Friday, April 06, 2007

Canadian Injured Workers Society - Workers compensation. Medical profession, Independent Medical Examinations (IME s). WCB doctors.

The Journal of Disability Medicine | American Board of Independent Medical Examiners

Workers Compensation Board: History of WCB

ΛUSTIN ΛTHEIST ΛNØNYMØUS: Woody and Billy on Sunday Morning

ΛUSTIN ΛTHEIST ΛNØNYMØUS: Woody and Billy on Sunday Morning

There will always be a soft spot for Billy Graham in my heart. He is the only one of the evangelists that has not compromised his message by his rudeness and incivility (and "immorality" and double standards). Here is a wonderful video of two men with obviously differing views, who manage to be civil and courteous. Somehow I cannot imagine Jon Stewart eliciting the same response from "Dr. Dobson" in today's polarized and "other" centred religious climate.

Wednesday, April 04, 2007

Fewer Doctor Visits Approved for Rural, Isolated Towns :: News ::

Public Health Agency Linked to Chemical Industry | Mostly Water

Telling the Truth about Tar Sands Cancer Rates? Get Ready to Defend your Job... | Mostly Water

Famed environmentalist outraged by criticism of whistleblowing Alta. doctor

Famed environmentalist outraged by criticism of whistleblowing Alta. doctor

More on the Cancer Whistleblower situation:

Famed environmentalist outraged by criticism of whistleblowing Alta. doctor

Tim Naumetz
For CanWest News Service

Thursday, March 08, 2007

OTTAWA - The lawyer famous for his battle against a tannery that contaminated drinking water in a Massachusetts town says it is "outrageous" Health Canada complained about an Alberta doctor who suggested chemical contamination might be behind cancer deaths downstream from oilsands refineries.

Boston lawyer Jan Schlichtmann, played by John Travolta in A Civil Action, the Hollywood movie based on Schlichtmann's legal fight in the 1980s, says he was astonished at reports Health Canada filed a complaint against the Fort McMurray physician, Dr. John O'Connor.

"I think it's outrageous that they would try and shut up somebody who's trying to sound the alarm bell if there might be something going on," Schlichtmann said in an interview from his Massachusetts law office.

"The history is that environmental contamination can cause a population severe health effects, including cancer, and that the professionals who serve them have to be vigilant," added Schlichtmann, who won a long legal battle for leukemia victims in Woburn, Mass.

An Alberta government official confirmed Health Canada filed a complaint with the Alberta College of Physicians and Surgeons after O'Connor challenged the conclusions of a government analysis of cancer and other deaths in the mostly Cree population of Fort Chippewyan last year.

Details of the complaint are confidential, and Health Canada would not directly confirm the complaint, but the official said he understands it was submitted by Health Canada physicians.

"This is a professional practice issue and is a matter for the Alberta College of Physicians and Surgeons to address," Health Canada said in an e-mail response to questions.

O'Connor, who treated Fort Chippewyan residents by flying in from his Fort McMurray practice, said in May 2006 he was alarmed by what he considered high rates of cancer in the community. He speculated cancer-causing chemicals might have entered the Athabasca River from massive oilsands refineries upriver from the town.

A study of vital statistics by the Alberta Health and Wellness Department and the Alberta Cancer Board, with the support of Health Canada, concluded the overall cancer mortality rate for Fort Chippewyan was slightly lower than the rate for the rest of Alberta.

But more detailed figures released by the Alberta government this week show higher than expected cases of colorectal cancer, liver and bile duct cancers, leukemia and lung cancer.

The 2006 report noted rates of diabetes, hypertension and death by injury and poisoning were above provincial averages and said a focus on those areas would improve the "overall" health of the community.

Schlichtmann said public officials must be open to public scrutiny and O'Connor appeared to be acting "in the finest tradition of what a doctor should be doing."

"A community that polices itself and silences its members is a community that has a cloud over its future," he said. "If they have any doubts about that, let them go look to the communities in Woburn, Massachusetts. People suffered in ignorance."

Members of the Fort Chippewyan community are calling for a wider first-hand study, including statistics for all cancer patients, not just those who died of cancer.

The head nurse with the Nunee Health Authority in Fort Chippewyan says four of about 11 deaths she has recorded in the hamlet since last May have been caused by cancer.

"It seems we have a lot; as a nurse I have to say that," said Georg MacDonald. "We don't have a study, we don't have a study of the living patients in Fort Chippewyan. To my mind, just off the top, I would say there is an awful lot of liver cancer."

O'Connor has been unavailable to comment this week.

Ottawa Citizen

NRM: Health Canada muzzles oilsands whistleblower

NRM: Health Canada muzzles oilsands whistleblower

If I remember correctly, last year on CBC the Alberta Health and Wellness people were saying that this would be a peer reviewed process. So far they have not lived up to these expectations.

This is frightening beyond belief. The oilsands COULD be poisoning people , but government and industry and the medical establishment are essentially shooting the messenger- John O'Connor, a physician, who noted a fairly substantial rate of odd cancers in the mostly native population of Fort Chip. Now the doctor is a nervous wreck because he spoke out about this.

Does he deserve this? No. Unfortunately, it is easier to dispense with a doctor than it is to clean up the environment.

It is a national disgrace.

Full Article Here:

MARCH 30, 2007 VOLUME 4 NO. 6


Health Canada muzzles oilsands whistleblower

AB physician sounded cancer alarm, slapped with College complaint

By Peter Woodford

Elevated cancer rates in Fort Chipewyan support Dr O'Connor's claim
From Fort Chipewyan Health Data Analysis by Alberta Health & Wellness and Alberta Cancer Board, April 2006
A northern Alberta physician who publicly aired concerns over carcinogenic pollution from the massive oilsands development is being investigated by the province's College of Physicians and Surgeons. The complaint against him comes from none other than Health Canada, which claims the physician caused "undue alarm."

The doc — widely held to be Dr John O'Connor of Fort Chipewyan — says he's got a hunch the copious amounts of arsenic dumped into the water by the project might explain why so many of his mostly aboriginal patients are presenting with cancer — including rarer forms like cholangiocarcinoma (bile duct cancer).

The College won't confirm or deny that Dr O'Connor has indeed been targeted. The family doc is no firebrand and an unlikely martyr for the environmental cause. When the government released selected data from a study and concluded that people in the community were less likely than the average Albertan to die of cancer, it pained him to disagree (fuller data, released later, would suggest his hunches were largely right). "I would absolutely accept it, if I saw they had done a complete analysis..., had all the information that they needed, and had the report peer reviewed prior to publishing it," he said at the time.

In fact, the whole business of fighting with the government made him literally sick and he said that he's planning to leave Fort Chip (as it's known locally) in the summer because of it. "It's been so consuming and so frustrating that my blood pressure has gone up and I have difficulty sleeping," he told the CBC late last year — even before the complaint to the College was filed. "It's just I'm worn out by this."

Dr O'Connor is now refusing to speak to the media until the complaint with the College is settled, his lawyer says.

Colleagues and members of the community came to the quick conclusion that Dr O'Connor is paying the price for attacking a sacred cow — Alberta's multi-billion dollar oil industry.

"It's a similar scenario to what had me fired in 2002 for speaking in favour of ratifying the Kyoto Accord in the interest of public health," said Dr David Swann, Liberal MLA for Calgary Mountain View, on his blog. Dr Swann was medical officer for the Palliser Health Region at the time he got the axe.

"I admire Dr O'Connor for his courage in standing up and speaking out on issues that should concern all Albertans," added Dr Swann in a March 6 interview with Fort McMurray Today. "This is not acceptable. We're a free country. We, as professionals, are called upon to act in the public interest and to raise issues, to challenge vested interest whether it's government's or industry's monetary interest for the betterment of the society."

Dr Swann and internist Dr Michel Sauvé — who's head of the intensive care unit in the same Fort McMurray hospital where Dr O'Connor is based and also regularly flies in to Fort Chip to treat patients — both feel that this case is evidence that whistleblower legislation is needed to protect doctors. Dr Sauvé has said he thinks the complaint was "politically motivated."

The parties involved in the alleged complaint against Dr O'Connor aren't saying much.

"We can confirm that Health Canada physicians have lodged a complaint which involves several professional practice issues with the Alberta College of Physicians and Surgeons against a northern Alberta doctor," says Carole Saindon of Health Canada.

"The College of Physicians and Surgeons recommends that complaints not be discussed publicly. Health Canada respects this recommendation."

Unsurprisingly, the College won't comment on Dr O'Connor's case, nor will the Alberta government.

The Athabasca oilsands (formerly called the tar sands) were long thought impractical to exploit. But high oil prices and technological innovations have made the area feasible to develop — and all of a sudden the province's accessible oil reserves rival Saudi Arabia's. But the catch is that to get oil from the bitumen (natural tar) enormous amounts of toxic waste water are created. And this raises concerns that profits from this development come at the expense of aboriginal lives.

"We need to know if there are excessive toxins in these resins and we need to see if people are dying from rare cancer or some devastating immune disorders — that someone is collecting some samples on these people to see what is the concentration of toxins," explained Dr Sauvé to Fort McMurray Today.

There have been some studies looking at the arsenic levels found in the region's fauna — but findings were contradictory. A recent study by Suncor, an oil company, found that a proposed development would lead to arsenic levels in moose meat — a local staple — 453 times the acceptable limit. The province and Imperial Oil dismissed the study saying their own data said the levels were much lower. Imperial Oil spokesperson Kim Fox stated back in November that her company's study estimated arsenic levels were 15 times lower than the Suncor numbers. "The people who actually conduct these studies tend to be very, very conservative in their methodologies. Even with these conservative approaches, what we've found is that oilsands do not contribute to increase in arsenic in the area."

Locals are not convinced. "Those big shots running our government — they don't give a darn who dies, they're not concerned about us," said one Fort Chipewyan elder in a CBC radio interview. "I've fished since I was 13 in Lake Athabasca. I've seen fish in the last five or six years with great lumps on them, humpbacks, crooked tails, some of the pickerel rotting alive — I've never seen that before in all the years I commercial fished. What are they putting into the water?"

Such cynicism towards the provincial government is commonplace among First Nations communities living near the oilsands developments. On March 6, the Mikisew Cree in Fort Chipewyan pulled out of the Cumulative Environmental Management Association (CEMA), dismissing the watchdog institution as a crock. "CEMA is a parking lot where everything, all the major issues, are placed. Meanwhile approvals [for new oilsands projects] are given," Mikisew spokesperson Sherman Sheh told the CBC. Indeed, CEMA was initially given five years to release an assessment on how much oil development the province could sustain without permanently wrecking the environment. It's already been seven years and CEMA hasn't released its report, all the while oilsands development has been continuing apace. The Athabaska Cree have also given up on CEMA.

Apocrine HS

Infliximab Liver Transplant PCS IBD

Gut -- eLetters for Biancone et al., 55 (2) 228-233

Not a random post, but some serious research. Did a government agency deny funding for Remicade because of money or risk? One is unacceptable, one is understandable. Personal- becoming political. A letter that is completely and utterly devoid of answers. Bureaucratic and impersonal. I want to throw up - this person should not have to die for money's sake.

Electronic Letters to:

Inflammatory bowel disease:
L Biancone, A Orlando, A Kohn, E Colombo, R Sostegni, E Angelucci, F Rizzello, F Castiglione, L Benazzato, C Papi, G Meucci, G Riegler, C Petruzziello, F Mocciaro, A Geremia, E Calabrese, M Cottone, and F Pallone
Infliximab and newly diagnosed neoplasia in Crohn’s disease: a multicentre matched pair study
Gut 2006; 55: 228-233 [Abstract] [Full text] [PDF]

Electronic letters published:

Colon cancer after infliximab therapy for Crohn’s disease in a young liver transplant recipient
Laurent Peyrin-Biroulet, Aude Bressenot, Laurence Chone, Philippe Denjean, Patrick Boissel, Marc-Andre Bigard, and Jean-Pierre Bronowicki (21 December 2005)


Colon cancer after infliximab therapy for Crohn’s disease in a young liver transplant recipient 21 December 2005

Laurent Peyrin-Biroulet,
Department of Hepato-Gastroenterology, University Hospital of Nancy, and INSERM U 724,
Aude Bressenot, Laurence Chone, Philippe Denjean, Patrick Boissel, Marc-Andre Bigard, and Jean-Pierre Bronowicki
Send letter to journal:
Re: Colon cancer after infliximab therapy for Crohn’s disease in a young liver transplant recipient

Email Laurent Peyrin-Biroulet, et al.

Dear Editor,

In a recent issue of the Journal[1], Biancone et al. showed a comparable frequency of new diagnosis of neoplasia in inflammatory bowel disease (IBD) patients treated with infliximab and in patients who never received infliximab. These data seem to confirm reassuring message from clinical trials.[2,3] A peculiar situation may be IBD patients having had liver transplantation for primary sclerosing cholangitis and in whom an increased risk of colon cancer has been reported. We here report a case of rapidly progressing colon cancer in a liver transplant recipient suffering from Crohn’s disease treated with infliximab.

A 23-year-old man had a 12-year long history of Crohn’s disease characterized by ileitis, pancolitis and oral aphthous ulcers. He was treated with mesalasine (2 g/day) since 1991 and azathioprine (2.5 mg/kg/day) since 1994. In September 2003, he underwent orthotopic liver transplantation (OLT) for primary sclerosing cholangitis (PSC) complicated by several angiocholitis. Tacrolimus and steroids were introduced after transplantation to prevent organ rejection. In November 2004, he has a flare-up of colitis despite maintenance treatment with azathioprine, tacrolimus and steroids. Colonoscopy showed moderate inflammation of the whole colon and mild ileitis. The random biopsy pattern including biopsies of the caecum (total of 45 biopsies) did not reveal any evidence of dysplasia. Infliximab therapy was thus initiated. From December 2004 to July 2005, he received a total of six infliximab infusions at 5 mg/kg (weeks 0, 2, 6 and then every 8 weeks) and was in clinical remission after three infusions. In July 2005, two weeks after his last infliximab infusion, he presented with a small bowel obstruction.

Computed tomography showed a stenosis of the caecum related to a bulky tumor with multiple one centimeter regional lymph nodes. Colonoscopy confirmed mucosal healing and showed a tumor of the caecum (Fig. 1), with a poorly differentiated adenocarcinoma on biopsies. The endoscopist could not reach the terminal ileum. The patient underwent a coloproctectomy in August 2005. Macroscopic examination revealed an exophytic mass with extension through the bowel wall and the pericolonic fat and the tumor size was 5-cm. Histologic examination showed a poorly differentiated adenocarcinoma of the caecum with a mucinous component (10%) and 19 of the 126 regional lymph nodes removed during surgery were positive for metastatic disease. Microscopic examination also found venous and nerve invasion. As staging of the cancer was pT4N2M0, adjuvant chemotherapy with oxaliplatin, fluorouracil and leucovorin was started in September 2005.

Figure 1. Endoscopic view of the tumor: A colonoscopy performed in July 2005 showed an exophytic lesion of the caecum responsible for a colon stenosis. The ileo-caecal valve was not visible and the endoscopist could not reach the terminal ileum.

Almost 30 cases of colon cancer have been described in liver transplant recipients with ulcerative colitis, but no case has yet been reported to our knowledge in Crohn’s disease.[4-10] Similarly to former reports, colon cancer was diagnosed within 30 months of transplantation with a duration of colitis of more than 9 years. While the youngest patient in these case reports was 39 years old[10] (mean age:c46[6]) and some patients had a history of colorectal neoplasia[5], our patient was only 25 years old and had neither personal nor family history of colon neoplasia. Previous reports indicated that the risk of colorectal carcinoma in IBD patients is related to the extent and duration of disease and might be increased by the coexistence of PSC. In the present case, the combination of these factors might be necessary but not sufficient to explain the development of colon cancer, as a colonoscopy with random biopsies performed just before the first infliximab infusion was normal. Given the development in only seven months of a bulky cancer of the caecum with multiple regional lymph metastases, infliximab therapy might have promoted and/or accelerated colon carcinogenesis in this young patient. This case advocates for a cautious use of infliximab in IBD patients with liver transplant.

We are grateful to Mathias Chamaillard for helpful discussions, and to Professor Colombel for critical reading of this manuscript.


1. Biancone L, Orlando A, Kohn A, et al. Infliximab does not increase the risk of newly diagnosed neoplasia in Crohn’s disease: a multicenter matched-pair study. Gut doi:10.1136/gut.2005.075937

2. Present DH, Rutgeerts P, Targan S, et al.. Infliximab for the treatment of fistulas in patients with Crohn's disease. N Engl J Med 1999;340:1398- 1405.

3. Sands BE, Anderson FH, Bernstein CN, et al. Infliximab maintenance therapy for fistulizing Crohn's disease. N Engl J Med 2004;350:876-885.

4. Higashi H, Yanaga K, Marsh JW, et al. Development of colon cancer after liver transplantation for primary sclerosing cholangitis associated with ulcerative colitis. Hepatology 1990;11:477-480.

5. Narumi S, Roberts JP, Emond JC, et al. Liver transplantation for sclerosing cholangitis. Hepatology 1995;22:451-457.

6. Fabia R, Levy MF, Testa G, et al. Colon carcinoma in patients undergoing liver transplantation. Am J Surg 1998;176:265-269.

7. Loftus EV Jr, Aguilar HI, Sandborn WJ, et al. Risk of colorectal neoplasia in patients with primary sclerosing cholangitis and ulcerative colitis following orthotopic liver transplantation. Hepatology 1998;27:685 -690.

8. Vera A, Gunson BK, Ussatoff V, et al. Colorectal cancer in patients with inflammatory bowel disease after liver transplantation for primary sclerosing cholangitis. Transplantation 2003;75:1983-1988.

9. Knechtle SJ, D'Alessandro AM, Harms BA, et al. Relationships between sclerosing cholangitis, inflammatory bowel disease, and cancer in patients undergoing liver transplantation. Surgery 1995;118:615-619.

10. Bleday R, Lee E, Jessurun J, et al. Increased risk of early colorectal neoplasms after hepatic transplant in patients with inflammatory bowel disease. Dis Colon Rectum 1993;36:908-912

Tuesday, April 03, 2007

Smoking and BBPV

Pharmacological Treatment of Vertigo Neurology Report - Find Articles

Pharmacological Treatment of Vertigo Neurology Report - Find Articles

Hanging out with people with motor deficits and watching Awakenings in the middle of the night and reading an article in a magazine about a "wobbler' got me thinking about whether dopamine might be implicated in balance. There seems to be something to my wild thought- I typed in vestibular+dopamine into google and will search a bit more eventually.

Monday, April 02, 2007

CFS Information

Screw The Cameras


If insurance industry consultants, patients, physicians, attorneys and judges can agree that there is a problem that needs fixing, it should be fairly easy to design better tools. For example, one could make FCE testing more realistic by extending its duration from two hours to four, and by bringing the patient back to repeat the testing over several consecutive days. There’s a downside risk, of course: Some patients will become much worse, perhaps irreversibly. However, that risk could be limited by close medical monitoring, both during and after each test. Insurance company staff should accompany the patient home and/or check in with them by phone at intervals. To ensure the accuracy of their reports, patients might agree to keep a camera in their home or a radio location surveillance device on their person for several days.

For what OTHER disease would one be expected to be surveilled to be believed?

Maybe they ought to figure out a way to do blood tests for genetic markers and all that neat SCIENCE_Y kinda stuff real doctors are supposed to do, rather than relying on Orwellian/Kafka-esque techniques.... Jump through hoops on camera you unlucky person you...

I know that they are trying to help- but please- insurance companies already surveil people to their DISADVANTAGE, so why should we trust them now?

This is a VERY BAD IDEA.

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Wednesday, March 28, 2007

State To Release HMO's Documents On Claims | State To Release HMO's Documents On Claims

THe long and the short- If you make up your own criteria for what is medically necessary, and then deny people based on your narrow viewpoint, then you make money.

Toubman, who represents indigent clients as a member of the New Haven Legal Assistance Association, fears the HMOs have created their own definitions of what services are "medically necessary" or "medically appropriate" and are rejecting legitimate claims.

Since the Workers Insurance dudes do the same thing, it will be interesting to see what happens if the Insurance Co is found guilty. What will be the implications for other insurers???

Hehehe... I like this dude.

: Butt Out, Blumenthal- This Guy Has Pissed People Off!!

Contrast and Compare How Lyme Disease is Seen By Two Organizations

Wow- K**ser and Lyme Cover-ups...

Whenever anyone tells me that private medical insurance is better than public, I tell them they are trading one set of problems for another.

The problem here is that in order to not pay out to their clients,Kaiser just made up their own rules on what constitutes Lyme Disease.

Do I believe that governments are incapable of that kind of lunacy? No, the NHS in Britain has Simon Wessely, a psychiatrist, as their Lyme Disease expert. His trick is to blame the patient, and then the governement pays very little compared to what they would if they had to pay out for tests and the like. It looks like he would be in agreement with Kaiser. He is not an infectious disease specialist. (I beleive he had one year of education in infectious disease- BUT THAT DOES NOT A SPECIALIST MAKE!!) He is not a neurologist. He is someone who prescribes Paxil and exercise and if the patient is still not doing well they are malingerers with medically unexplained symptoms who deserve nothing.

Understand that there are two "books" on Lyme - one that essentially limits the scope and time frame that Lyme is recognized under, and one in which it is recognized as a possible chronic illness. The treatment guidelines are very different as are the diagnostic tests. All things I have been unaware of for all of Dr. Crippen's discussions on this illness. One is much cheaper than the other to pay for IF the patient is sick....

Neat. If only I could wave my magic wand and make free money and screw people up the ass at the same time!!

Saturday, March 24, 2007

You got some'splainin to do...

I have not blogged in a long time. I could blame it on a lot of things- working multiple jobs, ferrying teenagers to "contact ballet lessons" and work, having a nervous breakdown at my newest job, which entails being ripped a new asshole every few days by a supervisor who obviously failed the "How To Win Friends And Influence People" course, and just basic angst as I adjust to the role of parent to children who only want rides and money.

In other words life has dumped lemons on my head, and I have the concussions and all to prove it- grin!!

I have faithfully read Tara at Aetiology, Orac at Respectful Insolence, PZ at Pharyngula, And Dr. Crippen at NHS Blog Doctor. I have kept up with the rest of my faves. I have commented under another pseudonym, as I really had questions about whether or not I wanted to blog at all any more. I am depressed. I am sick--- low grade coughing, fluey, just off, and I am tired for three months at least, now.

I decided tonite that I probably ought to join the land of the living again. And proudly use the name ImpatientPatient for all the world to see. Because real life sucks so bad, I can at least attempt to pretend I am smart right here, knowing that no-one is going to make an ass out of me- and if they do, this being the Internets and all, I can just tell them to go jump in a lake- or cruder. I won't get my ass chewed off like I do with rude 60 year old assholes with cellphones attached to their heads, who think the world revolves around how their potatoes are cooked, and I won't have a boss SLAP MY HANDS when they are angry with me for not being in the right place at the right time, or use me as an example of WHAT NOT TO DO in front of my colleagues.

Happy to be back again, and cannot believe how Blogger has changed!!!

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Big Brother and On Star - Or why I do not want a new car....

Effect Measure#more

Funny thing that other people just happen to have the same healthy fear of government that I have- though we live in different parts of the world. Mine has something to do with the government doing something illegal when it linked information from one agency to another agency about 10 or so years ago. As well, the push for governments to be involved in "health choices" amd penalizing people for lifestyle factors makes me wonder when people will get fucked up the butt when they figure out their genetic profiles suck. Oh, and the schools insistence on knowing what the youngest child eats is annoying- thankfully the kid spoke up so I only had to say "hurrah"---- except for the fact that the kid had to do a study hall, it was all good. As the kid told the teacher- It really is our parent's decision and responsibility as to what we eat.

Yes!!!! That would be the person I wish to be, speaking in the child's body!!!

And I do wish to know more about the NTSB looking at ted light cameras and broken necks, as my municipality is about to use those bitches as speed recorders as well. Which means that if you speed through a red light you get a big fat ticket, and if you don't you get a broken neck. And since our government legislated a four thousand dollar cap on injury claims, the insurers of the people that hit the people in front of them will be scot free and that just pisses me off.

Friday, January 12, 2007

Junkfood Science: Should we care what works and what doesn’t?

Junkfood Science: Should we care what works and what doesn’t?

This is an interesting writer... Explore her site.

Friday, December 29, 2006


That is the number of profile views I have had in the last year. Cool!! I started blogging a last year about this time, and recently took a two month hiatus due to lack of time and a basic ennui. The last time I looked at how many profile views I had there was 85. So, someone, somewhere has been looking, and I thank you.

In the last few months I have started a new position full time, am working a second job as a waitress, and have been driving teenagers around to sports and jobs. It has been hectic. I have posted comments on other blogs, and will certainly begin a roundup of some of those, as I tend to get quite passionate about things I read.

Happy New Year!!! 431... so cool. Considering I started at zero.....

Clients In a Nutshell - Comments

Several years ago Edinburgh health services discussed dropping the term "patient" in favour of "client." One of the neurologists, a couthy Glaswegian, said "there are two professions which have clients - lawyers and whoors."

Monday, December 25, 2006

Words Matter- Patient

See- this is the Wiki article that in a nutshell says what I tried to say in my first "Words Matter - Client" short.

Endurance vs subservience??? What would you pick if you could?

Patient - Wikipedia, the free encyclopedia: "Patient
From Wikipedia, the free encyclopedia

Patient is any person who receives medical attention, care, or treatment.[1] The person is most often ill or injured and is being treated by, or in need of treatment by, a physician or other medical professional. Health consumer or health care consumer or client are other names for patient, usually used by some governmental agencies, insurance companies, and/or patient groups.

Origin of word
The word patient is derived from the Latin word patiens, the present participle of the deponent verb pati, meaning 'one who endures' or 'one who suffers'.
Patient is also the adjective form of patience. Both senses of the word share a common origin.
In itself the definition of patient doesn't imply suffering or passivity but the role it describes is often associated with the definitions of the adjective form: enduring trying circumstances with even temper. Some have argued recently that the term should be dropped, because it underlines the inferior status of recipients of health care. For them, 'the active patient is a contradiction in terms, and it is the assumption underlying the passivity that is the most dangerous'. Unfortunately none of the alternative terms seem to offer a better definition.
Client, whose Latin root cliens means 'one who is obliged to make supplications to a powerful figure for material assistance', carries a sense of subservience.
Consumer suggest both a financial rerelationship and a particular social/political stance, implying that health care services operate exactly like all other commercial markets. Many reject that term on the grounds that consumerism is an individualistic concept that fails to capture the particularity of health care systems"


Client (ancient Rome) - Wikipedia, the free encyclopedia

The Latin word cliens is formed of the earlier cluens, "hearing", in the sense that such an individual is at the call of his patron.

There is a discussion going on at NHS Blog Doctor about the use of client versus patient in the health care setting.

I thought this summed up the relationship I have with the workers insurance company that I have dealt with. We have been at their beck and call for a lot of years.

Went to the last medical evaluation. It was interesting to note that even though this was touted as an independant exam, the doctor making observations and supplying info to the company worked at their auxillary centre. This information was available on the College of Physicians and Surgeons site. I was wondering why nobody medically connected had heard of him through the hospital grapevine. I now know... I am very curious as to why he did not want an extra person there at first, even though our letter said that an acompanying person was allowed.

It was even more telling that there were so many levels of security going in and out of the building. They must be doing more Kama Sutra magic to their clientele, methinks.

Friday, October 13, 2006

the chutry experiment: Jesus Camp

the chutry experiment: Jesus Camp: ""

Seeing Red, the Movie - A Journey Through the Moral Divide

Wednesday, October 04, 2006 | Link probed between eating meat, C. difficile | Link probed between eating meat, C. difficile:

"'What does ingesting a few C. diff spores mean to a person? That's completely unclear,'' Weese said."

Ummm... IMHO it depends on their immune system, their antibiotic use previously in the last year, and the state of their gut flora. All things we usually don't think about when we are shopping for pork chops and hamburger.

I wonder if this is not a clue as to the origins of some colitis that just seems to happen spontaneously? That would be nice, as usually those people go through hell to get diagnosed when they get it, and then have to endure a million indignities, including the annoying - you need to calm down. This is all in your head bull poopy. Maybe real bull poopy caused this.

And- this SHOULD be a reportable disease. Everywhere. All the time. In every single instance. Wait until it is too late and this bug is going to take a lot of healthy people, including health care workers, right out.

I don't wanna DIE!!! | Top Stories | Health | Remember SARS? C. difficile may be worse

Low blood pressure, anemia nad wicked diarrhea.....

Still have anemia. Wish that every time I had diarrhea I was not afraid. Am terrified of taking antibiotics- what if I get pneumonia though? These are pretty scary things.

Now they have found C diff in the food chain- from cows that we eat. C Diff is a spore- so either cooking would make it explode, or it would not touch the spore.

I am a little bit worried. Community acquired C Diff is a bit scary.

Even more scary than getting it at the hospital.

Sunday, September 24, 2006

Instructivist: Contraband textbooks

Sunday, September 17, 2006

Pocket Guide to Inflammatory Bowel Disease - Cambridge University Press

Is God an Accident?

Saturday, September 16, 2006

Review Essay: Marshall Berman, All That is Solid Melts Into Air: The Experience of Modernity (New York: Penguin Books, 1982).

Thursday, September 14, 2006


Friday, September 01, 2006 : Worksheets

Thursday, August 17, 2006

IONS: Consciusness and Healing

PSYC 6800

A Statement in Defense of Scientific Medicine
from the Council for Scientific Medicine

Notes from Dr. RW: How did pseudoscience get admitted to medical school?

Elliott S. Dacher, M.D.: The Limits of Modern Medicine: Frontiers of Healing

eMJA: Chan & Chan, Medicine for the millennium: the challenge of postmodernism

II think I will hate this....

Postmodern Medicine

Our Values


Guardian Unlimited | Science | The brain genes that gave man a head start on chimpanzees

Better FCE performance was a weak predictor of faster benefit suspension, and was unrelated to sustained recovery.

Quarterly Performance Report to the WCB Board of Directors Quarter Ending September 30, 2005

WellSpring, Alberta Centre for Active Living

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Wednesday, August 16, 2006

TAKS April 2004 G7 Mathematics Online Test

Tuesday, August 15, 2006

SDAA Spring 2005 Level 8 Mathematics Online Test

Math lessons and teaching tips articles from

Monday, August 14, 2006

Treatment of Nonmalignant Chronic Pain - March 1, 2000 - American Academy of Family Physicians

Sunday, August 13, 2006

Brief calcium transients evoked by glutamate receptor agonists in rat dorsal horn neurons: fast kinetics and mechanisms.

fig002dcb: A proposed scheme for the neuroprotective effects of lithium

fig002dcb: A proposed scheme for the neuroprotective effects of lithium

Lithium and NMDA receptors- that I think are part of the dorsal horn, but I need to look up....

Friday, August 11, 2006

H Pylori, C Diff Probiotics

Thursday, August 10, 2006

2000-01 Academic Year Research: Jessica Scott

Type 1 Diabetes - Cerebral glutamate metabolism during hypoglycemia in TID m...

Type 1 Diabetes - Cerebral glutamate metabolism during hypoglycemia in TID m...

Implication of Glutamate in the Kinetics of Insulin Secretion in Rat and Mouse Perfused Pancreas -- Maechler et al. 51 (Supplement 1): 99 -- Diabetes

Implication of Glutamate in the Kinetics of Insulin Secretion in Rat and Mouse Perfused Pancreas -- Maechler et al. 51 (Supplement 1): 99 -- Diabetes

© 2002 by the American Diabetes Association This Article

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Diabetes 51:S99-S102, 2002
© 2002 by the American Diabetes Association, Inc.


Section 2: Biphasic Insulin Release: Pools and Signal Modulation

Implication of Glutamate in the Kinetics of Insulin Secretion in Rat and Mouse Perfused Pancreas
Pierre Maechler, Asllan Gjinovci, and Claes B. Wollheim
From the Division of Clinical Biochemistry, Department of Internal Medicine, University Medical Center, Geneva, Switzerland


It is intriguing that the kinetics of glucose-stimulated insulin secretion from the in situ perfused pancreas differ between the rat and the mouse. Here we confirm that insulin release in the rat is clearly biphasic, whereas in the mouse glucose essentially elicits a transient monophasic insulin release. Glucose-derived glutamate has been suggested to participate in the full development of the secretory response. The present report shows that the expression of glutamate dehydrogenase is lower in mouse than in rat or human islets, paralleling the insulin secretion profile. Addition of glutamic acid dimethyl ester mainly enhances insulin release at an intermediate glucose concentration in the rat pancreas. In the mouse preparation, glutamic acid dimethyl ester induces a sustained secretory response, both at 7.0 and 16.7 mmol/l glucose. These results are compatible with a role for glucose-derived glutamate principally in the sustained phase of nutrient-stimulated insulin secretion.


The kinetics of insulin secretion from the perfused pancreas stimulated by glucose vary according to the animal model. This is particularly evident regarding the two most widely used species, i.e., the rat and the mouse (1,2). In rats, glucose stimulation results in biphasic insulin release, with a transient first phase followed, after 4–5 min, by a gradually increasing second phase (3). In contrast, the perfused mouse pancreas exhibits a weak second phase compared with the first phase in response to glucose stimulation (1,2). Only a few studies have addressed the mechanisms underlying these species differences. Among others, it has been proposed that the divergence may reside in the cellular levels of cyclic adenosine monophosphate (cAMP) (4) or inositol phosphate (5).

In the consensus model of glucose-stimulated insulin secretion, ATP is generated by mitochondrial metabolism, promoting an increase in cytosolic Ca2+ concentration, which constitutes the main trigger initiating insulin exocytosis (6–8). Glucose generates additional factors participating in the stimulation of insulin secretion (8–11). We have previously proposed that, during glucose stimulation, glutamate is generated by the mitochondria and plays a role in stimulus-secretion coupling (12,13). Under conditions of permissive, clamped cytosolic Ca2+ levels in permeabilized cells, glutamate directly stimulates insulin exocytosis independently of mitochondrial function, suggesting that glutamate acts as an intracellular factor coupling glucose metabolism to insulin secretion (12). Glutamate can be formed in the mitochondria from the tricarboxylic acid cycle intermediate -ketoglutarate by glutamate dehydrogenase (GDH) (14). As a glucose-derived metabolic coupling factor, glutamate is postulated to participate mainly in the second phase of insulin secretion.

Glutamate does not penetrate efficiently into islet cells and is not insulinotropic (15), although induction of transient insulin release has been reported (16). Investigators have therefore used cell-permeant methyl ester derivatives. An insulinotropic action of glutamic acid dimethyl ester in the presence of intermediate glucose concentrations has been reported in the perfused rat pancreas (17). In the present study, we have examined the hypothesis that intracellular glutamate provision might be rate-limiting for full development of the second phase of insulin secretion. Deficient second phases are observed in the rat at intermediate glucose concentrations or in mice even at optimal glucose concentrations. Our results show that, in these incomplete secretory responses, glutamic acid dimethyl ester supplementation induces the development of a full, sustained phase of insulin secretion.


Insulin secretion.
Male Wistar rats and BALB/c mice were anesthetized with sodium pentothal 100 mg/kg body wt i.p. and prepared for pancreas perfusion as previously described (18). The pancreas was perfused at 37°C with modified Krebs-Ringer HEPES buffer supplemented with the indicated concentrations of glucose. The perfusion was maintained at 5 ml/min for rats and 1.5 ml/min for mice. The pancreatic effluent of the first 30 min of perfusion with basal glucose (2.8 mmol/l) was not collected. After this equilibration period, the effluent was collected in 1-min fractions from a catheter placed in the portal vein. The insulin content of each fraction was determined by radioimmunoassay (12). Where mentioned, the area under the curve (AUC) was calculated after subtraction of basal release determined by the first 15 min of fraction collection. Differences in insulin secretion between groups were analyzed by Student’s t test.

Pancreatic islets were obtained from a human donor (12) or isolated from rats and mice by collagenase digestion as previously described (19). They were centrifuged, resuspended in lysis buffer, and sonicated before protein determination (Bradford’s assay). Immunoblotting was performed after SDS-PAGE using 5 µg proteins of islet extract per lane or standard of GDH (Roche Diagnostics, Rotkreuz, Switzerland) on 11% gel. Proteins were transferred onto nitrocellulose membrane and incubated overnight at 4°C in the presence of rabbit anti-GDH polyclonal antibody (1:5,000) raised against bovine GDH (Rockland, Gilbertsville, PA). The membrane was then incubated for 1 h at room temperature with donkey anti–rabbit IgG antibody (1:5,000) conjugated to horseradish peroxidase (ECL; Amersham, Zürich, Switzerland), and the GDH protein was revealed by chemiluminescence (Pierce, Rockford, IL).


Control in situ pancreatic perfusions.
Control experiments show the typical species-specific patterns of the dynamics of insulin secretion in the perfused pancreas stimulated with glucose (Fig. 1). In the rat, raising glucose from basal 2.8 to 16.7 mmol/l glucose induced a transient first phase followed by a sustained second phase with similar amplitudes (Fig. 1A). In the mouse, the same high glucose concentration (16.7 mmol/l) elicited a rapid first phase but only a very weak second phase (Fig. 1 B). At 7.0 mmol/l glucose, the amplitudes of insulin release were smaller but the species difference was also observed, i.e., absence of the second phase in the mouse.

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FIG. 1. A and B: Control in situ pancreatic perfusions. The pancreas was perfused at 5 ml/min for rat (A) and 1.5 ml/min for mouse (B). After a 30-min equilibration period at basal 2.8 mmol/l glucose, the effluent was collected in 1-min fractions from a catheter placed in the portal vein. The pancreas was perfused sequentially at different glucose concentrations, first at 2.8 mmol/l for 45 min, next at 7.0 mmol/l for 30 min, then again at 2.8 mmol/l for 15 min followed by a 30-min stimulation at 16.7 mmol/l, and finally at 2.8 mmol/l for 15 min. C: Immunoblotting for GDH. Islets from rats, mice, and a human donor were isolated and immunoblotting was performed after SDS-PAGE using 5 µg proteins of islet extract per lane or standard of GDH. The data presented in panels A–C are representative of three independent experiments each.

GDH levels in pancreatic islets.
Islets from rats, mice, and a human donor were isolated, and the equivalent of 5 µg protein was subjected to immunoblotting for quantification of GDH. Human and rat samples exhibited similar levels of GDH, whereas the signal from the mouse was noticeably weaker (Fig. (Fig. 1 C). Compared with the standards of GDH, the band from rat islet extracts was similar to the standard of 10 ng GDH. The intensity of the mouse band was situated between the standards 10 ng and 1 ng, the latter being undetectable. GDH concentration in rat islets could be estimated roughly at 0.2% of total proteins. This concentration is only indicative, since the reactivity of the antibody raised against bovine GDH may vary slightly between species, although this mitochondrial enzyme is extremely well conserved.
Effect of glutamic acid dimethyl ester on insulin secretion.
Rat pancreatic perfusion was performed at the rate of 5 ml/min and resulted in a basal insulin release of 0.54 ± 0.34 ng/ml per minute at 2.8 mmol/l glucose. Addition of 5 mmol/l L-glutamic acid dimethyl ester (dmGlut) at low glucose (2.8 mmol/l) for 15 min induced only marginal, slow-onset insulin secretion over basal release (Fig. 2). Stimulation with 7.0 mmol/l glucose for 15 min resulted in biphasic insulin secretion with an AUC of 219.2 ± 76.6 ng/ml, and supplementation with 5 mmol/l dmGlut for the next 15 min induced a 3.6-fold increase in the AUC (786.2 ± 201.2 ng/ml, P < 0.05). After a 15-min period at low glucose (2.8 mmol/l), 16.7 mmol/l glucose stimulated insulin secretion, with a pronounced first and second phase (AUC = 1,194 ± 176 ng/ml for 15 min, 5.5-fold vs. 7.0 mmol/l glucose, P < 0.05). Application of 5 mmol/l dmGlut on top of high glucose for the subsequent 15 min resulted in a further modest 1.6-fold elevation of insulin release (AUC = 1,971 ± 218 ng/ml for 15 min, P < 0.01).

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FIG. 2. Rat pancreatic perfusion. The pancreata from male Wistar rats were perfused at 5 ml/min, first for a 30-min equilibration period at basal 2.8 mmol/l glucose. The effluent was then collected in 1-min fractions from a catheter placed in the portal vein. The pancreas was perfused sequentially at different glucose concentrations without or with 5.0 mmol/l dmGlut. Each condition or combination was applied for 15 min. Values are means ± SE of three independent experiments.

In the mouse, pancreatic perfusion of 5 mmol/l dmGlut at 2.8 mmol/l glucose did not modify basal insulin release (Fig.3). In the presence of 7.0 mmol/l glucose, there was a transient, first phase–like stimulation of insulin secretion (AUC = 8.4 ± 4.0 ng/ml for 15 min), without establishment of a second phase. Addition of dmGlut (5 mmol/l) in the continuous presence of 7.0 mmol/l glucose induced biphasic, sustained insulin release (AUC = 2.5-fold compared with 7.0 mmol/l glucose alone, P < 0.05). Stimulation with 16.7 mmol/l glucose resulted in a similar pattern of insulin secretion both in the absence and the presence of dmGlut.

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FIG. 3. Mouse pancreatic perfusion. The pancreata from male BALB/c mice were perfused at 1.5 ml/min, first for a 30-min equilibration period at basal 2.8mmol/l glucose. The effluent was then collected in 1-min fractions from a catheter placed in the portal vein. The pancreas was perfused sequentially at different glucose concentrations without or with 5.0 mmol/l dmGlut. Each condition or combination was applied for 15 min. Values are means ± SE of three independent experiments.


The kinetics of insulin secretion from the in situ perfused pancreas were studied in rats and mice. Our control experiments confirmed the species difference in insulin release, with typical transient first and sustained second phases in rats compared with a transient first phase followed by only a very weak second phase in mice (1,2). Biphasic insulin secretion in response to stimulatory glucose is also observed in humans (20), rendering the mouse questionable as a relevant model. However, the lack of a sustained second phase in mice provides a useful tool for the dissection of mechanisms involved in the establishment of prolonged and robust insulin release. This might also be useful in the search for new treatments of impaired insulin secretion.
Studying the species difference, it has been proposed that a larger production of cAMP in rat ß-cells may account for the pronounced second phase of insulin secretion compared with mice (4). Zawalich et al. (5) have shown that the increase in inositol phosphates upon glucose stimulation was much more marked in rat compared with mouse islets, correlating with phospholipase C expression. Differences between rat and mouse pancreatic islets were also reported regarding membrane potential oscillations and changes in cytosolic Ca2+ concentration in response to glucose (21).

In the present report, we have shown that the expression of GDH is lower in islets isolated from mice compared with those of rats or humans. This mitochondrial enzyme can generate glutamate from the tricarboxylic acid cycle intermediate -ketoglutarate (14). In conditions of permissive cytosolic Ca2+ concentrations, glutamate stimulated insulin exocytosis in permeabilized insulinoma cells (12). This led to the proposal that glutamate plays a role as an intracellular factor in the ß-cell (22). Glucose-derived glutamate might participate in the potentiation of insulin secretion rather than its initiation caused by a rise in cytosolic Ca2+. In the perfused rat pancreas, in the absence of glucose, non-nutrient stimulation of insulin secretion by a sulfonylurea was defective, but it was restored by the addition of dmGlut (17). It was further proposed that dmGlut might bypass glucose metabolism to enhance the insulinotropic action of sulfonylureas (23).

We have shown here that the incomplete second phase of insulin secretion observed in the perfused rat pancreas at intermediate glucose concentration was overcome by dmGlut supplementation. In mice, insulin secretion upon glucose stimulation was essentially transient, with a very weak second phase even at optimal glucose concentrations. Addition of dmGlut caused a biphasic release pattern at permissive glucose concentrations but had no effect at basal glucose. The reason for the biphasic response induced by dmGlut in the mouse, contrasting with the monophasic profile in the rat, is unclear. It could be speculated that the readily releasable pool of insulin granules accumulates and is larger in the mouse than in the rat because of the marked difference in the glucose-induced insulin secretion rate.

The present results are in accordance with a role for glutamate as a metabolic coupling factor potentiating rather than initiating insulin secretion. Conflicting data about the glutamate levels in insulin-secreting cells stimulated by glucose exist in the literature (22). Therefore, future work should attempt to clarify the role of intracellular glutamate in the rat and mouse ß-cell.


The authors thank C. Bartley and G. Chaffard for their skilled technical assistance and Drs. P. Morel and J. Oberholzer (Department of Surgery, University Hospital of Geneva) for providing human islets. This study was supported by the Paul Langerhans Research Fellowship from the European Association for the Study of Diabetes (to P.M.) and the Swiss National Science Foundation (grant no. 32-49755.96 to C.B.W.).


Address correspondence and reprint requests to

Accepted for publication 11 May 2001.

AUC, area under the curve; dmGlut, L-glutamic acid dimethylester; GDH, glutamate dehydrogenase.

The symposium and the publication of this article have been made possible by an unrestricted educational grant from Servier, Paris.


Lenzen S: Insulin secretion by isolated perfused rat and mouse pancreas. Am J Physiol 236:E391–E400, 1979[Abstract/Free Full Text]
Berglund O: Different dynamics of insulin secretion in the perfused pancreas of mouse and rat. Acta Endocrinol (Copenh) 93:54–60, 1980[Medline]
Curry DL, Bennett LL, Grodsky GM: Dynamics of insulin secretion by the perfused rat pancreas. Endocrinology 83:572–584, 1968[Medline]
Ma YH, Wang J, Rodd GG, Bolaffi JL, Grodsky GM: Differences in insulin secretion between the rat and mouse: role of cAMP. Eur J Endocrinol 132:370–376, 1995[Medline]
Zawalich WS, Bonnet-Eymard M, Zawalich KC: Insulin secretion, inositol phosphate levels, and phospholipase C isozymes in rodent pancreatic islets. Metabolism 49:1156–1163, 2000[Medline]
Rorsman P: The pancreatic beta-cell as a fuel sensor: an electrophysiologist’s viewpoint. Diabetologia 40:487–495, 1997[Medline]
Lang J: Molecular mechanisms and regulation of insulin exocytosis as a paradigm of endocrine secretion. Eur J Endocrinol 259:3–17, 1999
Wollheim CB: Beta-cell mitochondria in the regulation of insulin secretion: a new culprit in Type II diabetes. Diabetologia 43:265–277, 2000[Medline]
Matschinsky FM: A lesson in metabolic regulation inspired by the glucokinase glucose sensor paradigm. Diabetes 45:223–241, 1996[Abstract]
Prentki M: New insights into pancreatic ß-cell metabolic signaling in insulin secretion. Eur J Endocrinol 134:272–286, 1996[Medline]
Henquin JC: Triggering and amplifying pathways of regulation of insulin secretion by glucose. Diabetes 49:1751–1760, 2000[Abstract]
Maechler P, Wollheim CB: Glutamate acts as a mitochondrially derived messenger in glucose-induced insulin exocytosis. Nature 402:685–689, 1999[Medline]
Maechler P, Antinozzi PA, Wollheim CB: Modulation of glutamate generation in the mitochondria affects hormone secretion in INS-1E beta cells. IUBMB Life 50:27–31, 2000[Medline]
Hudson RC, Daniel RM: L-GDHs: distribution, properties and mechanism. Comp Biochem Physiol B 106:767–792, 1993[Medline]
Malaisse WJ, Sener A, Carpinelli AR, Anjaneyulu K, Lebrun P, Herchuelz A, Christophe J: The stimulus-secretion coupling of glucose-induced insulin release. XLVI. Physiological role of L-glutamine as a fuel for pancreatic islets. Mol Cell Endocrinol 20:171–189, 1980[Medline]
Bertrand G, Gross R, Puech R, Loubatieres-Mariani MM, Bockaert J: Evidence for a glutamate receptor of the AMPA subtype which mediates insulin release from rat perfused pancreas. Br J Pharmacol 106:354–359, 1992[Abstract]
Sener A, Conget I, Rasschaert J, Leclercq-Meyer V, Villanueva-Penacarrillo ML, Valverde I, Malaisse WJ: Insulinotropic action of glutamic acid dimethyl ester. Am J Physiol 267:E573–E584, 1994[Abstract/Free Full Text]
Trimble ER, Bruzzone R, Gjinovci A, Renold AE: Activity of the insulo-acinar axis in the isolated perfused rat pancreas. Endocrinology 117:1246–1252, 1985[Abstract]
Pralong WF, Spat A, Wollheim CB: Dynamic pacing of cell metabolism by intracellular Ca2+ transients. J Biol Chem 269:27310–27314, 1994[Abstract/Free Full Text]
van Haeften TW, Boonstra E, Veneman TF, Gerich JE, van der Veen EA: Dose-response characteristics for glucose-stimulated insulin release in man and assessment of influence of glucose on arginine-stimulated insulin release. Metabolism 39:1292–1299, 1990[Medline]
Antunes CM, Salgado AP, Rosario LM, Santos RM: Differential patterns of glucose-induced electrical activity and intracellular calcium responses in single mouse and rat pancreatic islets. Diabetes 49:2028–2038, 2000[Abstract]
Maechler P, Wollheim CB: Mitochondrial signals in glucose-stimulated insulin secretion in the beta cell. J Physiol 529:49–56, 2000[Abstract/Free Full Text]
Vicent D, Garcia-Martinez JA, Villanueva-Penacarrillo ML, Valverde I, Malaisse WJ: Stimulation of insulin secretion and potentiation of glibenclamide-induced insulin release by the dimethyl ester of glutamic acid in anaesthetized rats. Diabetes Res Clin Pract 27:27–30, 1995[Medline]

This article has been cited by other articles: (Search Google Scholar for Other Citing Articles)

Glutamate and NMDA Receptors and Diabetes

It’s all about location and balance,” says Dr. Smith. If glutamate accumulates outside of the cell, it can over-stimulate the cell by binding to a glutamate receptor. One such receptor, the NMDA receptor, is particularly sensitive to excessive levels of glutamate. Over-stimulation of NMDA receptors allows too much calcium to enter the cells where it triggers formerly dormant cell-death pathways.

Monday, August 07, 2006

Blogthings - The Five Factor Values Test

Blogthings - The Five Factor Values Test: "

Your Values Profile


You don't really value loyalty.

In your opinion, friendship should be earned.

If you don't agree with someone, it doesn't matter how close you are.

You'll let them (and everyone else know) exactly what you think.


You don't really value honesty.

You do value getting your way, no matter what.

And if a little lying is required to do that, no problem.

A few white lies never hurt anyone (at least, that's what you tell yourself!)


You value generosity a fair amount.

You are all about giving, as long as there's some give and take.

Supportive and kind, you don't mind helping out a friend in need.

But you know when you've given too much. You have no problem saying 'no'!

br />"Humility:

You value humility a fair amount.

You tend to be an easy going, humble person.Humility:

You value humility a fair amount.
You tend to be an easy going, humble person.
But occasionally your ego takes over.
You have a slight competitive streak - and the need to be the best.


You value tolerance highly.
Not only do you enjoy the company of those very different from you...
You do all that you can to seek it out interesting and unique friends.
You think there are many truths in life, and you're open to many of them.


Sunday, August 06, 2006

Drew Curtis'



By Giles Weaver"

Count to Twelve and pay up....



Political Forums > trade sick, disabled for working illegals

Political Forums > trade sick, disabled for working illegals

I am utterly disgusted by some guy on here named geoffrey----- stupid stupid man who thinks that Alberta will put the disabled at the top of the list for surgery if they are unable to work because of an injury.

Thoughts from a Management Lawyer: Reasonable Apprehension of Bias - A Tough Subject

Saturday, August 05, 2006

BBC NEWS | Health | Sticky DNA helps spot leukaemia

BBC NEWS | Health | Sticky DNA helps spot leukaemia

Sticky DNA helps spot leukaemia
By Louisa Cheung

Researchers use fluorescence to identify cells
US researchers have developed a new technique to distinguish leukaemia cells from healthy ones.
Though cancer cells do not look the same as normal cells, it can be tough for doctors to spot the difference.

A University of Florida team has developed a set of DNA probes which only stick to cancer cells, making it easier to identify them.

The Proceedings of National Academy of Sciences study could lead to improved early diagnosis of cancers.

As cancers are generally easier to treat when diagnosed early, this could save many lives

Ed Yong

Leukaemia is the fifth most common cancer in the UK and accounts for about half of all cancers in children. Men are more prone to leukaemia than women.

Cancer cells usually have genetic changes that modify the appearance of the cell.

Nine out of 10 tumour cases are diagnosed by pathologists, looking for these changes under a microscope.

Researchers have recently found that DNA can bind to proteins on the surface of cells.

Using this knowledge, the Florida team designed hundreds of DNA probes labelled with a fluorescent protein.

Following tests, they were able to identify those probes that stuck only to proteins found on the surface of cancer cells.

They were then able to identify the "labelled" cancer cells using a cell-sorting machine more accurately than could be done by the human eye using a microscope.


The researchers are now trying to develop probes which will only stick to specific types of cancer cell.

This raises the possibility that the probes could be used to give a specific diagnosis of cancer sub-type.

The researchers do not actually know which specific proteins the probe actually binds to.

But they say this is an advantage, because it means that cancer cells can be identified without having to pin down the precise molecular markers which make them different from healthy cells.

Once the technology becomes more sophisticated, however, the researchers believe it could be used to identify slight individual differences among cancer patients - allowing doctors to give more personalised treatment.

Researcher Dr Ying Li said it might also be possible to use the technique to target drug treatments more precisely at cancer cells.

He said: "If we have a marker that can recognise the tumour better than the normal tissue, the marker can be attached with a drug to do target therapy."

Ed Yong, cancer information officer at Cancer Research UK, said: "This is a promising start for what is essentially a completely new method for diagnosing cancer.

"If it proves to be successful in human trials, it could allow doctors to spot tumours much earlier and distinguish between subtly different cancer types.

"As cancers are generally easier to treat when diagnosed early, this could save many lives."

The miracle worker - Sunday Times - Times Online

The miracle worker - Sunday Times - Times Online


The miracle worker
This is p53. The gene keeps cancer at bay, and scientists are racing to find a wonder drug to harness its power. If they get it right, we’ll live longer, healthier, cancer-free lives. If they get it wrong — well, you don’t want to know. Sue Armstrong reports

::nobreak::In 2002 some scientists in Texas who were working with genetically engineered mice made a mistake and got a mighty surprise. In investigating a gene known to be crucial in protecting us from cancer, they created some mice without the gene (so-called “null mice”). The creatures proved highly prone to cancer and developed tumours at an early age, exactly as expected. In another group of mice, the researchers modified the gene, but it turned out rather more active than they intended.

Sure enough, their offspring proved well protected from cancer, as the researchers would have predicted. What nobody expected to
see was that the mice aged exceptionally fast. In just a few months, they looked like very old mice. “They had hunchback spines, ruffled fur, grey hair; things like that,” says Larry Donehower of Baylor College of Medicine in Houston. “And they lived only about two-thirds of their normal life span.” This accidental finding is opening up a new area of research about how this important cancer gene can also modify the ageing process.

People have known for a long time that ageing and cancer are related, in that the chances of getting cancer increase with age. But nobody suspected they might be two sides of the same coin, sharing a common mechanism in which the scales can be tipped either way. In other words, that wrinkled skin, thinning bones and failing organs may be the price we pay in the long run for holding cancer at bay. “We don’t know the full picture yet,” says Professor Sir David Lane of Dundee University, a superstar in the field of cancer genetics, “but it certainly seems there’s a balance to be struck here.”

This discovery has hugely excited scientists studying both cancer and ageing, who have begun to collaborate seriously for the first time. “The clinical implications are clear,” says Lane. “People are beginning to ask, ‘Can I manipulate the system to get the best of both worlds?’” But the discovery raises other, more immediate – and alarming – questions. Could existing treatments for cancer, which often stimulate the activity of this important gene, accelerate ageing in the patient and lead to age-related disorders, such as dementia, later on? Or, conversely, could the use of drugs to try to slow the effects of ageing in people put them at higher risk of cancer? In meddling with genes without fully appreciating what might result, are we playing with fire? Nobody yet knows.

The gene at the centre of this flurry of interest is known simply as p53, because 53,000 is the molecular weight of the protein the gene produces when it is active. (Genes are, in effect, just recipes for proteins, which do all the work in our cells. The proteins are made only when and where they are needed, at which point the relevant gene is “switched on”.) P53 functions as a tumour suppressor. It senses when the DNA of a cell – the material inside the cell’s nucleus that carries all the genetic information – has been damaged. It can either stop the unnatural cell from reproducing itself – as it’s programmed to do in the normal course of body maintenance – until the DNA is repaired, or it may induce “cell suicide”. Nicknamed by Lane “the guardian of the genome”, because of its vital role in seeing that cells with scrambled DNA aren’t allowed to replicate and set off on the road towards cancer, the gene is found to be mutant and useless in more than half of all human tumours. Thus, while all cancers are caused by faulty genes, mutant p53 is the single most common genetic fault of all (see the graph on page 21).

Once the role of p53 was recognised, hundreds of molecular biologists worldwide dropped their own projects and took up with this little gene, beguiled by the prospect of conquering cancer – a disease you and I have a one-in-three chance of suffering from at some point in our lives, and a one-in-four chance of being killed by it. P53 has become the most widely studied single gene in history, generating nearly 36,000 published papers to date and bringing together every two years an ever-widening community of scientists working on the frontiers of cancer research to share their latest findings on the gene.

Like so many great scientific discoveries, p53 was found by accident in the late 1970s. When the protein made by the active gene cropped up unexpectedly in laboratory experiments looking at the activity of a monkey virus that causes tumours, most researchers dismissed it as an irritating contaminant. However, David Lane, then doing a post-doctoral fellowship in cancer research in London, was intrigued. The “rogue” protein appeared so regularly in his experiments, and he was so sure he had avoided contamination, that he felt compelled to find out what it was. His discovery that the “rogue” protein was a key player in the cancerous cells he was investigating was the cover story in Nature in 1979. Papers from other researchers, most notably Arnold Levine of Princeton University, New Jersey – who made the same discovery of a protein active in tumour cells – followed quickly. Scientists have learnt a great deal about how p53 works, which is essentially to orchestrate a cascade of events in response to cellular stress.

Conditions such as low oxygen or nutrient levels within cells, overexposure to sunlight and radiation, as well as DNA damage, send out alarm signals that switch on p53. The p53 then activates a series of genes “downstream” that put the brake on cell division, or induce cell suicide – a process known as “apoptosis”, from the Greek meaning “to drop out” and used poetically to describe the shedding of autumn leaves. (Researchers say this is what the dead cells scattered among the living in human tissue look like under the microscope.)

In 1992, impatient to find out whether what scientists were learning in the lab is what actually happens in us, Lane and Peter Hall, a cancer specialist and fellow p53 researcher, cooked up a maverick experiment over a pint in a Dundee pub, using Hall as the guinea pig. The experiment involved subjecting Hall’s arm to radiation from a sun lamp – “equivalent to 20 minutes on a Greek beach” – and taking a series of time-staggered skin biopsies to watch the activity of p53. “We reckoned that if this gene does respond to stress in living organisms, we should see the accumulation of p53 protein in the cells in my radiated skin. And that’s exactly what we did see,” says Hall, rolling up his sleeve to reveal nine neat scars. “We did the experiment on me because we wanted quick results. It would have taken months to get a licence for animal experiments. The scars all got infected,” he laughs, “but the experiment worked brilliantly, and it moved the field on considerably.”

The sun-lamp session was enough to trigger p53 but not damage the DNA and, as anticipated, Hall and Lane saw the protein level subside in time without causing cell arrest or apoptosis. They observed the normal functioning of p53 as it surveys our cells for signs of trouble. When the gene is unable to do its policing job, cells are at risk of becoming cancerous. Most often this is because p53 is damaged by mutation. There is a rare condition, for instance, called Li-Fraumeni syndrome, where people are born with mutant p53 in all their cells. Affected individuals are extremely vulnerable to cancer, tending to develop tumours – perhaps even in babyhood – and often several different types of cancer across their lives. (Among the rest of us, the proportion of patients who develop more than one of the 200-plus types of cancer is vanishingly small.)

Being inherited rather than acquired, Li-Fraumeni syndrome runs in families, explains Rosalind Eeles, who has a specialist clinic at the Royal Marsden hospital in London for people with the syndrome. “But because the cancers are so devastating and they occur at such a young age, the families are generally not very big.”

However, the gene can be disabled by means other than mutation – which helps explain what’s happening in the roughly half of all cancers in which this vital tumour-suppressor appears to be intact. When p53 was first seen in the experiments with the monkey virus, for example, the protein had been trapped and crippled by the virus (though of course nobody realised it at the time). Researchers have discovered, too, that in cervical-cancer cases caused by the human papilloma virus (HPV) – a sexually transmitted infection that can also cause genital warts – p53 is chopped up and devoured by the virus so that the cancer cells have none of the tumour-suppressor at all.

Very recently, Levine’s laboratory at Princeton uncovered a mechanism that explains why healthy p53 cannot prevent breast cancer developing in some cases. Researchers had already found that because it’s such a powerful gene, able to kill or arrest cells, p53 is kept under tight control by another gene called mdm2 that switches it on and off. “It’s like a policeman and his guard dog,” explains one scientist of the relationship between mdm2 and p53. “The policeman decides when to let the dog off the leash to fight a threat, and when to pull it in. If the policeman loses his grip, the dog can cause havoc.” So too with p53: “Mdm2 is what stops p53 killing all our cells – killing us!”

Now Levine and his colleagues discovered that in some people the mdm2 gene is more active than in others, holding p53 on a tighter leash and thus heightening the risk of developing cancer. “What surprised us,” says Levine of the breast-cancer study, “was that this [variant of mdm2] has its largest effect in pre-menopausal women, who have high levels of oestrogen.” So the “policeman” is influenced by the hormone, which amplifies its curbing effect on p53.

Having an overactive version of mdm2 is also bad news for smokers, says Levine. “Tobacco is a stress signal, a carcinogen in the lungs, and smoking alone might double or treble the risk for lung cancer. But two studies make it quite clear that, if you have this genetic risk factor plus tobacco, you have a tenfold increase in the odds of developing cancer.” Lung cancer is the most common cause of death in the UK, with one person newly diagnosed every 15 minutes, according to Action on Smoking and Health. For decades the tobacco industry sought to undermine the case against smoking by claiming that evidence of a link between tobacco and lung cancer, first mooted in the 1950s, was purely circumstantial – there was no physical proof that smoking caused the disease. But p53 has finally nailed the case against tobacco. Since the early 1990s, the International Agency for Research on Cancer (IARC) in Lyons, France, has kept a database of the mutations found in p53 in different tumour types. In the lung cancer of smokers, p53 is overwhelmingly mutated at a particular “hot spot” on the gene. In other words, the gene carries the fingerprint of the cancer-causing agent. Scientists found benzo(a)pyrene, a component of tobacco smoke, is the culprit.

The first paper pinning it down was published in 1996, followed closely by another presenting the evidence from the database. But Big Tobacco had been waiting in the wings. When the papers appeared, it launched an attack questioning the science and challenging the scientists via learned journals. “We’re used to trust within the scientific community, and you expect people to be fair,” says Pierre Hainaut of the IARC. “So the first reaction when you see a paper attacking your work is: ‘Oh my God, I’ve missed something important; I’ve made a big mistake!’”

But when he set out to answer his critics, Hainaut discovered a network of scientists and journal editors not only being paid by the tobacco industry to do their own research on p53, but colluding with the industry to hide the source of their funding and frustrate the scientific debate. They used their contacts to alert tobacco companies to forthcoming publications and helped to prepare papers challenging the data and get them into print as quickly and prominently as possible.

Hainaut followed the trail to secretive institutes set up by the tobacco industry, into the boardrooms of key journals and even the labs of some eminent scientists, and he was shocked. “It may seem very naive, but I had no idea something like this could happen,” he says. “It was like falling into a detective story.”

However, the battle, which turned nasty and personal at times and is well documented in a Lancet article of 2005, did have some positive spin-offs. The rules about declaring conflicts of interest when publishing scientific papers have been tightened. And Hainaut and his colleagues acknowledged the weakness of some data they used to make their original case, and started again from scratch to generate watertight data on the effect of tobacco on p53. Their paper was published in 2005.

Tobacco isn’t the only cancer-causing agent to leave a fingerprint on p53. Many cases of skin cancer have p53 mutations characteristic of ultraviolet radiation from sunlight. And most liver cancers in tropical countries are caused by aflatoxin, a poison secreted by a fungus that infects grains and peanuts, and leave a clear fingerprint on p53.

“Liver cancer is absolutely impossible to treat when it reaches a late stage, so the challenge is to have early detection,” says Hainaut. “The liver releases DNA into the bloodstream, and we can identify the presence of the mutation in it.

Two recent papers demonstrate that we have a very, very strong correlation between the presence of the mutation and cancer. “The feasibility of screening for liver cancer in high-prevalence tropical countries is currently being tested by the IARC and the UK Medical Research Council in west Africa.

Similar studies are under way in the US to see if screening heavy smokers with chronic bronchitis and other “cancer-predisposing symptoms” for mutant p53 in blood or spit samples could be used to identify people likely to develop cancer or to detect early tumours. And Levine believes screening younger women for the higher-acting version of mdm2 that stops p53 working properly might be used to single out those at risk from breast cancer who would benefit from regular mammograms well before their fifties. At the Royal Marsden, Eeles awaits new guidelines from the National Institute for Clinical Excellence (Nice) any day now “that will suggest breast-screening for women under 30 if they have the inherited p53 mutation”.

Though not many places are doing so yet, Hainaut believes the potential to use p53 for the detection and management of cancer is “huge and very important”. P53 research promises novel ways of treating cancer too. Several drugs currently being developed and tested make a virtue of the way viruses invade cells and take over the machinery for their own purposes. In one approach, a common-cold virus, genetically engineered so it cannot cause harm, is used to carry good copies of p53 into cancer cells where it is mutant and useless, thereby reactivating the stress-response machinery. In another, a the virus is engineered so it can infect only cells with dysfunctional p53 – cancer cells – where it grows and multiplies until the cells literally burst.

Besides gene therapy, researchers are looking for small molecules that can be used as tiny tools to tinker with the stress response at various points upstream or downstream of p53. Chemical compounds called “nutlins”, for example – developed by the pharmaceutical giant Hoffman-La Roche, and which interfere with the interaction between p53 and mdm2 – are causing a lot of excitement. Finding a molecule that would “cut the leash between the policeman and his dog”, enabling scientists to switch p53 on and off at will, has become a holy grail.

“I’m very excited about the results with nutlin,” says Lane, who set up a biotech company in the late 1990s to search for such a molecule. “It works very well in tissue culture and animal models, and appears to have good activity in the half of tumours where p53 is not mutant.” That is the case in most leukaemias, half of colon cancer, two-thirds of breast cancer, half of prostate cancer, “so very big numbers”.

Lane stresses, however, that nutlin is still a long way from the marketplace. “It’s not sufficiently drug-like yet to be in clinical trials. But what we call ‘target validation’ – that is, being certain that if we get a drug like this, it will work – is looking very good.”

Drugs to manipulate the p53 system to protect against cancer and slow down ageing at the same time are even further over the horizon, but scientists working to understand this relationship are making some sensational discoveries. Judith Campisi, a p53 and age researcher from Berkeley, California, studies a process called cell senescence. This means cells that lose the ability to divide but remain alive and active, which is one of the options that p53 can choose in responding to stress. “Inability to divide is good news if it means a damaged cell can’t form a tumour,” says Campisi. “But as these non-dividing cells accumulate over time, it’s not such good news, because we’ve seen they’re dysfunctional.”

During normal metabolism, senescent cells produce large amounts of waste material that seep from the cell and begins “to chew up the extra-cellular matrix – the stuff that keeps cells glued together”, explains Campisi. “The major extra-cellular molecule that keeps your skin looking young is collagen. Sure enough, senescent cells produce molecules that destroy collagen.” Hence, wrinkles.

Another theory about how tumour suppression might drive ageing is that, over time, we may simply run out of the stem cells we need to replenish our tissues and organs, as the cells are killed off or stopped from dividing by the stress-response mechanism. “The simplest model would be that you’re born with a limited number of stem cells,” explains Lane. “Those cells are very easily killed off by DNA damage, so they’re the ones most tightly controlled by p53. If you set a [stress-response] threshold where they’re too easily killed, you don’t get cancer but you run out of stem cells more quickly. If you set the threshold where they’re hard to kill, you could live a long time but you’re likely to get cancer.”

With compounds such as nutlins, scientists can manipulate p53 in ways that were once impossible – and for all kinds of therapeutic effects, says Lane, whose belief in the promise of the gene he discovered 27 years ago remains undiminished. “I think one can imagine really quite extraordinary results in the next few years as we begin to be able to control this system,” he says.

Even the idea of resetting our bodies’ stress response to suppress both cancer and ageing does not seem wacky to Lane. But the stakes are high: get the balance right and we will be on the way to longer and healthier lives; get it wrong and we could expire fast and messily in an orgy of apoptosis, as p53, like a guard dog out of control, runs riot in every cell of our bodies.


Natasha Dean has a rare inherited condition that leaves her highly susceptible to cancer. But she is determined to lead a normal life

Natasha Dean’s mother had her first mastectomy at the age of 15, following breast cancer. She had her other breast removed at 19, when cancer recurred, and died from secondaries in the bones at 39, when her daughter was 11. “I was always told by my father and my aunts that I should be careful,” she says. “So I was vigilant from an early age.”

She was on holiday in Australia in 2000 when she went for a routine checkup and discovered a lump in her breast. She was 24. After surgery, chemo- and radiotherapy, she returned to England, where she was referred to the cancer-genetics clinic of the Royal Marsden, London, for a p53 test. “The specialists in Sydney told me I fitted three of the five criteria that would classify someone as having Li-Fraumeni [syndrome],” says Dean. The Royal Marsden confirmed the diagnosis. She and her boyfriend looked it up on the internet, “but it was all quite scary, so I stopped,”she says.“They were very supportive at the hospital and made sure we were aware of the implications. Apparently, there are patients who don’t cope with it very well.” Dean has done so by carrying on with her everyday life.

In January 2004, a routine scan picked up secondary tumours in her liver. She asked to postpone chemotherapy for a few weeks while she married her boyfriend and visited her family in Australia. Treatment with Herceptin and tamoxifen while she was away kept cancer at bay. “The tumours shrank right down till you couldn’t see them any more,” she says. “But after 18 months they started to pop back up. So I had another four cycles of chemotherapy.” With each cycle she returned to her job with an investment bank for two weeks out of three. “Being able to work made it a lot easier getting through it,” she says.

Recently Dean has undergone radio-ablation, a new treatment that involves burning the cancer cells away with radio waves delivered through fine needles directly into the tumour. She is now recovering from a repeat of the procedure after new growth appeared at the edge of the scar.

The mutation in p53 can occur spontaneously in a sperm or egg at any point in a family’s history. Dean believes it began with her grandparents. She and her mother, both only children, are so far the only people affected. “My maternal grandmother passed away at 80, with no cancer. Her mother, my great-grandmother, had breast cancer, but post-menopausal.”

Dean knows she could pass the Li-Fraumeni on to her children. She and her husband have discussed their options with the oncologists. “Until I got the recurrence it was nice to know those options were there. But that’s not something I’m thinking about now,” she says.

Thursday, August 03, 2006

IL4 and IL10 and Pain

Health briefs

August1 2006

CHRONIC PAIN: Lack of proteins could be culprit

Low blood levels of two anti-inflammatory proteins could be key to chronic pain, researchers report.

Low concentrations of two cytokines, IL-4 and IL-10, were found in patients with chronic widespread pain, according to a German study published in the August issue of Arthritis & Rheumatism.

Cytokines are proteins that act as messengers between cells.

The study included 40 patients who'd received intravenous immunoglobulin (IVIG) as a novel treatment for pain that hadn't responded to standard therapy and another 15 patients who did not receive IVIG. The study also included a control group of 40 healthy people.

Compared with the control group, the 40 pain patients had significantly lower levels of IL-4 and IL-10. The 15 patients in the second group had similar results, although the difference in their levels of IL-10 compared to people in the control group was not statistically significant.

Several factors may be involved in low levels of these cytokines and how they influence pain, the study authors said. They noted that previous studies have shown that IL-10 reduces sensitivity to pain and that IL-4 can also dull pain response.

Genetic variations in different cytokine genes are associated with certain diseases. For example, IL-4 gene variations are associated with asthma, Crohn's disease and chronic polyarthritis, the researchers said.

the honda case


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Disability Law Guide - Bayda Ludwar Law Firm

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eMJA: Management of chronic low back pain

eMJA: Management of chronic low back pain

They are correct in stating that reductionist procedures performed to the required standard are available in only a few centres. However, this does not invalidate these procedures; it reflects only a political and ideological problem in healthcare delivery. They also fail to reveal that in many places where these procedures are available, they are not performed according to best-practice standards. It is not the procedures, but misguided and unscrupulous practitioners, who render patients bewildered and dysfunctional

eMJA: Management of chronic low back pain

Multidisciplinary rehabilitation for chronic low back pain: systematic review -- Guzm�n et al. 322 (7301): 1511 -- BMJ

NEJM -- The Promise and Problems of Meta-Analysis

NEJM -- The Promise and Problems of Meta-Analysis

Previous Volume 337:559-561 August 21, 1997 Number 8

The Promise and Problems of Meta-Analysis


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Meta-analysis has acquired a substantial following among both statisticians and clinicians. The technique was developed as a way to summarize the results of different research studies of related problems. Meta-analysis may be applied even when the studies are small and there is substantial variation in the specific issues studied, the research methods applied, the source and nature of the study subjects, and other factors that may have an important bearing on the findings. In this issue of the Journal, LeLorier et al.1 compare the findings of 12 large randomized, controlled trials with the results of meta-analyses of the same problems. They find important discrepancies. When a large randomized, controlled trial — commonly considered the gold standard for determining the effects of medical interventions — disagrees with a meta-analysis, what should the reader conclude? Perhaps more important, when only one of the two tools is used, how much uncertainty should the reader add to the confidence limits and other statistical measures of uncertainty reported by the author?

The core of meta-analysis is its systematic approach to the identification and abstracting of critical information from research reports. Doing a meta-analysis correctly demands expertise in both the method and the substance and hence almost always requires collaboration between clinicians and an experienced statistician. The questions must be defined carefully to maximize the relevance of the reports to be included and to reduce uncertainties about procedures. The investigators must then try to find every relevant report by searching data bases, reviewing bibliographies, and asking widely about unpublished work. The collected reports are then winnowed to the few (often less than 10 percent) that meet the requirements for the meta-analysis. The reports must be searched carefully to identify problems and validate the quantitative findings of interest. These findings must be expressed on a common scale (often as odds ratios), and some reports may have to be dropped for lack of information. Those doing a meta-analysis may also abstract information from each report to produce a quantitative measure of research quality. Each of the individual quantitative estimates must be scrutinized for problems, and this may require the efforts of a range of specialists. When the analysis is completed and submitted for publication, the editor and the reviewers must assure themselves of its quality. A rigorous technical review of a meta-analysis requires the reviewer to identify, reabstract, and interpret a fair sample of the original papers. Very few editors and reviewers will do this, which may be one reason why there are so many poor meta-analyses in the literature.

Although some meta-analyses stop with the presentation and discussion of the results of the individual studies, many others proceed further and combine the results into a single, comprehensive "best" estimate, generally with statistical confidence bounds, that is meant to summarize what is known about the clinical problem. This last step — preparing and presenting a single estimate as the distillation of all that is known — is the one that has drawn the most criticism. This is because there are often biologic reasons, statistical evidence, or both, showing that the studies included in the meta-analysis have in fact measured somewhat different things, so that a combined estimate cannot be meaningful unless additional, doubtful assumptions are made. One such assumption is that the effects reported in the studies actually performed can be seen as a random sample of the effects observed in all possible studies that might have met the author's criteria. Unfortunately, there is little evidence to support an assumption such as this.

LeLorier et al.1 searched four leading general medical journals to identify all the large randomized, controlled trials (those with 1000 subjects or more) whose results were published from 1991 through 1994, then searched for meta-analyses of similar topics that were published before each trial. Twelve large randomized, controlled trials and 19 meta-analyses met their criteria. Because some of the trials and meta-analyses reported on more than 1 outcome, they studied a total of 40 outcomes. Overall, there was somewhat better than chance agreement between these meta-analyses and the subsequent large randomized, controlled trials, with kappa values in a range commonly considered to represent "fair-to-slight agreement." In terms of an ordinary diagnostic test, the results could be described as average. The results obtained with the two approaches usually pointed in the same direction, and there were no cases in which they gave statistically significant results in opposite directions. However, the discrepancies with regard to the estimated size of an effect were sometimes quite substantial, and occasionally they differed significantly despite their agreement in direction. Stewart and Parmar2 have shown how some such differences can arise.

It is impossible to say, on the basis of present evidence alone, whether the results of a large randomized, controlled trial or those of a meta-analysis of many smaller studies are more likely to be close to the truth. Much depends on the details of both the research studies and the analyses. When both the trial and the meta-analysis seem to be of good quality, however, I tend to believe the results of the trial. A history of 40 years of generally successful use of randomized, controlled trials that have made important contributions to progress in many branches of medicine must not be overlooked. In addition, major problems with the implementation of meta-analyses have been common.3,4,5,6 There have been a wide variety of these, including failure of the investigator performing the meta-analysis to understand the basic issues, carelessness in abstracting and summarizing appropriate papers, failure to consider important covariates, bias on the part of the meta-analyst, and, perhaps most often, overstatements of the strength and precision of the results. It is not uncommon to find that two or more meta-analyses done at about the same time by investigators with the same access to the literature reach incompatible or even contradictory conclusions.7,8,9,10 Such disagreement argues powerfully against any notion that meta-analysis offers an assured way to distill the "truth" from a collection of research reports.

Other observers, including policy makers, also have reservations about meta-analyses, and there is some general concern about the credibility of the findings of meta-analysis. I know of no instance in medicine in which a meta-analysis led to a major change in policy before the time when a careful, conventional review of the literature led to the same change. Showing that a sequence of meta-analyses performed over time converged to have some value as published findings accumulated does not mean that it was the meta-analyses that gave a convincing answer to the particular clinical question.

In my own review of selected meta-analyses,3 problems were so frequent and so serious, including bias on the part of the meta-analyst, that it was difficult to trust the overall "best estimates" that the method often produces. On present evidence, we can generally accept the results of a well-done meta-analysis as a way to present the results of disparate studies on a common scale (as is shown by the two figures in the article by LeLorier et al.), but any attempt to reduce the results to a single value, with confidence bounds, is likely to lead to conclusions that are wrong, perhaps seriously so. I still prefer conventional narrative reviews of the literature, a type of summary familiar to readers of the countless review articles on important medical issues.

Meta-analysis may still be improved, by a combination of experience and theory, to the point at which its findings can be taken as sufficiently reliable when there is no other analysis or confirmation available, but that day seems to be well ahead of us. LeLorier et al. also imply, however, that large randomized, controlled trials should be regarded more circumspectly than published reports commonly suggest. We never know as much as we think we know.

John C. Bailar III, M.D., Ph.D.
University of Chicago
Chicago, IL 60637


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Meta-Analyses and Large Randomized, Controlled Trials
Ioannidis J. P.A., Cappelleri J. C., Lau J., Bent S., Kerlikowske K., Grady D., Song F.-J., Sheldon T. A., Khan S., Williamson P., Sutton R., Stewart L. A., Parmar M. K.B., Tierney J. F., Sim I., Lavori P., Imperiale T. F., LeLorier J., Grégoire G., Bailar J. C.
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N Engl J Med 1998; 338:59-62, Jan 1, 1998. Correspondence

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