000 international units and the safe upper limit of intake is 10,000 international units. 10,000 international unit is equivalent to about 3000 micrograms.
Vitamin A found in foods that come from animals is called preformed vitamin A. It is absorbed in the form of retinol, one of the most usable forms of vitamin A. Sources include liver, whole milk, and some fortified food products. Retinol can be made into retinal and retinoic acid in the body. Provitamin A is found in colorful fruits and vegetables and is called carotenoid. It can be made into retinol in the body. Common provitamin A carotenoids found in foods that come from plants are beta-carotene, alpha-carotene, and beta-cryptoxanthin. Among these, beta-carotene is most efficiently made into retinol. Alpha-carotene and beta-cryptoxanthin are also converted to vitamin A, but only half as efficiently as beta-carotene.
Actually, of the 563 identified carotenoids, fewer than 10% can be made into vitamin A in the body. Some provitamin A carotenoids have been shown to function as antioxidants in laboratory studies; however, this role has not been consistently demonstrated in humans. Antioxidants protect cells from free radicals, which are potentially damaging by-products of oxygen metabolism that may contribute to the development of some chronic diseases.
Vitamin A is interesting for hematologists. The cell line HL60 is a myeloid leukemic cell line much loved by experimental hematologists. These blast-like cells can be made to differentiate into neutrophil granulocytes if exposed to vitamin A (vitamin D on the other hand turns them into monocytes) It appears that developing white cells have a receptor specifically designed for vitamin A.
Vitamin A deficiency is common in developing countries but rarely seen in the United States and Europe. Approximately 250,000 to 500,000 malnourished children in the developing world become blind each year from a deficiency of vitamin A. In Western countries, vitamin A deficiency is most often associated with strict dietary restrictions and excess alcohol intake. Strict dietary restrictions can also lead to zinc deficiency. Zinc is required to make retinol binding protein (RBP) which transports vitamin A. Therefore, a deficiency in zinc limits the body's ability to move vitamin A stores from the liver to body tissues.
Night blindness is one of the first signs of vitamin A deficiency. In ancient Egypt, it was known that night blindness could be cured by eating liver, which was later found to be a rich source of the vitamin. Vitamin A deficiency also contributes to blindness by making the surface of the eye very dry, thus it damages both the retina and the cornea.
As with other vitamins there has been interest in low storage levels of vitamin A that do not cause obvious deficiency symptoms. This supposedly mild degree of vitamin A deficiency is said to increase children's risk of developing respiratory and diarrheal infections, decrease growth rate, slow bone development, and decrease likelihood of survival from serious illness. Children living at or below the poverty level, who have children with inadequate health care or immunizations, especially those from immigrant communities and those with abnormalities of fat absorption are believed to be especially at risk.
Unless a person falls into one of these groups it is entirely likely that a normal diet will provide sufficient vitamin A. Three ounces of liver, for example, provides five times the daily requirement. Vegetarians and those who do not take dairy products will have to rely on the conversion of pro-retinoids from vegetables like carrots, cabbage, spinach or broccoli.
For those who like to take megadoses of vitamins, Vitamin A is one to be wary of. Overdoses are possible and can cause birth defects, liver abnormalities, reduced bone mineral density that may result in osteoporosis, and central nervous system disorders. The pro-retinoids have also been recommended as a prophylactic against cancer. A very large study of the use of beta-carotene had to be stopped when it was found that there was a 46% increase in lung cancer in those taking beta-carotene compared with controls.
However, retinoids can be used as medicines. For about 15 years synthetic retinoids (Roaccutane® or Accutane®)) have been used to treat certain skin diseases such as acne and psoriasis, and another retinoid, all trans retinoic acid (ATRA) is used to treat acute promyelocytic leukemia. Nevertheless, even these drugs should be avoided by those likely to get pregnant, and liver function tests should be monitored.
The daily requirement for vitamin A depends on your body size, but it is about 3000 international units and the safe upper limit of intake is 10,000 international units. 10,000 international unit is equivalent to about 3000 micrograms.
Sunday, January 11, 2009
A Certain Hope
I have friends who really believe that this life is all there is. They are quite content to believe that there is no overall point to life except what matters at the moment. They believe that morality is a survival factor for society, selected for by Darwinian processes, and that what is not discovered doesn't matter. They live lives on the basis that it doesn't matter what you do as long as you harm no-one else. From this it follows that there is no such thing as sin, that euthanasia is sensible, abortion is a matter of personal choice and 'victimless crime' is fine as long as no-one finds out about it.
Yet to me such a life would be intolerable. Imagine a world where Adolf Hitler faced no eternal judge. He spent his whole life inflicting intolerable cruelty on millions of people and then when the Soviet Armies were closing in he escaped justice by killing himself.
When Peter wrote to the Christians scattered throughout Turkey his basis for living was entirely different. He talks about hope. This is not the sort of hope that looks forward to the possibility of the USA winning the soccer World Cup. Possible if Brazil and Argentina, Italy, France and Germany got wiped out by a virus, but even then no better than a 20-1 shot. No, this is a hope that you can bet your life on. And I have.
1 Peter 1:3 calls it a living hope through the resurrection of the Lord Jesus. It is a hope grounded in an historical event. The apostle Paul tells us that if Christ be not risen we are of all men most miserable. Why? Because we would have bet our lives on a false premise. Everything depends on the Resurrection. It tells us that there is life after death. If you like, Christ is the earnest of our inheritance; He is the deposit that guarantees full payment. He is the hostage to our fortune.
If someone were to prove that Christ did not rise from the dead than our faith would be groundless. Oh, I dare say a case could be made for Christianity being a fine set of morals, that 'turning the other cheek' and 'loving your enemies' are fine ways to live, but without the hope of everlasting life we might as well connive, cheat, act, pretend and otherwise appear to be good in order to gain the approval of men, but in the meantime secretly feather our own nests by lying, stealing, fraudulently deceiving and cleverly evading detection.
Is the Resurrection historical fact? Did Julius Caesar land in Britain? We only have eye witness accounts of both these events, which took place within 100 years of each other. There are, in fact, much better historical records for the former than the latter. But you may say, men land on the beaches of Britain every day of the week; they don't rise from the dead quite so frequently.
But suppose I were to propose that Julius Caesar was a self-seeking fraud who was only concerned with gaining power and glory - there is a lot of evidence that might well be so - who is to say that, sure, the Romans came to Britain, but it wasn't Julius Caesar who undertook the Channel crossing, he sent a surrogate and took the glory without any of the risk. We have only the written record to say that it wasn't so. But who disbelieves Caesar's Gallic Wars?
The Bible claims that men don't rise from the dead as a general rule. But on a unique occasion one man rose miraculously because he was not simply a man. The thing about unique events is that you can't use the run of the mill to disprove them. Bournemouth once beat Manchester United at football. Now that doesn't happen as a rule of thumb. But you can't use that as a reason for saying it couldn't happen. It was a unique event. Eye witnesses were present. Some will have said, "If I hadn't seen it with my own eyes I would not have believed it." I wasn't there, but I do believe it happened because there is a reliable written record that it did happen.
Just how reliable is the written record that Jesus rose from the dead. Contrary to popular belief, the earliest records of the resurrection do not date from centuries later. It was not an invention by the Catholic Church. We have eye-witness accounts of those who saw the risen Jesus, touched him and ate with him. These accounts were shared among his followers orally, but within a decade or so they were being written down.
OK, you say, show us the documents so that we can carbon-date them. As a mater of fact we don’t have the originals, but then we don’t have the originals of Caesar’s Gallic Wars either. In fact the earliest copy we have of that was written in 900AD, about 1000 years after it was composed. In contrast, the earliest copy we have of bits of the New Testament dates from 130 AD. This is a portion of John’s Gospel held in the John Rylands Museum in Manchester, UK. Even that is interesting. Much of the doubt about the authenticity of the historical record comes from the German Higher Critics of the 19th Century. The brilliant Professor Ferdinand Christian Baur from Tubingen argued that John’s Gospel could not have been written any earlier than 160 AD. Doh!
We also have the evidence of the Early Church Fathers. Not only can the whole New Testament (minus eleven verses) be found quoted by the Church Fathers such as Irenaeus (180 AD), Clement (150-211AD), Tertullian (160-220AD) and Hippolytus (170-235AD), but Ignatius, a prolific letter writer who died at the age of 40 in 110 AD has quotes from 13 of the 27 books of the New Testament in his letters.
Unique though it was, the resurrection of Jesus was believed by thousands of people within weeks of its occurrence. Despite attempts by the authorities to disparage it, the story would not go away. If it were just a story then it would only have been the few in the in-crowd who had actually witnessed it, say Peter, James and John and perhaps Mary Magdalene, but on one occasion the risen Jesus appeared to a crowd of 500.
The lawyer, Frank Morrison, who was trained in the rules of evidence set out to prove that the whole thing was a fraud. He considered all the other possible explanations – he didn’t really die, it was mass hypnosis, there was a conspiracy between the disciples – but in the end he comes to the conclusion that it really happened. He wrote it all down in his book, “Who Moved the Stone?”
The argument that really impressed me was the fact that the believers were tortured. This was not water boarding or being made to stand in a stressed position, these men were crucified, fed to the lions, covered with oil and set alight to provide floodlights for the gladiators. Now, people will withstand torture if they really believe in something, but I can’t believe they would withstand it for something that they knew was a lie. Remember that Peter himself was crucified.
The resurrection of Jesus is the most reliable historical fact from 2000 years ago. You’d better believe it.
Yet to me such a life would be intolerable. Imagine a world where Adolf Hitler faced no eternal judge. He spent his whole life inflicting intolerable cruelty on millions of people and then when the Soviet Armies were closing in he escaped justice by killing himself.
When Peter wrote to the Christians scattered throughout Turkey his basis for living was entirely different. He talks about hope. This is not the sort of hope that looks forward to the possibility of the USA winning the soccer World Cup. Possible if Brazil and Argentina, Italy, France and Germany got wiped out by a virus, but even then no better than a 20-1 shot. No, this is a hope that you can bet your life on. And I have.
1 Peter 1:3 calls it a living hope through the resurrection of the Lord Jesus. It is a hope grounded in an historical event. The apostle Paul tells us that if Christ be not risen we are of all men most miserable. Why? Because we would have bet our lives on a false premise. Everything depends on the Resurrection. It tells us that there is life after death. If you like, Christ is the earnest of our inheritance; He is the deposit that guarantees full payment. He is the hostage to our fortune.
If someone were to prove that Christ did not rise from the dead than our faith would be groundless. Oh, I dare say a case could be made for Christianity being a fine set of morals, that 'turning the other cheek' and 'loving your enemies' are fine ways to live, but without the hope of everlasting life we might as well connive, cheat, act, pretend and otherwise appear to be good in order to gain the approval of men, but in the meantime secretly feather our own nests by lying, stealing, fraudulently deceiving and cleverly evading detection.
Is the Resurrection historical fact? Did Julius Caesar land in Britain? We only have eye witness accounts of both these events, which took place within 100 years of each other. There are, in fact, much better historical records for the former than the latter. But you may say, men land on the beaches of Britain every day of the week; they don't rise from the dead quite so frequently.
But suppose I were to propose that Julius Caesar was a self-seeking fraud who was only concerned with gaining power and glory - there is a lot of evidence that might well be so - who is to say that, sure, the Romans came to Britain, but it wasn't Julius Caesar who undertook the Channel crossing, he sent a surrogate and took the glory without any of the risk. We have only the written record to say that it wasn't so. But who disbelieves Caesar's Gallic Wars?
The Bible claims that men don't rise from the dead as a general rule. But on a unique occasion one man rose miraculously because he was not simply a man. The thing about unique events is that you can't use the run of the mill to disprove them. Bournemouth once beat Manchester United at football. Now that doesn't happen as a rule of thumb. But you can't use that as a reason for saying it couldn't happen. It was a unique event. Eye witnesses were present. Some will have said, "If I hadn't seen it with my own eyes I would not have believed it." I wasn't there, but I do believe it happened because there is a reliable written record that it did happen.
Just how reliable is the written record that Jesus rose from the dead. Contrary to popular belief, the earliest records of the resurrection do not date from centuries later. It was not an invention by the Catholic Church. We have eye-witness accounts of those who saw the risen Jesus, touched him and ate with him. These accounts were shared among his followers orally, but within a decade or so they were being written down.
OK, you say, show us the documents so that we can carbon-date them. As a mater of fact we don’t have the originals, but then we don’t have the originals of Caesar’s Gallic Wars either. In fact the earliest copy we have of that was written in 900AD, about 1000 years after it was composed. In contrast, the earliest copy we have of bits of the New Testament dates from 130 AD. This is a portion of John’s Gospel held in the John Rylands Museum in Manchester, UK. Even that is interesting. Much of the doubt about the authenticity of the historical record comes from the German Higher Critics of the 19th Century. The brilliant Professor Ferdinand Christian Baur from Tubingen argued that John’s Gospel could not have been written any earlier than 160 AD. Doh!
We also have the evidence of the Early Church Fathers. Not only can the whole New Testament (minus eleven verses) be found quoted by the Church Fathers such as Irenaeus (180 AD), Clement (150-211AD), Tertullian (160-220AD) and Hippolytus (170-235AD), but Ignatius, a prolific letter writer who died at the age of 40 in 110 AD has quotes from 13 of the 27 books of the New Testament in his letters.
Unique though it was, the resurrection of Jesus was believed by thousands of people within weeks of its occurrence. Despite attempts by the authorities to disparage it, the story would not go away. If it were just a story then it would only have been the few in the in-crowd who had actually witnessed it, say Peter, James and John and perhaps Mary Magdalene, but on one occasion the risen Jesus appeared to a crowd of 500.
The lawyer, Frank Morrison, who was trained in the rules of evidence set out to prove that the whole thing was a fraud. He considered all the other possible explanations – he didn’t really die, it was mass hypnosis, there was a conspiracy between the disciples – but in the end he comes to the conclusion that it really happened. He wrote it all down in his book, “Who Moved the Stone?”
The argument that really impressed me was the fact that the believers were tortured. This was not water boarding or being made to stand in a stressed position, these men were crucified, fed to the lions, covered with oil and set alight to provide floodlights for the gladiators. Now, people will withstand torture if they really believe in something, but I can’t believe they would withstand it for something that they knew was a lie. Remember that Peter himself was crucified.
The resurrection of Jesus is the most reliable historical fact from 2000 years ago. You’d better believe it.
Foodless in Gaza
Whatever your feelings about the war in Gaza, there is one group who are wholly innocent of any wrongdoing there. I refer to the 3000 Christians who live there. It costs $70 a week to provide food for a Christian family marooned there and caught up in a bitter war between Islamist and Jew.
Barnabas Fund has been assisting Christians in both the West Bank and Gaza since 2001 with food and basic needs. Please donate to Project 65-377 to enable them to continue helping.
You can donate here . Please quote project reference 65-377
Barnabas Fund has been assisting Christians in both the West Bank and Gaza since 2001 with food and basic needs. Please donate to Project 65-377 to enable them to continue helping.
You can donate here . Please quote project reference 65-377
Thursday, January 08, 2009
Vitamins
This is the beginning of a new series of articles on Vitamins.
The word was coined by Sir Jack Cecil Drummond D.Sc., FRIC, FRS (12 Jan 1891—4 Aug or 5 Aug 1952). He was a distinguished biochemist, noted for his work on nutrition as applied to the British diet under rationing during the Second World War. He was murdered, together with his wife and 10-year old daughter, on the night of 4 Aug - 5 Aug 1952 near Lurs, a village or commune in the Basses-Alpes region (now Alpes-de-Haute-Provence) of Southern France. The name derives from 'vital amine' which Polish biochemist Kazimierz Funk contacted to 'Vitamine'. Drummond merely suggested dropping the final 'e' when it became clear that not all vitamins are amines.
The story of vitamins begins with Scottish surgeon James Lind who in 1749, the discovered that citrus foods such as lemons and limes prevented scurvy, disease of sailors in which collagen is not properly formed, causing poor wound healing, bleeding of the gums, severe pain, and death. In 1753, Lind published his Treatise on the Scurvy, which recommended using lemons and limes to avoid scurvy, which was adopted by the Royal Navy. So British sailors and later all Englishmen became known as Limeys.
Others such as Estonian surgeon Nikolai Lunin, Takaki Kanehiro, a British trained doctor of the Japanese Navy, Christiaan Eijkman, a Dutch pathologist working in the Dutch East Indies (now Indonesia) and Sir Frederick Gowland Hopkins OM FRS from Cambridge all made contributions to the realisation that some foods contained "accessory factors" in addition to proteins, carbohydrates, fats, etc. that are necessary for the functions of the human body. Hopkins and Eijkman were awarded the Nobel Prize in Physiology or Medicine in 1929 for the discovery of vitamins.
Vitamins are cheap and although we all need them, most are found in a normal diet. Some substances have been proposed as vitamins and are not and for some it has been proposed that we need far higher doses than are in a normal diet. We shall look at this proposition.
The story of vitamins is an exciting one and I shall enjoy writing it over the next few weeks.
The word was coined by Sir Jack Cecil Drummond D.Sc., FRIC, FRS (12 Jan 1891—4 Aug or 5 Aug 1952). He was a distinguished biochemist, noted for his work on nutrition as applied to the British diet under rationing during the Second World War. He was murdered, together with his wife and 10-year old daughter, on the night of 4 Aug - 5 Aug 1952 near Lurs, a village or commune in the Basses-Alpes region (now Alpes-de-Haute-Provence) of Southern France. The name derives from 'vital amine' which Polish biochemist Kazimierz Funk contacted to 'Vitamine'. Drummond merely suggested dropping the final 'e' when it became clear that not all vitamins are amines.
The story of vitamins begins with Scottish surgeon James Lind who in 1749, the discovered that citrus foods such as lemons and limes prevented scurvy, disease of sailors in which collagen is not properly formed, causing poor wound healing, bleeding of the gums, severe pain, and death. In 1753, Lind published his Treatise on the Scurvy, which recommended using lemons and limes to avoid scurvy, which was adopted by the Royal Navy. So British sailors and later all Englishmen became known as Limeys.
Others such as Estonian surgeon Nikolai Lunin, Takaki Kanehiro, a British trained doctor of the Japanese Navy, Christiaan Eijkman, a Dutch pathologist working in the Dutch East Indies (now Indonesia) and Sir Frederick Gowland Hopkins OM FRS from Cambridge all made contributions to the realisation that some foods contained "accessory factors" in addition to proteins, carbohydrates, fats, etc. that are necessary for the functions of the human body. Hopkins and Eijkman were awarded the Nobel Prize in Physiology or Medicine in 1929 for the discovery of vitamins.
Vitamins are cheap and although we all need them, most are found in a normal diet. Some substances have been proposed as vitamins and are not and for some it has been proposed that we need far higher doses than are in a normal diet. We shall look at this proposition.
The story of vitamins is an exciting one and I shall enjoy writing it over the next few weeks.
Dalziel and Pascoe
One of the few things that my father left me when he died 31 years ago was a battered paperback entitled 'A Clubable Woman'. It was the the volume that introduced PC Peter Pascoe to Superintendent Andy Dalziel (pronounced DEE-al). In my opinion Reginald Hill's inventions are the best creations in cop-show literature. If you have only seen the TV films you are missing a treat. To be sure Colin Buchanan and Warren Clarke are a great improvement on Hale and Pace who filmed 'A Pinch of Snuff' but even Clarke's ugliness and growing obesity do not do justice to Hill's description of the 'Fat Man' (Sidney Greenstreet perhaps, though I'm not sure he could do the Yorkshire accent). Incidentally, I watched the Anthony Hopkins film of Le Carre's 'Looking Glass War' the other day and was surprised to see a young slim and handsome Warren Clarke with fine blond hair. Colin Buchanan was fine as a young copper, but age and avoir du pois have turned him into a passable imitation of Andy. Watching them plod together with sour looks on their faces reminds one of how people and their dogs tend to resemble one another.
The books and the films diverged from one another after the first series, with the dropping of Ellie Pascoe and Sergeant Wield. They are both still in the books and the films are poorer for their loss.
I have just finished the two latest novels, 'The death of Dalziel' and 'The cure for all diseases' and I'm pleased to say that Reginald Hill is still in fine literary form.
The books and the films diverged from one another after the first series, with the dropping of Ellie Pascoe and Sergeant Wield. They are both still in the books and the films are poorer for their loss.
I have just finished the two latest novels, 'The death of Dalziel' and 'The cure for all diseases' and I'm pleased to say that Reginald Hill is still in fine literary form.
Wednesday, January 07, 2009
Polar Bears Saved!
The shot of the polar bear marooned on a small piece of floating ice was the most potent weapon in the armory of the global warming zealots. Despite the fact that the shot was contrived and the fact that polar bear numbers are actually increasing, (from 5000 in 1950 to 25,000 now) in May concerns over disappearing sea ice led the U.S. to officially list the polar bear a threatened species, over objections from experts.
Earlier this year, predictions were rife that the North Pole could melt entirely in 2008. Instead, the Arctic ice saw a substantial recovery. Thanks to a rapid rebound in recent months, global sea ice levels now equal those seen 29 years ago, when the year 1979 also drew to a close. Ice levels had been tracking lower throughout much of 2008, but rapidly recovered in the last quarter. In fact, the rate of increase from September onward is the fastest rate of change on record, either upwards or downwards.
Bill Chapman, a researcher with the University of Illinois's Arctic Climate Research Center, claims that this was due in part to colder temperatures in the region. Chapman says wind patterns have also been weaker this year. Strong winds can slow ice formation as well as forcing ice into warmer waters where it will melt.
Why were predictions so wrong? Researchers had expected the newer sea ice, which is thinner, to be less resilient and melt easier. Instead, the thinner ice had less snow cover to insulate it from the bitterly cold air, and therefore grew much faster than expected, according to the National Snow and Ice Data Center.
Earlier this year, predictions were rife that the North Pole could melt entirely in 2008. Instead, the Arctic ice saw a substantial recovery. Thanks to a rapid rebound in recent months, global sea ice levels now equal those seen 29 years ago, when the year 1979 also drew to a close. Ice levels had been tracking lower throughout much of 2008, but rapidly recovered in the last quarter. In fact, the rate of increase from September onward is the fastest rate of change on record, either upwards or downwards.
Bill Chapman, a researcher with the University of Illinois's Arctic Climate Research Center, claims that this was due in part to colder temperatures in the region. Chapman says wind patterns have also been weaker this year. Strong winds can slow ice formation as well as forcing ice into warmer waters where it will melt.
Why were predictions so wrong? Researchers had expected the newer sea ice, which is thinner, to be less resilient and melt easier. Instead, the thinner ice had less snow cover to insulate it from the bitterly cold air, and therefore grew much faster than expected, according to the National Snow and Ice Data Center.
Tuesday, January 06, 2009
Lists
What's with it with men and lists? Some of the TV schedules are filled with them. 'The hundred best comedy classics'. 'Twenty worst turkeys of the noughties'. 'Ten best cop shows'. And of course we have the 'Billboard Hot Hundred' and the NME top twenty. Sports fans want to know the position in the league of their favorite football team and now we have league tables for schools and hospitals.
I first started making lists when I was under ten. Following the 1951 census I made a list of the largest cities in the United Kingdom. London was 8 million plus, Both Birmingham and Glasgow around one million, one hundred thousand, Manchester and Liverpool both in the seven hundred and eighty thousands, then it was Leeds, Sheffield, Bristol, Cardiff, Edinburgh and Belfast, then Newcastle, Nottingham and Hull, and when we reached cities of about a quarter of a million people there were too many - Stoke, Southampton, Portsmouth, Plymouth, Coventry, Leicester. It all got a lot more complicated when you started to define what a city is. What was the edge of London? Should you count the London boroughs like Croydon and Bromley - each with more than 300,000 people as part of London or separate entities? Is Newcastle just Newcastle or should you include Gateshead, Jarrow, North and South Shields and Wallsend? Bournemouth is only 150,000, but if you include Poole, Christchurch and all the contiguous towns it has nearly half a million people. When we say that Glasgow has declined to 600,000 people, is that real or due to boundary changes? What about Manchester? it is much smaller now, but Greater Manchester has 2.5 million people. If London is defined as everywhere withing the M25, the London orbital motorway, then it include a third of the population of England - about 16 million people.
Once you have a list there is this temptation to start analysing it. When I was first appointed a consultant hematologist I started making lists of my patients. Although all the excitement was in acute leukemia, by far the largest list I had was of patients with chronic lymphocytic leukemia. It was when I started subclassifying this list that my interest in CLL began.
Over the past few days I have been making a list of my DVDs. I have noticed one thing, at least. Although film is said to be a director's medium, and who has not heard of Hitchcock, Stanley Kubrick, John Ford, Marin Scorsese and the rest, but some quite famous films have quite obscure directors. Who's ever heard of Rowdy Herrington or Robby Henson or Peter Webber? Yet they managed to attract actors like Jim Caviezel, Malcolm McDowell, Billy Bob Thornton, Tom Wilkinson and Scarlet Johansson to their films. Perhaps after paying the stars, the producers didn't have much left to pay the director?
The occasion for my list is a determination to replace my old technology with new. I am ditching my VHS tapes and replacing with DVDs. Whether this is a wise decision I am not sure. Already DVDs are passing into history and Blu-Ray is taking their place. While we now have equipment to play our old LPs, is there really any reason to replace our tapes? I am not sure.
There is a pleasure in owning things, though the pleasure is not so much using them as listing them. Kids at school collect swap cards of various sorts. Collecting is the pleasure. They will collect anything that has absolutely no use. I have not watched 90 of my DVDs yet. That's about 180 hours of sitting down watching television. I doubt I shall have completed this by this time next year. Note to self: Don't buy any more DVDs.
I first started making lists when I was under ten. Following the 1951 census I made a list of the largest cities in the United Kingdom. London was 8 million plus, Both Birmingham and Glasgow around one million, one hundred thousand, Manchester and Liverpool both in the seven hundred and eighty thousands, then it was Leeds, Sheffield, Bristol, Cardiff, Edinburgh and Belfast, then Newcastle, Nottingham and Hull, and when we reached cities of about a quarter of a million people there were too many - Stoke, Southampton, Portsmouth, Plymouth, Coventry, Leicester. It all got a lot more complicated when you started to define what a city is. What was the edge of London? Should you count the London boroughs like Croydon and Bromley - each with more than 300,000 people as part of London or separate entities? Is Newcastle just Newcastle or should you include Gateshead, Jarrow, North and South Shields and Wallsend? Bournemouth is only 150,000, but if you include Poole, Christchurch and all the contiguous towns it has nearly half a million people. When we say that Glasgow has declined to 600,000 people, is that real or due to boundary changes? What about Manchester? it is much smaller now, but Greater Manchester has 2.5 million people. If London is defined as everywhere withing the M25, the London orbital motorway, then it include a third of the population of England - about 16 million people.
Once you have a list there is this temptation to start analysing it. When I was first appointed a consultant hematologist I started making lists of my patients. Although all the excitement was in acute leukemia, by far the largest list I had was of patients with chronic lymphocytic leukemia. It was when I started subclassifying this list that my interest in CLL began.
Over the past few days I have been making a list of my DVDs. I have noticed one thing, at least. Although film is said to be a director's medium, and who has not heard of Hitchcock, Stanley Kubrick, John Ford, Marin Scorsese and the rest, but some quite famous films have quite obscure directors. Who's ever heard of Rowdy Herrington or Robby Henson or Peter Webber? Yet they managed to attract actors like Jim Caviezel, Malcolm McDowell, Billy Bob Thornton, Tom Wilkinson and Scarlet Johansson to their films. Perhaps after paying the stars, the producers didn't have much left to pay the director?
The occasion for my list is a determination to replace my old technology with new. I am ditching my VHS tapes and replacing with DVDs. Whether this is a wise decision I am not sure. Already DVDs are passing into history and Blu-Ray is taking their place. While we now have equipment to play our old LPs, is there really any reason to replace our tapes? I am not sure.
There is a pleasure in owning things, though the pleasure is not so much using them as listing them. Kids at school collect swap cards of various sorts. Collecting is the pleasure. They will collect anything that has absolutely no use. I have not watched 90 of my DVDs yet. That's about 180 hours of sitting down watching television. I doubt I shall have completed this by this time next year. Note to self: Don't buy any more DVDs.
Saturday, January 03, 2009
Africa
It was good to see Dennis and Sheila Eaton, home from Malawi this Christmas. I have known Dennis and Sheila for 30 years and played a part in bringing them together as a couple. Dennis was until recently on the staff as minister for pastoral care at our church but last year they were sent as missionaries to Malawi, to one of the poorest parts of one of the poorest countries in Africa. It was interesting therefore to read this article in the Times by Matthew Parris. I shall quote large sections of it.
"travelling in Malawi refreshed another belief, too: one I've been trying to banish all my life, but an observation I've been unable to avoid since my African childhood. It confounds my ideological beliefs, stubbornly refuses to fit my world view, and has embarrassed my growing belief that there is no God."
"Now a confirmed atheist, I've become convinced of the enormous contribution that Christian evangelism makes in Africa: sharply distinct from the work of secular NGOs, government projects and international aid efforts. These alone will not do. Education and training alone will not do. In Africa Christianity changes people's hearts. It brings a spiritual transformation. The rebirth is real. The change is good."
"I used to avoid this truth by applauding - as you can - the practical work of mission churches in Africa. It's a pity, I would say, that salvation is part of the package, but Christians black and white, working in Africa, do heal the sick, do teach people to read and write; and only the severest kind of secularist could see a mission hospital or school and say the world would be better without it. I would allow that if faith was needed to motivate missionaries to help, then, fine: but what counted was the help, not the faith."
"But this doesn't fit the facts. Faith does more than support the missionary; it is also transferred to his flock. This is the effect that matters so immensely, and which I cannot help observing."
He then relates his childhood in Africa, traveling as a young man in many parts of sub-Saharan Africa.
"Whenever we entered a territory worked by missionaries, we had to acknowledge that something changed in the faces of the people we passed and spoke to: something in their eyes, the way they approached you direct, man-to-man, without looking down or away. They had not become more deferential towards strangers - in some ways less so - but more open."
"This time in Malawi it was the same. I met no missionaries. You do not encounter missionaries in the lobbies of expensive hotels discussing development strategy documents, as you do with the big NGOs. But instead I noticed that a handful of the most impressive African members of the Pump Aid team (largely from Zimbabwe) were, privately, strong Christians. “Privately” because the charity is entirely secular and I never heard any of its team so much as mention religion while working in the villages. But I picked up the Christian references in our conversations. One, I saw, was studying a devotional textbook in the car. One, on Sunday, went off to church at dawn for a two-hour service."
"It would suit me to believe that their honesty, diligence and optimism in their work was unconnected with personal faith. Their work was secular, but surely affected by what they were. What they were was, in turn, influenced by a conception of man's place in the Universe that Christianity had taught."
He goes on about the state of Africa today, about how fashionable it is to laud the 'tribal value system' that is native to the continent and to condemn the white man's interference and imposition of his own culture on the Africa.
"I don't follow this. I observe that tribal belief is no more peaceable than ours; and that it suppresses individuality. People think collectively; first in terms of the community, extended family and tribe. This rural-traditional mindset feeds into the “big man” and gangster politics of the African city: the exaggerated respect for a swaggering leader, and the (literal) inability to understand the whole idea of loyal opposition. Anxiety - fear of evil spirits, of ancestors, of nature and the wild, of a tribal hierarchy, of quite everyday things - strikes deep into the whole structure of rural African thought. Every man has his place and, call it fear or respect, a great weight grinds down the individual spirit, stunting curiosity. People won't take the initiative, won't take things into their own hands or on their own shoulders."
"Christianity, post-Reformation and post-Luther, with its teaching of a direct, personal, two-way link between the individual and God, unmediated by the collective, and unsubordinate to any other human being, smashes straight through the philosphical/spiritual framework I've just described. It offers something to hold on to to those anxious to cast off a crushing tribal groupthink. That is why and how it liberates."
He concludes: "Those who want Africa to walk tall amid 21st-century global competition must not kid themselves that providing the material means or even the knowhow that accompanies what we call development will make the change. A whole belief system must first be supplanted. And I'm afraid it has to be supplanted by another. Removing Christian evangelism from the African equation may leave the continent at the mercy of a malign fusion of Nike, the witch doctor, the mobile phone and the machete."
Shortly before Christmas I was supposed to appear on a local radio station called Hope FM. I was to be interviewed by Alan Clarredge. He is the man who services our water softener. Wearing another hat he pastors a small evangelical church, but his training is as a water engineer. Any money he makes is recycled into his trips to Africa to bring water to barren villages. He knows the former Central African Federation well (Zimbabwe, Zambia and Malawi - before that, Southern and Northern Rhodesia and Nyassaland). He also knows Robert Mugabe as he serviced the kidney dialysis machine of his late wife. She was a devout Christian and he says, "Kept Robert in check". Without that influence Zimbabwe has become Hell.
The Matthew Parris piece has attracted 227 comments, overwhelmingly supportive. One struck a chord with me, "Then why, of why are you still an atheist? Truth is truth - for the African, for me, for you and for the whole world. God's truth liberates - Frees us to worship our Creator, acknowledging that He alone is worthy of our trust. He alone gives purpose to life! . Insightful article - thanks!"
"travelling in Malawi refreshed another belief, too: one I've been trying to banish all my life, but an observation I've been unable to avoid since my African childhood. It confounds my ideological beliefs, stubbornly refuses to fit my world view, and has embarrassed my growing belief that there is no God."
"Now a confirmed atheist, I've become convinced of the enormous contribution that Christian evangelism makes in Africa: sharply distinct from the work of secular NGOs, government projects and international aid efforts. These alone will not do. Education and training alone will not do. In Africa Christianity changes people's hearts. It brings a spiritual transformation. The rebirth is real. The change is good."
"I used to avoid this truth by applauding - as you can - the practical work of mission churches in Africa. It's a pity, I would say, that salvation is part of the package, but Christians black and white, working in Africa, do heal the sick, do teach people to read and write; and only the severest kind of secularist could see a mission hospital or school and say the world would be better without it. I would allow that if faith was needed to motivate missionaries to help, then, fine: but what counted was the help, not the faith."
"But this doesn't fit the facts. Faith does more than support the missionary; it is also transferred to his flock. This is the effect that matters so immensely, and which I cannot help observing."
He then relates his childhood in Africa, traveling as a young man in many parts of sub-Saharan Africa.
"Whenever we entered a territory worked by missionaries, we had to acknowledge that something changed in the faces of the people we passed and spoke to: something in their eyes, the way they approached you direct, man-to-man, without looking down or away. They had not become more deferential towards strangers - in some ways less so - but more open."
"This time in Malawi it was the same. I met no missionaries. You do not encounter missionaries in the lobbies of expensive hotels discussing development strategy documents, as you do with the big NGOs. But instead I noticed that a handful of the most impressive African members of the Pump Aid team (largely from Zimbabwe) were, privately, strong Christians. “Privately” because the charity is entirely secular and I never heard any of its team so much as mention religion while working in the villages. But I picked up the Christian references in our conversations. One, I saw, was studying a devotional textbook in the car. One, on Sunday, went off to church at dawn for a two-hour service."
"It would suit me to believe that their honesty, diligence and optimism in their work was unconnected with personal faith. Their work was secular, but surely affected by what they were. What they were was, in turn, influenced by a conception of man's place in the Universe that Christianity had taught."
He goes on about the state of Africa today, about how fashionable it is to laud the 'tribal value system' that is native to the continent and to condemn the white man's interference and imposition of his own culture on the Africa.
"I don't follow this. I observe that tribal belief is no more peaceable than ours; and that it suppresses individuality. People think collectively; first in terms of the community, extended family and tribe. This rural-traditional mindset feeds into the “big man” and gangster politics of the African city: the exaggerated respect for a swaggering leader, and the (literal) inability to understand the whole idea of loyal opposition. Anxiety - fear of evil spirits, of ancestors, of nature and the wild, of a tribal hierarchy, of quite everyday things - strikes deep into the whole structure of rural African thought. Every man has his place and, call it fear or respect, a great weight grinds down the individual spirit, stunting curiosity. People won't take the initiative, won't take things into their own hands or on their own shoulders."
"Christianity, post-Reformation and post-Luther, with its teaching of a direct, personal, two-way link between the individual and God, unmediated by the collective, and unsubordinate to any other human being, smashes straight through the philosphical/spiritual framework I've just described. It offers something to hold on to to those anxious to cast off a crushing tribal groupthink. That is why and how it liberates."
He concludes: "Those who want Africa to walk tall amid 21st-century global competition must not kid themselves that providing the material means or even the knowhow that accompanies what we call development will make the change. A whole belief system must first be supplanted. And I'm afraid it has to be supplanted by another. Removing Christian evangelism from the African equation may leave the continent at the mercy of a malign fusion of Nike, the witch doctor, the mobile phone and the machete."
Shortly before Christmas I was supposed to appear on a local radio station called Hope FM. I was to be interviewed by Alan Clarredge. He is the man who services our water softener. Wearing another hat he pastors a small evangelical church, but his training is as a water engineer. Any money he makes is recycled into his trips to Africa to bring water to barren villages. He knows the former Central African Federation well (Zimbabwe, Zambia and Malawi - before that, Southern and Northern Rhodesia and Nyassaland). He also knows Robert Mugabe as he serviced the kidney dialysis machine of his late wife. She was a devout Christian and he says, "Kept Robert in check". Without that influence Zimbabwe has become Hell.
The Matthew Parris piece has attracted 227 comments, overwhelmingly supportive. One struck a chord with me, "Then why, of why are you still an atheist? Truth is truth - for the African, for me, for you and for the whole world. God's truth liberates - Frees us to worship our Creator, acknowledging that He alone is worthy of our trust. He alone gives purpose to life! . Insightful article - thanks!"