1581
Physiology & Medicine / Re: Vitamin D deficiency in Leukemia?
« on: 12/08/2006 18:35:46 »
...Taking advantage of this relatively uncrowded topic of the forum,
please allow me to squeeze in a sort of essay (and forgive my italian-english).
In memory of my father and our long discussions about aircraft and medical sciences.
running title:
...
Engineers (fiction)
…In 1988, analyzing routine maintenance reports related to a particular type of airplane, engineers discover that the aircrafts in which red fluid had been used, had significantly less troubles in the hydraulic system, compared to the ones with blue fluid. Even the plane that recently crashed had blue fluid, but the causes of that accident didn’t seem related to a hydraulic system failure. There is no evidence suggesting that red fluid is chemically superior, compared to the other.
http://blog.lib.umn.edu/cdescomm/cdes_memo/images/tuning_meeting.jpg
http://www.exxonmobil.com/lubes/exxonmobil/emal/images/article_240x240_plane_orange_sky.jpg
http://www.claytonleather.com/seals.gif
After a meeting with all the technical staff, a decision is taken. A dispatch is immediately sent to all the airliners flying that type of plane with an official recommendation to use red fluid for the hydraulic system. A technical team working for the company will try to find out all the differences between the two chemicals and solve the problem. Results will eventually be published in a special Aviation bulletin.
Medical Doctors (reality)
…In 1988 a group of epidemiologists analyze data related to children suffering from different types of leukemia in Shanghai. Data from a similar group of healthy children are used as reference control. They surprisingly find a significantly lower incidence of leukemia in children taking cod liver oil for more than one year.
A scientific report is sent to a widely known medical journal (Cancer), peer-reviewed, accepted and published after a few weeks.
Strangely enough, a possible therapeutic effect of cod liver oil administration to leukemic children is not even mentioned by the Authors.
Click down here to see the abstract:
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=3164642&query_hl=6&itool=pubmed_DocSum
Cod liver oil contains vitamin A, which has well established positive effects in a particular type of leukemia, and vitamin D3, known to be necessary for bone (marrow?) growth and suspected to be important in controlling immune reactions.
Long term use (more than one year) to reach the protective effect would be feasible in leukemia: most treatment protocols last more than one year and during the 3-5 years after diagnosis the risk of disease relapse is high.
Cod liver oil is considered a nutrient, not a drug: nontoxic at normal dosages, it does not interfere with most of the commonly used pharmaceutical products. It should be defined 'historically safe', having been extensively used since the beginning of the last century for various ailments (rickets, tuberculosis, etc.).
…In 1999 an italian doctor reads the article and decides to get more information writing a letter to the Author (who moved to USA in the meantime). He basically asks two questions:
1) are there further studies to confirm a protective effect of cod liver oil?
2) was the protective effect stronger in older children, suspected to develop leukemia after an overridden immune response to a common pathogen? (Mel Greaves’s hypothesis: “the final hit may be infectious”).
He gets a kind reply from the Author in a short while, but the content is pretty dismal for human science as a whole.
No further data are available to confirm those results: cod liver oil is not anymore commonly used. The over ten year old study is unfortunately “buried” in 5 inches diskettes and a detailed revision of those data is almost impossible.
Tricky Note:
The "Shanghai report" is almost unreachable by a rough search through Medline databases. A peculiar text-string: "cod liver oil containing vitamins A and D" makes it impossible to find it out just crossing "leukemia" and "vitamin d"...you have to go for cod liver.
Getting close
…In late 1999 a team of Finnish pediatricians investigate bone turn over in children suffering from cancer (40% leukemias) at completion of therapy. They find abnormal data related to calcium and bone metabolism that explain the high incidence of osteoporosis and pathological fractures observed in these patients. Together with calcium, vitamin D is found significantly lower (P<0.0001). These alterations are referred to bone invasion by cancer initially, but most of all to chemotherapy damage later. These Authors suggest to consider a controlled clinical trial to evaluate the possibility of vitamin D and calcium supplementation.
Click down here to see the abstract:
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=10531569&query_hl=2&itool=pubmed_docsum
Suprisingly, in 1999, writing from the very same country (Finland) the bright hematologist T.T.Timonen gets published in Ann.Hematol. "A hypothesis concerning deficiency of sunlight, cold temperature, and influenza epidemics associated with the onset of acute lymphoblastic leukemia in northern Finland." In the end of the summary: "is hypothesized that sunlight deprivation in the arctic winter can lead to a deficiency of the 1, 25(OH)2D3 vitamin, which might stimulate leukemic cell proliferation and block cell differentiation through dysregulation of growth factors in the bone marrow stromal cells, causing one mutation and an overt ALL in progenitor cells damaged during the current or the previous winter by influenza virus, the other mutation."
"A hypothesis concerning deficiency of sunlight, cold temperature, and influenza epidemics associated with the onset of acute lymphoblastic leukemia in northern Finland." by T.T. Timonen, 1999.
Click down here to see the abstract:
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=10525828&query_hl=6&itool=pubmed_docsum
...but all this is just supporting Mel Greaves’s hypothesis: “the final hit may be infectious”.
Timonen T.T. actually introduces the concept that vitamin D3 deficiency itself might cause leukemia in some patients.
Closer and closer…
…In 2005 a group of pediatricians in Mansoura, Egypt, investigate bone turnover in 43 children with leukemia. They measure bone mineral density (BMD) and markers of calcium homeostasis (including vitamin D3) at diagnosis, after induction chemotherapy (3months), and during maintenance therapy (12months). They find that osteopenia is a serious problem at presentation and after chemotherapy and it seems to be of the low turnover type. Vitamin D3 is reported significantly lower (P<0.0001) in all patients, lowest at presentation but even later it is rarely close to the half of the control value. They conclude that osteopenia in childhood acute leukemia can get benefit from osteoblastic stimulation by sodium fluoride and vitamin D3, which help mineralization of bone.
The Authors of this astonishing research never suggest that the impressive and persistent vitamin D3 deficiency found in all the children might have been present much before the diagnosis of leukemia.
http://www.christophundgabi.de/bilder/egypt/sphinx.jpg
Click down here to see the abstract:
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=16085546&query_hl=4&itool=pubmed_docsum
...one paragraph missing
(it might sound too much personal
I'll leave it empty for now).
...in 2008 at the annual congress of the most famous association for Hematology and Oncology a little group of doctors joining the Childhood Leukemia Conference are celebrating the 20th anniversary of the “Shanghai report”, together with the Authors and a bunch of epidemiologists. Some folks tell funny stories about fishes and make the usual jokes about vitamins.
The first results available are not statistically significant yet (no placebo group, no double blind, it's hard to tell), but patients seem to grow up much better and may be -fingers crossed- have fewer relapses. There is skepticism about the decision to recommend the stinky natural association of vitamins A and D instead of purified synthetic compounds, and the supposed synergistic action of the two cofactors has not been demonstrated yet.
Research to develop and test vitamin D analogues is still far behind: Randomized Clinical Trials will take years but a major pharmaceutical company is supporting them.
A researcher from Israel is showing his final results related to the synergistic effects of carnosic acid (rosemary) and vitamin D on leukemic cells.
A couple of years have past since the Wisdom In Medicine Panel (WIMP!) and the Association of Parents Against Leukemia together with the Commonsense Committee revised the data and took a decision. They immediately issued a special recommendation to be sent to all the families concerned.
Now every evening, everywhere in the world, some parent is reminding one of the kids to take his ‘cod’.
...Epilogue.
Engineers (final fiction)
…In 2008 a Polytechnic professor is illustrating the now famous “blue-fluid case” to a group of students of the Aviation Safety course. She is one of the engineers who 20 years before decided to send as soon as possible a dispatch to all the owners of that type of plane. For various reasons, the recommendation to use red fluid for the hydraulic system was not taken into account by few of them. Over the years, there had been other three near-accidents due to a major hydraulic system failure: two planes had to rush to emergency landings, one was flying in bad weather conditions and almost hit the peak of a mountain. All of them were still using blue fluid. Further and stronger official recommendations were issued, mentioning the incidents and the “growing evidence” that blue fluid could have been the cause.
It took years of investigation to solve the problem: obviously multiple factors were involved. After checking all the data again and again the puzzle was completed. The final piece was an "innocent" chemical in the blue fluid, a stabilyzer substance that had been able to damage only seals from a specific defective batch, and only after a certain period of time. It had been extremely hard and difficult for the whole team of investigators.
The results of this study were finally published in a special Aviation bulletin.
The professor is stressing her point:
"Once you have looked at your results and redone all the calculations, if it is all statistically sound, do not waste anymore time...just move! What did you do all that work for...if you do not put it into practice?"
She is smiling a bit saying:
"Sometimes it is tough to keep on the ground hundreds of planes...but it may happen, and you must be perfectly sure of your results. It takes guts".
At the end of the lesson a student asks:
"How many lives did you and your team save by informing everybody so early?"
The teacher now becomes serious again:
"Do not forget that there is a backup emergency system, reliable enough in normal weather conditions. By the way, our duty is to make aircrafts safer and safer, doctors save lives".
Yes. The professor is right. Doctors and nurses run from emergency rooms to operating theater, from clinic to outpatients, day and night, taking care of their patients in an endless struggle with time (and budget problems). Technology has finally "invaded" Medicine: CATscan, ECHO, MRI and even fiberoptics (that started in aircrafts much before) brought a sort of peaceful revolution into this branch of Science.
The old stethoscope is now almost obsolete and finally engineers work close to doctors these days.
Engineers respect doctors and probably think that they must be special to manage in such a peculiar discipline full of "black holes" and unknown causes...they are a bit scared when they see treatment protocols being improved by trial and error.
They trust medical doctors anyway.
Nevertheless, back in 1988, a couple of open-minded medical doctors discussing the results of the "Shanghai report" together with one or two engineers and a parent of a leukemic child, could have made the difference.
...even now, in this new hypertech century, "it takes guts" to propose cod liver oil use as a nutrient for leukemic patients.
The End
Iko
please allow me to squeeze in a sort of essay (and forgive my italian-english).
In memory of my father and our long discussions about aircraft and medical sciences.
running title:
"The Shanghai Report"
Engineers versus medical doctors: practical application of statistical analysis
...
Engineers (fiction)
…In 1988, analyzing routine maintenance reports related to a particular type of airplane, engineers discover that the aircrafts in which red fluid had been used, had significantly less troubles in the hydraulic system, compared to the ones with blue fluid. Even the plane that recently crashed had blue fluid, but the causes of that accident didn’t seem related to a hydraulic system failure. There is no evidence suggesting that red fluid is chemically superior, compared to the other.
http://blog.lib.umn.edu/cdescomm/cdes_memo/images/tuning_meeting.jpg
http://www.exxonmobil.com/lubes/exxonmobil/emal/images/article_240x240_plane_orange_sky.jpg
http://www.claytonleather.com/seals.gif
After a meeting with all the technical staff, a decision is taken. A dispatch is immediately sent to all the airliners flying that type of plane with an official recommendation to use red fluid for the hydraulic system. A technical team working for the company will try to find out all the differences between the two chemicals and solve the problem. Results will eventually be published in a special Aviation bulletin.
Medical Doctors (reality)
…In 1988 a group of epidemiologists analyze data related to children suffering from different types of leukemia in Shanghai. Data from a similar group of healthy children are used as reference control. They surprisingly find a significantly lower incidence of leukemia in children taking cod liver oil for more than one year.
A scientific report is sent to a widely known medical journal (Cancer), peer-reviewed, accepted and published after a few weeks.
Strangely enough, a possible therapeutic effect of cod liver oil administration to leukemic children is not even mentioned by the Authors.
Click down here to see the abstract:
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=3164642&query_hl=6&itool=pubmed_DocSum
Cod liver oil contains vitamin A, which has well established positive effects in a particular type of leukemia, and vitamin D3, known to be necessary for bone (marrow?) growth and suspected to be important in controlling immune reactions.
Long term use (more than one year) to reach the protective effect would be feasible in leukemia: most treatment protocols last more than one year and during the 3-5 years after diagnosis the risk of disease relapse is high.
Cod liver oil is considered a nutrient, not a drug: nontoxic at normal dosages, it does not interfere with most of the commonly used pharmaceutical products. It should be defined 'historically safe', having been extensively used since the beginning of the last century for various ailments (rickets, tuberculosis, etc.).
…In 1999 an italian doctor reads the article and decides to get more information writing a letter to the Author (who moved to USA in the meantime). He basically asks two questions:
1) are there further studies to confirm a protective effect of cod liver oil?
2) was the protective effect stronger in older children, suspected to develop leukemia after an overridden immune response to a common pathogen? (Mel Greaves’s hypothesis: “the final hit may be infectious”).
He gets a kind reply from the Author in a short while, but the content is pretty dismal for human science as a whole.
No further data are available to confirm those results: cod liver oil is not anymore commonly used. The over ten year old study is unfortunately “buried” in 5 inches diskettes and a detailed revision of those data is almost impossible.
Tricky Note:
The "Shanghai report" is almost unreachable by a rough search through Medline databases. A peculiar text-string: "cod liver oil containing vitamins A and D" makes it impossible to find it out just crossing "leukemia" and "vitamin d"...you have to go for cod liver.
Getting close
…In late 1999 a team of Finnish pediatricians investigate bone turn over in children suffering from cancer (40% leukemias) at completion of therapy. They find abnormal data related to calcium and bone metabolism that explain the high incidence of osteoporosis and pathological fractures observed in these patients. Together with calcium, vitamin D is found significantly lower (P<0.0001). These alterations are referred to bone invasion by cancer initially, but most of all to chemotherapy damage later. These Authors suggest to consider a controlled clinical trial to evaluate the possibility of vitamin D and calcium supplementation.
Click down here to see the abstract:
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=10531569&query_hl=2&itool=pubmed_docsum
Suprisingly, in 1999, writing from the very same country (Finland) the bright hematologist T.T.Timonen gets published in Ann.Hematol. "A hypothesis concerning deficiency of sunlight, cold temperature, and influenza epidemics associated with the onset of acute lymphoblastic leukemia in northern Finland." In the end of the summary: "is hypothesized that sunlight deprivation in the arctic winter can lead to a deficiency of the 1, 25(OH)2D3 vitamin, which might stimulate leukemic cell proliferation and block cell differentiation through dysregulation of growth factors in the bone marrow stromal cells, causing one mutation and an overt ALL in progenitor cells damaged during the current or the previous winter by influenza virus, the other mutation."
http://www.yukonhelmut.de/Winter/Artic1.jpg
"A hypothesis concerning deficiency of sunlight, cold temperature, and influenza epidemics associated with the onset of acute lymphoblastic leukemia in northern Finland." by T.T. Timonen, 1999.
Click down here to see the abstract:
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=10525828&query_hl=6&itool=pubmed_docsum
...but all this is just supporting Mel Greaves’s hypothesis: “the final hit may be infectious”.
Timonen T.T. actually introduces the concept that vitamin D3 deficiency itself might cause leukemia in some patients.
Closer and closer…
…In 2005 a group of pediatricians in Mansoura, Egypt, investigate bone turnover in 43 children with leukemia. They measure bone mineral density (BMD) and markers of calcium homeostasis (including vitamin D3) at diagnosis, after induction chemotherapy (3months), and during maintenance therapy (12months). They find that osteopenia is a serious problem at presentation and after chemotherapy and it seems to be of the low turnover type. Vitamin D3 is reported significantly lower (P<0.0001) in all patients, lowest at presentation but even later it is rarely close to the half of the control value. They conclude that osteopenia in childhood acute leukemia can get benefit from osteoblastic stimulation by sodium fluoride and vitamin D3, which help mineralization of bone.
The Authors of this astonishing research never suggest that the impressive and persistent vitamin D3 deficiency found in all the children might have been present much before the diagnosis of leukemia.
http://www.christophundgabi.de/bilder/egypt/sphinx.jpg
Click down here to see the abstract:
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=16085546&query_hl=4&itool=pubmed_docsum
...one paragraph missing
(it might sound too much personal
I'll leave it empty for now).
http://www.continuingeducation.net/images/caribbean11.gif
Future...in 2008 at the annual congress of the most famous association for Hematology and Oncology a little group of doctors joining the Childhood Leukemia Conference are celebrating the 20th anniversary of the “Shanghai report”, together with the Authors and a bunch of epidemiologists. Some folks tell funny stories about fishes and make the usual jokes about vitamins.
The first results available are not statistically significant yet (no placebo group, no double blind, it's hard to tell), but patients seem to grow up much better and may be -fingers crossed- have fewer relapses. There is skepticism about the decision to recommend the stinky natural association of vitamins A and D instead of purified synthetic compounds, and the supposed synergistic action of the two cofactors has not been demonstrated yet.
Research to develop and test vitamin D analogues is still far behind: Randomized Clinical Trials will take years but a major pharmaceutical company is supporting them.
A researcher from Israel is showing his final results related to the synergistic effects of carnosic acid (rosemary) and vitamin D on leukemic cells.
A couple of years have past since the Wisdom In Medicine Panel (WIMP!) and the Association of Parents Against Leukemia together with the Commonsense Committee revised the data and took a decision. They immediately issued a special recommendation to be sent to all the families concerned.
Now every evening, everywhere in the world, some parent is reminding one of the kids to take his ‘cod’.
...Epilogue.
Engineers (final fiction)
…In 2008 a Polytechnic professor is illustrating the now famous “blue-fluid case” to a group of students of the Aviation Safety course. She is one of the engineers who 20 years before decided to send as soon as possible a dispatch to all the owners of that type of plane. For various reasons, the recommendation to use red fluid for the hydraulic system was not taken into account by few of them. Over the years, there had been other three near-accidents due to a major hydraulic system failure: two planes had to rush to emergency landings, one was flying in bad weather conditions and almost hit the peak of a mountain. All of them were still using blue fluid. Further and stronger official recommendations were issued, mentioning the incidents and the “growing evidence” that blue fluid could have been the cause.
It took years of investigation to solve the problem: obviously multiple factors were involved. After checking all the data again and again the puzzle was completed. The final piece was an "innocent" chemical in the blue fluid, a stabilyzer substance that had been able to damage only seals from a specific defective batch, and only after a certain period of time. It had been extremely hard and difficult for the whole team of investigators.
The results of this study were finally published in a special Aviation bulletin.
The professor is stressing her point:
"Once you have looked at your results and redone all the calculations, if it is all statistically sound, do not waste anymore time...just move! What did you do all that work for...if you do not put it into practice?"
She is smiling a bit saying:
"Sometimes it is tough to keep on the ground hundreds of planes...but it may happen, and you must be perfectly sure of your results. It takes guts".
At the end of the lesson a student asks:
"How many lives did you and your team save by informing everybody so early?"
The teacher now becomes serious again:
"Do not forget that there is a backup emergency system, reliable enough in normal weather conditions. By the way, our duty is to make aircrafts safer and safer, doctors save lives".
Yes. The professor is right. Doctors and nurses run from emergency rooms to operating theater, from clinic to outpatients, day and night, taking care of their patients in an endless struggle with time (and budget problems). Technology has finally "invaded" Medicine: CATscan, ECHO, MRI and even fiberoptics (that started in aircrafts much before) brought a sort of peaceful revolution into this branch of Science.
The old stethoscope is now almost obsolete and finally engineers work close to doctors these days.
Engineers respect doctors and probably think that they must be special to manage in such a peculiar discipline full of "black holes" and unknown causes...they are a bit scared when they see treatment protocols being improved by trial and error.
They trust medical doctors anyway.
Nevertheless, back in 1988, a couple of open-minded medical doctors discussing the results of the "Shanghai report" together with one or two engineers and a parent of a leukemic child, could have made the difference.
...even now, in this new hypertech century, "it takes guts" to propose cod liver oil use as a nutrient for leukemic patients.
The End
Flying over Sicily at sunrise: the Etna volcano
http://www.n4ls.com/images/linch_sunrise_over_med_enroute_to_desert_small.jpg
http://www.n4ls.com/images/linch_sunrise_over_med_enroute_to_desert_small.jpg
Iko
"Il sole dona la vita, il sole se la riprende" M.U. Dianzani 1975
http://www.thenakedscientists.com/forum/index.php?topic=4987.msg241504#msg241504
http://www.thenakedscientists.com/forum/index.php?topic=4987.msg241504#msg241504
Thank you Zoey,
for asking about my favourite quote. Well, to explain it properly, in a short 'essay' in english... it will take me more than a few minutes! But translating it is the easiest thing:"The sun gives life, the sun takes it back"
These words concluded one of the best lectures I attended in my life. At the 3rd year of Medical school, General Pathology course, more than thirty years ago. Professor Mario Umberto Dianzani was our teacher, Dean of the Medical Faculty and a distinguished scientist, totally dedicated to his students. Later on he has been Rector of the University of Turin for several years before retiring.
In those days biochemistry was 'the' thing: new cofactors and vitamins were deeply explored by medical research.
I'm sure I owe to his excellent lectures my following research interest in cofactors.
"Aging of cells and living organisms" was the subject of the lecture.
In less than one hour we went from the origin of life on our Planet to the present time.
Volcanoes and oceans plus UV light to catalyze the synthesis of organic compounds (Miller's experiment), then nucleic acid formation after million years of random combinations.
Primitive organisms, bacteria and algae. Again the sunlight creates energy through photosynthetic processes and here come trees and forests! Different species of primitive life, unicellular, multicellular towards more and more complex organisms, thanks to spontaneous mutations, natural selection and evolution. For the whole 'biosphere' survival is always tightly bound to its origin, to the sunlight.
Sunlight and ultraviolet rays give energy and feed the whole system, nevertheless they are responsible -in the end- for lipid peroxidation and DNA damage. A series of biochemical reactions lead to senescence in multicellular organisms too.
Complex systems are progressively deranged: skin, bones, muscles, nerves, glands and immune cells get older...diseases follow.
The sun itself puts an end to our lives.
Magic
..."Il sole dona la vita, il sole se la riprende"Mario Umberto Dianzani, 1975.